Translational research : the journal of laboratory and clinical medicine
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Sulfonylureas, widely used as hypoglycemic agents in adults with type 2 diabetes, have neuroprotective effects in preclinical models of central nervous system injury, and in children with neuropsychomotor impairments linked to neonatal diabetes secondary to ATP-sensitive potassium channel mutations. In the human and rodent retina, we show that the glibenclamide-activated channel sulfonylurea receptor 1 (SUR1) is expressed in the retina and enriched in the macula; we also show that it colocalizes with the potassium channel Kir6.2, and with the cation channel transporter TRPM4. ⋯ The glibenclamide effects include the transcriptional regulation of antioxidant and neuroprotective genes. Ocular glibenclamide could be repurposed for diabetic retinopathy.
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Friedreich's Ataxia is an autosomal recessive genetic disease causing the defective gene product, frataxin. A body of literature has been focused on the attempts to counteract frataxin deficiency and the consequent iron imbalance, in order to mitigate the disease-associated pro-oxidant state and clinical course. The present mini review is aimed at evaluating the basic and clinical reports on the roles and the use of a set of iron chelators, antioxidants and some cofactors involved in the key mitochondrial functions. ⋯ Other studies have suggested mitoprotective roles for other mitochondrial cofactors, involved in Krebs cycle, such as alpha-lipoic acid and carnitine, involved in acyl transport across the mitochondrial membrane. A body of evidence points to the strong antioxidant properties of these cofactors, and to their potential contribution in mitoprotective strategies in Friedreich's Ataxia clinical evolution. Thus, we suggest the rationale for planning combination strategies based on the 3 mitochondrial cofactors and of some antioxidants and iron binders as mitoprotective cocktails in Friedreich Ataxia patients, calling attention to clinical practitioners of the importance to implement clinical trials.
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B-cell secretion of autoantibodies drives autoimmune diseases, including systemic lupus erythematosus and idiopathic inflammatory myositis. Few therapies are presently available for treatment of these patients, often resulting in unsatisfactory effects and helping only some of the patients. ⋯ Probes inhibiting bromodomain family proteins and histone methyl transferases demonstrated abrogation of B-cell functions to a degree comparable to a positive control, the JAK inhibitor tofacitinib. Inhibition of each target rendered a specific functional cell and potential disease modifying effect, indicating specific epigenetic protein targets as potential new intervention points for future drug discovery and development efforts.
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An increasing amount of evidence reveals that the gut microbiota is involved in the pathogenesis and progression of various cardiovascular diseases. In patients with heart failure (HF), splanchnic hypoperfusion causes ischemia and intestinal edema, allowing bacterial translocation and bacterial metabolites to enter the blood circulation via an impaired intestinal barrier. This results in local and systemic inflammatory responses. ⋯ These landmark findings suggest that gut microbiota influences the host's metabolic health, either directly or indirectly by producing several metabolites. In this review, we mainly discuss a newly identified gut microbiota-dependent metabolite, trimethylamine N-oxide (TMAO), which appears to participate in the pathologic processes of HF and can serve as an early warning marker to identify individuals who are at the risk of disease progression. We also discuss the potential of the gut-TMAO-HF axis as a new target for HF treatment and highlight the current controversies and potentially new and exciting directions for future research.
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Neurofibromatosis type 1 (NF1) is a heritable cancer predisposition syndrome resulting from mutations in the NF1 tumor suppressor gene. Genotype-phenotype correlations for NF1 are rare due to the large number of NF1 mutations and role of modifier genes in manifestations of NF1; however, emerging reports suggest that persons with NF1 display a distinct anthropometric and metabolic phenotype featuring short stature, low body mass index, increased insulin sensitivity, and protection from diabetes. Nf1 heterozygous (Nf1+/-) mice accurately reflect the dominant inheritance of NF1 and are regularly employed as a model of NF1. ⋯ Additionally, Nf1+/- mice are highly reliant on carbohydrates as an energy substrate and display increased glucose clearance and insulin sensitivity, but normal response to pyruvate suggesting enhanced glucose utilization and preserved gluconeogenesis. Finally, WT and Nf1+/- mice subjected to high glucose diet were protected from diet-induced obesity and hyperglycemia. Our data suggest that Nf1+/- mice closely recapitulate the anthropometric and metabolic phenotype identified in persons with NF1, which will impact the interpretation of previous and future translational studies of NF1.