Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 881, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ejphar.2020.173215
Keywords
Mesenchymal stem cells; Insulin resistance; Type 2 diabetes mellitus and inflammation
Categories
Funding
- Council of Scientific and Industrial Research (CSIR), Government of India
- Sinhgad College of Engineering, Pune (India)
- Dr. D. Y. Patil Vidyapeeth, Pune (India)
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Insulin resistance (IR) is a constituent part of Type 2 Diabetes Mellitus (T2DM). Conditioned medium from Adipose derived Mesenchymal Stem Cells (ADMSCs-CM) has been shown to reverse IR. However, its effect on cellular stress is not well established. The objective of this study was to explore the effect of ADMSCs-CM on reactive oxygen species, mitochondrial membrane potential (Delta Psi m), endoplasmic reticulum (ER) stress and expression of oxidative and inflammatory stress induced serine kinases (SISK) which are pathophysiologically linked to IR. In insulin resistant, 3T3-L1 adipocytes and C2C12 myoblast cell culture models, glucose uptake was assayed by 2-NBDG uptake. Immunomodulatory cytokines, intracellular reactive oxygen species generation, Ailim and protein expression of JNK1, IKK beta and phospho-IRS1 (307) were analyzed using FACS. mRNA expression of ER stress markers (CHOP1 and IRE1) and SISK (JNK1, IKK beta, ERK1 and S6K1) were analyzed using RT-PCR. ADMSCs-CM effectively improve glucose uptake as evidenced by 2-NBDG uptake assay. FACS analysis showed that ADMSCs-CM possessed significantly higher levels of IL-6 and IL-10. ADMSCs-CM decreased intracellular generation of reactive oxygen species where it restored Delta Psi m in C2C12 cells. ADMSCs-CM mediated reduction in ER stress was confirmed by down-regulation in CHOP1 and IRE1 mRNA expression. ADMSCs-CM treatment showed significant down-regulation of SISK mRNA expression including IKK beta, JNK, ERK and S6K1. Our results unequivocally demonstrate for the first time the mechanism of action of ADMSCs-CM in amelioration IR by reducing oxidative and inflammatory cellular stress. This study identifies SISK as potential therapeutic targets for T2DM therapy.
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