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1.
Exp Mol Med ; 56(4): 904-921, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38556548

RESUMEN

Sarcopenia, the progressive decline in skeletal muscle mass and function, is observed in various conditions, including cancer and aging. The complex molecular biology of sarcopenia has posed challenges for the development of FDA-approved medications, which have mainly focused on dietary supplementation. Targeting a single gene may not be sufficient to address the broad range of processes involved in muscle loss. This study analyzed the gene expression signatures associated with cancer formation and 5-FU chemotherapy-induced muscle wasting. Our findings suggest that dimenhydrinate, a combination of 8-chlorotheophylline and diphenhydramine, is a potential therapeutic for sarcopenia. In vitro experiments demonstrated that dimenhydrinate promotes muscle progenitor cell proliferation through the phosphorylation of Nrf2 by 8-chlorotheophylline and promotes myotube formation through diphenhydramine-induced autophagy. Furthermore, in various in vivo sarcopenia models, dimenhydrinate induced rapid muscle tissue regeneration. It improved muscle regeneration in animals with Duchenne muscular dystrophy (DMD) and facilitated muscle and fat recovery in animals with chemotherapy-induced sarcopenia. As an FDA-approved drug, dimenhydrinate could be applied for sarcopenia treatment after a relatively short development period, providing hope for individuals suffering from this debilitating condition.


Asunto(s)
Autofagia , Transcriptoma , Animales , Autofagia/efectos de los fármacos , Ratones , Humanos , Biosíntesis de Proteínas/efectos de los fármacos , Modelos Animales de Enfermedad , Músculo Esquelético/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Perfilación de la Expresión Génica , Sarcopenia/tratamiento farmacológico , Sarcopenia/metabolismo , Sarcopenia/patología , Distrofia Muscular de Duchenne/tratamiento farmacológico , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patología
2.
Biochim Biophys Acta Mol Basis Dis ; 1864(6 Pt A): 2097-2107, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29601978

RESUMEN

Prolactin regulatory element-binding (PREB) protein is a transcription factor that regulates prolactin (PRL) gene expression. PRL, also known as luteotropic hormone or luteotropin, is well known for its role in producing milk. However, the role of PREB, in terms of hepatic glucose metabolism, is not well elucidated. Here, we observed expression of Preb in the mouse liver, in connection with glucose homeostasis. Morevoer, Preb was downregulated in db/db, ob/ob and high-fat diet-induced obese (DIO) mice, concurrent with upregulation of the liver genes glucose-6-phosphatase (G6pc) and phosphoenolpyruvate carboxykinase-1 (Pck). Administration of adenovirus-Preb (Ad-Preb) to db/db, ob/ob, and DIO mice diminished glucose, insulin, and pyruvate tolerance, which analogously, were impaired in normal (C57BL/6) mice knocked down for Preb, via infection with Ad-shPreb (anti-Preb RNA), indicating Preb to be a negative regulator of liver gluconeogenic genes. We further demonstrate that Preb negatively influences gluconeogenic gene expression, by directly binding to their promoters at a prolactin core-binding element (PCBE). A better understanding of Preb gene expression, during the pathogenesis of hepatic insulin resistance, could ultimately provide new avenues for therapies for metabolic syndrome, obesity, and type-2 diabetes mellitus, disorders whose worldwide incidences are increasing drastically.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Gluconeogénesis , Glucosa/metabolismo , Factores de Intercambio de Guanina Nucleótido/metabolismo , Hígado/metabolismo , Factores de Transcripción/metabolismo , Animales , Glucemia , Proteínas de Unión al ADN/genética , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Regulación hacia Abajo , Ayuno , Factores de Intercambio de Guanina Nucleótido/genética , Células HEK293 , Hepatocitos/metabolismo , Humanos , Insulina/metabolismo , Hígado/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Obesos , Obesidad/sangre , Obesidad/etiología , Obesidad/metabolismo , Cultivo Primario de Células , Prolactina/metabolismo , Regiones Promotoras Genéticas , ARN Interferente Pequeño/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Factores de Transcripción/genética , Regulación hacia Arriba
3.
Yonsei Med J ; 56(5): 1251-7, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26256967

RESUMEN

PURPOSE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low density lipoprotein receptor (LDLR) and promotes degradation of the LDLR. Inhibition of PCSK9 either by reducing its expression or by blocking its activity results in the upregulation of the LDLR and subsequently lowers the plasma concentration of LDL-cholesterol. As a modality to inhibit PCSK9 action, we searched the chemical library for small molecules that block the binding of PCSK9 to the LDLR. MATERIALS AND METHODS: We selected 100 chemicals that bind to PCSK9 where the EGF-AB fragment of the LDLR binds via in silico screening of the ChemBridge chemical library, using the computational GOLD algorithm analysis. Effects of chemicals were evaluated using the PCSK9-LDLR binding assay, immunoblot analysis, and the LDL-cholesterol uptake assay in vitro, as well as the fast performance liquid chromatography assay for plasma lipoproteins in vivo. RESULTS: A set of chemicals were found that decreased the binding of PCSK9 to the EGF-AB fragment of the LDLR in a dose-dependent manner. They also increased the amount of the LDLR significantly and subsequently increased the uptake of fluorescence-labeled LDL in HepG2 cells. Additionally, one particular molecule lowered the plasma concentration of total cholesterol and LDL-cholesterol significantly in wild-type mice, while such an effect was not observed in Pcsk9 knockout mice. CONCLUSION: Our findings strongly suggest that in silico screening of small molecules that inhibit the protein-protein interaction between PCSK9 and the LDLR is a potential modality for developing hypercholesterolemia therapeutics.


Asunto(s)
Colesterol/sangre , Proproteína Convertasas/metabolismo , Receptores de LDL/metabolismo , Serina Endopeptidasas/metabolismo , Bibliotecas de Moléculas Pequeñas , Animales , LDL-Colesterol/sangre , Células Hep G2 , Humanos , Ratones , Ratones Noqueados , Proproteína Convertasa 9
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