2024-03-29T13:32:10Zhttps://ebuah.uah.es/oai/requestoai:ebuah.uah.es:10017/604562024-02-07T01:16:43Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Sánchez Gómez, Belén
Bort Bueno, Alicia Carmen
Mora Rodríguez, José María
Díaz-Laviada Marturet, Inés Cecilia
2024-02-06T11:42:20Z
2024-02-06T11:42:20Z
2022-01-29
Pharmaceutics, 2022, v. 14, n. 2, p. 1-14
1999-4923
http://hdl.handle.net/10017/60456
doi.org/10.3390/pharmaceutics14020329
AR/0000039104
Pharmaceutics
14
14
2
1
The natural bioactive compound capsaicin has been reported to have anticancer activity, although the underlying mechanism of action has not been completely clarified. Herein, we investigated the mechanism whereby capsaicin exerts antitumor effects on prostate cancer cells. We found that capsaicin activated AMP-activated kinase (AMPK) and promoted cell death in the LKB1- expressing prostate cancer cell lines LNCaP and PC3, but not in the liver kinase B1 (LKB1)-none cell line DU-145. Capsaicin treatment stimulated LKB1 phosphorylation and activated AMPK in LKB1- expressing cells. In addition, LKB1 silencing in LNCaP and PC3 cells abrogated capsaicin-induced AMPK activation, while the overexpression of LKB1 by lentiviral infection in DU-145 cells induced capsaicin-triggered AMPK phosphorylation. Moreover, the calcium/calmodulin-dependent kinase kinase 2 (CaMKK2) inhibitor STO-609 did not modify the activation of AMPK induced by capsaicin, suggesting a CaMKK2-independent mechanism. Capsaicin-induced LKB1 phosphorylation was dependent on the transient receptor potential cation channel subfamily V member 1 (TRPV1), since TRPV1 knocked down by shRNA abolished LKB1 and AMPK phosphorylation in LKB1-expressing cells. Altogether, our results showed that capsaicin affected AMPK activity in an LKB1- and TRPV1- dependent fashion, linking TRPV1 with cell fate. These data also suggest that capsaicin may be a rational chemotherapeutic option for prostate tumors.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© 2022 by the authors.
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
capsaicin
AMPK
LKB1
TRPV1
PC3
LNCaP
DU-145
prostate cancer
The natural chemotherapeutic capsaicin activates AMPK through LKB1 kinase and TRPV1 receptor on prostate cancer cells
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/600872024-02-02T01:16:39Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Baquero Valls, Pablo
Sánchez Hernández, Irene
Jiménez Mora, Eva María
Orgáz, José L.
Jiménez, Benilde
Chiloeches Gálvez, Antonio
2024-01-30T12:55:03Z
2024-01-30T12:55:03Z
2013
Cancer Letters, 2013, v. 335 (1), n. 10, p. 232-241
0304-3835
http://hdl.handle.net/10017/60087
10.1016/j.canlet.2013.02.033
AR/0000019890
Cancer Letters
335 (1)
241
10
232
BRAF is a main oncogene in human thyroid cancer. Here, we show that BRAF depletion by siRNA or inhibition of its activity by treatment with BRAF inhibitor PLX4720 decreases migration and invasion in thyroid cancer cells expressing oncogenic V600EBRAF through a MEK/ERK-dependent mechanism, since treatment with the MEK inhibitor U0126 exerts the same effect. Moreover, over-expression of V600EBRAF increases migration and invasion of wild-type BRAF thyroid cells. Using the same strategies, we demonstrate that these effects are mediated by upregulation of the transcriptional repressor Snail with a concomitant decrease of its target E-cadherin, both hallmarks of EMT. These results reveal a novel V600EBRAF-induced mechanism in thyroid tumours progression and provides a rationale for using the PLX4720 inhibitor to target V600EBRAF signalling to effectively control progression of thyroid cancer.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© Elsevier
BRAF
Snail
E-cadherin
EMT
Invasion
Thyroid cancer
V600EBRAF promotes invasiveness of thyroid cancer cells by decreasing E-cadherin expression through a Snail-dependent mechanism
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/588902023-12-16T01:16:08Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Baquero Valls, Pablo
Dawson, Amy
Helgason, Gudmundur Vignir
2023-12-15T08:12:40Z
2023-12-15T08:12:40Z
2018-09-17
FEBS Journal, 2018, v. 286, n. 7, p. 1271-1283
1742-464X
http://hdl.handle.net/10017/58890
10.1038/s41375-018-0252-4
AR/0000028966
FEBS Journal
286
1283
7
1271
Despite the development of selective BCR-ABL-targeting tyrosine kinase inhibitors (TKIs) transforming the management of chronic myeloid leukaemia (CML), therapy-resistant leukaemic stem cells (LSCs) persist after TKI treatment and present an obstacle to a CML cure. Recently, we and others have made significant contributions to the field by unravelling survival dependencies in LSCs to work towards the goal of eradicating LSCs in CML patients. In this review, we describe these findings focusing on autophagy and mitochondrial metabolism, which have recently been uncovered as two essential processes for LSCs quiescence and survival respectively. In addition, we discuss the therapeutic potential of autophagy and mitochondrial metabolism inhibition as a strategy to eliminate CML cells in patients where the resistance to TKI is driven by BCR-ABL-independent mechanism(s).
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
autophagy
chronic myeloid leukaemia
metabolism
mitochondria
oxidative phosphorylation
therapeutics
Autophagy and Mitochondrial Metabolism: Insights into their Role and Therapeutic Potential in Chronic Myeloid Leukaemia
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/590032023-12-20T08:04:14Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Huertas Lárez, Raquel
Muñoz Moreno, Laura
Recio Aldavero, Jorge
Román Curto, Irene De Los Dolores
Arenas Jiménez, María Isabel
Blasco Martínez, Ana
Sanchis Bonet, Angeles
Bajo Chueca, Ana María
2023-12-19T11:28:04Z
2023-12-19T11:28:04Z
2023-08-01
International Journal of Cancer, 2023, v. 153, n. 10, p. 1829-1841
0020-7136
http://hdl.handle.net/10017/59003
10.1002/ijc.34673
AR/0000045625
International Journal of Cancer
153
1841
10
1829
Prostate cancer (PCa) is the second most frequent and sixth most fatal cancer in men worldwide. Despite its high prevalence, our understanding of its etiology and the molecular mechanisms involved in the progression of the disease is substantially limited. In recent years, the potential participation of exosomes in this process has been suggested. Therefore, we aim to study the effect of exosomes isolated from the serum of patients with PCa on various cellular processes associated with increased tumor aggressiveness in two PCa cell lines: LNCaP-FGC and PC3. The exosomes were isolated by filtration wand ultracentrifugation. Their presence was confirmed by immunodetection of specific markers and their size distribution was analyzed by Dynamic Light Scattering (DLS). The results obtained demonstrated that serum exosomes from PCa patients increased migration of PC3 cells and neuroendocrine differentiation of LNCaP-FGC cells regardless of the grade of the tumor. PCa serum exosomes also enhanced the secretion of enzymes related to invasiveness and resistance to chemotherapeutics, such as extracellular matrix metalloproteases 2 and 9, and gamma-glutamyltransferase in both cell lines. Altogether, these findings support the pivotal participation of exosomes released by tumoral cells in the progression of PCa. Future studies on the molecular mechanisms involved in the observed changes could provide crucial information on this disease and help in the discovery of new therapeutic targets.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© 2023 The Authors
Prostate cancer
serum exosomes
LNCaP-FGC
PC3
tumor progression
Induction of more aggressive tumoral phenotypes in LNCaP and PC3 cells by serum exosomes from prostate cancer patients
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/596582024-03-11T07:03:25Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Marrodán, M. Dolores
Román, Estela María
Carmenate, M. M.
González Montero De Espinosa, Marisa
Herráez Sánchez, Ángel
Alfaro Gómez, Emma Laura
Lomaglio, D. B.
López-Ejeda, Noemí
Mesa, M. S.
Vázquez, V.
Méndez de Pérez, B.
Meléndez, J. M.
Moreno Romero, S.
Prado, Consuelo
Dipierri, José Edgardo
2024-01-19T07:57:49Z
2024-01-19T07:57:49Z
2021-05-12
American Journal of Human Biology, 2021, v. 33, n. 3 (E23496), p. 1-11
1042-0533
http://hdl.handle.net/10017/59658
10.1002/ajhb.23496
AR/0000035549
American Journal of Human Biology
33
11
3 (e23496)
1
Introduction Waist circumference (WC) constitutes an indirect measurement of central obesity in children and adolescents. Objective To provide percentiles of WC for Hispanic-American children and adolescents, and compare them with other international references. Materials and methods The sample comprised 13 289 healthy children between 6 and 18 years coming from public schools of middle and low socioeconomic levels in different parts of Argentina, Cuba, Spain, Mexico, and Venezuela. The LMS method to calculate WC percentiles was applied. Sex and age differences were assessed using Student'sttest and ANOVA (SPSS v.21.0). Comparisons were established with references from the United States, Colombia, India, China, Australia, Kuwait, Germany, Tunisia, Greece, and Portugal. Results WC increases with age in both sexes. Boys show higher WC in P3, P50, and P97. Comparison of 50th and 90th percentiles among populations from diverse sociocultural and geographical contexts shows high variability, not all justified by the measurement method. Discussion and conclusions Specific WC percentiles for sex and age, and P90 cut-off points are provided; these values are potentially useful to assess central obesity in Hispanic-American adolescent children.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© 2020 Wiley Periodicals LLC
Waist circumference percentiles for Hispanic-American children and comparison with other international references
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/589942023-12-20T01:15:48Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Sánchez Murcia, Pedro Alejandro
Ruiz Santaquiteria, Marta
Toro Londoño, Miguel Ángel
Lucio Ortega, Héctor Elessar de
Jiménez , María Ángeles
Gago Badenas, Federico
Jiménez Ruiz, Antonio
Camarasa Rius, María José
Velázquez , Sonsoles
2023-12-19T09:49:34Z
2023-12-19T09:49:34Z
2015-06-19
RSC Advances, 2015, v. 5, n. 69, p. 55784-55794
2046-2069
http://hdl.handle.net/10017/58994
10.1039/c5ra06853c
AR/0000031216
RSC Advances
5
55794
69
55784
All-hydrocarbon and lactam-bridged staples linking amino acid side-chains have been used to stabilize the ¿-helical motif in short 13-mer peptides that target critical protein-protein interactions at the dimerization interface of Leishmania infantum trypanothione reductase (Li-TryR). The design of the best positions for covalent hydrocarbon closure relied on a theoretical prediction of the degree of helicity of the corresponding cyclic peptides in water. Selected (i, i + 4) and (i, i + 7) hydrocarbon-stapled peptides were prepared by using solid-phase synthesis protocols and optimized ring-closing metathesis reactions under microwave conditions. Structural analysis by NMR spectroscopy confirmed high helical contents in aqueous TFE solutions for both types of helix-constrained cyclic peptides. Remarkably, the ability to prevent Li-TryR dimerization was reduced in both (i, i + 4) and (i, i + 7) hydrocarbon stapled peptides but was retained in the corresponding (i, i + 4) Glu-Lys lactam-bridged analogue, which also showed a higher resistance to proteolytic degradation by proteinase K relative to the linear peptide prototype. In silico studies indicated that the introduction of a hydrocarbon staple vs. a lactam bridge likely perturbs critical interactions required for proper binding of the peptide to the Li-TryR monomer.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© The Royal Society of Chemistry, 2015
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© The Royal Society of Chemistry, 2015
Comparison of hydrocarbon-and lactam-bridged cyclic peptides as dimerization inhibitors of Leishmania infantum trypanothione reductase
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/594092024-01-16T01:16:06Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Sotomayor Núñez, Sandra
Carmena Sierra, María José
Schally, A.V.
Varga, J. L.
Sánchez Chapado, Manuel Vicente
Prieto Villapún, Juan Carlos
Bajo Chueca, Ana María
2024-01-15T07:23:13Z
2024-01-15T07:23:13Z
2007-11-01
International Journal of Oncology, 2007, v. 31, n. 5, p. 1223-1230
1019-6439
http://hdl.handle.net/10017/59409
10.3892/ijo.31.5.1223
AR/0000011100
International Journal of Oncology
31
1230
5
1223
Receptors for vasoactive intestinal peptide (VIP) and the human epidermal growth factor family of tyrosine kinase receptors (HER) are potent promoters of cell proliferation, survival, migration, adhesion and differentiation in prostate cancer cell lines. In this study, we analyzed the cross-talk between both classes of receptors through the regulation of HER2 transactivation and expression by VIP. Three growth-hormone-releasing hormone analogs endowed with antagonistic activity for VIP receptors (JV-1-51, -52, and -53) abrogated the autocrine/paracrine stimuli of VIP on androgen-independent PC3 cells in the absence or the presence of 10% fetal bovine serum. Semiquantitative and real-time quantitative RT-PCR together with Western blotting showed increased expression levels of both mRNA and proteins for HER2 and HER3 in PC3 and androgen-dependent LNCaP prostate cancer cells as compared to non-neoplastic RWPE-1 cells. VIP (100 nM) stimulated the expression levels of both HER2 and HER3 in PC3 cells in a time-dependent manner. Whereas these effects were relatively slow, VIP rapidly (0.5 min) increased HER2 tyrosine phosphorylation. This pattern of HER transactivation was blocked by H89, a protein kinase A (PKA) inhibitor, as well as by the specific VIP antagonist JV-1-53, indicating the involvement of VIP receptors and PKA activity in phosphorylated HER2 formation. These findings support the merit of further studies on the potential usefulness of VIP receptor antagonists and both HER2 antibodies and tyrosine kinase inhibitors for prostate cancer therapy.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© Spandidos Publications
Vasoactive intestinal peptide receptors
HER2
HER3
growth-hormone-releasing hormone analogs
prostate cancer
Transactivation of HER2 by vasoactive intestinal peptide in experimental prostate cancer. Antagonistic action of an analog of growth-hormone-releasing hormone
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/590372023-12-21T01:16:19Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Lucio Ortega, Héctor Elessar de
Revuelto Pérez, Alejandro
Carriles Linares, Alejandra Ángela
De Castro De La Osa, Sonia
García González, Sonia
García Soriano, Juan Carlos
Alcón Calderón, María de las Mercedes
Sánchez Murcia, Pedro Alejandro
Hermoso Domínguez, Juan Antonio
Gago Badenas, Federico
Camarasa Rius, María José
Jiménez Ruiz, Antonio
Velázquez Díaz, Sonsoles
2023-12-20T06:56:21Z
2023-12-20T06:56:21Z
2022-10-29
European Journal of Medicinal Chemistry, 2022, v. 244, n. 114878, p. 1-21
0223-5234
http://hdl.handle.net/10017/59037
10.1016/j.ejmech.2022.114878
AR/0000042640
European Journal of Medicinal Chemistry
244
21
114878
1
N-methylation of the triazole moiety present in our recently described triazole-phenyl-thiazole dimerization disruptors of Leishmania infantum trypanothione disulfide reductase (LiTryR) led to a new class of potent inhibitors that target different binding sites on this enzyme. Subtle structural changes among representative library members modified their mechanism of action, switching from models of classical competitive inhibition to time-dependent mixed noncompetitive inhibition. X-ray crystallography and molecular modeling results provided a rationale for this distinct behavior. The remarkable potency and selectivity improvements, particularly against intracellular amastigotes, of the LiTryR dimerization disruptors 4c and 4d reveal that they could be exploited as leishmanicidal agents. Of note, L. infantum promastigotes treated with 4c significantly reduced their low-molecular-weight thiol content, thus providing additional evidence that LiTryR is the main target of this novel compound.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© The Author(s), 2022
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
1,2,3-Triazolium salts
Competitive inhibitor
Dimerization disruptor
Leishmania infantum
N-alkylation
Trypanothione disulfide reductase
Identification of 1,2,3-triazolium salt-based inhibitors of Leishmania infantum trypanothione disulfide reductase with enhanced antileishmanial potency in cellulo and increased selectivity
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/590662024-01-30T12:46:34Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Kuntz, Elodie M.
Baquero Valls, Pablo
Michie, Alison M.
Dunn, Karen
Tardito, Saverio
Holyoake, Tessa L.
Helgason, Vignir G
Gottlieb, E
2023-12-21T09:09:51Z
2023-12-21T09:09:51Z
2017-10-23
Nature Medicine, 2017, v. 23, n. 10, p. 1234-1240
1078-8956
http://hdl.handle.net/10017/59066
doi: 10.1038/nm.4399
AR/0000026475
Nature Medicine
23
1240
10
1234
Treatment of chronic myeloid leukemia (CML) with imatinib mesylate and other second-and/or third-generation c-Abl-specific tyrosine kinase inhibitors (TKIs) has substantially extended patient survival(1). However, TKIs primarily target differentiated cells and do not eliminate leukemic stem cells (LSCs)(2-4). Therefore, targeting minimal residual disease to prevent acquired resistance and/or disease relapse requires identification of new LSC-selective target(s) that can be exploited therapeutically(5,6). Considering that malignant transformation involves cellular metabolic changes, which may in turn render the transformed cells susceptible to specific assaults in a selective manner(7), we searched for such vulnerabilities in CML LSCs. We performed metabolic analyses on both stem cell-enriched (CD34(+) and CD34(+)CD38(-)) and differentiated (CD34(-)) cells derived from individuals with CML, and we compared the signature of these cells with that of their normal counterparts. Through combination of stable isotope-assisted metabolomics with functional assays, we demonstrate that primitive CML cells rely on upregulated oxidative metabolism for their survival. We also show that combination treatment with imatinib and tigecycline, an antibiotic that inhibits mitochondrial protein translation, selectively eradicates CML LSCs both in vitro and in a xenotransplantation model of human CML. Our findings provide a strong rationale for investigation of the use of TKIs in combination with tigecycline to treat patients with CML with minimal residual disease.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© Nature
Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/600622024-03-04T09:01:26Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Ropero Salinas, Santiago
Angulo Cuesta, Javier
González Corpas, Ana
Colás Escudero, María Begoña
López, José Ignacio
Martín, Ana
Sánchez Chapado, Manuel Vicente
2024-01-30T07:32:59Z
2024-01-30T07:32:59Z
2017-09-01
APMIS : acta pathologica, microbiologica, et immunologica Scandinavica, 2017, v. 125, n. 9, p. 787-796
0903-4641
http://hdl.handle.net/10017/60062
10.1111/apm.12719
AR/0000043609
APMIS : acta pathologica, microbiologica, et immunologica Scandinavica
125
796
9
787
DNA hypermethylation has emerged as a molecular biomarker for the evaluation of cancer diagnosis and prognosis. We define a methylation signature of bladder cancer and evaluate whether this profile assesses prognosis of patients. Genome-wide methylation analysis was performed on 70 tumor and 10 normal bladder samples. Hypermethylation status of 1505 CpGs present in the promoter region of 807 genes was studied. Thirty-three genes were significantly hypermethylated in >= 10% of the tumors. Three clusters of patients were characterized by their DNA methylation profile, one at higher risk of dead of disease (p = 0.0012). Association between cluster distribution and stage (p = 0.02) or grade (p = 0.02) was demonstrated. Hypermethylation of JAK3 and absence of hypermethylation of EYA4, GAT6, and SOX1 were associated with low-grade non-invasive disease. On the other hand, in high-grade invasive disease hypermethylation of CSPG2, HOXA11, HOXA9, HS3ST2, SOX1, and TWIST1 was associated with muscle invasiveness. A panel of hypermethylated genes including APC, CSPG2, EPHA5, EYA4, HOXA9, IPF1, ISL1, JAK3, PITX2, SOX1, and TWIST1 predicted cancer-specific survival and SOX1 (HR = 3.46), PITX2 (HR = 4.17), CSPG2 (HR = 5.35), and JAK3 hypermethylation (HR = 0.19) did so independently. Silencing of genes by hypermethylation is a common event in bladder cancer and could be used to develop diagnostic and prognostic markers. Combined hypermethylation of SOX1, PITX2, or CSPG2 signals patients at higher risk of death from bladder cancer.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© Wiley
Bladder cancer
DNA methylation
biomarkers
epigenetics
disease-specific survival
A DNA hypermethylation profile reveals new potential biomarkers for the evaluation of prognosis in urothelial bladder cancer
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/606352024-02-10T01:16:14Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Mora Rodríguez, José María
Sánchez Gómez, Belén
Bort Bueno, Alicia Carmen
Díaz Yuste, Alba
Ballesteros Gonzalez, Ruben
Arrieta Blanco, Francisco Jesús
Sebastián Martín, Alba
Díaz-Laviada Marturet, Inés Cecilia
2024-02-09T09:47:09Z
2024-02-09T09:47:09Z
2023-11-21
Life Sciences, 2023, v. 336, n. 122292, p. 1-13
0024-3205
http://hdl.handle.net/10017/60635
10.1016/j.lfs.2023.122292
AR/0000046312
Life Sciences
336
13
122292
1
Aims: Dipeptidyl peptidase 4 (DPP4) has been proposed as a coreceptor for SARS-CoV-2 cellular entry. Considering that type 2 diabetes mellitus (T2DM) has been identified as the most important risk factor for SARS-CoV-2, and that gliptins (DPP4 inhibitors) are a prescribed diabetic treatment, this study aims to unravel the impact of DPP4 in the intersection of T2DM/COVID-19. Materials and methods: We analyzed 189 serum human samples, divided into six clinical groups (controls, T2DM, T2DM + gliptins, COVID-19, COVID-19 + T2DM, and COVID-19 + T2DM + gliptins), measuring DPP4 protein concentration and activity by Western blot, ELISA, and commercial activity kits. The obtained results were verified in Huh-7 cellular models. Key findings: Both DPP4 concentration and activity were decreased in COVID-19 patients, and as in T2DM patients, compared to controls. Despite these lower levels, the ratio of DPP4 activity/concentration in COVID-19 sera was the highest (0.782 ± 0.289 ?U/ng vs. 0.547 ± 0.050 ?U/ng in controls, p < 0.0001), suggesting a compensating mechanism in these patients. Supernatants of Huh-7 cells incubated with COVID-19 serum showed a consistent and significantly lower DPP4 concentration and activity. Furthermore, COVID-19 + T2DM + gliptins patients showed a higher serum DPP4 concentration and activity than T2DM + gliptin subjects (p < 0.05), indicating that sera from COVID-19 convalescents interfere with gliptins. Significance: Either SARS-CoV-2 or some metabolites present in the sera of COVID-19-convalescent patients interact with soluble DPP4 or even gliptins themselves since the inhibitory effect of gliptins on DPP4 activity is being prevented. The interactions between DPP4, gliptins, and SARS-CoV-2 should be further elucidated to reveal the mechanism of action for these interesting observations.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© 2023 The Authors
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
DPP4
Gliptins
COVID-19
Type 2 diabetes
Enzymatic activity
Diabetic individuals with COVID-19 exhibit reduced efficacy of gliptins in inhibiting dipeptidyl peptidase 4 (DPP4). A suggested explanation for increased COVID-19 susceptibility in patients with type 2 diabetes mellitus (T2DM)
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/588512023-12-15T01:16:04Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Jiménez Mora, Eva María
Gallego Tamayo, Beatriz
Díaz Gago, Sergio
Baquero Valls, Pablo
Lasa Benito, Marina Paloma
Chiloeches Gálvez, Antonio
2023-12-14T07:25:13Z
2023-12-14T07:25:13Z
2021-06
Int J Mol Sci., 2021, v. 22, n. 6033, p. 1-17
1661-6596
http://hdl.handle.net/10017/58851
10.3390/ijms22116033
AR/0000037811
Int J Mol Sci.
22
17
6033
1
The dysregulation of autophagy is important in the development of many cancers, including thyroid cancer, where (V600E)BRAF is a main oncogene. Here, we analyse the effect of (V600E)BRAF inhibition on autophagy, the mechanisms involved in this regulation and the role of autophagy in cell survival of thyroid cancer cells. We reveal that the inhibition of (V600E)BRAF activity with its specific inhibitor PLX4720 or the depletion of its expression by siRNA induces autophagy in thyroid tumour cells. We show that (V600E)BRAF downregulation increases LKB1-AMPK signalling and decreases mTOR activity through a MEK/ERK-dependent mechanism. Moreover, we demonstrate that PLX4720 activates ULK1 and increases autophagy through the activation of the AMPK-ULK1 pathway, but not by the inhibition of mTOR. In addition, we find that autophagy blockade decreases cell viability and sensitize thyroid cancer cells to (V600E)BRAF inhibition by PLX4720 treatment. Finally, we generate a thyroid xenograft model to demonstrate that autophagy inhibition synergistically enhances the anti-proliferative and pro-apoptotic effects of (V600E)BRAF inhibition in vivo. Collectively, we uncover a new role of AMPK in mediating the induction of cytoprotective autophagy by (V600E)BRAF inhibition. In addition, these data establish a rationale for designing an integrated therapy targeting (V600E)BRAF and the LKB1-AMPK-ULK1-autophagy axis for the treatment of (V600E)BRAF-positive thyroid tumours.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© The Authors
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
(V600E)BRAF
autophagy
LKB1
AMPK
ULK1
survival
thyroid cancer
V600E BRAF Inhibition Induces Cytoprotective Autophagy through AMPK in Thyroid Cancer Cells
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/595392024-01-20T01:16:06Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Kuhn, Stefan
Wieske, Lianne H. E.
Trevorrow, Paul
Schober, Daniel
Schlörer, Nils E.
Nuzillard, Jean-Marc
Kessler, Pavel
Junker, Jochen
Herráez Sánchez, Ángel
Farés, Christophe
Erdelyi, Mate
Jeannerat, Damien
2024-01-17T09:52:36Z
2024-01-17T09:52:36Z
2021-03-17
Magnetic Resonance in Chemistry, 2021, v. 59, n. 8, p. 792-803
0749-1581
http://hdl.handle.net/10017/59539
10.1002/mrc.5146
AR/0000036778
Magnetic Resonance in Chemistry
59
803
8
792
The NMReDATA format has been proposed as a way to store, exchange, and to disseminate NMR data and physical and chemical metadata of chemical compounds. In this paper we report on analytical work?ows that take advantage of the uniform and standardized NMReDATA format. We also give access to a repository of sample data, which can serve for validating software packages that encode or decode ?les in NMReDATA format.
eng
http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
© 2021 The Authors
Attribution 4.0 International (CC BY 4.0)
Nuclear Magnetic Resonance (NMR)
NMReDATA
chemical information
data standard
peak assignment
NMReDATA: Tools and applications
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/606302024-02-14T01:15:59Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Bort Bueno, Alicia Carmen
Sánchez Gómez, Belén
Miguel García, Irene de
Mateos Gómez, Pedro Antonio
Díaz-Laviada Marturet, Inés Cecilia
2024-02-09T09:06:31Z
2024-02-09T09:06:31Z
2020-03-03
Molecular Biology Reports, 2020, v. 47, n. 4, p. 2635-2647
0301-4851
http://hdl.handle.net/10017/60630
10.1007/s11033-020-05352-3
AR/0000033185
Molecular Biology Reports
47
2647
4
2635
According to the stem cell theory for cancer, hepatocellular carcinomas are sustained by a group of cancer stem cells (CSCs) which are responsible for resistance to chemotherapy. In the present study we aimed to examine lipid metabolism in cancer stem cells induced by long-term treatment with sorafenib and its relationship with acquisition of a CSC-like phenotype. Two cell lines (HepG2SF1 and Huh7SF1) were generated by incubation with a step-wise increase of sorafenib concentrations for 10 months. These cell lines displayed stem-like characteristics like increase in the expression of ABCB1A, Nanog and Oct4 as well as an E-cadherin/N-cadherin switch. HepG2SF1 and Huh7SF1 cells showed intracellular accumulation of neutral lipids, assessed by flow cytometry and confocal microscopy. The exam of lipid metabolism revealed that HepG2SF1 and Huh7SF1 cells increased the expression of the enzymes involved in de novo lipid synthesis ATP-citrate lyase (ACLY), acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN) and that of the fatty acid transporter CD36. In addition, these CSC-like cells had enhanced expression of the lipogenic transcription factor SREBP1c. Analysis of the key metabolic sensor AMP-activated kinase (AMPK) demonstrated that both AMPK phosphorylation and levels were decreased in the CSC-like cells compared to their parental cells. Interestingly, transfection of HepG2SF1 and Huh7SF1 cells with AMPK, restored the levels of the lipogenic enzymes and SREBP1c and decreased the intracellular lipid accumulation. Furthermore, AMPK transfection decreased the stemness markers and inhibited the E-cadherin/N-cadherin switch. Targeting AMPK and lipid metabolism of hepatocellular cancer stem cells is a promising strategy to face stemness and chemotherapy resistance.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© Springer Nature
HepG2
Hepatocellular carcinoma
Huh7
Lipid metabolism
Sorafenib
cancer stem cells
Dysregulated lipid metabolism in hepatocellular carcinoma cancer stem cells
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/603972024-03-14T18:11:43Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Sánchez Gómez, Belén
Gasalla Herráiz, José Manuel
Sánchez Chapado, Manuel Vicente
Bort Bueno, Alicia Carmen
Díaz-Laviada Marturet, Inés Cecilia
2024-02-05T12:43:22Z
2024-02-05T12:43:22Z
2021-11-23
Journal of Clinical Investigation, 2021, v. 10, n. 23, p. 5474-
0021-9738
http://hdl.handle.net/10017/60397
10.3390/jcm10235474
AR/0000038117
Journal of Clinical Investigation
10
23
5474
This study was undertaken due to the urgent need to explore reliable biomarkers for early SARS-CoV-2 infection. We performed a retrospective study analyzing the serum levels of the cardiovascular biomarkers IL-6, TNF-?, N-terminal pro-B natriuretic peptide, cardiac troponin T (cTnT), ischemia-modified albumin (IMA) and pregnancy-associated plasma protein-A (PAPP-A) in 84 patients with COVID-19.Patients were divided into three groups according to their RT-qPCR and IgG values: acute infection (n = 35), early infection (n = 25) or control subjects (n = 24). Levels of biomarkers were analyzed in patient serum samples using commercially available ELISA kits. Results showed a significant increase in IMA and PAPP-A levels in the early infected patients. Moreover, multivariate analysis and receiver operating characteristic (ROC) curve showed that IMA and PAPP-A had excellent discrimination value for the early stage of COVID-19. For IMA, the area under the ROC curve (AUC) had a value of 0.94 (95% confidence interval (CI): 0.881-0.999). Likewise, the serum level of PAPP-A was significantly higher in patients with early infection than in the control subjects (AUC = 0.801 (95% CI: 0.673-0.929)). The combined use of IMA and PAPP-A enhanced the sensitivity for total SARS-CoV-2-infected patients to 93%. These results suggest that the increased levels of PAPP-A and IMA shed light on underlying mechanisms of COVID-19 physiopathology and might be used as efficient biomarkers with high sensitivity and specificity for the early stage of COVID-19. Importantly, when monitoring pregnancy and cardiovascular diseases using PAPP-A or IMA levels, a SARS-CoV-2 infection should be discarded for proper interpretation of the results.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© 2021 by the authors
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Pregnancy-associated plasma protein-A
Ischemia-modified albumin
Biomarkers
COVID-19
SARS-CoV-2
Coronavirus
Increase in Ischemia-Modified Albumin and Pregnancy-Associated Plasma Protein-A in COVID-19 Patients
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/590842023-12-22T01:16:10Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Calleros Basilio, Laura
Sánchez Hernández, Irene
Baquero Valls, Pablo
Toro Nozal, María Josefa
Chiloeches Gálvez, Antonio
2023-12-21T15:22:58Z
2023-12-21T15:22:58Z
2009
Carcinogenesis, 2009, v. 30, n. 10, p. 1670-1677
0143-3334
http://hdl.handle.net/10017/59084
10.1093/carcin/bgp188
AR/0000012097
Carcinogenesis
30
1677
10
1670
Cholesterol is necessary for proliferation and survival of transformed cells. Here we analyse the effect of cholesterol depletion on apoptosis and the mechanisms underlying this effect in colorectal cancer cells carrying oncogenic Ras or B-V600E-RAF mutations. We show that chronic cholesterol depletion achieved with lipoprotein-deficient serum (LPDS) and 25-hydroxycholesterol (25-HC) treatment results in a significant increase in apoptosis in HT-29 and Colo-205 cells containing the B-V600E-RAF mutation, but not in HCT-116 and LoVo cells harbouring the (G13D)Ras mutation, or BE cells, which possess two mutations, (G13D)Ras and B-G463V-RAF. We also demonstrate that oncogenic Ras protects from apoptosis induced by cholesterol depletion through constitutive activation of the phosphatidylinositol-3 kinase (PI3K)/AKT pathway. The specific activation of the PI3K/AKT pathway by overexpression of the (V12)RasC40 mutant or a constitutively active AKT decreases the LPDS plus 25-HC-induced apoptosis in HT-29 cells, whereas PI3K inhibition or abrogation of AKT expression renders HCT-116 sensitive to cholesterol depletion-induced apoptosis. Moreover, our data show that LPDS plus 25-HC increases the activity of c-Jun N-terminal kinase proteins only in HT-29 cells and that the inhibition of this kinase blocks the apoptosis induced by LPDS plus 25-HC. Finally, we demonstrate that AKT hyperactivation by oncogenic Ras protects from apoptosis, preventing the activation of c-Jun N-terminal kinase by cholesterol depletion. Thus, our data demonstrate that low levels of cholesterol induce apoptosis in colorectal cancer cells without oncogenic Ras mutations. These results reveal a novel molecular characteristic of colon tumours containing Ras or B-RAF mutations and should help in defining new targets for cancer therapy.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© The Authors
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Oncogenic Ras, but not V600EB-RAF, protects from cholesterol depletion-induced apoptosis through the PI3K/AKT pathway in colorectal cancer cells
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/597142024-01-23T01:16:21Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Bajo Chueca, Ana María
Carmena Sierra, María José
Fernández Martínez, Ana B
Vacas Oliva, Eva
Sánchez Chapado, Manuel Vicente
Prieto, Juan C.
2024-01-22T09:46:54Z
2024-01-22T09:46:54Z
2015-02
Fernández-Martínez, A.B., Carmena, M.J., Bajo, A.M., Vacas, E., Sánchez-Chapado, M. & Prieto, J.C. 2015, "VIP induces NF-κB1-nuclear localisation through different signalling pathways in human tumour and non-tumour prostate cells", Cellular signalling, vol. 27, no. 2, pp. 236-244.
http://hdl.handle.net/10017/59714
10.1016/j.cellsig.2014.11.005
Cellular Signalling
27
244
2
236
The nuclear factor kappa B (NF-kappa B) is a powerful activator of angiogenesis, invasion and metastasis. Transactivation and nuclear localisation of NF-kappa B is an index of recurrence in prostate cancer. Vasoactive intestinal peptide (VIP) exerts similar effects in prostate cancer models involving increased expression of vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) which are related to NF-kappa B transactivation. Here we studied differential mechanisms of VIP-induced NF-kappa B transactivation in non-tumour RWPE-1 and tumour LNCaP and PC3 human prostate epithelial cells. Immunofluorescence studies showed that VIP increases translocation of the p50 subunit of NF-kappa B1 to the nucleus, an effect that was inhibited by curcumin. The signalling transduction pathways involved are different depending on cell transformation degree. In control cells (RWPE1), the effect is mediated by protein kinase A (PKA) activation and does not implicate extracellular signal-regulated kinase (ERK) or phosphoinositide 3-kinase (PI3-K) pathways whereas the opposite is true in tumour LNCaP and PC3 cells. Exchange protein directly activated by CAMP (EPAC) pathway is involved in transformed cells but not in control cells. Curcumin blocks the activating effect of VIP on COX-2 promoter/prostaglandin E-2 (PGE(2)) production and VEGF expression and secretion. The study incorporates direct observation on COX-2 promoter and suggests that VIP effect on VEGF may be indirectly mediated by PGE(2) after being synthesised by COX-2, thus amplifying the initial signal. We show that the signalling involved in VIP effects on VEGF is CAMP/PKA in non-tumour cells and cAMP/EPAC/ERK/PI3K in tumour cells which coincides with pathways mediating p50 nuclear translocation. Thus, VIP appears to use different pathways for NF-kappa B1 (p50) transactivation in prostate epithelial cells depending on whether they are transformed or not. Transformed cells depend on pro-survival and pro-proliferative signalling pathways involving ERK, PI3-K and cAMP/EPAC which supports the potential therapeutic value of these targets in prostate cancer.
eng
http://creativecommons.org/licenses/by-nc-sa/4.0/
info:eu-repo/semantics/openAccess
Atribución-NoComercial-CompartirIgual 4.0 Internacional
© Elsevier
VIP induces NF-κB1-nuclear localisation through different signalling pathways in human tumour and non-tumour prostate cells
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/600822024-01-31T01:16:31Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Sánchez Gómez, Belén
Bort Bueno, Alicia Carmen
Mateos Gómez, Pedro Antonio
Rodríguez Henche, María de las Nieves
Díaz-Laviada Marturet, Inés Cecilia
2024-01-30T12:10:56Z
2024-01-30T12:10:56Z
2019-03
Cancer Cell International, 2019, v. 19, n. 54, p. 1-14
1475-2867
http://hdl.handle.net/10017/60082
10.1186/s12935-019-0769-2
AR/0000029621
Cancer Cell International
19
14
54
1
Background Current chemotherapy for castration-resistant prostate cancer is established on taxane-based compounds like docetaxel. However, eventually, the development of toxic side effects and resistance limits the therapeutic benefit being the major concern in the treatment of prostate cancer. Combination therapies in many cases, enhance drug efficacy and delay the appearance of undesired effects, representing an important option for the treatment of castration-resistant prostate cancer. In this study, we tested the efficacy of the combination of docetaxel and capsaicin, the pungent ingredient of hot chili peppers, on prostate cancer cells proliferation. Methods Prostate cancer LNCaP and PC3 cell lines were used in this study. Levels of total and phosphorylated forms of Akt, mTOR, S6, LKB1, AMPK and ACC were determined by Western blot. AMPK, LKB1 and Akt knock down was performed by siRNA. PTEN was overexpressed by transient transfection with plasmids. Xenograft prostate tumors were induced in nude mice and treatments (docetaxel and capsaicin) were administered intraperitoneally. Statistical analyses were performed with GraphPad software. Combination index was calculated with Compusyn software. Results Docetaxel and capsaicin synergistically inhibited the growth of LNCaP and PC3 cells, with a combination index lower than 1 for most of the combinations tested. Co-treatment with docetaxel and capsaicin notably decreased Akt and its downstream targets mTOR and S6 phosphorylation. Overexpression of PTEN phosphatase abrogated the synergistic antiproliferative effect of docetaxel and capsaicin. The combined treatment also increased the phosphorylation of AMP-activated kinase (AMPK) and the phosphorylation of its substrate ACC. In addition, pharmacological inhibition of AMPK with dorsomorphin (compound C) as well as knock down by siRNA of AMPK or its upstream kinase LKB1, abolished the synergy of docetaxel and capsaicin. Mechanistically, we showed that the synergistic anti-proliferative effect may be attributed to two independent effects: Inhibition of the PI3K/Akt/mTOR signaling pathway by one side, and AMPK activation by the other. In vivo experiments confirmed the synergistic effects of docetaxel and capsaicin in reducing the tumor growth of PC3 cells. Conclusion Combination of docetaxel and capsaicin represents a therapeutically relevant approach for the treatment of Prostate Cancer.
eng
http://creativecommons.org/licenses/by-nc-sa/4.0/
info:eu-repo/semantics/openAccess
© The Author(s) 2019
Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)
AMPK
Capsaicin
Docetaxel
LNCaP cells
PC3 cells
Prostate cancer
Combination of the natural product capsaicin and docetaxel synergistically kills human prostate cancer cells through the metabolic regulator AMP-activated kinase
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/590392023-12-21T01:16:20Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Revuelto Pérez, Alejandro
Lucio Ortega, Héctor Elessar de
García Soriano, Juan Carlos
Sánchez Murcia, Pedro Alejandro
Gago Badenas, Federico
Jiménez Ruiz, Antonio
Camarasa Rius, María José
Velázquez Díaz, Sonsoles
2023-12-20T07:49:00Z
2023-12-20T07:49:00Z
2021-05-04
Journal of Medicinal Chemistry, 2021, v. 64, n. 9, p. 6137-6160
0022-2623
http://hdl.handle.net/10017/59039
10.1021/acs.jmedchem.1c00206
AR/0000040825
Journal of Medicinal Chemistry
64
6160
9
6137
Inhibition of Leishmania infantum trypanothione disulfide reductase (LiTryR) by disruption of its homodimeric interface has proved to be an alternative and unexploited strategy in the search for novel antileishmanial agents. Proof of concept was first obtained by peptides and peptidomimetics. Building on previously reported dimerization disruptors containing an imidazole-phenyl-thiazole scaffold, we now report a new 1,2,3-triazole-based chemotype that yields noncompetitive, slow-binding inhibitors of LiTryR. Several compounds bearing (poly)aromatic substituents dramatically improve the ability to disrupt LiTryR dimerization relative to reference imidazoles. Molecular modeling studies identified an almost unexplored hydrophobic region at the interfacial domain as the putative binding site for these compounds. A subsequent structure-based design led to a symmetrical triazole analogue that displayed even more potent inhibitory activity over LiTryR and enhanced leishmanicidal activity. Remarkably, several of these novel triazole-bearing compounds were able to kill both extracellular and intracellular parasites in cell cultures.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© American Chemical Society, 2021
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Efficient dimerization disruption of Leishmania infantum trypanothione reductase by triazole-phenyl-thiazoles
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/590082024-03-11T07:13:53Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Ashour Fernández, Nadia
Angulo Cuesta, Javier
González-Corpas , Ana
Orea , María J.
Toledo Lobo, María Del Val
Colomer , Ramón
Colás Escudero, María Begoña
Esteller , Manel
Ropero Salinas, Santiago
2023-12-19T13:03:22Z
2023-12-19T13:03:22Z
2020-06-30
International Journal of Molecular Sciences, 2020, v. 21, n. 13, p. 4687-
1422-0067
http://hdl.handle.net/10017/59008
10.3390/ijms21134687
AR/0000034826
International Journal of Molecular Sciences
21
13
4687
Prostate and breast cancer constitute the most common cancers among men and women worldwide. The aging population is one of the main risk factors for prostate and breast cancer development and accumulating studies link aging with epigenetic changes. Growth factor independence-1 (Gfi1) is a transcriptional repressor with an important role in human malignancies, including leukemia, colorectal carcinoma, and lung cancer, but its role in prostate and breast cancer is unknown. We have found that Gfi1 epigenetic silencing is a common event in prostate and breast cancer. Gfi1 re-expression in prostate and breast cancer cell lines displaying Gfi1 epigenetic silencing decreases cell proliferation, reduced colony formation density, and tumor growth in nude mice xenografts. In addition, we found that Gfi1 repress alpha 1-anti-trypsin (AAT) and alpha 1-anti-chymotrypsin (ACT) expression, two genes with important functions in cancer development, suggesting that Gfi1 silencing promotes tumor growth by increasing AAT and ACT expression in our system. Finally, Gfi1 epigenetic silencing could be a promising biomarker for prostate cancer progression because it is associated with shorter disease-free survival. In conclusion, our findings strongly indicate that Gfi1 epigenetic silencing in prostate and breast cancer could be a crucial step in the development of these two-well characterized endocrine related tumors.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© 2020 by the authors
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Prostate cancer
Breast cancer
Gfi1
DNA methylation
Epigenetic Regulation of Gfi1 in Endocrine-Related Cancers: A Role Regulating Tumor Growth
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/593012024-01-12T01:16:28Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Muñoz Moreno, Laura
Bajo Chueca, Ana María
Prieto Villapún, Juan Carlos
Carmena Sierra, María José
2024-01-11T12:31:28Z
2024-01-11T12:31:28Z
2017-05-05
Molecular and Cellular Endocrinology, 2017, v. 446, p. 59-69
0303-7207
http://hdl.handle.net/10017/59301
10.1016/j.mce.2017.02.011
AR/0000031036
Molecular and Cellular Endocrinology
446
69
59
The involvement of growth hormone-releasing hormone (GHRH) in several relevant processes that contribute to prostate cancer progression was analyzed. Firstly, we evaluated GHRH effects on cell proliferation and adhesion in human cancer prostate cell lines, LNCaP and PC3, by using specific assays (BrdU incorporation and collagen adhesion). The expression levels of the main marker molecules of these processes were measured by RT-PCR, Western blotting and zymography assays. GHRH increased both cell proliferation and proliferating cell nuclear antigen (PCNA) levels in LNCaP cells and in PC3 cells; however, such a rise was faster in the PC3 cells that represent the most aggressive stage of prostate cancer. Furthermore, GHRH significantly reduced cell adhesion and E-cadherin levels in LNCaP and PC3 cells and up-regulated the total and nuclear expression of ?-catenin in PC3 cells. In addition, we assessed cell cycle, cell migration and VEGF secretion in PC3 cells. GHRH augmented the number of cells in G2/M-phase but diminished that corresponding to G1-phase. Cell-cycle specific markers were evaluated since GHRH effects may be related to their differential expression; we observed a decrease of p53, p21, and Bax/Bcl2 ratio. Furthermore, GHRH increased the expression of CD44, c-myc and cyclin D1, MMP-2 and MMP-9 activity, and VEGF secretion. We also observed that EGFR and/or HER2 transactivation is involved in cell adhesion, cell migration and VEGF secretion produced by GHRH. Consequently, present results define GHRH as a proliferative, anti-apoptotic and migratory agent in prostate cancer.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© Elsevier
Cell adhesion
Cell migration
GHRH
Prostate cancer
VEGF secretion
Growth hormone-releasing hormone (GHRH) promotes metastatic phenotypes through EGFR/HER2 transactivation in prostate cancer cells
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/589742024-03-11T07:09:00Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Muñoz Moreno, Laura
Carmena Sierra, María José
Prieto Villapún, Juan Carlos
Schally, Andrew V.
Bajo Chueca, Ana María
2023-12-18T14:40:56Z
2023-12-18T14:40:56Z
2022-03-01
Prostate, 2022, v. 82, n. 2, p. 933-941
0270-4137
http://hdl.handle.net/10017/58974
10.1002/pros.24339
AR/0000041070
Prostate
82
941
2
933
Background: Growth hormone-releasing hormone (GHRH) and its receptors have been implicated in the progression of various tumors. In this study, we analyzed the carcinogenetic potential of exposure to GHRH of a nontumor human prostate epithelial cell line (RWPE-1) as well as its transforming effect in a xenograft model. Methods: We performed cell viability, cell proliferation, adhesion and migration assays. In addition, metalloprotease (MMP)-2 activity by means gelatin zymography, GHRH-R subcellular location using confocal immunofluorescence microscopy and vascular endothelial growth factor (VEGF) levels by enzyme-linked immunoassay were assessed. Besides, we developed an in vivo model in order vivo model to determine the role of GHRH on tumorigenic transformation of RWPE-1 cells. Results: In cell cultures, we observed development of a migratory phenotype consistent with the gelatinolytic activity of MMP-2, expression of VEGF, as well as E-cadherin-mediated cell-cell adhesion and increased cell motility. Treatment with 0.1 µM GHRH for 24 h significantly increased cell viability and cell proliferation. Similar effects of GHRH were seen in RWPE-1 tumors developed by subcutaneous injection of GHRH-treated cells in athymic nude mice, 49 days after inoculation. Conclusions: Thus, GHRH appears to act as a cytokine in the transformation of RWPE-1 cells by mechanisms that likely involve epithelial-mesenchymal transition, thus reinforcing the role of GHRH in tumorigenesis of prostate.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© 2022 The Authors
GHRH
RWPE-1 cells
epithelial-mesenchymal transition
prostate cancer
tumorigenesis
Tumorigenic transformation of human prostatic epithelial cell line RWPE-1 by growth hormone-releasing hormone (GHRH)
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/593092024-01-12T01:16:29Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Vacas Oliva, Eva
Muñoz Moreno, Laura
Valenzuela Ruiz, Pedro Luis
Prieto Villapún, Juan Carlos
Schally, Andrew V
Carmena Sierra, María José
Bajo Chueca, Ana María
2024-01-11T13:53:55Z
2024-01-11T13:53:55Z
2016-12
Peptides, 2016, v. 86, p. 153-161
0196-9781
http://hdl.handle.net/10017/59309
10.1016/j.peptides.2016.11.004
AR/0000031747
Peptides
86
161
153
Triple-negative breast cancer (TNBC) is a subset of breast cancers which is negative for expression of estrogen and progesterone receptors and human epidermal growth factor receptor-2 (HER2). Chemotherapy is currently the only form of treatment for women with TNBC. Growth hormone-releasing hormone (GHRH) and epidermal growth factor (EGF) are autocrine/paracrine growth factors in breast cancer and a substantial proportion of TNBC expresses receptors for GHRH and EGF. The aim of this study was to evaluate the interrelationship between both these signaling pathways in MDA-MB-468 human TNBC cells. We evaluated by Western blot assays the effect of GHRH on transactivation of EGF receptor (EGFR) as well as the elements implicated. We assessed the effect of GHRH on migration capability of MDA-MB-468 cells as well as the involvement of EGFR in this process by means of wound-healing assays. Our findings demonstrate that in MDA-MB-468 cells the stimulatory activity of GHRH on tyrosine phosphorylation of EGFR is exerted by two different molecular mechanisms: i) through GHRH receptors, GHRH stimulates a ligand-independent activation of EGFR involving at least cAMP/PKA and Src family signaling pathways; ii) GHRH also stimulates a ligand-dependent activation of EGFR implicating an extracellular pathway with an important role for metalloproteinases. The cross-talk between EGFR and GHRHR may be impeded by combining drugs acting upon GHRH receptors and EGFR family members. This combination of GHRH receptors antagonists with inhibitors of EGFR signalling could enhance the efficacy of both types of agents as well as reduce their doses increasing therapeutic benefits in management of human breast cancer.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
GHRH
Triple-negative breast cancer
EGFR Transactivation
Cell migration
GHRH antagonist
Growth hormone-releasing hormone induced transactivation of epidermal growth factor receptor in human triple-negative breast cancer cells
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/604012024-03-14T18:14:27Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Mora Rodríguez, José María
Sánchez Gómez, Belén
Sebastián Martín, Alba
Díaz Yuste, Alba
Sánchez Chapado, Manuel Vicente
Palacín Esteban, Ana María
Sánchez Rodríguez, Carlos
Bort Bueno, Alicia Carmen
Díaz-Laviada Marturet, Inés Cecilia
2024-02-05T12:59:31Z
2024-02-05T12:59:31Z
2023-10-26
International Journal of Molecular Sciences, 2023, v. 24, n. 21, p. 15626-
1661-6596
http://hdl.handle.net/10017/60401
10.3390/ijms242115626
AR/0000046311
International Journal of Molecular Sciences
24
21
15626
In this study, we examined the metabolic adaptations of a chemoresistant prostate cancer cell line in comparison to a sensitive cell line. We utilized prostate cancer LNCaP cells and subjected them to a stepwise increase in the antiandrogen 2-hydroxy-flutamide (FLU) concentration to generate a FLU-resistant cell line (LN-FLU). These LN-FLU cells displayed characteristics of cancer stem cells, exhibited drug resistance, and showed a significantly reduced expression of Cyclin D1, along with the overexpression of p16, pointing to a proliferation arrest. In comparing the cancer stem-like LN-FLU cells to the LNCaP cells, we observed a decrease in the expression of CTP-choline cytidylyl transferase ? (CCT?), as well as a decline in choline kinase, suggesting altogether a downregulation of the phosphatidylcholine biosynthetic pathway. In addition, we found decreased levels of the protein methyl transferase PRMT2 and the upregulation of the histone deacetylase Sirtuin1 (Sirt1). Analysis of the human prostate cancer samples revealed similar results in a population with high expressions of the stem cell markers Oct4 and ABCB1A1. Our findings suggest that the adaptation of prostate cancer cells to antiandrogens could induce reprogramming into stem cells that survive in a low phosphocholine metabolism and cell cycle arrest and display drug resistance.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© 2023 by the authors
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
LNCaP cells
Antiandrogens
Dormant cells
Flutamide
Phosphatidylcholine metabolism
Resistant prostate cancer
Resistance to 2-Hydroxy-Flutamide in Prostate Cancer Cells Is Associated with the Downregulation of Phosphatidylcholine Biosynthesis and Epigenetic Modifications
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/600332024-02-02T01:16:35Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Sanchís Bonet, Ángeles
Barrionuevo González, Marta
Bajo Chueca, Ana María
Pulido Fonseca, Lina Alexandra
Ortega Polledo, Luis Enrique
Tamayo Ruiz, Juan Carlos
Sánchez Chapado, Manuel Vicente
2024-01-29T06:21:01Z
2024-01-29T06:21:01Z
2018
Actas Urologicas Espanolas, 2018, v. 42, n. 1, p. 25-32
0210-4806
http://hdl.handle.net/10017/60033
10.1016/j.acuro.2017.06.003
AR/0000032054
Actas Urologicas Espanolas
42
32
1
25
Objectives: To validate and analyse the clinical usefulness of a predictive model of prostate cancer that incorporates the biomarker ?[-2] pro prostate-specific antigen? using the prostate health index (PHI) in decision making for performing prostate biopsies. Material and methods: We isolated serum from 197 men with an indication for prostate biopsy to determine the total prostate-specific antigen (tPSA), the free PSA fraction (fPSA) and the [-2] proPSA (p2PSA). The PHI was calculated as p2PSA/fPSA×?tPSA. We created 2 predictive models that incorporated clinical variables along with tPSA or PHI. The performance of PHI was assessed with a discriminant analysis using receiver operating characteristic curves, internal calibration and decision curves. Results: The areas under the curve for the tPSA and PHI models were 0.71 and 0.85, respectively. The PHI model showed a better ability to discriminate and better calibration for predicting prostate cancer but not for predicting a Gleason score in the biopsy ?7. The decision curves showed a greater net benefit with the PHI model for diagnosing prostate cancer when the probability threshold was 15-35% and greater savings (20%) in the number of biopsies. Conclusions: The incorporation of p2PSA through PHI in predictive models of prostate cancer improves the accuracy of the risk stratification and helps in the decision-making process for performing prostate biopsies.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© Elsevier
Prostate cancer
Prostate health index
Predictive models
Decision curve analysis
Prostate biopsy
Validation of the prostate health index in a predictive model of prostate cancer
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/606892024-02-14T01:16:03Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Rodríguez Henche, María de las Nieves
Calleros Basilio, Laura
Saura Redondo, Marta
Román Curto, Irene de los Dolores
Muñoz Moreno, Laura
Bajo Chueca, Ana María
2024-02-13T10:24:31Z
2024-02-13T10:24:31Z
2022
EDULEARN22 Proceedings. España: International Academy Of Technology, Education And Development (Iated), 2022, Vol. , pp. 6977-6982
978-84-09-42484-9
http://hdl.handle.net/10017/60689
10.21125/edulearn.2022.1641
CO/0000020123
EDULEARN22 Proceedings
6982
6977
The pandemic has forced us to reinvent ourselves and to consider new strategies in education. Motivation, fundamental to student performance, has been seriously compromised. In this sense, the type of motivation we are interested in "fostering" is intrinsic motivation, closely linked to the concept of learning-centered goals and objectives. The action implemented is committed to the approach to challenge-based learning-gamification in the Degree in Nursing (UAH), in order to develop an integrative training with an interdisciplinary focus. Biochemistry and Physiology came together in Integra BioFis 5.0 and through participatory and collaborative techniques we pursued meaningful learning. All the students of the Biochemistry and Physiology subjects (n = 120) took part in the learning experience, organized in 12 teams. The action was carried out online through the virtual platform: - An initial session, in which the objectives, methodology, timetable and evaluation criteria were clarified. Topics that aroused the students? interest were randomly assigned (https://bit.ly/3tfJaCi). The assigned tutors guided the students in overcoming the challenges of each stage. - The development of the action consisted of a series of phases: i) documentation and literature search; ii) integration of objectives and choice of presentation format; iii) elaboration of the graphical document; iv) peer review of presentations and voting for the best contribution. The students' papers, as well as the rubrics with comments and suggestions from each of the instructors, were returned to the teams immediately. - A final session, in which they reflected on the activity they had carried out, highlighting the positive aspects of the training for the development of competences and skills: i) search for information from quality sources; ii) synthesis of contents; iii) work as a team; iv) elaboration of an original and own work. Voting was then shown for the papers presented, revealing the names of the three teams with the most votes, finalists and winners. Learning assessment was conducted by taking into account the influence of learning on motivation and the student's self-esteem and competences, with indicators such as progress, content, sources, graphical document production, teamwork and responsibility, among others. As an important element that makes gamification work, a reward for participation (awarding of a participation diploma) and for the best Integra BioFis 5.0 graphic document presented (awarding of diplomas and prizes-gifts to the members of the winning team) was considered as an important element that makes gamification work. From this educational strategy, it can be concluded that gamification is a constructive experience, taking advantage of all the benefits of implementing the overcoming of challenges in the educational environment. This has had an impact on teaching practice, to the extent that what has been "reflected" and "worked" in Integra BioFis 5.0 has contributed to improving the quality of virtual teaching, "fostering" intrinsic motivation in students.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Motivation
Biochemistry
Physiology
Interdisciplinary
Collaborative
Participative
Undergraduates
Game-based Learning.
Integra BioFis 5.0. A collaborative, participatory and interdisciplinary experience for undergraduates in nursing
info:eu-repo/semantics/bookPart
oai:ebuah.uah.es:10017/590502023-12-21T01:16:22Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Alelú Paz, Raúl
Carmona , Francisco J
Sanchez Mut, Jose V
Cariaga Martínez, Ariel Ernesto
González Corpas, Ana
Ashour Fernández, Nadia
Orea Martínez, María Jesús
Escanilla , Ana
Monje , Alfonso
Guerrero Márquez, Cármen
Saiz Ruiz, Jerónimo
Esteller , Manel
Ropero Salinas, Santiago
2023-12-20T12:21:58Z
2023-12-20T12:21:58Z
2016-09-30
Frontiers in psychology, 2016, v. 7, n. 1496, p. 1-10
1664-1078
http://hdl.handle.net/10017/59050
doi.org/10.3389/fpsyg.2016.01496
AR/0000024725
Frontiers in psychology
7
10
1496
1
Attempts to discover genes that are involved in the pathogenesis of major psychiatric disorders have been frustrating and often fruitless. Concern is building about the need to understand the complex ways in which nature and nurture interact to produce mental illness. We analyze the epigenome in several brain regions from schizophrenic patients with severe cognitive impairment using high-resolution (450K) DNA methylation array. We identified 139 differentially methylated CpG sites included in known and novel candidate genes sequences as well as in and intergenic sequences which functions remain unknown. We found that altered DNA methylation is not restricted to a particular region, but includes others such as CpG shelves and gene bodies, indicating the presence of different DNA methylation signatures depending on the brain area analyzed. Our findings suggest that epimutations are not relatables between different tissues or even between tissues' regions, highlighting the need to adequately study brain samples to obtain reliable data concerning the epigenetics of schizophrenia.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© The Authors
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Psychology
cognition
executive function
memory
epigenetics
DNA methylation
schizophrenia
human brain
Epigenetics in schizophrenia: a pilot study of global DNA methylation in different brain regions associated with higher cognitive functions
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/590002024-03-04T09:01:26Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Angulo Cuesta, Javier
Manini , Claudia
López , Jose I.
Pueyo , Angel
Colás Escudero, María Begoña
Ropero Salinas, Santiago
2023-12-19T10:26:21Z
2023-12-19T10:26:21Z
2021-04-25
Cancers, 2021, v. 13, n. 9, p. 2071-
2072-6694
http://hdl.handle.net/10017/59000
10.3390/cancers13092071.
AR/0000041855
Cancers
13
9
2071
Clear cell renal cell carcinoma (ccRCC) is curable when diagnosed at an early stage, but when disease is non-confined it is the urologic cancer with worst prognosis. Antiangiogenic treatment and immune checkpoint inhibition therapy constitute a very promising combined therapy for advanced and metastatic disease. Many exploratory studies have identified epigenetic markers based on DNA methylation, histone modification, and ncRNA expression that epigenetically regulate gene expression in ccRCC. Additionally, epigenetic modifiers genes have been proposed as promising biomarkers for ccRCC. We review and discuss the current understanding of how epigenetic changes determine the main molecular pathways of ccRCC initiation and progression, and also its clinical implications. Despite the extensive research performed, candidate epigenetic biomarkers are not used in clinical practice for several reasons. However, the accumulated body of evidence of developing epigenetically-based biomarkers will likely allow the identification of ccRCC at a higher risk of progression. That will facilitate the establishment of firmer therapeutic decisions in a changing landscape and also monitor active surveillance in the aging population. What is more, a better knowledge of the activities of chromatin modifiers may serve to develop new therapeutic opportunities. Interesting clinical trials on epigenetic treatments for ccRCC associated with well established antiangiogenic treatments and immune checkpoint inhibitors are revisited.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© 2021 by the authors
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Renal cell carcinoma
Biomarker
DNA methylation
Epigenetics
The Role of Epigenetics in the Progression of Clear Cell Renal Cell Carcinoma and the Basis for Future Epigenetic Treatments
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/606862024-02-14T01:16:03Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Bajo Chueca, Ana María
Muñoz Moreno, Laura
Rodríguez Henche, María de las Nieves
Saura Redondo, Marta
Calleros Basilio, Laura
Díez Ballesteros, José Carlos
Herráez Sánchez, Ángel
Puebla Jiménez, Lilian
Román Curto, Irene de los Dolores
2024-02-13T09:26:47Z
2023-07-13
La innovación en competencias personales, sociales y emocionales (soft skills). Universidad y ámbito profesional. España: Editorial Universidad De Alcalá, 2023, Vol. 37, Pp. 15-24
978-84-19745-49-1
http://hdl.handle.net/10017/60686
CO/0000019427
La innovación en competencias personales, sociales y emocionales (soft skills). Universidad y ámbito profesional
24
15
Las competencias personales, sociales y emocionales (soft skills) son esenciales para el desarrollo personal, la participación social y el éxito profesional. La formación en la comunicación, el pensamiento crítico, la creatividad, la colaboración, el trabajo en equipo, el espíritu empresarial, la enseñanza y el fomento de las habilidades de aprendizaje permanente aumenta considerablemente la empleabilidad de los/as estudiantes. El grupo de innovación docente de la UAH InDoBio 5.0 (UAH-GI21-171) apuesta por el aprendizaje significativo, implementando metodologías que no solo impliquen la adquisición de conocimientos, sino que desarrollen un amplio abanico de habilidades intra- e interpersonales desde los primeros cursos de las enseñanzas universitarias oficiales. La utilización de rúbricas sencillas nos ha permitido realizar la evaluación de los aprendizajes y del desarrollo de las competencias. En este trabajo se detallan las distintas estrategias utilizadas, así como las soft skills promovidas.
spa
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/embargoedAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© Editorial Universidad de Alcalá
Aprendizaje significativo
motivación
aprendizaje basado en retos
aprendizaje basado en juegos
empleabilidad
habilidades intra- e interpersonales
Indobio 5.0 Comprometido en innovación en competencias personales, sociales y emocionales
info:eu-repo/semantics/bookPart
oai:ebuah.uah.es:10017/595172024-01-19T01:15:55Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Herráez Sánchez, Ángel
López-Ejeda , Noemí
Marrodán, M. Dolores
González Montero De Espinosa, Marisa
2024-01-17T07:41:50Z
2024-01-17T07:41:50Z
2019-08-09
American Journal of Physical Anthropology, 2019, v. 170, n. 2, p. 163-175
0002-9483
http://hdl.handle.net/10017/59517
10.1002/ajpa.23907
AR/0000031436
American Journal of Physical Anthropology
170
175
2
163
OBJECTIVES: Around the aim of gaining knowledge on the secular trends in nutritional status of the Spanish population, we found a collection of historical records compiled by La Institución Libre de Enseñanza and their alumni association along 47?years. These data had been collected from boys and girls attending summer camps, with a policy of improving health of children with unfavorable socioeconomic conditions. The objective is to extract all possible information about growth changes, and eventually any interpretation related to status of the originating families. MATERIALS AND METHODS: Primary data were collected from both unpublished manuscripts containing the original records and publications of the organizing institutions. They had been gathered from 86 summer camps in Spain from 1887 to 1934. In these camps, detailed anthropometric data were collected from every attendee, including body height and weight. The sample population amounts to 1,791 boys and 1,281 girls, between 7 and 16?years of age. RESULTS: Body height and weight, pooled by camp year, age and sex, displayed variable secular increases. A similar observation appears for the body mass index (BMI). As a complement, a comparison was done to contemporary published references from both Spanish and international studies. DISCUSSION: Height, weight, and BMI from the camps may be judged as retardation of growth and malnutrition by modern standards but it is not the case when coetaneous references are considered: no overall significant differences were found with respect to several publications from Spanish and European populations.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© Wiley
BMI
body weight and height
children
historical anthropometric data
summer camp
Historical recollection of anthropometric data from schoolchildren attending summer camps from 1887 to 1934 in Spain: Interpretations and comparison with coetaneous and modern references
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/589882023-12-20T01:15:46Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Genes Robles, Carlos Mario
Lucio Ortega, Héctor Elessar de
Sánchez Murcia, Pedro Alejandro
Gago Badenas, Federico
Jiménez Ruiz, Antonio
2023-12-19T08:18:30Z
2023-12-19T08:18:30Z
2016-07-28
Cell Death and Disease, 2016, v. 7, n. E2318, p. 1-2
2041-4889
http://hdl.handle.net/10017/58988
10.1038/cddis.2016.229
AR/0000030593
Cell Death and Disease
7
2
e2318
1
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© The Author(s), 2016
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Pro-death activity of a BH3 domain in an aquaporin from the protozoan parasite Leishmania
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/600792024-01-31T01:16:31Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Morell, María Cecilia
Bort Bueno, Alicia Carmen
Vara Ciruelos, Diana
Ramos Torres, Ágata
Altamirano Dimas, Manuel
Díaz-Laviada Marturet, Inés Cecilia
Rodríguez Henche, María de las Nieves
2024-01-30T12:01:42Z
2024-01-30T12:01:42Z
2016-09-14
PLoS ONE, 2016, v. 11, n. 9, p. 1-24
1932-6203
http://hdl.handle.net/10017/60079
10.1371/journal.pone.0162977
AR/0000029592
PLoS ONE
11
24
9
1
Neuroendocrine (NE) prostate cancer (PCa) is a highly aggressive subtype of prostate cancer associated with resistance to androgen ablation therapy. In this study, we used LNCaP prostate cancer cells cultured in a serum-free medium for 6 days as a NE model of prostate cancer. Serum deprivation increased the expression of NE markers such as neuron-specific enolase (NSE) and ?III tubulin (?III tub) and decreased the expression of the androgen receptor protein in LNCaP cells. Using cDNA microarrays, we compared gene expression profiles of NE cells and non-differentiated LNCaP cells. We identified up-regulation of 155 genes, among them LAMP2, a lysosomal membrane protein involved in lysosomal stability and autophagy. We then confirmed up-regulation of LAMP2 in NE cells by qRT-PCR, Western blot and confocal microscopy assays, showing that mRNA up-regulation correlated with increased levels of LAMP2 protein. Subsequently, we determined autophagy activity in NE cells by assessing the protein levels of SQSTM/p62 and LC3 by Western blot and LC3 and Atg5 mRNAs content by qRT-PCR. The decreased levels of SQSTM/p62 was accompanied by an enhanced expression of LC3 and ATG5, suggesting activation of autophagy in NE cells. Blockage of autophagy with 1?M AKT inhibitor IV, or by silencing Beclin 1 and Atg5, prevented NE cell differentiation, as revealed by decreased levels of the NE markers. In addition, AKT inhibitor IV as well as Beclin1 and Atg5 kwockdown attenuated LAMP2 expression in NE cells. On the other hand, LAMP2 knockdown by siRNA led to a marked blockage of autophagy, prevention of NE differentiation and decrease of cell survival. Taken together, these results suggest that LAMP2 overexpression assists NE differentiation of LNCaP cells induced by serum deprivation and facilitates autophagy activity in order to attain the NE phenotype and cell survival. LAMP2 could thus be a potential biomarker and potential target for NE prostate cancer.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© The Author 2016
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Up-Regulated Expression of LAMP2 and Autophagy Activity during Neuroendocrine Differentiation of Prostate Cancer LNCaP Cells
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/597742024-02-23T09:54:20Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Vacas Oliva, Eva
Arenas Jiménez, María Isabel
Muñoz Moreno, Laura
Bajo Chueca, Ana María
Sánchez Chapado, Manuel
Prieto Villapún, Juan Carlos
Carmena Sierra, María José
2024-01-23T09:29:55Z
2024-01-23T09:29:55Z
2013-08-09
Cancer Letters, 2013, v. 1, n. 336, p. 196-203
0304-3835
http://hdl.handle.net/10017/59774
doi: 10.1016/j.canlet.2013.04.033
AR/0000018172
Cancer Letters
1
203
336
196
We studied antitumor effect of VIP in human renal cell carcinoma (RCC) (A498 cells xenografted in immunosuppressed mice). VIP-treated cells gave resulted in p53 upregulation and decreased nuclear ?-catenin translocation and NFKB expression, MMP-2 and MMP-9 activities, VEGF levels and CD-34 expression. VIP led to a more differentiated tubular organization in tumours and less metastatic areas. Thus, VIP inhibits growth of A498-cell tumours acting on the major issues involved in RCC progression such as cell proliferation, microenvironment remodelling, tumour invasion, angiogenesis and metastatic ability. These antitumoral effects of VIP offer new therapeutical possibilities in RCC treatment.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© Elsevier
VIP
MMP
VEGF
NFKB
ccRCC
Antitumoral effects of vasoactive intestinal peptide in human renal cell carcinoma xenografts in athymic nude mice
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/590692023-12-22T01:16:04Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Díaz Hernando, Marta
Lucio Ortega, Héctor Elessar de
Moreno Amatria, Esther
Espuelas Millán, María Socorro
Aydillo Miguel, Carlos
Jiménez Ruiz, Antonio
Toro Londoño, Miguel Ángel
Gutiérrez Viñas, Kilian Jesús
Martínez Merino, Víctor
Cornejo Ibergallartu, Alfonso
Palop Cubillo, Juan Antonio
Sanmartín Grijalba, Carmen
Plano Amatriain, Daniel
2023-12-21T09:56:39Z
2023-12-21T09:56:39Z
2019-04-25
Antimicrobial Agents and Chemotherapy, 2019, v. 63, n. 5, p. E02200-18-
0066-4804
http://hdl.handle.net/10017/59069
10.1128/AAC.02200-18
AR/0000031222
Antimicrobial Agents and Chemotherapy
63
5
e02200-18
A novel series of thirty-one N-substituted urea, thiourea, and selenourea derivatives containing diphenyldiselenide entities were synthesized, fully characterized by spectroscopic and analytical methods, and screened for their in vitro leishmanicidal activities. The cytotoxic activity of these derivatives was tested against Leishmania infantum axenic amastigotes, and selectivity was assessed in human THP-1 cells. Thirteen of the synthesized compounds showed a significant antileishmanial activity, with 50% effective concentration (EC50) values lower than that for the reference drug miltefosine (EC50, 2.84¿¿M). In addition, the derivatives 9, 11, 42, and 47, with EC50 between 1.1 and 1.95¿¿M, also displayed excellent selectivity (selectivity index ranged from 12.4 to 22.7) and were tested against infected macrophages. Compound 11, a derivative with a cyclohexyl chain, exhibited the highest activity against intracellular amastigotes, with EC50 values similar to those observed for the standard drug edelfosine. Structure-activity relationship analyses revealed that N-aliphatic substitution in urea and selenourea is recommended for the leishmanicidal activity of these analogs. Preliminary studies of the mechanism of action for the hit compounds was carried out by measuring their ability to inhibit trypanothione reductase. Even though the obtained results suggest that this enzyme is not the target for most of these derivatives, their activity comparable to that of the standards and lack of toxicity in THP-1 cells highlight the potential of these compounds to be optimized for leishmaniasis treatment.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© American Society for Microbiology, 2019
selenium
selenourea
thiourea
trypanothione reductase
urea
Synthesis and Leishmanicidal Activity of Novel Urea, Thiourea, and Selenourea Derivatives of Diselenides
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/606882024-02-14T01:16:03Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Román Curto, Irene de los Dolores
Domingo Galán, Alberto
Menor Salvan, César Ángel
Muñoz Moreno, Laura
Bajo Chueca, Ana María
2024-02-13T09:52:22Z
2024-02-13T09:52:22Z
2022
EDULEARN22 Proceedings. España: International Academy Of Technology, Education And Development (Iated), 2022, Vol. , Pp. 7097-7101
978-84-09-42484-9
http://hdl.handle.net/10017/60688
10.21125/edulearn.2022.1667
CO/0000020122
EDULEARN22 Proceedings
7101
7097
One of the aspects that best captures the interest of students, and the most neglected, is the possibility of offering the practical application of what is learned, favoring experiences that make this possible. Promoting interrelation and involvement with reality is one of the most motivating elements. For all these reasons, we present the action developed in which we are committed to participatory techniques, more specifically, to the development of projects related to the professional interests of the first-year students of the Degree in Chemistry. According to the surveys we carried out with our students, the main orientations were Research, Teaching and Bio-Entrepreneurship. The specific teaching objectives were: i) to strengthen the group, integrate, disinhibit, encourage; ii) to stimulate the exchange of experiences, ideas and opinions; iii) to develop divergent and creative thinking; iv) to quickly promote student participation, capturing their interest and involving them in the teaching/learning process; and v) to promote the learning of diverse knowledge and its collective construction, among others. The experience was carried out by all the students of the Biology subject, who were distributed in work teams of 4-6 students. The groups chose a topic from among the orientations requested by the students: i) Research (Support Centres); ii) Teaching (Institute of Education Sciences); iii) Bio-Entrepreneurship (Office for the Transfer of Research Results); iv) Forensic Science Police. The dynamic of the action is based on three main phases: - Initial session. In this session, objectives, methodology and evaluation criteria were clarified. The instructors involved provided the working groups with the corresponding contact. At this point, the enquiry of the group members began. - Development sessions. Throughout several meetings with the instructors, the members of the teams had to undertake the following objectives: i) search for information from the contact provided (description of the services studied, equipment, function and applications); ii) interview with experts; iii) contextualization according to their professional interests; iv) organization of the information and preparation of communications (posters). All this was supervised by the instructors involved. They were also presented with the "digital" portfolio that they had to prepare during the course of the action. - Final session. The students presented their work in a public event at the Building our Future Conference. Assessment for learning was carried out, taking into account the influence of this one on the motivation and self-esteem of the student; and the assessment of competences, having as indicators communication skills, teamwork and responsibility, among others. The development of a "digital" portfolio per team was used: i) to improve reflection on learning, ii) to stimulate student motivation, iii) to incorporate students in the evaluation and focus it on performance, and iv) to bring the learning achieved closer to the professional tasks of the discipline. We .can conclude that the action implemented had an impact on teaching practice to the extent that what was "investigated" was motivated by the reality of professional practice, putting into context all the subjects being reviewed in the Degree and contributing to the improvement of the quality of face-to-face teaching.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Motivation
Collaborative
Participative
Project-Based Learning
Professional interests
Undergraduates
Building our future, a collaborative, participatory and motivating experience for undergraduates in chemistry
info:eu-repo/semantics/bookPart
oai:ebuah.uah.es:10017/590022023-12-20T01:15:48Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Lucio Ortega, Héctor Elessar de
Toro Londoño, Miguel Ángel
Camarasa Rius, María José
Velázquez Díaz, Sonsoles
Gago Badenas, Federico
Jiménez Ruiz, Antonio
2023-12-19T11:23:37Z
2023-12-19T11:23:37Z
2020-10-02
British Journal of Pharmacology, 2020, v. 177, n. 22, p. 5163-5176
0007-1188
http://hdl.handle.net/10017/59002
10.1111/bph.15250
AR/0000035594
British Journal of Pharmacology
177
5176
22
5163
Background and Purpose: Peptide P4 was described as a dimerization disruptor of trypanothione reductase (TryR), a homodimeric enzyme essential for survival of trypanosomatids. Determination of the true inhibitory constant (Ki) for P4 was not achieved because reaction rates continuously decreased with time, even when substrate concentration was kept constant. The aim of this study was to find a suitable kinetic model that could allow characterization of the complex pattern of TryR inhibition caused by P4.
Experimental Approach: After showing the slow-binding and pseudoirreversible activity of P4 against Leishmania infantum trypanothione reductase (Li-TryR), analysis of the curvatures of the reaction progress curves at different inhibitor concentrations allowed us to define the apparent inhibitory constants (Kiapp) at five different substrate concentrations. Analysis of the changes in Kiapp values allowed precise definition of the type of inhibition.
Key Results: Li-TryR inhibition by P4 requires two sequential steps that involve rapid generation of a reversible enzyme-inhibitor complex followed by a pseudoirreversible slow inactivation of the enzyme. Recovery of enzyme activity after inhibitor dissociation is barely detectable. P4 is a non-competitive pseudoirreversible inhibitor of Li- TryR that displays an overall inhibition constant (Ki*) smaller than 0.02 ¿M.
Conclusion and Implications: Li-TryR dimer disruption by peptide P4 is a pseudoirreversible time-dependent process which is non-competitive with respect to the oxidized trypanothione (TS2) substrate. Therefore, unlike reversible Li-TryR competitive inhibitors, enzyme inhibition by P4 is not affected by the TS2 accumulation observed during oxidant processes such as the oxidative burst in host macrophages.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© The British Pharmacological Society, 2020
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© The British Pharmacological Society, 2020
dimerization disruptor
Leishmania infantum
protein-protein interactions
pseudoirreversible inhibition
slow-binding inhibitor
time-dependent inhibition
trypanothione reductase
Pseudoirreversible slow-binding inhibition of trypanothione reductase by a protein-protein interaction disruptor
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/588912023-12-16T01:16:08Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Mitchell, Rebecca
Hopcroft, Lisa E.M.
Baquero Valls, Pablo
Allan, Elaine K.
Hewit, Kay
James, Daniel
Hamilton, Graham
Mukhopadhyay, Arunima
O'Prey, Jim
Hair, Alan
Melo, Junia V.
Chan, Edmond
Ryan, Kevin M.
Maguer-Satta, Véronique
Druker, Brian J.
Clark, Richard E.
Mitra, Subir
Herzyk, Pawel
Nicolini, Franck E.
Salomoni, Paolo
Shanks, Emma
Calabretta, Bruno
Holyoake, Tessa L.
Helgason, G.Vignir
2023-12-15T08:26:21Z
2023-12-15T08:26:21Z
2018-05-01
Journal of the National Cancer Institute, 2018, v. 110, n. 5, p. 467-478
0027-8874
http://hdl.handle.net/10017/58891
10.1093/jnci/djx236
AR/0000028968
Journal of the National Cancer Institute
110
478
5
467
Background: Imatinib and second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib have statistically significantly improved the life expectancy of chronic myeloid leukemia (CML) patients; however, resistance to TKIs remains a major clinical challenge. Although ponatinib, a third-generation TKI, improves outcomes for patients with BCR-ABL-dependent mechanisms of resistance, including the T315I mutation, a proportion of patients may have or develop BCR-ABL-independent resistance and fail ponatinib treatment. By modeling ponatinib resistance and testing samples from these CML patients, it is hoped that an alternative drug target can be identified and inhibited with a novel compound.
Methods: Two CML cell lines with acquired BCR-ABL-independent resistance were generated following culture in ponatinib. RNA sequencing and gene ontology (GO) enrichment were used to detect aberrant transcriptional response in ponatinibresistant cells. A validated oncogene drug library was used to identify US Food and Drug Administration-approved drugs with activity against TKI resistant cells. Validation was performed using bone marrow (BM)-derived cells from TKI-resistant patients (n = 4) and a human xenograft mouse model (n =4=6 mice per group). All statistical tests were two-sided.
Results: We show that ponatinib-resistant CML cells can acquire BCR-ABL-independent resistance mediated through alternative activation of mTOR. Following transcriptomic analysis and drug screening, we highlight mTOR inhibition as an alternative therapeutic approach in TKI-resistant CML cells. Additionally, we show that catalytic mTOR inhibitors induce autophagy and demonstrate that genetic or pharmacological inhibition of autophagy sensitizes ponatinib-resistant CML cells to death induced by mTOR inhibition in vitro (% number of colonies of control[SD], NVP-BEZ235 vs NVP-BEZ235+1HCQ: 45.0(17.9]% vs 24.0[8.4]%, P =.002) and in vivo (median survival of NVP-BEZ235-vs NVP-BEZ235+HCQ-treated mice: 38.5 days vs 47.0 days, P =.04).
Conclusion: Combined mTOR and autophagy inhibition may provide an attractive approach to target BCR-ABL-independent mechanism of resistance.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© The authors
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Targeting BCR-ABL-Independent TKI Resistance in Chronic Myeloid Leukemia by mTOR and Autophagy Inhibition
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/589872023-12-20T01:15:46Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Ruiz Santaquiteria, Marta
De Castro , Sonia
Toro, Miguel A.
Lucio Ortega, Héctor Elessar de
Gutiérrez Viñas, Kilian Jesús
Sánchez Murcia, Pedro Alejandro
Jiménez Martínez, María Ángeles
Gago Badenas, Federico
Jiménez Ruiz, Antonio
Camarasa Rius, María José
Velázquez , Sonsoles
2023-12-19T07:54:59Z
2023-12-19T07:54:59Z
2018-04-10
European Journal of Medicinal Chemistry, 2018, v. 149, p. 238-247
0223-5234
http://hdl.handle.net/10017/58987
10.1016/j.ejmech.2018.02.071
AR/0000029519
European Journal of Medicinal Chemistry
149
247
238
Trypanothione reductase (TryR) is a well-established target in the search for novel antitrypanosomal and antileishmanial agents. We have previously identified linear and lactam-bridged 13-residue peptides derived from an ¿-helical region making up part of the dimeric interface of Leishmania infantum TryR (Li-TryR) which prevent trypanothione reduction by disrupting enzyme dimerization. We now show that i,i + 4 side-chain cross-linking with an all-hydrocarbon staple stabilizes the helical structure of these peptides and significantly improves their resistance to protease cleavage relative to previous linear and cyclic lactam analogues. Interestingly, replacement of the amide bridge by the hydrocarbon staple at the same cyclization positions generates derivatives (2 and 3) that similarly inhibit oxidoreductase activity of the enzyme but unexpectedly stabilize the TryR homodimer. The most proteolytically stable peptide 2 covalently linked to oligoarginines displayed potent in vitro leishmanicidal activity against L. infantum parasites.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© Elsevier Masson SAS, 2018
Stapled peptides
Protein-protein interactions
Trypanothione reductase
Leishmania infantum
Cell-penetrating peptides
Trypanothione reductase inhibition and anti-leishmanial activity of all-hydrocarbon stapled alfa-helical peptides with improved proteolytic stability
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/602852024-02-07T01:16:21Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Sanchís Bonet, Ángeles María
Barrionuevo González, Marta
Bajo Chueca, Ana María
Morales Palacios, Nelson
Sánchez Chapado, Manuel Vicente
2024-02-02T09:21:33Z
2024-02-02T09:21:33Z
2018
Urologia Internationalis, 2018, v. 100, n. 2, p. 146-154
0042-1138
http://hdl.handle.net/10017/60285
10.1159/000481439
AR/0000032053
Urologia Internationalis
100
154
2
146
lntroduction: To assess whether [-2]pro-prostate-specific antigen (p2PSA) meets the criteria to justify its inclusion in a predictive model of prostate cancer (PCa) diagnosis and in the clinical decision-making process. Materials and Methods: A total 172 men with total prostate-specific antigen of 2-10 ng/ml underwent measurement of free PSA and p2PSA before prostate biopsy in an observational and prospective study. From these measurements, the Prostate Health lndex (PHI) was calculated. Clinical and analytical predictive models were created incorporating PHI. Results: Of 172 men, 72 (42%) were diagnosed with PCa, 33 (46%) of whom were found to be with high-grade disease. PHI score was the most predictive of biopsy outcomes in terms of discriminative ability (area under the curve = 0.79), with an added gain in predictive accuracy of 17%. AII the models that incorporated PHI worked better in terms of calibration close to 45º on the slope. In the decision curve analysis, a threshold probability of 40% we could prevent 82 biopsies, missing only 16 tumors and 5 high-grade tumors. Conclusions: PHI score is a more discriminant biomarker, has superior calibration and superior net benefit, and provides a higher rate of avoided biopsies; thus, it can be useful for aiding in making a more informed decision for each patient.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© Karger AG Basel
Prostatic neoplasms
Prostate-specific antigen
[-2]pro-prostate specific antigen
Prostate Health Index
Clinical decision-making
Does [-2]Pro-Prostate Specific Antigen Meet the Criteria to Justify Its Inclusion in the Clinical Decision-Making Process?
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/603822024-02-06T01:17:36Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Bort Bueno, Alicia Carmen
Spinola Lasso, Elena
Rodríguez Henche, María de las Nieves
Díaz-Laviada Marturet, Inés Cecilia
2024-02-05T10:01:12Z
2024-02-05T10:01:12Z
2017-09-23
Oncotarget, 2017, v. 8, n. 50, p. 87684-87698
1949-2553
http://hdl.handle.net/10017/60382
10.18632/oncotarget.21196
AR/0000031205
Oncotarget
8
87698
50
87684
In this study, we investigated the antitumoral effects of combined treatment using sorafenib and capsaicin in hepatocellular carcinoma (HCC) cells. Here we showed that the combination of the two drugs had a much stronger inhibitory effect on both HepG2 and Huh-7 human HCC cells growth than either drug alone. The isobolograms demonstrated that the combinations investigated in this study produced a synergistic interaction. In the combination treatment using capsaicin and sorafenib, increased apoptosis, followed by the activation of caspase-9 and PARP, was observed. In addition, the present study demonstrated that sorafenib treatment induces activation of Akt, probably as a mechanism of resistance, whereas capsaicin inhibits Akt providing a possible pathway whereby capsaicin sensitizes to sorafenib in HCC cells. Moreover, capsaicin singly and the combination of capsaicin and sorafenib induce AMPK activation and Acetyl CoA carboxylase phosphorylation in HCC cells. Knocking down of AMPK by selective siRNA abrogates capsaicin-induced Akt inhibition, suggesting the involvement of AMPK in the antiproliferative effect. In vivo experiments further showed that that the anti-tumor effect of sorafenib was enhanced by its combination with 2.5 mg/Kg of capsaicin. Overall, these results show that combined treatment with capsaicin and sorafenib might improve sorafenib sensitivity and therefore it represents a promising and attractive strategy for the treatment of HCC.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© by the Author(s)
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
capsaicin
sorafenib
AMPK
Akt
hepatocellular carcinoma
Capsaicin exerts synergistic antitumor effect with sorafenib inhepatocellular carcinoma cells through AMPK activation
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/603762024-02-06T01:17:35Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Morell, María Cecilia
Bort Bueno, Alicia Carmen
Vara Ciruelos, Diana
Ramos Torres, Ágata
Rodríguez Henche, María de las Nieves
Díaz-Laviada Marturet, Inés Cecilia
2024-02-05T09:29:39Z
2024-02-05T09:29:39Z
2016-06-21
Prostate Cancer and Prostatic Diseases, 2016, v. 19, n. 3, p. 248-257
1365-7852
http://hdl.handle.net/10017/60376
10.1038/pcan.2016.19
AR/0000031203
Prostate Cancer and Prostatic Diseases
19
257
3
248
BACKGROUND: Neuroendocrine (NE) differentiation represents a common feature of prostate cancer and is associated with accelerated disease progression and poor clinical outcome. Nowadays, there is no treatment for this aggressive form of prostate cancer. The aim of this study was to determine the influence of the cannabinoid WIN 55,212-2 (WIN, a non-selective cannabinoid CB1 and CB2 receptor agonist) on the NE differentiation of prostate cancer cells. METHODS: NE differentiation of prostate cancer LNCaP cells was induced by serum deprivation or by incubation with interleukin-6, for 6 days. Levels of NE markers and signaling proteins were determined by western blotting. Levels of cannabinoid receptors were determined by quantitative PCR. The involvement of signaling cascades was investigated by pharmacological inhibition and small interfering RNA. RESULTS: The differentiated LNCaP cells exhibited neurite outgrowth, and increased the expression of the typical NE markers neuron-specific enolase and ?III tubulin (?III Tub). Treatment with 3??M WIN inhibited NK differentiation of LNCaP cells. The cannabinoid WIN downregulated the PI3K/Akt/mTOR signaling pathway, resulting in NE differentiation inhibition. In addition, an activation of AMP-activated protein kinase (AMPK) was observed in WIN-treated cells, which correlated with a decrease in the NE markers expression. Our results also show that during NE differentiation the expression of cannabinoid receptors CB1 and CB2 dramatically decreases. CONCLUSIONS: Taken together, we demonstrate that PI3K/Akt/AMPK might be an important axis modulating NE differentiation of prostate cancer that is blocked by the cannabinoid WIN, pointing to a therapeutic potential of cannabinoids against NE prostate cancer.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© by the Authors
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
The cannabinoid WIN 55,212-2 prevents neuroendocrine differentiation of LNCaP prostate cancer cells
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/588532023-12-15T01:16:05Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Cilleros Rodríguez, Darío
Toledo Lobo, María del Val
Martínez Martínez, Desirée
Baquero Valls, Pablo
Angulo Cuesta, Javier
Chiloeches Gálvez, Antonio
Iglesias , Teresa
Lasa Benito, Marina Paloma
2023-12-14T08:31:47Z
2023-12-14T08:31:47Z
2023-08-21
Biochimica et Biophysica Acta - Molecular Basis of Disease, 2023, v. 1870, n. 166851, p. 1-10
0925-4439
http://hdl.handle.net/10017/58853
10.1016/j.bbadis.2023.166851
AR/0000045602
Biochimica et Biophysica Acta - Molecular Basis of Disease
1870
10
166851
1
Protein kinase D (PKD) family members play controversial roles in prostate cancer (PC). Thus, PKD1 is nearly absent in advanced tumours, where PKD2 and PKD3 are upregulated. Additionally, consequences of activation of these kinases on PC progression remain largely unclear. Here, we first investigated PKD function on PC cell motility, analysing the underlying molecular mechanisms. We find a striking decrease of Snail levels after PKD inhibition followed by cell migration and invasion impairment, demonstrating an unprecedented role of PKD activity on the regulation of this key transcription factor in PC progression. Specifically, we show that PKD2 activity mediates the effects of MEK/ERK pathway on Snail expression, establishing a joint function of ERK/ PKD2/Snail cascade in PC cell invasion regulation. These results led us to address the clinical relevance of the correlation between PKD2 and ERK activities with Snail abundance in samples from PC patients at different stages, analysing its impact on tumour prognosis and patients & PRIME;survival. Importantly, this is the first study defining a direct correlation between active PKD2 and Snail levels, further linked to ERK activity. We also evidence that PKD2 activity is associated with important poor prognostic factors. Thus, PC patients with the expression pattern: active PKD2high/active ERKhigh/Snailhigh exhibit increased invasiveness and metastasis, and decreased survival. Our findings provide new insights for understanding the molecular mechanisms involved in PC progression, pinpointing the combination of active PKD2 and Snail levels, with the additional measurement of active ERK, as a confident biomarker to predict clinical outcome of patients with advanced PC.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© The Authors
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Prostate cancer
Prognostic biomarkers
PKD2 activity
ERK activity
Snail
Protein kinase D activity is a risk biomarker in prostate cancer that drives cell invasion by a Snail/ERK dependent mechanism
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/590382023-12-21T01:16:20Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Alcón Calderón, María de las Mercedes
Lucio Ortega, Héctor Elessar de
García Soriano, Juan Carlos
Revuelto Pérez, Alejandro
De Castro De La Osa, Sonia
López Gutiérrez, Celia
San Félix García, Ana
Quesada Del Sol, Ernesto
Gago Badenas, Federico
Camarasa Rius, María José
Jiménez Ruiz, Antonio
Velázquez Díaz, Sonsoles
2023-12-20T07:18:27Z
2023-12-20T07:18:27Z
2022-08-18
European Journal of Medicinal Chemistry, 2022, v. 243, n. 114675, p. 1-14
0223-5234
http://hdl.handle.net/10017/59038
10.1016/j.ejmech.2022.114675
AR/0000042632
European Journal of Medicinal Chemistry
243
14
114675
1
Redox homeostasis in trypanosomatids is based on the low-molecular-weight trypanothione, an essential dithiol molecule that is synthetized by trypanothione synthetase (TryS) and maintained in its reduced state by trypanothione disulfide reductase (TryR). The fact that both enzymes are indispensable for parasite survival and absent in the mammalian hosts makes them ideal drug targets against leishmaniasis. Although many efforts have been directed to developing TryR inhibitors, much less attention has been focused on TryS. The screening of an in-house library of 144 diverse molecules using two parallel biochemical assays allowed us to detect 13 inhibitors of L. infantum TryS. Compounds 1 and 3 were characterized as competitive inhibitors with Ki values in the low micromolar range and plausible binding modes for them were identified by automated ligand docking against refined protein structures obtained through computational simulation of an entire catalytic cycle. The proposed binding site for both inhibitors overlaps the polyamine site in the enzyme and, additionally, 1 also occupies part of the ATP site. Compound 4 behaves as a mixed hyperbolic inhibitor with a Ki of 0.8 ¿M. The activity of 5 is clearly dependent on the concentration of the polyamine substrate, but its kinetic behavior is clearly not compatible with a competitive mode of inhibition. Analysis of the activity of the six best inhibitors against intracellular amastigotes identified 5 as the most potent leishmanicidal candidate, with an EC50 value of 0.6 ¿M and a selectivity index of 35.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© The Author(s), 2022
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Trypanothione synthetase
Leishmania infantum
Competitive and non-competitive inhibitors
Molecular docking
Molecular dynamics
Identification of L. infantum trypanothione synthetase inhibitors with leishmanicidal activity from a (non-biased) in-house chemical library
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/606342024-02-10T01:16:13Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Sánchez Gómez, Belén
Bort Bueno, Alicia Carmen
Vara Ciruelos, Diana
Díaz-Laviada Marturet, Inés Cecilia
2024-02-09T09:37:27Z
2024-02-09T09:37:27Z
2020-06-10
Cells, 2020, v. 9, n. 6 (1441), p. 1-19
2073-4409
http://hdl.handle.net/10017/60634
10.3390/cells9061441
AR/0000046308
Cells
9
19
6 (1441)
1
In the past few years, cell plasticity has emerged as a mode of targeted therapy evasion in prostate adenocarcinoma. When exposed to anticancer therapies, tumor cells may switch into a different histological subtype, such as the neuroendocrine phenotype which is associated with treatment failure and a poor prognosis. In this study, we demonstrated that long-term androgen signal depletion of prostate LNCaP cells induced a neuroendocrine phenotype followed by re-differentiation towards a ?stem-like? state. LNCaP cells incubated for 30 days in charcoal-stripped medium or with the androgen receptor antagonist 2-hydroxyflutamide developed neuroendocrine morphology and increased the expression of the neuroendocrine markers ?III-tubulin and neuron specific enolase (NSE). When cells were incubated for 90 days in androgen-depleted medium, they grew as floating spheres and had enhanced expression of the stem cell markers CD133, ALDH1A1, and the transporter ABCB1A. Additionally, the pluripotent transcription factors Nanog and Oct4 and the angiogenic factor VEGF were up-regulated while the expression of E-cadherin was inhibited. Cell viability revealed that those cells were resistant to docetaxel and 2-hidroxyflutamide. Mechanistically, androgen depletion induced the decrease in AMP-activated kinase (AMPK) expression and activation and stabilization of the hypoxia-inducible factor HIF-1?. Overexpression of AMPK in the stem-like cells decreased the expression of stem markers as well as that of HIF-1? and VEGF while it restored the levels of E-cadherin and PGC-1?. Most importantly, docetaxel sensitivity was restored in stem-like AMPK-transfected cells. Our model provides a new regulatory mechanism of prostate cancer plasticity through AMPK that is worth exploring.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© 2020 by the authors.
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
AMPK
cancer stem cells
lineage plasticity
neuroendocrine cells
prostate cancer
Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/600952024-02-08T18:54:03Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Bort Bueno, Alicia Carmen
Sánchez Gómez, Belén
Mateos Gómez, Pedro Antonio
Vara Ciruelos, Diana
Rodríguez Henche, María de las Nieves
Díaz-Laviada Marturet, Inés Cecilia
2024-01-30T14:00:54Z
2024-01-30T14:00:54Z
2019-04-15
Molecular Oncology, 2019, v. 13, n. 5, p. 1311-1331
1878-0261
http://hdl.handle.net/10017/60095
10.1002/1878-0261.12488
AR/0000030742
Molecular Oncology
13
1331
5
1311
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. HCC treatment is hindered by the frequent emergence of chemoresistance to the multikinase inhibitor sorafenib, which has been related to the presence of cancer stem cells (CSCs) that self-renew and often escape therapy. The key metabolic sensor AMP-activated kinase (AMPK) has recently been recognized as a tumour growth regulator. In this study, we aimed to elucidate the role of AMPK in the development of a stem cell phenotype in HCC cells. To this end, we enriched the CSC population in HCC cell lines that showed increased expression of drug resistance (ALDH1A1, ABCB1A) and stem cell (CD133, Nanog, Oct4, alpha fetoprotein) markers and demonstrated their stemness phenotype. These cells were refractory to sorafenib-induced cell death. We report that sorafenib-resistant cells had lower levels of total and phosphorylated AMPK as well as its downstream substrate, ACC, compared with the parental cells. Interestingly, AMPK knockdown with siRNA or inhibition with dorsomorphin increased the expression of stem cell markers in parental cells and blocked sorafenib-induced cell death. Conversely, the upregulation of AMPK, either by transfection or by pharmacological activation with A-769662, decreased the expression of ALDH1A1, ABCB1A, CD133, Nanog, Oct4, and alpha fetoprotein, and restored sensitivity to sorafenib. Analysis of the underlying mechanism points to hypoxia-inducible factor HIF-1? as a regulator of stemness. In vivo studies in a xenograft mouse model demonstrated that stem-like cells have greater tumourigenic capacity. AMPK activation reduced xenograft tumour growth and decreased the expression of stem cell markers. Taken together, these results indicate that AMPK may serve as a novel target to overcome chemoresistance in HCC.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© 2019 The Authors
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
AMP-activated kinase
cancer stem cells
drug resistance
hepatocellular carcinoma
sorafenib
Targeting AMP-activated kinase impacts hepatocellular cancer stem cells induced by long-term treatment with sorafenib
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/589902023-12-20T01:15:47Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Genes Robles, Carlos Mario
Lucio Ortega, Héctor Elessar de
Manuel González, Víctor
Sánchez Murcia, Pedro Alejandro
Rico , Eva
Gago Badenas, Federico
Fasel , Nicholas
Jiménez Ruiz, Antonio
2023-12-19T08:39:02Z
2023-12-19T08:39:02Z
2016-07-04
Cell Death Discovery, 2016, v. 2, n. 16043, p. 1-10
2058-7716
http://hdl.handle.net/10017/58990
10.1038/cddiscovery.2016.43
AR/0000030594
Cell Death Discovery
2
10
16043
1
Despite the absence of sequences showing significant similarity to any of the members of the Bcl-2 family of proteins in protozoa, experiments carried out in yeast or trypanosomatids have demonstrated that ectopic expression of some of these members alters their response to different death stimuli. Because the BH3 domain is the smallest common signature in all the proteins of this family of apoptosis regulators and also because they are essential for molecular interactions between antagonistic members, we looked for sequences with significant similarity to the BH3 motif in the Leishmania infantum genome. Among the top scoring ones, we found the MYLALQNLGDEV amino-acid stretch at the C terminus of a previously described aquaporin, now renamed as Li-BH3AQP. This motif is highly conserved in homologous proteins from other species of the Leishmania genus. The association of Li-BH3AQP with human Bcl-XL was demonstrated by both co-immunoprecipitation and yeast two-hybrid experiments. Ectopic expression of Li-BH3AQP reduced viability of HeLa cells and this deleterious effect was abrogated by the simultaneous overexpression of Bcl-XL. Although we were not able to demonstrate a reduction in parasite viability when the protein was overexpressed in Leishmania promastigotes, a prodeath effect could be observed when the parasites overexpressing Li-BH3AQP were treated with staurosporine or antimycin A. Surprisingly, these parasites were more resistant, compared with wild-type parasites, to hypotonic stress or nutrient deprivation. The prodeath activity was abolished upon replacement of two highly conserved amino acids in this BH3 domain. Taken together, these results point to Li-BH3AQP as the first non-enzymatic protein ever described in trypanosomatids that is involved in cell death.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© The Author(s), 2016
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
A functional BH3 domain in an aquaporin from Leishmania infantum
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/604282024-02-07T01:16:35Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Sampedro, Ángel
Ramos Torres, Ágata
Schwoeppe, Christian
Mueck Lichtenfeld, Christian
Helmers , Ingo
Bort Bueno, Alicia Carmen
Díaz-Laviada Marturet, Inés Cecilia
Fernández, Gustavo
2024-02-06T08:14:14Z
2024-02-06T08:14:14Z
2018-11-28
Angewandte Chemie - International Edition, 2018, v. 57, n. 52, p. 17235-17239
1433-7851
http://hdl.handle.net/10017/60428
10.1002/anie.201804783
AR/0000031207
Angewandte Chemie - International Edition
57
17239
52
17235
Capsaicin (CAP) has been long known for its analgesic properties and more recently for its antitumor activity in various cell types. However, its pungency and the high doses needed to achieve a significant activity have precluded its application in cancer therapy. Herein, we propose a straightforward novel strategy to improve the antitumor effect of CAP based on the enhancement of its aggregation propensity in aqueous media by covalent attachment of a BODIPY (BDP) dye. The target CAP-BDP 1 self-assembles in aqueous solutions into weakly fluorescent globular assemblies that become highly emissive upon cell uptake-induced disassembly. Remarkably, due to the improved delivery to the tumour tissue upon aggregation, we have succeeded in reducing the doses of CAP-based drugs in vivo in prostate cancer by two orders of magnitude while maintaining a substantial antitumor activity.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© The Author(s) 2018
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
BODIPY dyes
amphiphilic Systems
aqueous self-assembly
capsaicin
fluorescent probes.
Hierarchical Self-Assembly of BODIPY Dyes as a Tool to Improve the Antitumor Activity of Capsaicin in Prostate Cancer
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/593032024-01-12T01:16:28Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Muñoz Moreno, Laura
Schally, Andrew V
Prieto Villapún, Juan Carlos
Carmena Sierra, María José
Bajo Chueca, Ana María
2024-01-11T12:44:53Z
2024-01-11T12:44:53Z
2018-09-01
Prostate, 2018, v. 78, n. 12, p. 915-926
0270-4137
http://hdl.handle.net/10017/59303
10.1002/pros.23648
AR/0000031748
Prostate
78
926
12
915
Background: Therapeutic strategies should be designed to transform aggressive prostate cancer phenotypes to a chronic situation. To evaluate the effects of the new growth hormone-releasing hormone receptor (GHRH-R) antagonists: MIA-602, MIA-606, and MIA-690 on processes associated with cancer progression as cell proliferation, adhesion, migration, and angiogenesis. Methods: We used three human prostate cell lines (RWPE-1, LNCaP, and PC3). We analyzed several molecules such as E-cadherin, ?-catenin, Bcl2, Bax, p53, MMP2, MMP9, PCNA, and VEGF and signaling mechanisms that are involved on effects exerted by GHRH-R antagonists. Results: GHRH-R antagonists decreased cell viability and provoked a reduction in proliferation in LNCaP and PC3 cells. Moreover, GHRH-R antagonists caused a time-dependent increase of cell adhesion in all three cell lines and retarded the wound closure with the highest value with MIA-690 in PC3 cells. GHRH-R antagonists also provoked a large number of cells in SubG0 phase revealing an increase in apoptotic cells in PC3 cell line. Conclusions: Taken all together, GHRH-R antagonists of the MIAMI series appear to be inhibitors of tumor progression in prostate cancer and should be considered for use in future therapeutic strategies on this malignancy.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© Wiley
GHRH-R
angiogenesis
antagonists
cell adhesion
cell proliferation
prostate cancer
Growth hormone-releasing hormone receptor antagonists modify molecular machinery in the progression of prostate cancer
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/588932023-12-16T01:16:08Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Fernández-Barral, Asunción
Orgaz, José Luis
Baquero Valls, Pablo
Ali, Zaheer
Moreno, Alberto
Tiana, María
Gómez, Valentí
Riveiro-Falkenbach, Erica
Cañadas, Carmen
Zazo, Sandra
Bertolotto, Corine
Davidson, Irvin
Rodríguez Peralto, José Luis
Palmero, Ignacio
Rojo, Federico
Jensen, Lasse Dahl
Peso, Luis del
Jiménez, Benilde
2023-12-15T08:55:52Z
2023-12-15T08:55:52Z
2014-06-16
Neoplasia, 2014, v. 16, n. 6, p. 529-542
1522-8002
http://hdl.handle.net/10017/58893
10.1016/j.neo.2014.06.001
AR/0000028969
Neoplasia
16
542
6
529
Pigment epithelium-derived factor (PEDF), a member of the serine protease inhibitor superfamily, has potent anti-metastatic effects in cutaneous melanoma through its direct actions on endothelial and melanoma cells. Here we show that PEDF expression positively correlates with microphthalmia-associated transcription factor (MITF) in melanoma cell lines and human samples. High PEDF and MITF expression is characteristic of low aggressive melanomas classified according to molecular and pathological criteria, whereas both factors are decreased in senescent melanocytes and naevi. Importantly, MITF silencing down-regulates PEDF expression in melanoma cell lines and primary melanocytes, suggesting that the correlation in the expression reflects a causal relationship. In agreement, analysis of Chromatin immunoprecipitation coupled to high throughput sequencing (ChIP-seq) data sets revealed three MITF binding regions within the first intron of SERPINF1, and reporter assays demonstrated that the binding of MITF to these regions is sufficient to drive transcription. Finally, we demonstrate that exogenous PEDF expression efficiently halts in vitro migration and invasion, as well as in vivo dissemination of melanoma cells induced by MITF silencing. In summary, these results identify PEDF as a novel transcriptional target of MITF and support a relevant functional role for the MITF-PEDF axis in the biology of melanoma.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Regulatory and functional connection of microphthalmia-associated transcription factor and anti-metastatic pigment epithelium derived factor in melanoma
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/601112024-02-08T19:11:36Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Bort Bueno, Alicia Carmen
Quesada Sánchez, Sergio
Ramos Torres, Ágata
Gargantilla, Marta
Priego, Eva Maria
Raynal, Sophie
Lepifre, Franck
Gasalla Herráiz, José Manuel
Rodríguez Henche, María de las Nieves
Castro Morera, Ana
Díaz-Laviada Marturet, Inés Cecilia
2024-01-30T15:26:07Z
2024-01-30T15:26:07Z
2018-03-12
Scientific Reports, 2018, v. 8, n. 1 (4370), p. 1-18
2045-2322
http://hdl.handle.net/10017/60111
10.1038/s41598-018-22690-2
AR/0000031206
Scientific Reports
8
18
1 (4370)
1
The key metabolic sensor adenosine monophosphate-dependent kinase (AMPK) has emerged as a promising therapeutic target for cancer prevention and treatment. Besides its role in energy homeostasis, AMPK blocks cell cycle, regulates autophagy and suppresses the anabolic processes required for rapid cell growth. AMPK is especially relevant in prostate cancer in which activation of lipogenic pathways correlate with tumor progression and aggressiveness. This study reports the discovery of a new series of 2-oxindole derivatives whose AMPK modulatory ability, as well as the antitumoral profile in prostate cancer cells, was evaluated. One of the assayed compounds, compound 8c, notably activated AMPK in cultured PC-3, DU145 and LNCaP prostate cancer cells. Likewise, compound 8c caused PC-3, DU145 and LNCaP cells viability inhibition. Selective knocking down of ?1 or ?2 isoforms as well as in vitro assays using human recombinant ?1?1?1 or ?2?1?1 AMPK isoforms revealed that compound 8c exhibit preference for AMPK?1. Consistent with efficacy at the cellular level, compound 8c was potent in suppressing the growth of PC-3 xenograft tumors. In conclusion, our results show that a new 2-oxindole fluorinated derivative exerts potent in vivo antitumor actions against prostate cancer cells, indicating a promising clinical therapeutic strategy for the treatment of androgen-independent prostate cancer.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© The Author(s) 2018
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Identification of a novel 2-oxindole fluorinated derivative as in vivo antitumor agent for prostate cancer acting via AMPK activation
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/604122024-03-14T18:16:24Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Sánchez Gómez, Belén
Bort Bueno, Alicia Carmen
Mora Rodríguez, José María
Díaz Yuste, Alba
Gasalla Herráiz, José Manuel
Sánchez Chapado, Manuel Vicente
Sebastián Martín, Alba
Díaz-Laviada Marturet, Inés Cecilia
2024-02-05T15:17:25Z
2024-02-05T15:17:25Z
2022-11-11
Biomedicines, 2022, v. 10, n. 11, p. 2897-
2227-9059
http://hdl.handle.net/10017/60412
10.3390/biomedicines10112897
AR/0000041887
Biomedicines
10
11
2897
Throughout the pandemic, serological assays have been revealed as crucial for detecting previous exposures to the virus and determining the timing of antibody maintenance after vaccination or natural infection. This study aimed to develop an optimized enzyme-linked immunosorbent assay (ELISA)-based serology, which could be used in case of reagent shortages, such as that occurred in the beginning of this health emergency. As a result, we present a high-sensitive immunoassay for the determination of IgG levels in venous serum samples, using 2 ?g/mL antigen (receptor-binding domain of the spike protein S1) for coating the plate and utilizing human samples at a dilution 1:1000. This method showed non-inferiority features versus a commercial kit, is less expensive, and has a higher spectrophotometric range that allows for a better quantification of the antibody titers. The optical density values before and after heating venous serum samples at 56 °C during 30 min was quite similar, showing that heat inactivation can be used to reduce the biohazardous risks while handling samples. Furthermore, we show that finger-stick capillary blood samples can also serve as a suitable source for IgG detection, bypassing the need for serum isolation and being suitable for point-of-care application (Pearson's coefficient correlation with capillary serum was 0.95, being statistically significant).
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© 2022 by the authors
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
COVID-19
SARS-CoV-2
ELISA
IgG
Serology
Point-of-care
Capillary blood
A highly sensitive immunoassay for determination of immune response to SARS-CoV-2 in capillary blood samples.
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/589682023-12-19T12:49:58Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Baquero Valls, Pablo
Jiménez Mora, Eva María
Santos, Adrián
Lasa, Marina
Chiloeches Gálvez, Antonio
2023-12-18T12:23:27Z
2023-12-18T12:23:27Z
2016-11
Molecular Carcinogenesis, 2016, v. 55, n. 11, p. 1639-1654
0899-1987
http://hdl.handle.net/10017/58968
AR/0000031329
Molecular Carcinogenesis
55
1654
11
1639
The epithelial-mesenchymal transition (EMT) is a crucial process in tumour progression, by which epithelial cells acquire a mesenchymal phenotype, increasing its motility and the ability to invade distant sites. Here, we describe the molecular mechanisms by which (V600E)BRAF, TGF beta and the Src/FAK complex cooperatively regulate EMT induction and cell motility of anaplastic thyroid cancer cells. Analysis of EMT marker levels reveals a positive correlation between TGF beta and Snail expression, with a concomitant downregulation of E-cadherin, accompanied by an increase of cell migration and invasion. Furthermore, we show that (V600E)BRAF depletion by siRNA or inhibition of its activity by treatment with its inhibitor PLX4720 reverses the TGF beta-mediated effects on Snail, E-cadherin, migration and invasion. Moreover, (V600E)BRAF induces TGF beta secretion through a MEK/ERK-dependent mechanism. In addition, TGF beta activates the Src/FAK complex, which in turn regulates the expression of Snail and E-cadherin as well as cell migration. The inhibition of Src with the inhibitor SU6656 or abrogation of FAK expression with a specific siRNA reverses the TGF beta-induced effects. Interestingly, we demonstrate that activation of the Src/FAK complex by TGF beta is independent of (V600E)BRAF signalling, since inhibition of this oncogene does not affect its phosphorylation. Our data strongly suggest that TGF beta induces EMT and aggressiveness of thyroid cancer cells by parallel mechanisms involving both the (V600E)BRAF/MEK/ERK and Src/FAK pathways independently. Thus, we describe novel functions for Src/FAK in mediating the EMT program and aggressiveness regulated by TGF beta, establishing the inhibition of these proteins as a possible effective approach in preventing tumour progression of (V600E)BRAF-expressing thyroid tumours.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© 2015 Wiley
(V600E)BRAFT
GF beta
Src/FAK
EMT
thyroid cancer
TGFß induces epithelial-mesenchymal transition of thyroid cancer cells by both the BRAF/MEK/ERK and Src/FAK pathways
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/594082024-01-16T01:16:06Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Vacas Oliva, Eva
Muñoz Moreno, Laura
Fernández Martínez, Ana Belén
Bajo Chueca, Ana María
Sánchez Chapado, Manuel Vicente
Prieto Villapún, Juan Carlos
Carmena Sierra, María José
2024-01-15T06:56:30Z
2024-01-15T06:56:30Z
2014-06-04
The International Journal of Biochemistry & Cell Biology, 2014, v. 53, p. 295-301
13572725
http://hdl.handle.net/10017/59408
10.1016/j.biocel.2014.05.036
AR/0000019581
The International Journal of Biochemistry & Cell Biology
53
301
295
Vasoactive intestinal peptide (VIP) decreases cell proliferation through PI3K signalling and prevents tumour progression in clear renal cell carcinoma (RCC). Here we analyzed the signalling pathways that mediate such VIP effects by using human RCC A498 cells. The effects of treatment with 1 mM VIP and/or speci?c protein kinase inhibitors such as H89, Wortmannin and PD98059 were studied by cell adhesion assay, ELISA of VEGF165 and ROS production assays. Semiquantitative RT-PCR and western blot were performed to study p53 expression. VIP increased cell adhesion and ROS production, and decreased VEGF165 secretion through PI3K signalling. Moreover, VIP increased nuclear expression of tumour suppressor p53. VIP effects could be blocked by cell incubation with a speci?c p53 inhibitor, cyclin pi?thrin-a hydrobro- mide (CPFT-?H). In conclusion, this study provides a p53-dependent mechanism by which VIP regulates cell proliferation in RCC development. It supports a potential usefulness of VIP in new therapies of RCC.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© Elsevier
PI3K
Renal cell carcinoma
VEGF
VIP
p53
Signalling pathways involved in antitumoral effects of VIP in human renal cell carcinoma A498 cells: VIP induction of p53 expression
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/590792023-12-22T01:16:08Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Ropero Salinas, Santiago
Orea Martínez, María Jesús
González Corpas, Ana
Colás Escudero, María Begoña
Echegaray García, David
Marvá Ruiz, Marcos
Toledo Lobo, María del Val
2023-12-21T13:02:13Z
2023-12-21T13:02:13Z
2023-01-02
International Journal of Molecular Sciences, 2023, v. 24, n. 803, p. 1-14
1422-0067
http://hdl.handle.net/10017/59079
doi.org/10.3390/ijms24010803
AR/0000043608
International Journal of Molecular Sciences
24
14
803
1
Castration-resistant prostate cancer (CRPC) development is the foremost concern after treatment of patients with high risk with locally advanced or metastatic prostate cancer. Androgen receptor (AR) is the main driver of CRPC development, through its interaction with epigenetic modifier genes, placing epigenetics modifications in the forefront of CRPC development. Comparing the DNA methylation and expression profile of androgen-sensitive and -refractory prostate cancer cells, we describe the epigenetic silencing of claudin-3 (CLDN3) in AR positive cells resistant to androgen deprivation (LNCaP-abl). CLDN3 silencing was associated with DNA methylation, loss of histone acetylation and H3K27 methylation, and was re-expressed by the combined treatment with the epigenetic modulators Aza and SAHA. From a functional point of view, CLDN3 loss was associated with increased cellular invasion. Immunohistochemical analysis showed decreased CLDN3 expression in samples from CRPC patients. Interestingly, CLDN3 expression was significantly decreased in samples from patients with high total Gleason score (>= 8) and locally advanced tumors. Finally, CLDN3 loss of expression was associated with worse disease-free survival and time to clinical progression. In conclusion, our findings strongly indicate that epigenetic silencing of CLDN3 is a common event in CRPC that could be useful as a molecular marker for the prognosis of prostate cancer patients and to discriminate aggressive from indolent prostate tumors.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© The Authors
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
prostate
castration-resistant prostate cancer
DNA methylation
CLDN3
prognosis
Claudin-3 Loss of Expression Is a Prognostic Marker in Castration-Resistant Prostate Cancer
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/604612024-02-07T15:37:56Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Sebastián Martín, Alba
Sánchez Gómez, Belén
Mora Rodríguez, José María
Bort Bueno, Alicia Carmen
Díaz-Laviada Marturet, Inés Cecilia
2024-02-06T11:53:28Z
2024-02-06T11:53:28Z
2022-08-19
Biomedicines, 2022, v. 10, n. 8 (2026), p. 1-21
2227-9059
http://hdl.handle.net/10017/60461
10.3390/biomedicines10082026
AR/0000042489
Biomedicines
10
21
8 (2026)
1
DPP4/CD26 is a single-pass transmembrane protein with multiple functions on glycemic control, cell migration and proliferation, and the immune system, among others. It has recently acquired an especial relevance due to the possibility to act as a receptor or co-receptor for SARS-CoV-2, as it has been already demonstrated for other coronaviruses. In this review, we analyze the evidence for the role of DPP4 on COVID-19 risk and clinical outcome, and its contribution to COVID-19 physiopathology. Due to the pathogenetic links between COVID-19 and diabetes mellitus and the hyperinflammatory response, with the hallmark cytokine storm developed very often during the disease, we dive deep into the functions of DPP4 on carbohydrate metabolism and immune system regulation. We show that the broad spectrum of functions regulated by DPP4 is performed both as a protease enzyme, as well as an interacting partner of other molecules on the cell surface. In addition, we provide an update of the DPP4 inhibitors approved by the EMA and/or the FDA, together with the newfangled approval of generic drugs (in 2021 and 2022). This review will also cover the effects of DPP4 inhibitors (i.e., gliptins) on the progression of SARS-CoV-2 infection, showing the role of DPP4 in this disturbing disease.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© 2022 by the authors
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
DPP4
CD26
type 2 diabetes
inflammation
SARS-CoV-2
COVID-19
gliptins
Role of dipeptidyl peptidase-4 (DPP4) on COVID-19 physiopathology
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/600602024-01-31T01:16:21Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Beauchamp, Lucie de
Baquero Valls, Pablo
Kuntz, Elodie M.
Gottlieb, Eyald
Helgason, G.Vignir
2024-01-30T07:02:49Z
2024-01-30T07:02:49Z
2017-12-18
Molecular& Cellular Oncology, 2017, v. 5, n. 1 (E1403532), p. 1-3
2372-3556
http://hdl.handle.net/10017/60060
10.1038/s41375-018-0252-4
AR/0000028967
Molecular& Cellular Oncology
5
3
1 (e1403532)
1
We have recently uncovered an abnormal increase in mitochondrial oxidative metabolism in therapy-resistantchronic myeloid leukaemia stem cells (LSCs). By simultaneously disrupting mitochondrial respiration andinhibiting BCR-ABL kinase activity using the antibiotic tigecycline and imatinib respectively, we effectivelyeradicated LSCs and prevented disease relapse in pre-clinical animal models.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© Taylor & Francis
Cancer stem cells
CML
Cancer stem cells
Metabolism
Imatinib
Leukaemia
OXPHOS
Tyrosine kinase inhibitor
Tigecycline
TCA cycle
Auto-Commentary on: "Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells"
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/590452023-12-21T01:16:21Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Henríquez Figuereo, Andreina
Alcón Calderón, María de las Mercedes
Moreno Amatria, Esther
Sanmartín Grijalba, Carmen
Espuelas Millán, María Socorro
Lucio Ortega, Héctor Elessar de
Jiménez Ruiz, Antonio
Plano Amatriain, Daniel
2023-12-20T10:08:03Z
2023-12-20T10:08:03Z
2023-05-24
Bioorganic Chemistry, 2023, v. 138, n. 106624, p. 1-12
0045-2068
http://hdl.handle.net/10017/59045
10.1016/j.bioorg.2023.106624
AR/0000043986
Bioorganic Chemistry
138
12
106624
1
Nowadays, leishmaniasis is still treated with outdated drugs that present several obstacles related to their high toxicity, long duration, parenteral administration, high costs and drug resistance. Therefore, there is an urgent demand for safer and more effective novel drugs. Previous studies indicated that selenium compounds are promising derivatives for innovative therapy in leishmaniasis treatment. With this background, a new library of 20 selenocyanate and diselenide derivatives were designed based on structural features present in the leishmanicidal drug miltefosine. Compounds were initially screened against promastigotes of L. major and L. infantum and their cytotoxicity was evaluated in THP-1 cells. Compounds B8 and B9 were the most potent and less cytotoxic and were further screened for the intracellular back transformation assay. The results obtained revealed that B8 and B9 showed EC50 values of 7.7 µM and 5.7 µM, respectively, in L. major amastigotes, while they presented values of 6.0 µM and 7.4 µM, respectively, against L. infantum amastigotes. Furthermore, they exerted high selectivity (60 70) towards bone marrow-derived macrophages. Finally, these compounds exhibited higher TryR inhibitory activity than mepacrine (IC50 7.6 and 9.2 µM, respectively), and induced nitric oxide (NO) and reactive oxygen species (ROS) production in macrophages. These results suggest that the compounds B8 and B9 could not only exert a direct leishmanicidal activity against the parasite but also present an indirect action by activating the microbicidal arsenal of the macrophage. Overall, these new generation of diselenides could constitute promising leishmanicidal drug candidates for further studies.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© The Author(s), 2023
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Selenocyanate
Diselenide
Leishmanicidal agents
Selenocompounds
Trypanothione reductase
Next generation of selenocyanate and diselenides with upgraded leishmanicidal activity
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/589532023-12-19T01:18:26Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Ruiz Santaquiteria, Marta
Sánchez Murcia, Pedro Alejandro
Toro Londoño, Miguel Ángel
Lucio Ortega, Héctor Elessar de
Gutiérrez Viñas, Kilian Jesús
De Castro , Sonia
Carneiro , Filipa A. C.
Gago Badenas, Federico
Jiménez Ruiz, Antonio
Camarasa , María José
Velázquez , Sonsoles
2023-12-18T10:26:34Z
2023-12-18T10:26:34Z
2017-07-28
European Journal of Medicinal Chemistry, 2017, v. 135, p. 49-59
ISSN: 0223-5234
http://hdl.handle.net/10017/58953
10.1016/j.ejmech.2017.04.020
AR/0000031220
European Journal of Medicinal Chemistry
135
59
49
A series of 9-mer and 13-mer amide-bridged cyclic peptides derived from the linear prototype Ac-PKIIQSVGIS-Nle-K-Nle-NH2 (Toro et al. ChemBioChem 2013) has been designed and synthesized by introduction of the lactam between amino acid side chains that are separated by one helical turn (i, i+4). All of these compounds were tested in vitro as both dimerization and enzyme inhibitors of Leishmania infantum trypanothione reductase (Li-TryR). Three of the 13-mer cyclic peptide derivatives (3, 4 and 6) inhibited the oxidoreductase activity of Li-TryR in the low micromolar range and they also disrupted enzyme dimerization. Cyclic analogues 3 and 4 were more resistant to proteases than was the linear prototype. Furthermore, the most potent TryR inhibitors in the linear and cyclic series displayed potent in vitro activity against Leishmania infantum upon conjugation with cationic cell-penetrating peptides. To date, these conjugated peptides can be considered the first example of TryR dimerization inhibitors that are active in cell culture.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© The Author(s), 2017
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Peptides
Helix stabilization
Protein-protein interactions
Trypanothione reductase
Leishmania infantum
Cell-penetrating peptides
First example of peptides targeting the dimer interface of Leishmania infantum trypanothione reductase with potent in vitro antileishmanial activity
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/598192024-01-28T01:15:55Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Muñoz Moreno, Laura
Arenas Jiménez, María Isabel
Schally, Andrew V
Fernández Martínez, Ana Belén
Zarka, Elias
González-Santander Martínez, Marta
Carmena Sierra, María José
Vacas Oliva, Eva
Prieto Villapún, Juan Carlos
Bajo Chueca, Ana María
2024-01-24T07:46:34Z
2024-01-24T07:46:34Z
2013-02-15
International Journal of Cancer, 2013, v. 132, n. 4, p. 755-765
0020-7136
http://hdl.handle.net/10017/59819
10.1002/ijc.27716
AR/0000016738
International Journal of Cancer
132
765
4
755
New approaches are needed to the therapy of advanced prostate cancer. This study determined the effect of growth hormone- releasing hormone (GHRH) antagonists, JMR-132 and JV-1-38 on growth of PC3 tumors as well as on angiogenesis and metastasis through the evaluation of various factors that contribute largely to the progression of prostate cancer. Human PC3 androgen-independent prostate cancer cells were injected subcutaneously into nude mice. The treatment with JMR-132 (10 ug/day) or JV-1-38 (20 ug/day) lasted 41 days. We also evaluated the effects of JMR-132 and JV-1-38 on proliferation, cell adhesion and migration in PC-3 cells in vitro. Several techniques (Western blot, reverse transcription polymerase chain reaction, immunohistochemistry, ELISA and zymography) were used to evaluate the expression levels of GHRH receptors and its splice variants, GHRH, vascular endothelial growth factor (VEGF), hypoxia inducible factor (HIF)-1alpha, metalloproteinases (MMPs)-2 and -9, beta-catenin and E-cadherin. GHRH antagonists suppressed the proliferation of PC-3 cells in vitro and significantly inhibited growth of PC3 tumors. After treatment with these analogues, we found an increase in expression of GHRH receptor accompanied by a decrease of GHRH levels, a reduction in both VEGF and HIF-1alpha expression and in active forms of MMP-2 and MMP-9, a significant increase in levels of membrane-associated ?-catenin and a significant decline in E-cadherin. These results support that the blockade of GHRH receptors can modulate elements involved in angiogenesis and metastasis. Consequently, GHRH antagonists could be considered as suitable candidates for therapeutic trials in the management of androgen-independent prostate cancer.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© UICC
GHRH
GHRH antagonists
prostate cancer
angiogenesis
metastasis
Inhibitory Effects of Antagonists of Growth Hormone-Releasing Hormone (GHRH) on Growth and Invasiveness of PC3 Human Prostate Cancer
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/589922023-12-20T01:15:47Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Revuelto , Alejandro
Ruiz Santaquiteria, Marta
Lucio Ortega, Héctor Elessar de
Gamo , Ana
Carriles Linares, Alejandra Ángela
Gutiérrez Viñas, Kilian Jesús
Sánchez Murcia, Pedro Alejandro
Hermoso , Juan A.
Gago Badenas, Federico
Camarasa , María José
Jiménez Ruiz, Antonio
Velázquez , Sonsoles
2023-12-19T09:20:42Z
2023-12-19T09:20:42Z
2019-04-15
ACS Infectious Diseases, 2019, v. 5, n. 6, p. 873-891
2373-8227
http://hdl.handle.net/10017/58992
doi.org/10.1021/acsinfecdis.8b00355
AR/0000030649
ACS Infectious Diseases
5
891
6
873
Disruption of protein-protein interactions of essential oligomeric enzymes by small molecules represents a significant challenge. We recently reported some linear and cyclic peptides derived from an ¿-helical region present in the homodimeric interface of Leishmania infantum trypanothione reductase (Li-TryR) that showed potent effects on both dimerization and redox activity of this essential enzyme. Here, we describe our first steps toward the design of nonpeptidic small-molecule Li-TryR dimerization disruptors using a proteomimetic approach. The pyrrolopyrimidine and the 5-6-5 imidazole-phenyl-thiazole ¿-helix-mimetic scaffolds were suitably decorated with substituents that could mimic three key residues (K, Q, and I) of the linear peptide prototype (PKIIQSVGIS-Nle-K-Nle). Extensive optimization of previously described synthetic methodologies was required. A library of 15 compounds bearing different hydrophobic alkyl and aromatic substituents was synthesized. The imidazole-phenyl-thiazole-based analogues outperformed the pyrrolopyrimidine-based derivatives in both inhibiting the enzyme and killing extracellular and intracellular parasites in cell culture. The most active imidazole-phenyl-thiazole compounds 3e and 3f inhibit Li-TryR and prevent growth of the parasites at low micromolar concentrations similar to those required by the peptide prototype. The intrinsic fluorescence of these compounds inside the parasites visually demonstrates their good permeability in comparison with previous peptide-based Li-TryR dimerization disruptors.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© American Chemical Society, 2019
alpha-helix mimetics
protein-protein interactions
small-molecule dimerization disruptor
trypanothione reductase
Leishmania infantum
Pyrrolopyrimidine vs Imidazole-Phenyl-Thiazole Scaffolds in Nonpeptidic Dimerization Inhibitors of Leishmania infantum Trypanothione Reductase
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/590412023-12-21T01:16:21Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Revuelto Pérez, Alejandro
López Martín, Isabel
Lucio Ortega, Héctor Elessar de
García Soriano, Juan Carlos
Zanda , Nicola
De Castro De La Osa, Sonia
Gago Badenas, Federico
Jiménez Ruiz, Antonio
Velázquez Díaz, Sonsoles
Camarasa Rius, María José
2023-12-20T08:05:48Z
2023-12-20T08:05:48Z
2021-07-17
Pharmaceuticals, 2021, v. 14, n. 7, p. 1-15
1424-8247
http://hdl.handle.net/10017/59041
10.3390/ph14070689
AR/0000040826
Pharmaceuticals
14
15
7
1
Trypanothione disulfide reductase (TryR) is an essential homodimeric enzyme of trypanosomatid parasites that has been validated as a drug target to fight human infections. Using peptides and peptidomimetics, we previously obtained proof of concept that disrupting protein-protein interactions at the dimer interface of Leishmania infantum TryR (LiTryR) offered an innovative and so far unexploited opportunity for the development of novel antileishmanial agents. Now, we show that linking our previous peptide prototype TRL38 to selected hydrophobic moieties provides a novel series of small-molecule-peptide conjugates that behave as good inhibitors of both LiTryR activity and dimerization.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© The Author(s), 2021
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
leishmaniasis
small molecule¿peptide conjugates
dimerization inhibitors
trypanothione disulfide reductase
Small Molecule-Peptide Conjugates as Dimerization Inhibitors of Leishmania infantum Trypanothione Disulfide Reductase
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/596002024-02-26T08:59:11Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Sánchez Hernández, Irene
Baquero Valls, Pablo
Calleros Basilio, Laura
Chiloeches Gálvez, Antonio
2024-01-18T08:17:12Z
2024-01-18T08:17:12Z
2012-01-28
Cancer Letters, 2012, v. 314, n. 2, p. 244-255
0304-3835
http://hdl.handle.net/10017/59600
10.1016/j.canlet.2011.09.037
AR/0000014812
Cancer Letters
314
255
2
244
BRAF is a main oncogene in human melanomas. Here, we show that BRAF depletion by siRNA or inhibition of its activity by treatment with RAF inhibitor Sorafenib induces apoptosis in NPA melanoma cells expressing oncogenic (V600E)BRAF. This effect is mediated through a MEK/ERK-independent mechanism, since treatment with the MEK inhibitor U0126 does not exert any effect. Moreover, we demonstrate that inhibition of the PI3K/AKT/mTOR cascade alone does not increase apoptosis in these cells. However, the blockage of this pathway in cells lacking either BRAF expression or activity cooperates to induce higher levels of apoptosis than those achieved by inhibition of BRAF alone. Consistently, we demonstrate that abrogation of BRAF expression increases AKT and mTOR phosphorylation, suggesting the existence of a compensatory pro-survival mechanism after BRAF depletion. Together, our data provide a rationale for dual targeting of BRAF and PI3K/AKT/mTOR signalling to effectively control melanoma disease.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© Elsevier
BRAF
MEK/ERK
Melanoma
Apoptosis
PI3K/AKT/mTOR
Dual inhibition of V600EBRAF and the PI3K/AKT/mTOR pathway cooperates to induce apoptosis in melanoma cells through a MEK-independent mechanism
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/589912023-12-20T01:15:47Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Bravo , Ana
Lucio Ortega, Héctor Elessar de
Sánchez Murcia, Pedro Alejandro
Jiménez Ruiz, Antonio
Petrone , Paula M.
Gago Badenas, Federico
Cortés Cabrera, Álvaro
2023-12-19T08:58:06Z
2023-12-19T08:58:06Z
2019-02-12
Chemical Biology and Drug Design, 2019, v. 93, n. 5, p. 965-969
1747-0277
http://hdl.handle.net/10017/58991
10.1111/cbdd.13487
AR/0000031215
Chemical Biology and Drug Design
93
969
5
965
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© John Wiley & Sons A/S, 2019
axonal growth
bipolar disorder
GSK3B
lithium
MOK
NEK3
Identification of NEK3 and MOK as novel targets for lithium
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/596072024-01-20T01:16:07Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Herráez Sánchez, Ángel
Marrodán, M. Dolores
González Montero De Espinosa, Marisa
2024-01-18T09:22:51Z
2024-01-18T09:22:51Z
2021-09-17
American Journal of Human Biology, 2021, v. 34, n. 4 (E23681), p. 1-10
1042-0533
http://hdl.handle.net/10017/59607
10.1002/ajhb.23681
AR/0000037812
American Journal of Human Biology
34
10
4 (e23681)
1
-- Objectives -- The Spanish National Pedagogic Museum (Museo Pedagógico Nacional, MPN), founded by La Institución Libre de Enseñanza (ILE), organised the first summer school camps in Spain and their initiative was followed by other institutions in this country. MPN prepared anthropological forms for those sojourns, which included information about both metric and physiological measurements of the schoolchildren. The aim of the current work is to analyse hand grip strength data and to compare them with recent values. -- Methods -- The initial sample included 2418 schoolchildren from 6 to 16 years old (1467 males, 951 females) attending the camps, but after preliminary analyses the study was restricted to 1073 boys and 818 girls in the 1900-1925 interval. Three time periods were established and 13 categories of height at camp entry, every 5 cm. Normality tests were run as well as contrasts of means, and both average values and percentiles were calculated for hand grip strength in both hands, as a function of age and height categories. -- Results -- The 1900-1925 interval was chosen since there were no significant differences among hand grip data within that period. Results show that children attending the camps had dynamometry values in both hands well below the current ones, both with reference to their height and to their age. -- Conclusions -- Camp attendees displayed very low values of height and hand grip strength in both hands. Both are significantly lower than contemporary values, manifesting a secular effect.
eng
http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
© 2021 The Authors. American Journal of Human Biology published by Wiley Periodicals LLC.
Attribution 4.0 International (CC BY 4.0)
Hand grip strength in boys and girls from summer school camps in Spain, 1900-1925. A comparison with 21st century data
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/589892024-03-11T07:13:17Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Angulo Cuesta, Javier
Lopez, Jose I
Ropero Salinas, Santiago
2023-12-19T08:25:43Z
2023-12-19T08:25:43Z
2016-08-09
Molecular Diagnosis and Therapy, 2016
1177-1062
http://hdl.handle.net/10017/58989
10.1007/s40291-016-0231-2
AR/0000024723
Molecular Diagnosis and Therapy
Urologic malignancies are some of the com- monest tumors often curable when diagnosed at early stage. However, accurate diagnostic markers and faithful pre- dictors of prognosis are needed to avoid over-diagnosis leading to overtreatment. Many promising exploratory studies have identified epigenetic markers in urinary malignancies based on DNA methylation, histone modifi- cation and non-coding ribonucleic acid (ncRNA) expres- sion that epigenetically regulate gene expression. We review and discuss the current state of development and the future potential of epigenetic biomarkers for more accurate and less invasive detection of urological cancer, tumor recurrence and progression of disease serving to establish diagnosis and monitor treatment efficacies. The specific clinical implications of such methylation tests on thera- peutic decisions and patient outcome and current limita- tions are also discussed.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© Springer International Publishing Switzerland 2016
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
DNA methylation and urological cancer, a step towards personalized medicine: current and future prospects.
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/595362024-01-31T08:26:31Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Herráez Sánchez, Ángel
Marrodán, M. Dolores
González Montero De Espinosa, Marisa
2024-01-17T09:33:42Z
2024-01-17T09:33:42Z
2021-01-20
American Journal of Human Biology, 2021, v. 34, n. 1 (E23570), p. 1-15
1042-0533
http://hdl.handle.net/10017/59536
10.1002/ajhb.23570
AR/0000035470
American Journal of Human Biology
34
15
1 (e23570)
1
Objectives To assess a secular change in proportion between lower limbs and torso, we analyzed the evolution of cormic index in schoolchildren attending summer camps organized by the Spanish National Pedagogic Museum between 1887 and 1924, also comparing to later studies up to the present.
Subjects and methods Unpublished primary data for height and sitting height were collected from 805 individuals of both sexes. Data were pooled in cohorts according to age and year of measurement. Additionally, the analysis included comparison with published data from both national and international populations.
Results Among males, a noteworthy decrease of the cormic index is perceived from the first to the last camps, while in females this is only seen for the group under 11 years old. With data from published Spanish references (1900-2019) a decrease is observed for the male series but is not evident for females. Cormic index values from the camps overlap among the international references, despite the former being from much earlier years.
Conclusion The cormic index decreased among Spanish male children along the decades.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© 2021 Wiley
Variation of the cormic index since the onset of summer school camps in Spain (1887) up to present days
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/588952023-12-16T01:16:09Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Baquero Valls, Pablo
Dawson, Amy
Mukhopadhyay, Arunima
Kuntz, Elodie M.
Mitchell, Rebecca
Olivares, Orianne
Ianniciello, Angela
Scott, Mary T.
Dunn, Karen
Nicastri, Michael C.
Winkler, Jeffrey D
Michie, Alison M.
Ryan, Kevin M.
Halsey, Christina
Gottlieb, Eyal
Keaney, Erin P.
Murphy, Leon O.
Amaravadi, Ravi K.
Holyoake, Tessa L.
Helgason, G.Vignir
2023-12-15T09:30:46Z
2023-12-15T09:30:46Z
2019-04-01
Leukemia, 2019, v. 33, n. 4, p. 981-994
0887-6924
http://hdl.handle.net/10017/58895
10.1038/s41375-018-0252-4
AR/0000028965
Leukemia
33
994
4
981
In chronic myeloid leukemia (CML), tyrosine kinase inhibitor (TKI) treatment induces autophagy that promotes survival and TKI-resistance in leukemic stem cells (LSCs). In clinical studies hydroxychloroquine (HCQ), the only clinically approved autophagy inhibitor, does not consistently inhibit autophagy in cancer patients, so more potent autophagy inhibitors are needed. We generated a murine model of CML in which autophagic flux can be measured in bone marrow-located LSCs. In parallel, we use cell division tracing, phenotyping of primary CML cells, and a robust xenotransplantation model of human CML, to investigate the effect of Lys05, a highly potent lysosomotropic agent, and PIK-III, a selective inhibitor of VPS34, on the survival and function of LSCs. We demonstrate that long-term haematopoietic stem cells (LT-HSCs: Lin(-)Sca-1(+)c-kit (+)CD48(-)CD150(+)) isolated from leukemic mice have higher basal autophagy levels compared with non-leukemic LT-HSCs and more mature leukemic cells. Additionally, we present that while HCQ is ineffective, Lys05-mediated autophagy inhibition reduces LSCs quiescence and drives myeloid cell expansion. Furthermore, Lys05 and PIK-III reduced the number of primary CML LSCs and target xenografted LSCs when used in combination with TKI treatment, providing a strong rationale for clinical use of second generation autophagy inhibitors as a novel treatment for CML patients with LSC persistence.
eng
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
© The authors
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Targeting quiescent leukemic stem cells using second generation autophagy inhibitors
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/11172023-12-14T15:28:13Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Herráez Sánchez, Ángel
2007-10-23T08:09:39Z
2007-10-23T08:09:39Z
2007
Revista Cubana de Química, 2007, v. 19, n. 1, p. 3-5.
2224-5421
http://hdl.handle.net/10017/1117
Nowadays the usefulness of taking advantage of multimedia materials as a support tool in teaching is well established. Fortunately, the means to access these resources are increasingly available. This approach becomes particularly useful in the life sciences area, where perception of three-dimensional features of biomolecule structure and interactions is crucial, as well as of the dynamic nature of all processes that take place in living beings.
In this communication, we will present experiences on the use of diverse materials as a support for teaching in the classroom and, likewise, as a tool to assist the student in his/her personal study and learning process.
The development and use of these materials are structured through the web page format, since this offers a series of features ideally suited as "universal content container": a single environment is provided for different types of materials: text, images, animated diagrams, movies, sound, molecular models, exercises, self-assessment, interactive content...; everything is handled with a software familiar to the user, available easily and at no cost; the same material serves as support tool for the teacher during lectures and as a study resource for the students; it can be made available under multiple settings: in the classroom, in the laboratory, in the student's personal computer, on the hard disk, on CD-ROM, through a local network, through internet, etc.; it allows easy update of contents, as often as needed.
eng
info:eu-repo/semantics/openAccess
(c) Universidad de Oriente, 2007
Teaching
Learning
Multimedia
Web page
Biochemistry
Teaching aids
Molecules
Structure
Biomolecules
Three-dimensional
Molecular model
Molecular visualization
Animations
Web pages and multimedia as a tool for biochemistry instruction
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/23622024-01-09T15:00:19Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Burgos Ramos, Emma
Puebla Jiménez, Lilian
Arilla Ferreiro, Eduardo
2008-12-02T12:47:58Z
2008-12-02T12:47:58Z
2008
Neuroscience, 2008, v. 154, n. 4, p. 1458–1466
0306-4522
http://hdl.handle.net/10017/2362
10.1016/j.neuroscience.2008.04.036
Minocycline is a semi-synthetic second-generation tetracycline known to improve cognition in amyloid precursor protein transgenic mice. Whether it can protect the somatostatin (SRIF) receptor-effector system, also involved in learning and memory, from alterations induced by chronic i.c.v. infusion of ß-amyloid peptide (Aß)(25-35) is presently unknown. Hence, in the present study, we tested the effects of minocycline on the SRIF signaling pathway in the rat temporal cortex. To this end, male Wistar rats were injected with minocycline (45 mg/kg body weight) i.p. twice on the first day of treatment. On the following day and during 14 days, Aß(25-35) was administered i.c.v. via an osmotic minipump connected to a cannula implanted in the left lateral ventricle (300 pmol/day). Minocycline (22.5 mg/kg, i.p.) was injected once again the last 2 days of the Aß(25-35) infusion. The animals were killed by decapitation 24 h after the last drug injection. Our results show that minocycline prevents the decrease in SRIF receptor density and somatostatin receptor (sst) 2 expression and the attenuated capacity of SRIF to inhibit adenylyl cyclase (AC) activity, alterations present in the temporal cortex of Aß(25-35)-treated rats. Furthermore, minocycline blocks the Aß(25-35)-induced decrease in phosphorylated cyclic AMP (cAMP) response element binding protein (p-CREB) content and G-protein-coupled receptor kinase 2 (GRK) protein expression in this brain area. Altogether, the present data demonstrate that minocycline in vivo provides protection against Aß-induced impairment of the SRIF signal transduction pathway in the rat temporal cortex and suggest that it may have a potential as a therapeutic agent in human Alzheimer's disease, although further studies are warranted.
eng
info:eu-repo/semantics/openAccess
© Elsevier, 2008
Brain
Alzheimer's disease
Amyloid-ß
CREB
GRK
Somatostatin receptors
Minocycline provides protection against ß-amyloid(25-35)-induced alterations of the somatostatin signaling pathway in the rat temporal cortex
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/24572024-01-09T15:16:36Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Barrios Sabador, Vicente
Urrutia, M.J.M.
Hernández, M.
Lama, R.
García-Novo, M.D.
Hernanz, A.
Arilla Ferreiro, Eduardo
2009-04-20T13:35:58Z
2009-04-20T13:35:58Z
1994
Life Sciences, 1994, v. 55, n. 4, p. 317-325.
0024-3205
http://hdl.handle.net/10017/2457
10.1016/0024-3205(94)00734-9
Since somatostatin inhibits basal and stimulated gastric acid secretion and gastrin release, it is conceivable that decreased gastric somatostatin concentration may be one of the factors responsible for gastric hypersecretion found in patients who have undergone long-term pylorotomy for hypertrophic pyloric stenosis. To investigate this proposal the somatostatin-like immunoreactivity concentration was determined in antral and fundic mucosa samples from control and long-term pyloromyotomized children. In addition, somatostatin binding to cytosol from gastric (fundus and antrum) mucosa and fasting serum gastrin levels and serum gastrin response to a standard breakfast were also studied. The mean fundic and antral somatostatin-like immunoreactivity concentrations were significantly lower in long-term pyloromyotomized children than in control children. The depletion of fundic and antral somatostatin-like immunoreactivity content was associated with an increase in the number of gastric somatostatin binding sites. The fasting serum gastrin levels and serum gastrin response to a standard breakfast (after 60 min) in long-term pyloromyotomized children was significantly higher than those in control children. Since, together with the increase of somatostatin binding to gastric mucosa, there is an increase in the gastrin serum levels, despite the inhibitory effect of somatostatin on gastrin release, the binding capacity cannot be the main factor determining the response to somatostatin in long-term pyloromyotomized children. The present results suggest that both somatostatin and gastrin have some pathophysiologic importance in long-term pyloromyotomized children.
eng
info:eu-repo/semantics/openAccess
(c) Elsevier, 1994
Gastric somatostatin receptors
Gastrin
Hypertrophic pyloric stenosis
Pylorotomy
Serum gastrin level and gastric somatostatin content and binding in long-term pyloromyotomized children
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/24812024-01-10T11:48:58Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Barrios Sabador, Vicente
Puebla Jiménez, Lilian
Rodríguez Sánchez, María Nelly
Arilla Ferreiro, Eduardo
2009-04-21T13:59:56Z
2009-04-21T13:59:56Z
1993
Regulatory Peptides, 1993, v. 48, n. 3, p. 355-363
0167-0115
http://hdl.handle.net/10017/2481
10.1016/0167-0115(93)90164-4
During pregnancy and postpartum rats experience a wide varietv of behavioural changes. Since the soma-tostatinergic system has been iraplicated in the control of some of these changes, the present study examined somatostatin (SS) content and specific binding in the frontoparietal cortex and hippocampus of non-pregnant. pregnant (17 to 18 days), parturition and postpartum (10 and 30 days) rats as well as in ovariectomized rats which were or were not treated with estradiol valerianate. The content of somatostatin-like inimunoreactivity (SSLI) was increased at 17 days of pregnancy in frontoparietal cortex and decreased at parturition and 10 days postpartum in that región and the hippocampus under study when compared with SSLI levels in non-pregnant rats. At 30 days postpartum the SSLI content returned to non-pregnant valúes in both brain regions. Scatchard analysis showed that the decrease in [125I]Tyru-SS binding observed at 17 days of pregnancy in the frontoparietal cortex was due to the decrease in the number of SS receptors. In contrast, on the dav of delivery the number of SS receptors in the same brain región increased. The affinity of the SS receptors was consistently unchanged in pregnant and non-pregnant rats in both regions. At 10 days postpartum the valué of specific binding of the tracer to SS receptors in the frontoparietal cortex was not significantly different from that in the non-pregnant rats, although the actual number of receptors was slightly higher. Pregnancy did not change SS binding in the hippocampus. Neither ovariectomy ñor the treatment of ovariectomized rats with estradiol valerianate affected cortical and hippocampal SS content and binding in the rats. These changes in the somatostatinergic system associated with late pregnancy, parturition and the earlv postpartum period may well be important because of their possible role in some of the behavioural changes observed during these periods.
eng
info:eu-repo/semantics/openAccess
© Elsevier Science Publishers, 1993
Frontoparietal cortex
Hippocampus
Pregnancy
Rat
Somatostatin receptor
Pregnancy
Somaiostatin receptor
Frontoparietal cortex
Hippocampus
Rat
Brain somatostatinergic system at late pregnancy, parturition and the early postpartum period in the rat
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/24742024-01-10T11:46:44Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Colás Escudero, María Begoña
Bodega Magro, Guillermo
Sanz, Manuel
Prieto Villapún, Juan Carlos
Arilla Ferreiro, Eduardo
2009-04-21T13:17:23Z
2009-04-21T13:17:23Z
1988
Clinical Science, 1988, v. 74, n. 5, p. 499-505
0143-5221
http://hdl.handle.net/10017/2474
10.1042/cs0740499
Three weeks after partial enterectomy in the rabbit there was an increased somatostatin concentration and a decreased number of somatostatin-binding sites (without changes in the corresponding affinity values) in the cytosol of the residual intestinal tissue, except in the terminal ileum and the colon.
Five weeks after surgery both the somatostatin concentration and the number of somatostatin-binding sites returned towards control values.
These results suggest that an increase in bowel somatostatin content could lead to down-regulation of somatostatin-binding sites in the intestinal mucosa.
eng
info:eu-repo/semantics/openAccess
© The Biochemical Society and the Medical Research Society, 1988
Cytosol
Enterectomy
Somatostatin binding
Partial enterectomy decreases somatostatin-binding sites in residual intestine of rabbits
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/24772024-01-10T11:47:49Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
González Guijarro, Luis A.
Arilla Ferreiro, Eduardo
2009-04-21T13:34:40Z
2009-04-21T13:34:40Z
1988
Journal of Endocrinology, 1988, v. 118, n. 2, p. 227-232
0022-0795
http://hdl.handle.net/10017/2477
10.1677/joe.0.1180227
eng
info:eu-repo/semantics/openAccess
(c) Journal of Endocrinology Ltd, 1988
Somatostatin
Duodenal mucosa
Pancreatic duct
Rabbits
Somatostatin levels and binding in duodenal mucosa of rabbits with ligation of the pancreatic duct
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/31062024-03-13T10:42:51Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Rodríguez Sánchez, María Nelly
Arilla Ferreiro, Eduardo
2009-06-08T19:21:23Z
2009-06-08T19:21:23Z
1991
Neuroscience letters, 1991, v. 134, n. 1, p. 37-40
0304-3940
http://hdl.handle.net/10017/3106
10.1016/0304-3940(91)90503-L
Primiparous female Wistar rats were injected subcutancously with single daily doses of 40 mg of cocaine hydrochloride/kg from day 7 to 19 of gestation, from day 7 of gestation to day 15 postpartum or from parturation to day 15 postpartum. At birth, some of the offspring were fostered to control mothers to limit the effect of cocaine to the prenatal period and some were left with their mothers with the aim of studying prenatal plus postnatal exposure to cocaine. Prenatal and/or postnatal cocaine exposure did not affect the content of somatostatin (SS)-like iminunoreactivity (SLI) in the striatum of the offspring as compared with the control groups on day 15 in all experimental groups. Prenatal and prenatal-plus-postnatal exposure to cocaine increased the total number of binding sites for 125I-Tyr11-SS in the rat striatum at 15 days of age. Prenatal exposure to cocaine also decreased the apparent affinity of the receptors. Postnatal exposure to cocaine alone had no such post-treatment effect on 125I-Tyr11-SS binding. These results suggest that the development of SS receptors in the rat striatum can be altered by prenatal exposure to cocaine.
eng
info:eu-repo/semantics/openAccess
© Elsevier Scientific Publishers Ireland, 1991
Cocaine
Somatostatin
Offspring
Rat
Receptor
Striatum
Changes in striatal somatostatin receptors in pups after cocaine administration to pregnant and nursing dams
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/21772023-12-22T13:18:59Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Álvaro Alonso, Itziar
Boyano Adánez, María del Carmen
Arilla Ferreiro, Eduardo
2008-11-10T09:48:00Z
2008-11-10T09:48:00Z
1995
Biochimica et Biophysica Acta, 1995, v. 1268, p. 115 - 121
0006-3002
http://hdl.handle.net/10017/2177
10.1016/0167-4889(95)00052-T
Male rats were given 10% (w/v) ethanol in drinking fluid during the first week, 15% (w/v) during the second week, 20% (w/v) during the third, and 25% (w/v) during the fourth week, at the end of which they were kept on 25% (w/v) ethanol drinking water for 3 weeks. Some animals were then allowed the withdrawal of ethanol for a period of 2 weeks or 7 weeks. No significant differences were seen for the basal and forskolin (FK)-stimulated adenylate cyclase (AC) enzyme activities in the pancreatic acinar membranes of ethanol-treated and ethanol withdrawal rats as compared to the control group. Chronic ethanol ingestion resulted in an attenuation of somatostatin(SS)-inhibited FK-stimulated AC in rat pancreatic acinar membranes. The ability of the stable GTP analogue S'-guanylylimidodiphosphate (Gpp[NH]p) to inhibit FK-stimulated AC activity was also decreased in pancreatic acinar membranes from ethanol-treated rats. Gpp[NH]p was a much less potent inhibitor of SS binding in the pancreatic acinar membranes from chronic ethanol-treated animals than in those from controls, suggesting a change of G(i). A significant reduction in the number of 125I-Tyr11-SS receptors was observed after ethanol ingestion, when compared with control values. Two weeks after the replacement of the ethanol solution by water, the ethanol effect on the parameters cited above persisted. At week 7 of withdrawal, these parameters reached the level-of water controls. Ethanol administration did not affect either the number or the affinity of secretin receptors as compared to control values which suggests that the change in SS binding is not a non-specific effect. Neither chronic ethanol consumption nor withdrawal affected somatostatin-like immunoreactivity (SSLI). These results suggest that the attenuated inhibition of AC by SS in pancreatic acinar membranes from ethanol-treated rats and ethanol withdrawal (2 weeks) rats may be caused by decreases in both G; activity and in the number of SS receptors. Alternatively, an uncoupling of SS receptors from G(i) and/or a decrease in the level of functional G; may result in both a decrease in apparent B(max) for SS binding and in SS-mediated inhibition of AC. Since SS has been suggested to be an inhibitor of basal and cholecystokinin (CCK)- and/or secretin-stimulated exocrine pancreatic secretion, it is tempting to speculate that the impairment of the SS receptor/effector system seen in the present study can participate in the increase of basal pancreatic exocrine secretion described after chronic ethanol consumption.
eng
info:eu-repo/semantics/openAccess
(c) Elsevier, 1995
Ethanol
Somatostatin receptor
Adenylyl cyclase
G protein
Ethanol-induced modification of somatostatin-responsive adenylyl cyclase in rat exocrine pancreas
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/22602024-01-09T14:24:24Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Muñoz Acedo, Gema
Izquierdo Claros, Rosa María
Puebla Jiménez, Lilian
Rodríguez Martín, Eulalia
Arilla Ferreiro, Eduardo
2008-11-17T11:38:44Z
2008-11-17T11:38:44Z
1997
Molecular Brain Research, 1997, v. 47, p. 117–124
0169-328X
http://hdl.handle.net/10017/2260
10.1016/S0169-328X(97)00038-7
There is evidence that suggests a reciprocal functional link between the serotonergic and the somatostatinergic system in the rat frontoparietal cortex. However, to date, the role of endogenous 5-hydroxytryptamine (serotonin) on the regulation of the somatostatin (SS) receptor-adenylyl cyclase (AC) system remains unclear. In the present study, the administration of fluoxetine (10 mg/kg i.p.), a 5-hydroxytryptamine uptake inhibitor in a single dose or administered daily for 14 days increased the number of specific [125I]Tyr11-SS receptors, with no change in the receptor affinity, in rat frontoparietal cortical membranes. However, the capacity of SS to inhibit forskolin (FK)-stimulated AC activity in these membranes was lower than in the control groups. The ability of the stable GTP analogue 5'-guanylylimidodiphosphate (Gpp(NH)p) to inhibit FK-stimulated AC activity in frontoparietal cortical membranes was also decreased in rats acutely and chronically treated with fluoxetine. p-Chloroamphetamine (5 mg/kg i.p.), which leads to a lasting reduction of 5-hydroxytryptamine innervation, administered,on days 1, 3 and 5 and the rats sacrificed 1 or 3 weeks after the first injection, decreased the number of SS receptors without changing the receptor affinity. In this experimental group, SS also caused a significantly lower inhibition of FK-stimulated AC activity. p-Chloroamphetamine had no effect on the ability of Gpp(NH)p to inhibit FK-stimulated AC activity in frontoparietal cortical membranes at all the time periods studied. The present results suggest that under normal circumstances some SS receptors are under a tonic stimulatory control through the serotonergic system.
eng
info:eu-repo/semantics/openAccess
(c) Elsevier Science, 1997
Fluoxetine
p-Chloroamphetamine
Somatostatin receptor
Adenylyl cyclase
Rat
Frontoparietal cortex
Influence of fluoxetine and p-chloroamphetamine on the somatostatin receptor-adenylyl cyclase system in the rat frontoparietal cortex
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/22592024-01-09T12:42:41Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Izquierdo Claros, Rosa María
Boyano Adánez, María del Carmen
Arilla Ferreiro, Eduardo
2008-11-17T11:10:42Z
2008-11-17T11:10:42Z
2004
Molecular Brain Research, 2004, vol. 126, n. 2, p. 107-113
0169-328X
http://hdl.handle.net/10017/2259
10.1016/j.molbrainres.2004.03.010
If melatonin or its analogs are to be used therapeutically in humans, their chronic effects on responsiveness of melatonin target cells need to be assessed. We have previously demonstrated that acute melatonin treatment regulates the somatostatinergic system in the rat hippocampus. In the present study, we have investigated the effects of subchronic and chronic daily treatment with melatonin on the somatostatinergic system in the rat hippocampus. Male Wistar rats (200-250 g) were injected with melatonin (25 ¿g/kg body weight, subcutaneously) daily for 4, 7 or 14 days and sacrificed 24 h after the last injection. Melatonin administration for 4 days induced a decrease in the hippocampal somatostatin (SRIF)-like immunoreactivity content as well as a decrease in the number of SRIF receptors and an increase in their apparent affinity. The decreased number of SRIF receptors in the melatonin (4 days)-treated rats was associated with a decreased capacity of SRIF to inhibit both basal and forskolin-stimulated adenylyl cyclase activity. These melatonin-induced effects reversed to control values after 7 or 14 days of treatment. Hippocampal membranes from control and melatonin-treated rats showed similar Gi and Gs activities. Melatonin treatment altered neither the functional Gi activity nor the Gi¿1 or Gi¿2 levels at any of the time periods studied. The present results suggest that chronic exposure to melatonin results in a tolerance of the hippocampus to this hormone.
eng
info:eu-repo/semantics/openAccess
(c) Elsevier, 2004
Somatostatin receptors
Melatonin
Adenylyl cyclase
G proteins
Hippocampus
Rat
Activity of the hippocampal somatostatinergic system following daily administration of melatonin
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/22742024-01-09T14:28:46Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Boyano Adánez, María del Carmen
Bodega Magro, Guillermo
Barrios Sabador, Vicente
2008-11-18T11:07:35Z
2008-11-18T11:07:35Z
1996
Neurochemistry International, 1996, v. 29, n. 5, p. 469–476
0197-0186
http://hdl.handle.net/10017/2274
10.1016/0197-0186(96)00021-6
It has been reported that ingestion of an ammonium-containing diet produces hyperammonemia without encephalopathy, thus permitting the study of the specific effects of ammonia toxicity. The present study investigated the rat cerebral somatostatinergic system using this experimental model of hyperammonemia. Wistar rats were fed a high ammonia diet prepared by mixing a standard diet with ammonium acetate (20% w/w); in addition, 5 mM of ammonium acetate was added to their water supply. Control rats were fed with a standard diet. The animals were sacrificed at 3, 7 and 15 days of ammonia ingestion. Ammonia levels in blood had increased ¿3-fold at 7 days of ammonia ingestion. These changes were associated with a significant decrease in the specific binding of somatostatin (SS) to putative receptors sites in the frontoparietal cortex and hippocampus at 7 and 15 days after starting the high ammonia diet. Scatchard analysis shows that the decrease in SS binding resulted from a decrease in the number of available SS receptors rather than a change in receptor affinity. No changes in the somatostatin-like immunoreactivity content (SSLI) were detected in either brain area at the three study times. These results suggest that hyperammonemia alone can affect the rat brain somatostatinergic system. However, the animal model of hyperammonemia used here is insufficient to produce encephalopathy despite the significant increase in serum ammonia.
eng
info:eu-repo/semantics/openAccess
© Elsevier Science Ltd, 1996
Encephalopathy
Wistar rats
Ammonium acetate
Somatostatin
Frontoparietal cortex
Hippocampus
Somatostatin
Response of rat cerebral somatostatinergic system to a high ammonia diet
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/29772023-12-14T15:28:16Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Izquierdo Claros, Rosa María
Boyano Adánez, María del Carmen
Arilla Ferreiro, Eduardo
2009-05-22T12:25:33Z
2009-05-22T12:25:33Z
2000
Journal of Neuroscience Research, 2000, v. 62, p. 91-98
1097-4547
http://hdl.handle.net/10017/2977
10.1002/1097-4547(20001001)62:1<91::AID-JNR10>3.0.CO;2-D
The role of dopamine D1 and D2 receptor subtypes in the regulation, in vivo, of the somatostatin (SRIF) receptor-effector system in rat frontoparietal cortex was investigated. The D1-receptor agonist SKF 38393 (4 mg/kg) or the D2-receptor agonist bromocriptine (2 mg/kg), administered intraperitoneally to rats, increased the number of SRIF receptors without altering the affinity constant, an effect antagonized by both SCH 23390 (0.25 mg/kg) and raclopride (5 mg/kg), D1 and D2 receptor antagonists, respectively. These antagonists alone had no effect on [125I]Tyr3 octreotide binding to its receptors. No change in binding was detected when the dopamine agonists were added in vitro. Basal adenylyl cyclase (AC) activity was increased by SKF 38393 treatment and decreased by bromocriptine. Octreotide (SMS 201-995)-mediated inhibition of basal and forskolin-stimulated AC was increased by SKF 38393 or bromocriptine treatment. In frontoparietal cortical slices, basal inositol-1,4,5-triphosphate (IP3) levels were decreased by bromocriptine treatment but were unaffected by SKF 38393. SMS 201-995 increased the IP3 accumulation in control, SKF 38393-, and bromocriptine-treated rats. Insofar as SRIF and dopamine appear to be involved in motor regulation and could well modulate somatosensory functions in frontal and parietal cortex, respectively, heterologous receptor regulation may have important repercussions regarding the control exerted by these neurotransmitters on frontal and parietal cortical function in the intact animal. J. Neurosci. Res. 62:91–98, 2000. © 2000 Wiley-Liss, Inc.
eng
info:eu-repo/semantics/openAccess
© Wiley-Liss, 2000
SKF 38393
Bromocriptine
SCH 23390
Raclopride
Somatostatin receptor
Adenylyl cyclase
Inositol-1,4,5-triphosphate
Rat
Frontoparietal cortex
Activation of D1 and D2 dopamine receptors increases the activity of the somatostatin receptor-effector system in the rat frontoparietal cortex
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/29802024-03-08T10:14:00Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Muñoz Acedo, Gema
López Sañudo, Susana
Arilla Ferreiro, Eduardo
2009-05-22T12:53:26Z
2009-05-22T12:53:26Z
1993
Life Sciences, v. 52, n.9, p. 803-809
0024-3205
http://hdl.handle.net/10017/2980
10.1016/0024-3205(93)90078-H
In order to investigate the possibility that, in the rat, some cerebral cortex
somatostatin (SS) receptors may be localized presynaptically on the terminals of
serotonergic neurons, serotonin [5-hydroxytryptamine, (5-HT)] neurons in the
central nervous system were damaged with a local intracerebral injection of the
serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT). The injection of 5,7-
DHT (11 /~g free base dissolved in 10 t~l of isotonic saline containing 0.01%
ascorbic acid) in rats produced an reduction by about 74 % in frontoparietal cortical
5-HT content at 1 and 3 weeks after injection. These changes were associated with
a significant decrease by about 30 % in the total number of specific SS receptors
in the frontoparietal cortex at both times studied without influencing the apparent
affinity of the receptors. Together, these results suggest that a portion of the
frontoparietal cortex SS receptors may be localized presynaptically on the
serotonergic nerve terminals. The 5,7-DHT did not affect SS-like immunoreactivity
(SSLI) levels suggesting that SS and 5-HT are not colocalized within the same
neuronal elements in the rat frontoparietal cortex.
eng
info:eu-repo/semantics/openAccess
(c) Pergamon Press, 1993
Serotonin
Somatostatin
Frontoparietal cortex
Effect of serotonin axon injury on the somatostatinergic system in rat frontoparietal cortex
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/24682024-01-09T15:37:15Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Barrios Sabador, Vicente
Rodríguez Sánchez, María Nelly
Colás Escudero, María Begoña
Arilla Ferreiro, Eduardo
2009-04-21T12:30:01Z
2009-04-21T12:30:01Z
1990
European Journal of Pharmacology, 1990, v. 179, n. 3, p. 263-270
0014-2999
http://hdl.handle.net/10017/2468
10.1016/0014-2999(90)90164-2
Since nicotine and somatostin have regulatory effects on locomotor activity it was of interest to determine whether the receptors for somatostin are modulated by the cholinergic nicotine-like effects. An i.v. dose of 0.3 mg/kg nicotine induced an increase in the concentrations of somatostatin-like immunoreactivity at 4 min in the parietal cortex and at 15 min in the hippocampus. These changes were associated with a significant increase in the total number of specific somatostatin receptors in the parietal cortex at 15 min and in the hippocampus at 30 min following injection. To determine if the above mentioned changes are related to the nicotine activation of central nicotine-like acetylcholine receptors, a cholinergic nicotinic blocking agent, mecamylamine, was administered before the nicotine injection. Pretreatment with mecamylamine (5.0 mg/kg i.v.) prevented the nicotine-induced changes in somatostatin level and binding in both brain areas. Mecamylamine alone had no observable effect on the somatostatinergic system. These results suggest that the somatostatinergic system can be regulated by nicotine-like acetylcholine receptors and may be involved in some of the behavioral central effects of nicotine.
eng
info:eu-repo/semantics/openAccess
© Elsevier Science Publishers, 1990
Rat
Brain
Mecamylamine
Nicotine
Somatostatin receptors
Effects of acute nicotine and mecamylamine administration on somatostatin concentration and binding in the rat brain
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/24722024-01-10T11:45:36Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
González Guijarro, Luis A.
López Ruiz, María del Pilar
Bodega Magro, Guillermo
Prieto Villapún, Juan Carlos
Arilla Ferreiro, Eduardo
2009-04-21T13:12:18Z
2009-04-21T13:12:18Z
1987
Experimental and molecular pathology, 1987, v. 46, n. 2, p. 153-158
0014-4800
http://hdl.handle.net/10017/2472
10.1016/0014-4800(87)90061-X
Administration of cysteamine in rabbits elicited a rapid depletion of both duodenal mucosa and plasma somatostatin. A significant reduction was observed within 5 min, returning toward control values by 150 min. The depletion of somatostatin was associated with an increase in the binding capacity and a decrease in the affinity of both high- and low-affinity binding sites present in cytosol of duodenal mucosa. Incubation of cytosolic fraction from control rabbits with 1 mM cysteamine did not modify somatostatin binding. Furthermore, addition of cysteamine at the time of binding assay did not affect the integrity of 125I-Tyr11-somatostatin. It is concluded that in vivo administration of cysteamine to rabbits depletes both duodenal mucosa and plasma somatostatin and leads to up-regulation of duodenal somatostatin binding sites.
eng
info:eu-repo/semantics/openAccess
(c) Academic Press, 1987
Somatostatin
Rabbit
Mucosa
Effect of cysteamine on cytosolic somatostatin binding-sites in rabbit duodenal mucosa
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/23632024-01-09T15:01:20Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Roca, B.
Fernández-Valencia Rodríguez, Rafael
Arilla Ferreiro, Eduardo
2008-12-03T12:23:03Z
2008-12-03T12:23:03Z
1988
0017-5749
http://hdl.handle.net/10017/2363
10.1136/gut.29.5.642
Somatostatin like immunoreactivity and the density of somatostatin binding sites were measured in stomach (fundus and antrum) from either fed, 12 to 96 hours fasted, or 96 hours fasted plus 48 hours refed rabbits. The somatostatin concentration increased in fundic and antral mucosa after 24 h and reached its highest value after 96 h of fasting. The number of specific somatostatin binding sites with high and low affinity decreased with the duration of fasting. Refeeding of fasted animals resulted in a normalisation to control values of gastric mucosal somatostatin and somatostatin binding.
eng
info:eu-repo/semantics/openAccess
© BMJ Publishing Group Ltd, 1988
Somatostatin
Rabbit
Stomach
Mucosa
Effects of fasting and refeeding on somatostatin concentration and binding to cytosol from rabbit gastric mucosa
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/22822024-01-09T14:29:59Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Muñoz Acedo, Gema
Izquierdo Claros, Rosa María
Sánchez Alonso, Jesús Adolfo
Hoyo Medinilla, María Nancy del
Pérez Albarsanz, Miguel Ángel
Arilla Ferreiro, Eduardo
2008-11-20T09:10:38Z
2008-11-20T09:10:38Z
1995
Neuroscience Letters, 1995, v. 197, n. 1, p. 41–44
0304-3940
http://hdl.handle.net/10017/2282
10.1016/0304-3940(95)11896-5
Somatostatin-14 (SS) significantly increased inositol-1,4,5-triphosphate (IP3) accumulation in rat hypothalamic, striatal, frontoparietal cortical and hippocampal slices. However, this stimulation of IP3accumulation by SS was highest in the frontoparietal cortex and hippocampus. The effect was already significant with 0.01 μM in the frontoparietal cortex (P < 0.05) and hippocampus (P < 0.05) and the maximal accumulation was evident with 0.1 μM SS, in all areas studied. A concentration of 1 μM SS, lacked this effect in hypothalamus and striatum. SS rapidly increased IP3 accumulation in all brain areas studied. This effect was maximal at 15 s of incubation and decreased subsequently. At 60 s incubation, levels were still elevated in frontoparietal cortex and hippocampus but had returned to basal values in hypothalamus and striatum. Somatostatin-28 (SS-28) and the SS analogues, D-Trp8-D-Cys14 and SMS 201–995, also significantly stimulated IP3 accumulation although the effect of SMS 201–995 was greater than that of SS in the striatum in comparison with controls (P < 0.001 and P < 0.01, respectively). These results suggest that SS action at the hypothalamus, striatum, frontoparietal cortex and hippocampus is mediated at least in part by the accumulation of IP3, which may initiate intracellular processes responsible for some biological SS effects.
eng
info:eu-repo/semantics/openAccess
© Elsevier Science Ireland Ltd, 1995
Somatostatin
Inositol-1-4-5-trisphosphate
Brain
Rat
Effect of somatostatin on the mass accumulation of inositol-1,4,5- trisphosphate in rat hypothalamus, striatum, frontoparietal cortex and hippocampus
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/23162024-01-09T14:54:13Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
López Sañudo, Susana
Rodríguez Martín, Eulalia
Martín Espinosa, Ángela
Arilla Ferreiro, Eduardo
2008-11-24T12:38:46Z
2008-11-24T12:38:46Z
1994
Peptides, 1995, v. 16, n. 8, p. 1453-1459
0196-9781
http://hdl.handle.net/10017/2316
10.1016/0196-9781(95)02011-X
Somatostatin (SS) and noradrenaline (NA) are distributed in the rat cerebral cortex, and seizure activity is one of the aspects of behavior affected by both neurotransmitters. Due to the possible interaction between both neurotransmitter systems, we studied whether phenylphrine, an alpha(1)-adrenoceptor agonist, and prazosin, an alpha(1)-adrenoceptor antagonist, can modulate SS-like immunoreactivity (SS-LI) levels, binding of [I-125][Tyr(11)]SS to its specific receptors, the ability of SS to inhibit adenylate cyclase (AC) activity, and the guanine nucleotide binding regulatory protein G(1) and G(0), in the Sprague-Dawley rat frontoparietal cortex. An IP dose of 2 or 4 mg/kg of phenylephrine injected 7 h before decapitation decreased the number of SS receptors and increased the apparent affinity in frontoparietal cortex membranes. An IP dose of 20 or 25 mg/kg of prazosin administered 8 h before decapitation increased the number of SS receptors and decreased their apparent affinity. The administration of prazosin before the phenylephrine injection prevented the phenylephrine-induced changes in SS binding. The addition of phenylephrine and/or prazosin 10(-5) M to the incubation medium changed neither the number nor the affinity of the SS receptors in the frontoparietal cortex membranes. Phenylephrine or prazosin affected neither SS-LI content nor the basal or forskolin (FK)-stimulated AC activities in the frontoparietal cortex. In addition, SS caused an equal inhibition of AC activity in frontoparietal cortex membranes of phenylephrine- and prazosin-treated rats compared with the respective control group. Finally, phenylephrine and prazosin did not vary the pertussis toxin (PTX)-catalyzed ADP ribosylation of G(1)- and/or G(0)-proteins. These results suggest that the above mentioned changes are related to the phenylephrine activation of alpha(1)-adrenoceptors or to the blocking of these receptors by prazosin. In addition, these data provide further support for a functional interrelationship between the alpha(1)-adrenergic and somatostatinergic systems in the rat frontoparietal cortex.
eng
info:eu-repo/semantics/openAccess
(c) Elsevier Science, 1995
Phenylephrine
Prazosin
Somatostatin receptors
Adenylate cyclase
G-proteins
Frontoparietal cortex
Effect of phenylephrine and prazosin on the somatostatinergic system in the rat frontoparietal cortex
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/22502024-01-09T12:29:23Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Rodríguez Martín, Eulalia
Álvaro Alonso, Itziar
Bodega Magro, Guillermo
Arilla Ferreiro, Eduardo
2008-11-14T11:45:25Z
2008-11-14T11:45:25Z
1997
Life Sciences, 1997, v. 61, n. 23, p. 2255-2269
0024-3205
http://hdl.handle.net/10017/2250
10.1016/S0024-3205(97)00930-2
The mechanism whereby somatostatin (SS) produces beneficial effects in established pancreatitis induced by pancreaticobiliary duct ligation (PBDL) is still not clear. The aim of the work was to evaluate the possibility of a direct action of SS on pancreatic acinar cells from rats with acute pancreatitis. For this purpose, we studied the SS-receptor-adenylate cyclase system in pancreatic acinar membranes from both, control rats and rats with experimentally induced acute pancreatitis. On the other hand, it has been reported that cholecystokinin (CCK) diminishes the number of SS receptors in pancreatic acinar cells. Proglumide, a CCK receptor antagonist reduces the severity of acute pancreatitis in the rat. Therefore, we have also examined the effect of proglumide on the somatostatinergic system in controls and rats with acute pancreatitis. Fourteen hours after PBDL, the SS receptors, the capacity of the SS analogue SMS 201-995 to inhibit forskolin-stimulated adenylate cyclase activity and PTX-catalyzed [P-32] ADP-ribosylation of the alpha(1) subunits of Gi proteins could not be detected in pancreatic acinar membranes. One month after reopening the closed pancreaticobiliary duct (PBD), the pancreas showed regeneration of acinar cells, and the above-mentioned parameters were significantly lower than in the control group. Two months after reopening the closed PBD, all these parameters had returned to control values. The administration of proglumide (20 mg/kg i.p.), a cholecystokinin receptor antagonist, accelerated pancreatic regeneration and approached all these parameters to control values one month after reopening the closed PBD. The present study suggests that the beneficial effects of SS on established pancreatitis induced by PBDL may not be due to a direct action of the peptide on pancreatic acinar cells at least at 14 hours after PBDL. In addition, these findings suggest that in established pancreatitis the effect of proglumide on the SS receptor-adenylate cyclase system could be due to its action on pancreatic regeneration.
eng
info:eu-repo/semantics/openAccess
(c) Elsevier, 1997
Pancreatitis
Somatostatin receptors
Exocrine pancreas
CAMP
Gi proteins
The somatostatin receptor-adenylate cyclase system in rat pancreatic acinar membranes after temporary pancreaticobiliary duct ligation
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/22512024-01-09T12:41:00Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Álvaro Alonso, Itziar
Boyano Adánez, María del Carmen
Martín Espinosa, Ángela
Arilla Ferreiro, Eduardo
2008-11-14T11:53:35Z
2008-11-14T11:53:35Z
1995
Life Sciences, 1995, v.57, n.25, p. 2317–2323
0024-3205
http://hdl.handle.net/10017/2251
10.1016/0024-3205(95)02226-9
Adenylate cyclase activity in pancreatic acinar cell membranes was determined in rats that had undergone a treatment with pentagastrin (250 μg/kg, intraperitoneal three times daily) for 1 week or that had undergone small bower resection (90%) and were sacrified at 2 weeks, 1 month and 6 months after intervention. Both treatments are potent stimulators of pancreatic acinar cell proliferation. Adenylate cyclase activity was similar under basal conditions and after the diterpene forskolin stimulation in pancreatic acinar membranes from all groups studied. The ability of low concentrations of the stable GTP analogue, 5'-guanylylimidodiphosphate (Gpp[NH]p) to inhibit forskolin- stimulated adenylate cyclase activity was decreased in pancreatic acinar membranes from enterectomized rats at 2 weeks and 1 month after the operation and returned to control values at 6 months after enterectomy. Stimulation of adenylate cyclase by high concentration of Gpp[NH]p or by secretin (10-8 M) was higher in both pancreatic hyperplasia conditions as compared with control animals. These findings suggest that the coupling efficiency of the G(s) protein to adenylate cyclase from pancreatic acinar membranes is enhanced without any alterations in the catalytic activity of the enzyme during pancreatic proliferation. In addition, it is possible that the highly regulated pancreatic acinar adenylate cyclase activity may be necessary to regulate pancreatic acinar cell proliferation.
eng
info:eu-repo/semantics/openAccess
© Elsevier, 1995
Adenylate cyclase
Small bowel resection
Pentagastrin
Pancreas
Hyperplasia
Adenylate cyclase activity during exocrine pancreatic proliferation in the rat
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/23192023-12-14T15:28:18Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Puebla Jiménez, Lilian
Arilla Ferreiro, Eduardo
2008-11-25T08:14:49Z
2008-11-25T08:14:49Z
1995
Regulatory Peptides, 1995, n. 59, p. 111-120
0167-0115
http://hdl.handle.net/10017/2319
10.1016/0167-0115(95)00080-U
Slow-wave sleep, wakefulness, locomotor activity and learning and memory are regulated in similar ways by somatostatin
(SS) and histamine. To clarify the possible role of endogenous histamine on the somatostatinergic system of the rat
frontoparietal cortex, we studied the effect of 50 /xg of a-fluoromethylhistidine (a-FMH), a specific inhibitor of histidine
decarboxylase, administered intracerebroventricularly (i.c.v.) at 1, 4 and 6 h, on somatostatin-like immunoreactivity (SSLI)
content and the SS receptor/effector system. The histamine content in the frontoparietal cortex decreased to about 67, 60
and 72% of control values at 1, 4 and 6 h after ot-FMH administration, respectively. At 6 h after a-FMH injection, there was
an increase in SSLI content and a decrease in the number of SS receptors, with no change in the apparent affinity. No
significant differences were seen for the basal and forskolin (FK)-stimulated adenylyl cyclase (AC) activities in the
frontoparietal cortex of a-FMH-treated rats when compared to the control group at all times studied. At 6 h after a-FMH
administration, however, the capacity of SS to inhibit basal and FK-stimulated AC activity in the frontoparietal cortex was
significantly lower than in the control group. The ability of the stable GTP analogue 5'-guanylylimidodiphosphate
(Gpp(NH)p) to inhibit FK-stimulated AC activity in frontoparietal cortex membranes was the same in the a-FMH-treated (6
h) and control animals. Therefore, the decreased SS-mediated inhibition of AC activity observed in the t~-FMI-I-treated rats
is not due to an alteration at the guanine nucleotide-binding inhibitory protein (G i) level but rather may be due to the
decrease in the number of SS receptors. Taken together, these data suggest that a-FMH influences the sensitivity to SS in
the rat frontoparietal cortex.
eng
info:eu-repo/semantics/openAccess
© Elsevier Science, 1995
α-Fluoromethylhistidine
Somatostatin receptor
Adenylyl cyclase
Rat
Frontoparietal cortex
α-Fluoromethylhistidine influences somatostatin content, binding and inhibition of adenylyl cyclase activity in the rat frontoparietal cortex
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/23212024-01-09T14:58:00Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Rodríguez Martín, Eulalia
Boyano Adánez, María del Carmen
Bodega Magro, Guillermo
Martín, M.
Hernández, C.
Quin, Y.
Vadillo, M.
Arilla Ferreiro, Eduardo
2008-11-25T08:32:24Z
2008-11-25T08:32:24Z
1999
FEBS Letters, 1999, v. 445, n. 2–3, p. 356–360
0014-5793
http://hdl.handle.net/10017/2321
10.1016/S0014-5793(99)00133-7
Freshly enzymatically isolated pancreatic acini from lactating and weaning Wistar rats were used to investigate the role of protein kinase C (PKC) isoforms during these physiologically relevant pancreatic secretory and growth processes. The combination of immunoblot and immunohistochemical analysis shows that the PKC isoforms ¿, ¿, and ¿ are present in pancreatic acini from control, lactating and weaning rats. A vesicular distribution of PKC-¿, -¿, and -¿ was detected by immunohistochemical analysis in the pancreatic acini from all the experimental groups. PKC-¿ showed the strongest PKC immunoreactivity (PKC-IR). In this vesicular distribution, PKC-IR was located at the apical region of the acinar cells. No differences were observed between control, lactating and weaning rats. However, the immunoblot analysis of pancreatic PKC isoforms during lactation and weaning showed a significant translocation of PKC-¿ from the cytosol to the membrane fraction when compared with control animals. Translocation of PKC isoforms (¿, ¿ and ¿) in response to 12-O-tetradecanoyl phorbol 13-acetate (TPA) 1 ¿M (15 min, 37°C) was comparable in pancreatic acini from control, lactating and weaning rats. In the control group, a significant translocation of all the isoforms (¿, ¿ and ¿) from the cytosol to the membrane was observed. The PKC isoform most translocated by TPA was PKC-¿. In contrast, no statistically significant increase in PKC-¿ translocation was detected in pancreatic acini isolated from lactating or weaning rats. These results suggest that the PKC isoforms are already translocated to the surface of the acinar cells from lactating or weaning rats. In addition, they suggest that isoform specific spatial PKC distribution and translocation occur in association with the growth response previously described in the rat exocrine pancreas during lactation and weaning.
eng
info:eu-repo/semantics/openAccess
© Elsevier, 1999
Pancreatic acinus
Protein kinase C
Protein kinase C-δ
Immunohistochemistry
Lactation
Weaning
Redistribution of protein kinase C isoforms in rat pancreatic acini during lactation and weaning
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/29782024-03-08T09:40:24Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
López Sañudo, Susana
Arilla Ferreiro, Eduardo
2009-05-22T12:33:23Z
2009-05-22T12:33:23Z
1992
Regulatory Peptides, 1992, v. 41, n. 3, p. 227-236
0167-0115
http://hdl.handle.net/10017/2978
10.1016/0167-0115(92)90116-C
Several studies have shown anatomical and functional interconnections between catecholaminergic and somatostatinergic systems. To assess whether somatostatin (SS) may act presynaptically on catecholamine neurons, SS receptors were measured using radioligand test-tube binding assays on synaptosomes from hippocampus and frontoparietal cortex — areas that are innervated by catecholaminergic neurons with different densities and that have a high number of SS receptors — from control and 6-hydroxydopamine (6-OHDA)-treated rats. Intracerebroventricular (i.c.v.) injection of the catecholamine neurotoxin 6-OHDA (0.78 mg free base/kg of body weight in saline with 0.1% ascorbic acid) lowered hippocampal and frontoparietal cortical noradrenaline (NA) and dopamine (DA) levels at 1 week following the injection. Pretreatment of rats with desmethylimipramine (DMI) (40 mg/kg, intraperitoneal) prevented the drop in NA levels, but was not effective in attenuating DA depletion in the two brain areas studied. Treatment with 6-OHDA lowered the number of 125I-Tyr11-SS receptors in the hippocampus (130 ± 19 vs. , P < 0.001), whereas in the frontoparietal cortex a non significant 20% reduction in receptor number was found. The dissociation constants of 125I-Tyr11-SS binding to synaptosomes from frontoparietal cortex (0.65 ± 0.06 vs. 0.60 ± 0.04, P not significant) and hippocampus (0.44 ± 0.04 vs. 0.63 ± 0.14, P not significant) were similar in control and treated groups. Pretreatment with DMI reversed up to 80% of the effect of 6-OHDA on hippocampus SS receptors. DMI alone had no observable effect on the number and affinity of SS receptors. The 6-OHDA and the DMI treatment did not affect SLI levels in the brain areas studied. These results suggest that a portion of the hippocampal SS receptors may be localized presynaptically on the noradrenergic and dopaminergic nerve terminals.
eng
info:eu-repo/semantics/openAccess
© Elsevier B.V., 1992
6-Hydroxydopamine
Desmethylimipramine
Hippocampus
Rat
Somatostatin receptor
Desmethylimipramine pretreatment prevents 6-hydroxydopamine induced somatostatin receptor reduction in the rat hippocampus
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/22482024-01-09T12:26:14Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Muñoz Acedo, Gema
Rodríguez Martín, Eulalia
Puebla Jiménez, Lilian
Arilla Ferreiro, Eduardo
2008-11-14T11:28:40Z
2008-11-14T11:28:40Z
1997
Life Sciences, 1997, v. 60, n. 22, p. 1965-1976
0024-3205
http://hdl.handle.net/10017/2248
10.1016/S0024-3205(97)00161-6
Pretreatment of pancreatic acini with 5-hydroxytryptamine (5-HT) reduced the binding of the labeled somatostatin (SS) analogue 125I-Tyr3-SMS to pancreatic acinar membranes. This effect was dependent of the dose of 5-HT used and length of pretreatment. This inhibitory effect of 5-HT was abolished when pancreatic acini were pretreated with 5-HT in the presence of the 5-HT1P receptor-antagonist 5-hydroxytryptophyl-5-hydroxytryptophan amide (5-HTP-DP). Pretreatment of pancreatic acini with 5-HT reduced the inhibition by the stable SS analogue SMS 201-995 of basal and forskolin (FK)-stimulated adenylyl cyclase (AC) activity in pancreatic acinar membranes. There was no statistical difference established between IC50 values for the stable GTP analogue 5'-guanylylimidodiphosphate (Gpp(NH)p) which inhibits ligand binding to SMS receptors in controls and in 5-HT treated pancreatic cells, respectively. In addition, no significant differences were seen in the level of Gi proteins in the control and 5-HT treated panceatic acini. These data suggest that the decrease of the number of 125I-Tyr3-SMS receptors, would explain the decreased sensitivity of AC to SMS 201-995 in membranes from 5-HT-pretreated acini.
eng
info:eu-repo/semantics/openAccess
(c) Elsevier, 1997
Somatostatin
Serotonin
Pancreas
5-Hydroxytryptamine decreases somatostatin receptors and somatostatin-responsive adenylyl cyclase in rat pancreatic acinar membranes
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/29792024-03-08T09:42:36Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Pérez Oso, E.
López Ruiz, María del Pilar
González Guijarro, Luis A.
Arilla Ferreiro, Eduardo
2009-05-22T12:43:11Z
2009-05-22T12:43:11Z
1989
Life Sciences, 1989, v. 45, n. 25, p. 2451-2458
http://hdl.handle.net/10017/2979
10.1016/0024-3205(89)90010-6
Rats were kindled by intraperitoneal injection of pentylenetetrazol (PTZ) (30 mg/Kg) every 48 h. Once kindled, some of the animals received a single injection of cysteamine (200 mg/Kg). Somatostatin-like immunoreactivity (SLI) and 125 I-Tyr11 -somatostatin binding were measured in the frontoparietal cortex and hippocampus of the two experimental groups and the control rats. After PTZ kindling the following was observed: 1) SLI content was increased in the two areas; 2) Somatostatin receptor affinity decreased in the frontoparietal cortex and was unaltered in the hippocampus; 3) The number of somatostatin receptors decreased in the hippocampus and was unaltered in the frontoparietal cortex. Cysteamine, an agent which depletes brain somatostatin and suppresses kindled seizures in PTZ-treated rats, reversed the altered SLI levels and binding in these rats.
eng
info:eu-repo/semantics/openAccess
© 1989 Elsevier Inc.
Cysteamine
Rat
Pentylenetetrazol
Somatostatin
Cysteamine normalizes cerebral somatostatin level and binding in pentylenetetrazol-kindled rats
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/30682023-12-14T15:28:19Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Puebla Jiménez, Lilian
Arilla Ferreiro, Eduardo
2009-06-04T14:00:26Z
2009-06-04T14:00:26Z
1996
Journal of Neuroscience Research, 1996, v. 43, n. 3, p. 346-354
0360-4012
http://hdl.handle.net/10017/3068
10.1002/(SICI)1097-4547(19960201)43:3<346::AID-JNR9>3.0.CO;2-J
The glycine and somatostatin (SS) neurotransmission systems in the brain have been implicated in the function of sensory, motor, and nociceptive pathways. To investigate a possible relationship between these two components, we studied the influence of glycine on the binding of 125I-Tyr11-SS to its receptors and on SS-like immunoreactivity (SSLI) levels in the rat hippocampus and frontoparietal cortex. An intracerebroventricular (i.c.v.) dose of 16 or 160 nmol of glycine induced an increase in the total number of specific SS receptors in the hippocampus but not in the frontoparietal cortex at 15 min following injection, with no changes in the affinity constant. This effect seems to be mediated by inhibitory strychnine-sensitive glycine receptors since pretreatment with the antagonist strychnine (80 μg/100 g body weight, intravenously) abolished this response. No significant changes in SSLI content were detected in either brain region of glycine- and strychnine plus glycine-treated rats as compared to control values. Since SS receptors are coupled via guanine nucleotide-binding G proteins to the adenylyl cyclase (AC) system, we also examined the inhibitory effects of SS and the guanine nucleotide Gpp(NH)p on AC activity in hippocampal membranes of control, glycine- and strychnine plus glycine-treated rats since the increase in SS receptors was observed only in this brain area. No significant differences were observed for the forskolin (FK)-stimulated AC enzyme activities in hippocampal membranes from all the experimental groups studied. In the hippocampus of the glycine-(160 nmol) treated group, however, basal AC activity was significantly lower, and the capacity of SS to inhibit FK-stimulated AC activity was increased as compared to the control group. Pretreatment with strychnine prevented the increase in SS-mediated inhibition of AC activity. The functional activity of the inhibitory guanine nucleotide-binding protein G1, as determined by the inhibitory effect of the stable GTP analogue Gpp(NH)p on FK-stimulated AC activity, was significantly higher in hippocampal membranes of glycine- (160 nmol) treated rats as compared to controls. This suggests that the increased inhibition of AC activity by SS in the glycine-treated group may be due to the increase in G1 activity and/or the increase in the number of SS receptors observed. Alternatively, the greater G1 activity may be responsible for the increased binding of 125I-Tyr11-SS to its receptors observed after glycine administration. Altogether, these data suggest that the hippocampal somatostatinergic system can be regulated by strychnine-sensitive glycine receptors in the rat. © 1996 Wiley-Liss, Inc.
eng
info:eu-repo/semantics/openAccess
(c) Wiley-Liss, 1996
Glycine
Strychnine
Somatostatin
G-protein
Hippocampus
Glycine increases the number of somatostatin receptors and somatostatin-mediated inhibition of the adenylate cyclase system in the rat hippocampus
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/32162023-12-14T15:28:19Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Muñoz Acedo, Gema
Álvaro Alonso, Itziar
Arilla Ferreiro, Eduardo
2009-06-19T03:37:07Z
2009-06-19T03:37:07Z
1995
Journal of Endocrinology, 1995, v. 145, p. 227-234
0022-0795
http://hdl.handle.net/10017/3216
10.1677/joe.0.1450227
To date, it is unknown whether intrapancreatic serotonergic nerves can influence pancreatic somatostatin (SS) content and the SS receptor/effector system in the exocrine pancreas. In this study, the intrapancreatic serotonergic nerves were chemically ablated by injecting a specific serotonin (5-HT) neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), into the substance of the gland. Three days after the injection, the 5-HT-like immunoreactive levels in the pancreas were reduced by more than 85% whereas somatostatin-like immunoreactive levels had increased (86%). The number of SS receptors in the pancreatic acinar cell membranes of the 5,7-DHT-treated rats was also increased (72%). No significant differences were seen in basal or forskolin-stimulated adenylate cyclase (AC) enzyme activities in the control and the 5,7-DHT-treated groups. In spite of the increase in the number of SS receptors in the pancreatic acinar cell membranes of 5,7-DHT-treated rats, SS caused a significantly lower inhibition of AC activity in these membranes. This finding is related to the observed decrease of a 41 kD pertussis toxin-sensitive substrate, presumably the αi subunit of the guanine nucleotide inhibitory protein, in pancreatic acinar cell membranes 3 days after intrapancreatic 5,7-DHT administration when compared with the corresponding controls. The functions of pancreatic serotonergic nerves seem to be associated with enteropancreatic communication. These data together with the present results suggest that pancreatic SS content and the SS receptor/effector system in the exocrine pancreas may be regulated by enteropancreatic serotonergic nerve fibers and may participate in enteropancreatic reflexes.
eng
info:eu-repo/semantics/openAccess
© Journal of Endocrinology Ltd, 1995
Acinar cells
Guinea pig
Adenylate cyclase
Amylase secretion
Exocrine pancreas
5-HT1P receptors
Rat brain
Binding
Identification
Forskolin
Pancreatic changes in somatostatin content and receptor-effector system after intrapancreatic injection of 5,7-dihydroxytryptamine
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/23182024-01-09T14:55:06Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Rodríguez Martín, Eulalia
Valencia Torralba, Ana M.
Colás Escudero, María Begoña
García Escribano, Carmen
Rodríguez Puyol, Manuel
Susini, Christiane
Arilla Ferreiro, Eduardo
2008-11-25T07:58:48Z
2008-11-25T07:58:48Z
1995
Peptides, 1995, v. 16, n. 8, p. 1461-1467
0196-9781
http://hdl.handle.net/10017/2318
10.1016/0196-9781(95)02023-3
Gastrectomy increased pancreatic growth and this effect was associated with an increase in the number of somatostatin-14 (SS) receptors (146% of control) without altering their affinity. SS increased guanylate cyclase activity twofold in pancreatic acinar membranes from gastrectomized rats. The gastrectomy decreased pancreatic SS-like immunoreactivity (SS-LI) content (55% of control levels) and tyrosine phosphatase activity (74% of control levels). Administration of proglumide (20 mg/kg, IF), a gastrin/cholecystokinin (CCK) receptor antagonist, suppressed the inhibitory effect of gastrectomy on basal tyrosine phosphatase activity and SS-LI content, which returned to control levels. Furthermore, proglumide suppressed the increase of the number of SS receptors and of SS-stimulated guanylate cyclase activity induced by gastrectomy. All this suggests that pancreatic acinar cell growth is associated with upregulation of SS receptors, which could represent a mechanism promoted by the cell to negatively regulate the mitogenic activity of pancreatic growth factors such as CCK. In addition, the results also suggest that the negative regulation of tyrosine phosphatase activity may be important in the events involved in the pancreatic hyperplasia observed after gastrectomy.
eng
info:eu-repo/semantics/openAccess
(c) Elsevier, 1995
Gastrectomy
Guanylate cyclase
Somatostatin receptors
Pancreatic acinar membranes
Somatostatin like-immunoreactivity
Rat
Somatostatin binding capacity, guanylate cyclase and tyrosine phosphatase activities during pancreatic proliferation in the rat induced by gastrectomy
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/24652023-12-14T15:28:20Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Burgos Ramos, Emma
Hervás Aguilar, América
Puebla Jiménez, Lilian
Boyano Adánez, María del Carmen
Arilla Ferreiro, Eduardo
2009-04-21T11:48:18Z
2009-04-21T11:48:18Z
2007
Journal of Neuroscience Research, 2007, v. 85, n. 2, p. 433-442
1097-4547
http://hdl.handle.net/10017/2465
10.1002/jnr.21115
Although alterations in adenylate cyclase (AC) activity and somatostatin (SRIF) receptor density have been reported in Alzheimer's disease, the effects of amyloid β-peptide (Aβ) on these parameters in the hippocampus are unknown. Our aim was to investigate whether the peptide fragment Aβ(25–35) can affect the somatostatinergic system in the rat hippocampus. Hence, Aβ(25–35) was injected intracerebroventricularly (i.c.v.) to Wistar rats in a single dose or infused via an osmotic minipump connected to a cannula implanted in the right lateral ventricle during 14 days. The animals were decapitated 7 or 14 days after the single injection and 14 days after chronic infusion of the peptide. Chronic i.c.v. infusion of Aβ(25–35) decreased SRIF-like immunoreactive content without modifying the SRIF receptor density, SRIF receptor expression, or the Giα1, Giα2, and Giα3 protein levels in the hippocampus. This treatment, however, caused a decrease in basal and forskolin-stimulated AC activity as well as in the capacity of SRIF to inhibit AC activity. Furthermore, the protein levels of the neural-specific AC type I were significantly decreased in the hippocampus of the treated rats, whereas an increase in the levels of AC V/VI was found, with no alterations in type VIII AC. A single i.c.v. dose of Aβ(25–35) exerted no effect on SRIF content or SRIF receptors but induced a slight decrease in forskolin-stimulated AC activity and its inhibition by SRIF. Because chronic Aβ(25–35) infusion impairs learning and memory whereas SRIF facilitates these functions, the alterations described here might be physiologically important given the decreased cognitive behavior previously reported in Aβ-treated rats.
eng
info:eu-repo/semantics/openAccess
© Wiley-Liss Inc, 2006
Adenylate cyclase
Amyloid ß
Brain
Gi proteins
Hippocampus
Peptide
Rat
Chronic but not acute intracerebroventricular administration of amyloid ß-peptide(25-35) decreases somatostatin content, adenylate cyclase activity, somatostatin-induced inhibition of adenylate cyclase activity, and adenylate cyclase I levels in the rat hippocampus
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/30592024-03-08T11:43:09Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Roca, B.
Fernández-Valencia Rodríguez, Rafael
Rodríguez Sánchez, María Nelly
Arilla Ferreiro, Eduardo
2009-06-04T12:49:12Z
2009-06-04T12:49:12Z
1990
Life Sciences, 1990, v. 47, n. 22, p. 2041-2049
0024-3205
http://hdl.handle.net/10017/3059
10.1016/0024-3205(90)90439-X
The present study is an investigation of the effects of 12- to 96-hours' starvation and 96-hours' starvation plus 48-hours' refeeding on both somatostatin-like immunoreactivity (SLI) and cytosolic somatostatin binding sites in rabbit small intestinal mucosa. The SLI concentration increased after 24 h in duodenal and jejunal mucosa, but not in ileal mucosa, and reached its highest value after 96 h of fasting. The number of specific high and low-affinity somatostatin binding sites, but not their affinity, decreased with the duration of fasting in the same gut segments, refeeding of fasted animals resulted in a return to normal control values for small intestine mucosal SLI and somatostatin binding.
eng
info:eu-repo/semantics/openAccess
(c) Pergamon Press, 1990
Somatostatin
Intestinal mucosa
Rabbits
Somatostatin content and binding in small intestinal mucosa from fed, fasted and refed rabbits
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/23612024-01-09T14:59:25Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Álvaro Alonso, Itziar
Muñoz Acedo, Gema
Rodríguez Martín, Eulalia
Schally, Andrew Victor
Arilla Ferreiro, Eduardo
2008-12-02T12:29:27Z
2008-12-02T12:29:27Z
1999
Peptides, 1999, v. 20, n. 6, p. 723–730
0196-9781
http://hdl.handle.net/10017/2361
10.1016/S0196-9781(99)00054-6
To analyze the effect of bombesin on the somatostatin (SS) mechanism of action in the exocrine pancreas, male Wistar rats (250-270 g) were injected intraperitoneally with bombesin (10 ¿g/kg) three times daily at 8-h intervals for 7 or 14 days. Bombesin attenuated the ability of SS to inhibit forskolin-stimulated adenylyl cyclase activity in pancreatic acinar membranes. However, it did not decrease the ability of forskolin to stimulate the adenylyl cyclase catalytic subunit. The ability of 5'-guanylylimidodiphosphate [Gpp(NH)p] (a nonhydrolyzable GTP analog) to inhibit forskolin-stimulated adenylyl cyclase activity was diminished in pancreatic acinar cell membranes from bombesin-treated rats. Bombesin administration did not affect the ADP-ribosylation of a 41-kDa G protein catalyzed by pertussis toxin. The maximal SS binding capacity of pancreatic acinar membranes from bombesin-treated rats was decreased when compared with controls at the two time periods studied. The bombesin/gastrin-releasing peptide antagonist [D-Tpi6,Leu13¿(CH2NH)Leu14]bombesin (6-14) (RC-3095) (10 ¿g/kg ip), injected three times daily at 8-h intervals for 7 or 14 days, had a similar effect to that of bombesin on the SS mechanism of action. The combined administration of bombesin and its antagonist RC-3095 had a greater effect on the SS receptor-effector system than when administered separately. The present study indicates that the pancreatic SS receptor-effector system may be regulated by bombesin in vivo.
eng
info:eu-repo/semantics/openAccess
© Elsevier Science Inc., 1999
Bombesin
RC-3095
Proglumide
Somatostatin receptor
G-protein
Adenylyl cyclase
Bombesin induces a reduction of somatostatin inhibition of adenylyl cyclase activity, Gi function, and somatostatin receptors in rat exocrine pancreas
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/21752023-12-22T13:17:31Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Rodríguez Martín, Eulalia
Muñoz Acedo, Gema
Puebla Jiménez, Lilian
Arilla Ferreiro, Eduardo
2008-11-10T09:21:12Z
2008-11-10T09:21:12Z
1999
Biochimica et Biophysica Acta, 1999, v. 1450, n. 1, p. 61-67
0006-3002
http://hdl.handle.net/10017/2175
10.1016/S0167-4889(99)00032-4
Nitric oxide (NO) and somatostatin (SS) are two important mediators of the exocrine and endocrine pancreas, exerting opposite effects on this organ. There is strong evidence suggesting an interaction between pancreatic NO and SS. The aim of this study was to determine whether L-arginine (L-Arg), the substrate for NO synthase (NOS), and Nω-nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor, regulate pancreatic somatostatin-like immunoreactivity (SSLI) content and the SS mechanism of action in pancreatic acinar cell membranes. L-Arg (150 mg/kg, intraperitoneally (i.p.)), L-NAME (50 mg/kg, i.p.) or L-NAME plus L-Arg were injected twice daily at 8 h intervals for 8 days. L-Arg decreased pancreatic SSLI content as well as the number of SS receptors in pancreatic acinar cell membranes whereas L-NAME increased both parameters. The stable SS analogue SMS 201-995 induced a significantly lower inhibition of forskolin-stimulated adenylyl cyclase activity in pancreatic acinar cell membranes from L-Arg-treated rats whereas an increased inhibition was observed in pancreatic acinar membranes from L-NAME-treated rats. These results indicate that the NO system may contribute to the regulation of the pancreatic somatostatinergic system.
eng
info:eu-repo/semantics/openAccess
(c) Elsevier, 1999
Nitric oxide
Somatostatin receptor
Adenylyl cyclase
Somatostatin-like immunoreactivity
Pancreatic acinar membrane
Rat
Effect of nitric oxide on the somatostatinergic system in the rat exocrine pancreas
info:eu-repo/semantics/article
oai:ebuah.uah.es:10017/22232024-01-09T12:09:35Zcom_10017_153com_10017_17821com_10017_17761com_10017_17741col_10017_154
Izquierdo Claros, Rosa María
Boyano Adánez, María del Carmen
Arilla Ferreiro, Eduardo
2008-11-13T09:18:21Z
2008-11-13T09:18:21Z
2002
Journal of Pineal Research, 2002, v. 33, n. 4, p. 189–197
1600-079X
http://hdl.handle.net/10017/2223
10.1034/j.1600-079X.2002.02906.x
Melatonin and somatostatin are known to exert similar effects on locomotor activity. We have previously demonstrated that acute melatonin treatment regulates somatostatin receptor function in the rat frontoparietal cortex. However, the effects of subchronic and chronic melatonin treatment on the somatostatin receptor-G protein–adenylyl cyclase system in the rat frontoparietal cortex are unknown. Melatonin was administered subcutaneously at a daily dose of 25 μg/kg for 4 days, 1 wk or 2 wk. Twenty-four hours after the last injection, the animals were sacrificed. Melatonin did not alter the somatostatin-like immunoreactivity content in the frontoparietal cortex from control and melatonin-treated rats during any of the previously indicated periods. Four days of melatonin administration induced both an increase in the number of [125I]-Tyr11-somatostatin receptors and a decrease in the affinity of somatostatin for its receptors in frontoparietal cortical membranes. The increased number of somatostatin receptors in the melatonin-treated rats was associated with an increased capacity of somatostatin to inhibit basal and forskolin-stimulated adenylyl cyclase activity. Melatonin administration for 4 days induced a higher adenylyl cyclase activity both under basal conditions and after direct stimulation of the enzyme with forskolin. No significant differences were observed in the function of Gi proteins in the 4-day melatonin-treated rats. Western blot analyses showed that the 4-day melatonin treatment reduced Giα2 levels, without altering the amount of Giα1. These melatonin-induced changes reverted to control values after 7 or 14 days of treatment. Altogether, the present findings suggest that subchronic melatonin treatment modulates the somatostatin receptor/effector system in the rat frontoparietal cortex.
eng
info:eu-repo/semantics/openAccess
© John Wiley & Sons, 2002
Adenylyl cyclase
Frontoparietal cortex
G proteins
Melatonin
Rat
Somatostatin receptors
Effects of subchronic and chronic melatonin treatment on somatostatin binding and its effects on adenylyl cyclase activity in the rat frontoparietal cortex
info:eu-repo/semantics/article
mods///col_10017_154/100