Neuroinflammation and Oxidative Stress in Diabetic Neuropathy: Futuristic Strategies Based on These Targets

In Diabetes, the chronic hyperglycemia and associated complications affecting peripheral nerves are one of the most commonly occurring microvascular complications with an overall prevalence of 50–60%. Among the vascular complications of diabetes, diabetic neuropathy is the most painful and disabling, fatal complication affecting the quality of life in patients. Several theories of etiologies surfaced down the lane, amongst which the oxidative stress mediated damage in neurons and surrounding glial cell has gained attention as one of the vital mechanisms in the pathogenesis of neuropathy. Mitochondria induced ROS and other oxidants are responsible for altering the balance between oxidants and innate antioxidant defence of the body. Oxidative-nitrosative stress not only activates the major pathways namely, polyol pathway flux, advanced glycation end products formation, activation of protein kinase C, and overactivity of the hexosamine pathway, but also initiates and amplifies neuroinflammation. The cross talk between oxidative stress and inflammation is due to the activation of NF-κB and AP-1 and inhibition of Nrf2, peroxynitrite mediate endothelial dysfunction, altered NO levels, and macrophage migration. These all culminate in the production of proinflammatory cytokines which are responsible for nerve tissue damage and debilitating neuropathies. This review focuses on the relationship between oxidative stress and neuroinflammation in the development and progression of diabetic neuropathy

Decreased autophagy and fuel switching occur in a senescent hepatic cell model system

10.18632/aging.103740AGING-US121413958-1397

Semaphorin 3E/PlexinD1 Signaling Is Required for Cardiac Ventricular Compaction.

10.1172/jci.insight.125908JCI insight416e12590

Cardiac Tissue Factor Regulates Inflammation, Hypertrophy, and Heart Failure in Mouse Model of Type 1 Diabetes.

10.2337/db20-0719Diabetes7092131-214

Neural Crest-Specific Deletion of Rbfox2 in Mice Leads to Craniofacial Abnormalities Including Cleft Palate.

10.7554/eLife.45418.001eLife8e4541

Esrra regulates Rplp1-mediated translation of lysosome proteins suppressed in metabolic dysfunction-associated steatohepatitis and reversed by alternate day fasting

Objective: Currently, little is known about the mechanism(s) regulating global and specific protein translation during metabolic dysfunction-associated steatohepatitis (MASH; previously known as non-alcoholic steatohepatitis, NASH). Methods: Unbiased label-free quantitative proteome, puromycin-labelling and polysome profiling were used to understand protein translation activity in vitro and in vivo. Results: We observed a global decrease in protein translation during lipotoxicity in human primary hepatocytes, mouse hepatic AML12 cells, and livers from a dietary mouse model of MASH. Interestingly, proteomic analysis showed that Rplp1, which regulates ribosome and translation pathways, was one of the most downregulated proteins. Moreover, decreased Esrra expression and binding to the Rplp1 promoter, diminished Rplp1 gene expression during lipotoxicity. This, in turn, reduced global protein translation and Esrra/Rplp1-dependent translation of lysosome (Lamp2, Ctsd) and autophagy (sqstm1, Map1lc3b) proteins. Of note, Esrra did not increase its binding to these gene promoters or their gene transcription, confirming its regulation of their translation during lipotoxicity. Notably, hepatic Esrra-Rplp1-dependent translation of lysosomal and autophagy proteins also was impaired in MASH patients and liver-specific Esrra knockout mice. Remarkably, alternate day fasting induced Esrra-Rplp1-dependent expression of lysosomal proteins, restored autophagy, and reduced lipotoxicity, inflammation, and fibrosis in hepatic cell culture and in vivo models of MASH. Conclusions: Esrra regulation of Rplp1-mediated translation of lysosome/autolysosome proteins was downregulated during MASH. Alternate day fasting activated this novel pathway and improved MASH, suggesting that Esrra and Rplp1 may serve as therapeutic targets for MASH. Our findings also provided the first example of a nuclear hormone receptor, Esrra, to not only regulate transcription but also protein translation, via induction of Rplp1