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1.
Biomolecules ; 10(10)2020 09 24.
Artículo en Inglés | MEDLINE | ID: mdl-32987623

RESUMEN

Catalpol was tested for various disorders including diabetes mellitus. Numerous molecular mechanisms have emerged supporting its biological effects but with little information towards its insulin sensitizing effect. In this study, we have investigated its effect on skeletal muscle mitochondrial respiration and insulin signaling pathway. Type-2 diabetes (T2DM) was induced in male C57BL/6 by a high fat diet (60% Kcal) and streptozotocin (50 mg/kg, i.p.). Diabetic mice were orally administered with catalpol (100 and 200 mg/kg), metformin (200 mg/kg), and saline for four weeks. Fasting blood glucose (FBG), HbA1c, plasma insulin, oral glucose tolerance test (OGTT), insulin tolerance test (ITT), oxygen consumption rate, gene (IRS-1, Akt, PI3k, AMPK, GLUT4, and PGC-1α) and protein (AMPK, GLUT4, and PPAR-γ) expression in muscle were measured. Catalpol (200 mg/kg) significantly (p < 0.05) reduced the FBG, HbA1C, HOMA_IR index, and AUC of OGTT whereas, improved the ITT slope. Gene (IRS-1, Akt, PI3k, GLUT4, AMPK, and PGC-1α) and protein (AMPK, p-AMPK, PPAR-γ and GLUT4) expressions, as well as augmented state-3 respiration, oxygen consumption rate, and citrate synthase activity in muscle was observed in catalpol treated mice. The antidiabetic activity of catalpol is credited with a marked improvement in insulin sensitivity and mitochondrial respiration through the insulin signaling pathway and AMPK/SIRT1/PGC-1α/PPAR-γ activation in the skeletal muscle of T2DM mice.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos Iridoides/farmacología , PPAR gamma/genética , Proteínas Quinasas/genética , Sirtuina 1/genética , Quinasas de la Proteína-Quinasa Activada por el AMP , Animales , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Modelos Animales de Enfermedad , Humanos , Insulina/genética , Insulina/metabolismo , Resistencia a la Insulina/genética , Ratones Endogámicos NOD/genética , Enfermedades Mitocondriales , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Transducción de Señal/efectos de los fármacos
2.
Curr Pharm Des ; 25(26): 2828-2841, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31333092

RESUMEN

Adenosine is a ubiquitous signaling nucleoside molecule, released from different cells within the body to act on vasculature and immunoescape. The physiological action on the proliferation of tumour cell has been reported by the presence of high concentration of adenosine within the tumour microenvironment, which results in the progression of the tumour, even leading to metastases. The activity of adenosine exclusively depends upon the interaction with four subtypes of heterodimeric G-protein-coupled adenosine receptors (AR), A1, A2A, A2B, and A3-ARs on the cell surface. Research evidence supports that the activation of those receptors via specific agonist or antagonist can modulate the proliferation of tumour cells. The first category of AR, A1 is known to play an antitumour activity via tumour-associated microglial cells to prevent the development of glioblastomas. A2AAR are found in melanoma, lung, and breast cancer cells, where tumour proliferation is stimulated due to inhibition of the immune response via inhibition of natural killer cells cytotoxicity, T cell activity, and tumourspecific CD4+/CD8+ activity. Alternatively, A2BAR helps in the development of tumour upon activation via upregulation of angiogenin factor in the microvascular endothelial cells, inhibition of MAPK and ERK 1/2 phosphorylation activity. Lastly, A3AR is expressed in low levels in normal cells whereas the expression is upregulated in tumour cells, however, agonists to this receptor inhibit tumour proliferation through modulation of Wnt and NF-κB signaling pathways. Several researchers are in search for potential agents to modulate the overexpressed ARs to control cancer. Active components of A2AAR antagonists and A3AR agonists have already entered in Phase-I clinical research to prove their safety in human. This review focused on novel research targets towards the prevention of cancer progression through stimulation of the overexpressed ARs with the hope to protect lives and advance human health.


Asunto(s)
Adenosina/fisiología , Neoplasias/tratamiento farmacológico , Agonistas del Receptor Purinérgico P1/uso terapéutico , Antagonistas de Receptores Purinérgicos P1/uso terapéutico , Células Endoteliales , Humanos , Receptores Purinérgicos P1/fisiología , Transducción de Señal , Microambiente Tumoral
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