These results demonstrate that in addition to inhibited glucose uptake, modulated tumor growth regulatory molecular pathways are also implicated in the manifestation of the antineoplastic action of glutor. Adding fructose to the culture medium containing glutor reversed the latter’s inhibitory action on tumor cell survival. Glutor also enhanced the chemosensitivity of tumor cells to cisplatin, accompanied by decreased MDR1 expression. Moreover, glutor treatment modulated the expression of cell survival regulatory molecules p53, Hsp70, IL-2 receptor CD25, and C-myc along with mitochondrial membrane depolarization, increased intracellular ROS expression, and altered Bcl-2/BAX ratio. HIF-1α, HK-2, LDH-A, and MCT1 also decreased with diminished lactate production and deregulated pH homeostasis. It also caused a decrease in glucose uptake associated with altered expression of GLUT1 and GLUT3. Treatment of tumor cells with glutor caused a decrease in cell survival with augmented induction of apoptosis. To understand this better, tumor cells of thymic origin designated as Dalton’s lymphoma (DL) were treated with glutor and analyzed for survival and metabolism regulatory molecular events. However, several aspects of the underlying mechanisms remain obscure. Glutor, a piperazine-2-one derivative, is a newly reported pan-GLUT inhibitor with a promising antineoplastic potential.
Hence, novel strategies are being explored to effectively inhibit GLUTs for a daunting interference of glucose uptake. Neoplastic cells overexpress glucose transporters (GLUT), particularly GLUT1 and GLUT3, to support altered metabolism. Therefore, hUC-MSCs-sEVs could serve as a potential therapy for diabetes mellitus. The findings suggest that hUC-MSCs-sEVs could ameliorate insulin resistance and exert protective effects on T2DM rats. Histological analysis revealed that hUC-MSCs-sEVs relieved the structural damage to the pancreas, kidney and liver.
The biochemical tests of hUC-MSCs-sEVs treatment groups showed no significant creatinine changes, elevated alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels compared to the normal group. Moreover, an improvement in serum HbA1c was observed in diabetic rats treated with 0.5 and 1 mg/kg of hUC-MSCs-sEVs, and hUC-MSCs. The hUC-MSCs-sEVs treatment at 1 mg/kg improved glucose tolerance in T2DM rats and showed a protective effect on complete blood count. Interestingly, 20 μg/mL of hUC-MSCs-sEVs-treated HSkMCs increased glucose uptake by 80–90% compared to untreated cells. Treatment with hUC-MSCs-sEVs up to 100 μg/mL for 48 h showed no significant cytotoxicity. This study aims to investigate the efficacy of low-dose hUC-MSCs-sEVs treatment on human skeletal muscle cells (HSkMCs) and type 2 diabetes mellitus (T2DM) rats. However, the dosage of MSCs-sEVs in animal studies, up to 10 mg/kg, was considered high and may be impractical for future clinical application. Human umbilical cord mesenchymal stem cell-derived small extracellular vesicle (hUC-MSCs-sEVs) therapy has shown promising results to treat diabetes mellitus in preclinical studies.
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