Addressing the impact of high glucose microenvironment on the immunosuppressive characteristics of human mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are a therapeutically efficient type of stem cells validated by their ability to treat many inflammatory and chronic conditions. The biological and therapeutic characteristics of MSCs can be modified depending on the type of microenvironment at the site of transplantation. Diabetes mellitus (DM) is a commonly diagnosed metabolic disease characterized by hyperglycemia, which alters over time the cellular and molecular functions of many cells and causes their damage. Hyperglycemia can also impact the success rate of MSCs transplantation; therefore, it is extremely significant to investigate the effect of high glucose on the biological and therapeutic attributes of MSCs, particularly their immunomodulatory abilities. Thus, in this study, we explored the effect of high glucose on the immunosuppressive characteristics of human adipose tissue-derived mesenchymal stem cells (hAD-MSCs). We found that hAD-MSCs cultured in high glucose lost their immunomodulatory abilities and became detectable by immune cells. The decline in the immunosuppressive capabilities of hAD-MSCs was mediated by significant decrease in the levels of IDO, IL-10, and complement factor H and substantial increase in the activity of immunoproteasome. The protein levels of AMP-activated protein kinase (AMPK) and phosphofructokinase-1 (PFK-1), which are integral regulators of glycolysis, revealed a marked decline in high glucose exposed MSCs. The findings of our study indicated the possibility of immunomodulatory shift in MSCs after being cultured in high glucose, which can be translationally employed to explain their poor survival and short-lived therapeutic outcomes in diabetic patients.

The toxic profile of tramadol combined with nicotine on the liver and testicles: evidence from endoplasmic reticulum stress.

BACKGROUND: Tramadol is one of the most commonly abused substances in the Middle East. Furthermore, smoking is extremely common among the population. METHODS: An experimental study was performed on Sprague-Dawley rats to explore the effects of both nicotine and tramadol on the liver and testes. The tramadol was administered at 10 and 20 mg/kg, respectively, while the nicotine was administered at 125 mg/kg. Histological examination and androgen receptor ELISA assay showed mild effects on the liver and proofed safety on the testis. Western blot analysis of BIP (immunoglobulin heavy-chain binding protein) and CHOP (CCAAT-enhancer-binding protein homologous protein) revealed that fewer problems were induced by adding nicotine to tramadol. Autophagy marker LCIII and apoptosis marker caspase-8 showed similar effects to CHOP and BIP on liver samples. The real-time PCR of BIP expression showed similar but not identical results. CONCLUSIONS: The results showed mild endoplasmic reticulum stress, autophagy, and apoptosis in the liver samples. Histological examination revealed stable spermatogenesis with average androgen receptor blood levels in the different groups.