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- 검색키워드
- 저자 : Andrés M. García (검색결과 2 건)
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Sorafenib resistance in hepatocarcinoma: role of hypoxia-inducible factors
Carolina Méndez-Blanco,Flavia Fondevila,Andrés García-Palom,Javier González-Gallego,José L. Mauriz 생화학분자생물학회 2018 Experimental and molecular medicine Vol.50 No.-
Sorafenib, a multikinase inhibitor with antiproliferative, antiangiogenic, and proapoptotic properties, constitutes the only effective first-line drug approved for the treatment of advanced hepatocellular carcinoma (HCC). Despite its capacity to increase survival in HCC patients, its success is quite low in the long term owing to the development of resistant cells through several mechanisms. Among these mechanisms, the antiangiogenic effects of sustained sorafenib treatment induce a reduction of microvessel density, promoting intratumoral hypoxia and hypoxia-inducible factors (HIFs)-mediated cellular responses that favor the selection of resistant cells adapted to the hypoxic microenvironment. Clinical data have demonstrated that overexpressed HIF-1α and HIF-2α in HCC patients are reliable markers of a poor prognosis. Thus, the combination of current sorafenib treatment with gene therapy or inhibitors against HIFs have been documented as promising approaches to overcome sorafenib resistance both in vitro and in vivo. Because the depletion of one HIF-α subunit elevates the expression of the other HIF-α isoform through a compensatory loop, targeting both HIF-1α and HIF-2α would be a more interesting strategy than therapies that discriminate among HIF-α isoforms. In conclusion, there is a marked correlation between the hypoxic microenvironment and so
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Role of TRPV4 Channel in Human White Adipocytes Metabolic Activity
Julio C. Sánchez,Aníbal Valencia-Vásquez,Andrés M. García 대한내분비학회 2021 Endocrinology and metabolism Vol.36 No.5
Background: Intracellular calcium (Ca2+) homeostasis plays an essential role in adipocyte metabolism and its alteration is associatedwith obesity and related disorders. Transient receptor potential vanilloid 4 (TRPV4) channels are an important Ca2+ pathway in adipocytes and their activity is regulated by metabolic mediators such as insulin. In this study, we evaluated the role of TRPV4 channelsin metabolic activity and adipokine secretion in human white adipocytes. Methods: Human white adipocytes were freshly cultured and the effects of the activation and inhibition of TRPV4 channels on lipolysis, glucose uptake, lactate production, and leptin and adiponectin secretion were evaluated. Results: Under basal and isoproterenol-stimulated conditions, TRPV4 activation by GSK1016709A decreased lipolysis whereasHC067047, an antagonist, increased lipolysis. The activation of TRPV4 resulted in increased glucose uptake and lactate productionunder both basal conditions and insulin-stimulated conditions; in contrast HC067047 decreased both parameters. Leptin productionwas increased, and adiponectin production was diminished by TRPV4 activation and its inhibition had the opposite effect. Conclusion: Our results suggested that TRPV4 channels are metabolic mediators involved in proadipogenic processes and glucosemetabolism in adipocyte biology. TRPV4 channels could be a potential pharmacological target to treat metabolic disorders.
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