Diabetes
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Diabetes-induced oxidative stress is one of the major contributors to dysfunction of endothelial progenitor cells (EPCs) and impaired endothelial regeneration. Thus, we tested whether increasing antioxidant protein metallothionein (MT) in EPCs promotes angiogenesis in a hind limb ischemia (HLI) model in endothelial MT transgenic (JTMT) mice with high-fat diet- and streptozocin-induced diabetes. Compared with littermate wild-type (WT) diabetic mice, JTMT diabetic mice had improved blood flow recovery and angiogenesis after HLI. ⋯ Mechanistically, MT overexpression enhanced hypoxia-inducible factor 1α (HIF-1α), stromal cell-derived factor (SDF-1), and vascular endothelial growth factor (VEGF) expression and reduced oxidative stress in ischemic tissues. MT's pro-EPC effects were abrogated by siRNA knockdown of HIF-1α without affecting its antioxidant action. These results indicate that endothelial MT overexpression is sufficient to protect against diabetes-induced impairment of angiogenesis by promoting EPC function, most likely through upregulation of HIF-1α/SDF-1/VEGF signaling and reducing oxidative stress.
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MG53 is a member of the TRIM protein family that is predominantly expressed in striated muscles and participates in cell membrane repair. Controversy exists regarding MG53's role in insulin signaling and manifestation of diabetes. We generated db/db mice with either whole-body ablation or sustained elevation of MG53 in the bloodstream in order to evaluate the physiological function of MG53 in diabetes. ⋯ Daily intravenous administration of rhMG53 in rats at concentrations up to 10 mg/kg did not produce adverse effects on glucose handling. These findings challenge the hypothetical function of MG53 as a causative factor for the development of diabetes. Our data suggest that rhMG53 is a potentially safe and effective biologic to treat diabetic oculopathy in rodents.
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Available data from observational studies on the association of admission hyperglycemia (aHG) with outcomes of patients with acute ischemic stroke (AIS) treated with intravenous thrombolysis (IVT) are contradictory, especially when stratified by diabetes mellitus (DM) history. We assessed the association of aHG (≥144 mg/dL) with outcomes stratified by DM history using propensity score-matched (PSM) data from the SITS-ISTR. The primary safety outcome was symptomatic intracranial hemorrhage (SICH); 3-month functional independence (FI) (modified Rankin Scale [mRS] scores 0-2) represented the primary efficacy outcome. ⋯ In the non-DM group, patients with aHG had lower 3-month FI rates (53.3% vs. 57.9%, P < 0.001), higher 3-month mortality rates (19.2% vs. 16.0%, P < 0.001), and similar symptomatic intracerebral hemorrhage (SICH) rates (1.7% vs. 1.8%, P = 0.563) compared with patients without aHG. Similarly, in the DM group, patients with aHG had lower rates of 3-month favorable functional outcome (mRS scores 0-1, 34.1% vs. 39.3%, P < 0.001) and FI (48.2% vs. 52.5%, P < 0.001), higher 3-month mortality rates (23.7% vs. 19.9%, P < 0.001), and similar SICH rates (2.2% vs. 2.7%, P = 0.224) compared with patients without aHG. In conclusion, aHG was associated with unfavorable 3-month clinical outcomes in patients with and without DM and AIS treated with IVT.
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It has been appreciated for many years that there is a strong association between metabolism and immunity in advanced metazoan organisms. Distinct immune signatures and signaling pathways have been found not only in immune but also in metabolic cells. The newly discovered DNA-sensing cGAS-cGAMP-STING pathway mediates type I interferon inflammatory responses in immune cells to defend against viral and bacterial infections. ⋯ However, the regulation, mechanism of action, and tissue-specific role of the cGAS-cGAMP-STING signaling pathway in metabolic disorders remain largely elusive. It is also unclear whether targeting this signaling pathway is effective for the prevention and treatment of obesity-induced metabolic diseases. Answers to these questions would provide new insights for developing effective therapeutic interventions for metabolic diseases such as insulin resistance, NAFLD, and type 2 diabetes.
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MicroRNA-146a (miR-146a) regulates multiple immune diseases. However, the role of miR-146a in diabetic peripheral neuropathy (DPN) has not been investigated. We found that mice (db/db) with type 2 diabetes exhibited substantial downregulation of miR-146a in sciatic nerve tissue. ⋯ In addition, miR-146a treatment reduced and increased classically and alternatively activated macrophage phenotype markers, respectively. Analysis of miRNA target array revealed that miR-146a mimics greatly suppressed expression of many proinflammatory genes and downstream related cytokines. Collectively, our data indicate that treatment of diabetic mice with miR-146a mimics robustly reduces DPN and that suppression of hyperglycemia-induced proinflammatory genes by miR-146a mimics may underlie its therapeutic effect.