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.

Highlights d Prdm16 is dispensable for cardiac development d Prdm16 cKO mice develop hypertrophy, adverse remodeling, and mitochondrial dysfunction d Prdm16 cKO mice are predisposed to develop heart failure in response to metabolic stress d Prdm16 and Ehmts act together to repress expression of hypertrophic genes

diseases. Patients with LVNC are at a higher risk for developing systolic and diastolic dysfunction leading to heart failure, arrhythmias, and sudden cardiac death (17-19). The underlying molecular and cellular mechanisms that orchestrate ventricular trabeculation and compaction are governed by various transcription factors (e.g., Nkx2.5, T-box transcription factors, Gata4 and 6, Irx3 and 5, etc.) and signaling pathways (e.g., Notch, Neuregulin [Nrg1], Ephrin, ErbB, Bmp, etc.) (20). Genetic mutations in these genes lead to defects in cardiac chamber development and maturation including LVNC (21). Notch signaling is one of the most studied pathways in this process (22). Notch1 is expressed in the endocardial cells near the proximal end of the trabecular myocardium, where it controls the ventricular trabeculation and compaction by regulating Bmp10 signaling and Nrg1 expression (3, 23). Bmp10 is a cytokine and member of TGF-β superfamily. It is expressed as early as E9.5 in the trabecular myocardium and promotes cardiomyocyte proliferation (24). Although Bmp10 deletion leads to defective cardiomyocyte proliferation resulting in impaired ventricular trabeculation, its overexpression results in cardiac hypertrabeculation and noncompaction (24, 25). However, the exact molecular link between Notch signaling pathways and Bmp10 is yet to be elucidated. In contrast, the signaling pathway between Notch1 and Nrg1 is well established. Notch1 inhibits the transcriptional activation of Nrg1 by binding to its promoter region. This process affects the Nrg1/ErbB signaling pathway required for proliferation and differentiation of ventricular myocardial cells. Genetic deletion of Notch1 or its transcriptional cofactor Rbpjk within the endothelial cells results in hypotrabeculation (3, 23). In contrast, upregulation of Notch1 in endocardial cells leads to ventricular hypertrabeculation and noncompaction (26-29). The cardiac jelly located between the endocardium and myocardium facilitates this orchestration of molecules among the cardiac layers. It serves as a substrate for cell migration and diffusion of signaling molecules expressed in the 2 cardiac layers (4, 27, 30, 31). Synthesis and degradation of this ECM is a notable feature of cardiac remodeling. Although its synthesis is crucial for the above-mentioned molecular communication between the 2 cardiac layers, its degradation is essential for myocardial compaction (31). Thus, a fine balance between the synthesis and degradation of ECM components is required for proper regulation of trabeculation and the myocardial compaction process. Many studies have demonstrated that impaired ECM synthesis or degradation can cause trabeculation and compaction defects (4, 27, 32-36). Genetic deletions of genes required for cardiac jelly formation and degradation lead to hypotrabeculation and hypertrabeculation/noncompaction, respectively. Despite the essential role of ECM in trabeculation and compaction, pathways that control ECM dynamics remain poorly understood. Semaphorins (Semas) are a large...

Alternative splicing (AS) creates proteomic diversity from a limited size genome by generating numerous transcripts from a single protein-coding gene. Tissue-specific regulators of AS are essential components of the gene regulatory network, required for normal cellular function, tissue patterning, and embryonic development. However, their cell-autonomous function in neural crest development has not been explored. Here, we demonstrate that splicing factor Rbfox2 is expressed in the neural crest cells (NCCs), and deletion of Rbfox2 in NCCs leads to cleft palate and defects in craniofacial bone development. RNA-Seq analysis revealed that Rbfox2 regulates splicing and expression of numerous genes essential for neural crest/craniofacial development. We demonstrate that Rbfox2-TGF-β-Tak1 signaling axis is deregulated by Rbfox2 deletion. Furthermore, restoration of TGF-β signaling by Tak1 overexpression can rescue the proliferation defect seen in Rbfox2 mutants. We also identified a positive feedback loop in which TGF-β signaling promotes expression of Rbfox2 in NCCs.

The current study is aimed to assess the therapeutic potential of fisetin, a phytoflavonoid in streptozotocin (STZ)-induced experimental diabetic neuropathy (DN) in rats. Fisetin was administered (5 and 10 mg/kg) for 2 weeks (7th and 8th week) post STZ administration. Thermal and mechanical hyperalgesia were assessed by measuring tactile sensitivity to thermal and mechanical stimuli, respectively. Motor nerve conduction velocity (MNCV) was determined using power lab system and sciatic nerve blood flow (NBF) was determined using laser Doppler system. Nerve sections were processed for TUNEL assay and NF-κB, COX-2 immunohistochemical staining. Sciatic nerve homogenate was used for biochemical and Western blotting analysis. MNCV and sciatic NBF deficits associated with DN were ameliorated in fisetin administered rats. Fisetin treatment reduced the interleukin-6 and tumour necrosis factor-alpha in sciatic nerves of diabetic rats (p < 0.001). Protein expression studies have identified that the therapeutic benefit of fisetin might be through regulation of redox sensitive transcription factors such as nuclear erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa B (NF-κB). Our study provides an evidence for the therapeutic potential of fisetin in DN through simultaneous targeting of NF-κB and Nrf2.

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Although aging in the liver contributes to the development of chronic liver diseases such as NAFLD and insulin resistance, little is known about the molecular and metabolic details of aging in hepatic cells. To examine these issues, we used sequential oxidative stress with hydrogen peroxide to induce premature senescence in AML12 hepatic cells. The senescent cells exhibited molecular and metabolic signatures, increased SA-βGal and γH2A.X staining, and elevated senescence and pro-inflammatory gene expression that resembled livers from aged mice. Metabolic phenotyping showed fuel switching towards glycolysis and mitochondrial glutamine oxidation as well as impaired energy production. The senescent AML12 cells also had increased mTOR signaling and decreased autophagy which likely contributed to the fuel switching from β-oxidation that occurred in normal AML12 cells. Additionally, senescence-associated secretory phenotype (SASP) proteins from conditioned media of senescent cells sensitized normal AML12 cells to palmitate-induced toxicity, a known pathological effect of hepatic aging. In summary, we have generated senescent AML12 cells which displayed the molecular hallmarks of aging and also exhibited the aberrant metabolic phenotype, mitochondrial function, and cell signaling that occur in the aged liver.

Although general translation declines during fasting, maintaining the translation of a subset or proteins is necessary for metabolic homeostasis and cell viability. Using unbiased proteome analysis of hepatic cells during starvation, we identified a novel pathway in which Esrra-mediated transcription of Rplp1-dependent translation of lysosomal proteins declined during early starvation and recovered after prolonged starvation to restore autophagy-lysosome function. Interestingly, hepatic Esrra-Rplp1-dependent translation rate of lysosomal proteins also was impaired in patients and mice with non-alcoholic steatohepatitis (NASH), and translational response to starvation was dysregulated in mice with NASH. Remarkably, activation of Esrra pharmacologically, genetically, or by alternate day fasting restored protein translation, increased expression of lysosomal proteins, induced autophagy, and reduced lipotoxicity, inflammation, and fibrosis in cell culture and in vivo models of NASH. Thus, hepatic Esrra is essential for ribosome-dependent translation of lysosomal proteins during starvation, and prevention of lipotoxicity and progression in NASH.Lay summaryFasting for weight loss improves non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH); however, the mechanism is not well understood. Our study shows that a nuclear protein, estrogen related receptor alpha (Esrra), increases ribosome-mediated translation of autophagy and lysosome proteins during chronic starvation to maintain essential metabolic pathways for cell survival. Surprisingly, this translational pathway is impaired during NASH with reduced lysosome-autophagy activity accompanied by increased inflammation and fibrosis gene expression in the liver. Pharmacologic, genetic and dietary activation of Esrra decreases lipid-mediated toxicity in liver cells as well as inflammation and fibrosis in livers from mice with NASH. These findings suggest that the Esrra-ribosome-lysosome pathway is important for liver response to fasting and NASH and thus may be a good therapeutic target for the treatment of NASH.