cytochrome-c-t and morin

Long-term diabetes mellitus results in neuronal damage by increased intracellular glucose leading to oxidative stress. This condition is known as diabetic encephalopathy. Morin is a bioflavonoid, has significant antidiabetic, antioxidant and anti-inflammatory activities. The present study investigated whether the antioxidant properties of morin has beneficial effects on structural brain damage, neuronal apoptosis and dysregulation of TrkB/Akt signaling associated with diabetes. Adult male Sprague Dawley rats were induced diabetes by an intraperitoneal injection of 40 mg/kg of streptozotocin and kept untreated for 30 days to induce DE. Cognitive performance was assessed using the Morris water maze test followed by morin and metformin administration at the doses of 50 and 100 mg/kg, respectively, for 60 days. After 60 days of treatment, animals were subjected to the behavioral test and sacrificed to collect blood and brain and checked biochemical parameters. The treatment with morin could significantly reduce the escape latency time in Morris water maze test, blood glucose level, HbA1c, toxicity markers, lipid peroxidation products and protein carbonyl content, downregulated the expression of Bax, Caspase - 3 and Cytochrome C and upregulated Bcl-2, Bcl-XL, Akt, BDNF and TrkB expressions. Besides, enhanced the activities of antioxidant enzymes, and plasma insulin level. Histomorphological observations also confirmed the protective effect of morin on neuronal degeneration. Morin 50 mg once daily for 60 days was the most effective dose with a significant reduction in diabetes mediated complications in the brain associated with neuronal apoptosis and dysregulation of TrkB/Akt signaling.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; bcl-2-Associated X Protein; Blood Glucose; Brain-Derived Neurotrophic Factor; Cytochromes c; Diabetes Mellitus; Flavones; Flavonoids; Glycated Hemoglobin; Hypoglycemic Agents; Insulins; Male; Metformin; Neuroprotective Agents; Oxidative Stress; Protein Carbonylation; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Streptozocin

Acrylamide (ACR) is a heat-induced carcinogen substance that is found in some foods due to cooking or other thermal processes. The aim of present study was to assess the probable protective effects of morin against ACR-induced hepatorenal toxicity in rats. The rats were treated with ACR (38.27 mg/kg b.w., p.o.) alone or with morin (50 and 100 mg/kg b.w., p.o.) for 10 consecutive days. Morin treatment attenuated the ACR-induced liver and kidney tissue injury by diminishing the serum AST, ALP, ALT, urea and creatinine levels. Morin increased activities of SOD, CAT and GPx and levels of GSH, and suppressed lipid peroxidation in ACR induced tissues. Histopathological changes and immunohistochemical expressions of p53, EGFR, nephrin and AQP2 in the ACR-induced liver and kidney tissues were decreased after administration of morin. In addition, morin reversed the changes in levels of apoptotic, autophagic and inflammatory parameters such as caspase-3, bax, bcl-2, cytochrome c, beclin-1, LC3A, LC3B, p38α MAPK, NF-κB, IL-1β, IL-6, TNF-α and COX-2 in the ACR-induced toxicity. Morin also affected the protein levels by regulating the PI3K/Akt/mTOR signaling pathway and thus alleviated ACR-induced apoptosis and autophagy. Overall, these findings may shed some lights on new approaches for the treatment of ACR-induced hepatotoxicity and nephrotoxicity.

Topics: Acrylamide; Acute Kidney Injury; Animals; Autophagy; bcl-2-Associated X Protein; Beclin-1; Biomarkers; Caspase 3; Chemical and Drug Induced Liver Injury; Cyclooxygenase 2; Cytochromes c; Cytokines; Disease Models, Animal; Flavonoids; Kidney; Lipid Peroxidation; Liver; Male; Microtubule-Associated Proteins; Mitogen-Activated Protein Kinase 14; NF-kappa B; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; TOR Serine-Threonine Kinases

Evidence suggests that auranofin (AF) exhibits anticancer activity by inhibiting thioredoxin reductase (TrxR). Here, in this study, we have investigated the synergistic effects of AF and morin and their mechanism for the anticancer effects focusing on apoptosis in Hep3B human hepatocellular carcinoma cells. We assessed the anticancer activities by annexin V/PI double staining, caspase, and TrxR activity assay. Morin enhances the inhibitory effects on TrxR activity of AF as well as reducing cell viability. Annexin V/PI double staining revealed that morin/AF cotreatment induced apoptotic cell death. Morin enhances AF-induced mitochondrial membrane potential (ΔΨm) loss and cytochrome c release. Further, morin/AF cotreatment upregulated death receptor DR4/DR5, modulated Bcl-2 family members (upregulation of Bax and downregulation of Bcl-2), and activated caspase-3, -8, and -9. Morin also enhances AF-induced reactive oxygen species (ROS) generation. The anticancer effects results from caspase-dependent apoptosis, which was triggered via extrinsic pathway by upregulating TRAIL receptors (DR4/DR5) and enhanced via intrinsic pathway by modulating Bcl-2 and inhibitor of apoptosis protein family members. These are related to ROS generation. In conclusion, this study provides evidence that morin can enhance the anticancer activity of AF in Hep3B human hepatocellular carcinoma cells, indicating that its combination could be an alternative treatment strategy for the hepatocellular carcinoma.

Topics: Animals; Apoptosis; Auranofin; Carcinoma, Hepatocellular; Caspases; Cell Line, Tumor; Cell Survival; Cytochromes c; Down-Regulation; Flavonoids; Humans; Inhibitor of Apoptosis Proteins; Liver Neoplasms; Male; Membrane Potential, Mitochondrial; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptors, TNF-Related Apoptosis-Inducing Ligand; Signal Transduction; Up-Regulation