Differential dose-response effect of cyclosporine A in regulating apoptosis and autophagy markers in MCF-7 cells.

Cyclosporine A (CsA) is an immunosuppressant primarily used at a higher dosage in transplant medicine and autoimmune diseases with a higher success rate. At lower doses, CsA exhibits immunomodulatory properties. CsA has also been reported to inhibit breast cancer cell growth by downregulating the expression of pyruvate kinase. However, differential dose-response effects of CsA in cell growth, colonization, apoptosis, and autophagy remain largely unidentified in breast cancer cells. Herein, we showed the cell growth-inhibiting effects of CsA by preventing cell colonization and enhancing DNA damage and apoptotic index at a relatively lower concentration of 2 µM in MCF-7 breast cancer cells. However, at a higher concentration of 20 µM, CsA leads to differential expression of autophagy-related genes ATG1, ATG8, and ATG9 and apoptosis-associated markers, such as Bcl-2, Bcl-XL, Bad, and Bax, indicating a dose-response effect on differential cell death mechanisms in MCF-7 cells. This was confirmed in the protein-protein interaction network of COX-2 (PTGS2), a prime target of CsA, which had close interactions with Bcl-2, p53, EGFR, and STAT3. Furthermore, we investigated the combined effect of CsA with SHP2/PI3K-AKT inhibitors showing significant MCF-7 cell growth reduction, suggesting its potential to use as an adjuvant during breast cancer therapy.

Plant Flavonoids on Oxidative Stress-Mediated Kidney Inflammation.

The kidney is susceptible to reactive oxygen species-mediated cellular injury resulting in glomerulosclerosis, tubulointerstitial fibrosis, tubular cell apoptosis, and senescence, leading to renal failure, and is a significant cause of death worldwide. Oxidative stress-mediated inflammation is a key player in the pathophysiology of various renal injuries and diseases. Recently, flavonoids' role in alleviating kidney diseases has been reported with an inverse correlation between dietary flavonoids and kidney injuries. Flavonoids are plant polyphenols possessing several health benefits and are distributed in plants from roots to leaves, flowers, and fruits. Dietary flavonoids have potent antioxidant and free-radical scavenging properties and play essential roles in disease prevention. Flavonoids exert a nephroprotective effect by improving antioxidant status, ameliorating excessive reactive oxygen species (ROS) levels, and reducing oxidative stress, by acting as Nrf2 antioxidant response mediators. Moreover, flavonoids play essential roles in reducing chemical toxicity. Several studies have demonstrated the effects of flavonoids in reducing oxidative stress, preventing DNA damage, reducing inflammatory cytokines, and inhibiting apoptosis-mediated cell death, thereby preventing or improving kidney injuries/diseases. This review covers the recent nephroprotective effects of flavonoids against oxidative stress-mediated inflammation in the kidney and their clinical advancements in renal therapy.