The levels of miR-93, miR-191, and miR-499 have been reported to be up-regulated in the tissues of experimental traumatic brain injury (TBI) rat models. However, the clinical diagnostic and prognostic values of the serum signatures of these 3 miRNAs in TBI remain unclear. The purpose of this study was to determine the expression levels of these 3 microRNAs (miRNAs) in the sera of TBI patients and to evaluate their relationships with the severity and clinical outcome of TBI. The serum levels of these miRNAs were assessed in TBI patients (n = 76) and healthy controls (n = 38) by quantitative reverse-transcription PCR. The severities and clinical outcomes of the TBI patients were evaluated with the Glasgow coma scale and the Glasgow outcome scale. The serum miR-93, miR-191, and miR-499 levels were significantly increased in the TBI patients compared with the controls at all examined time points, and these levels were significantly higher in the patients with severe TBI than in those with moderate or mild TBI (p < 0.05). The serum miR-93, miR-191, and miR-499 levels were significantly higher in the patients with a poor outcome than in those with a good outcome (p < 0.05). The AUCs of miR-93, miR-191, and miR-499 for distinguishing the TBI patients from the healthy controls were 1.000 (p < 0.001), 0.727 (p < 0.001) and 0.801 (p < 0.001), respectively. Interestingly, the AUCs of miR-93, miR-191, and miR-499 for distinguishing the mild TBI patients from the healthy controls were 1.000 (p < 0.001), 0.742 (p < 0.001) and 0.819 (p < 0.001), respectively. Taken together, these results indicate that miR-93, miR-191, and miR-499 are potentially valuable indicators of the diagnosis, severity, and prognosis of TBI.

Circulating microRNAs (miRNAs) are emerging biomarkers for type 2 diabetes mellitus (T2DM). However, a comprehensive characterization of the serum miRNA profile in patients with T2DM-associated microvascular disease (T2DMC) has rarely been reported. In this study, we obtained serum samples from 184 T2DM patients (92 with microvascular complications and 92 free of complications) and 92 age/gender-matched controls. The levels of 754 miRNAs were initially analyzed using a TaqMan Low Density Array (TLDA) in three pooled samples from 24 T2DM patients, 24 T2DMC patients and 24 controls. Markedly upregulated miRNAs in the patients’ groups were subsequently validated individually by quantitative reverse-transcription PCR (RT-qPCR) in the same samples used for TLDA and further confirmed in another larger cohort consisting of 68 patients with T2DM, 68 patients with T2DMC and 68 controls. Five miRNAs were significantly upregulated in T2DM patients (p < 0.05) including miR-661, miR-571, miR-770-5p, miR-892b and miR-1303. Moreover, the levels of the five miRNAs were higher in patients with complications than in those without complications. Regression analyses revealed the five miRNAs were significantly correlated with microvascular complications (p < 0.05). The five serum miRNAs identified in our study hold potential as auxiliary biomarkers and novel risk factors for T2DM-associated microvascular complications.

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Diabetic cardiomyopathy (DCM) is a serious complication of diabetes mellitus (DM). One of the hallmarks of the DCM is enhanced oxidative stress in myocardium. The aim of this study was to research the underlying mechanisms involved in the effects of dapagliflozin (Dap) on myocardial oxidative stress both in streptozotocin-induced DCM rats and rat embryonic cardiac myoblasts H9C2 cells exposed to high glucose (33.0 mM). In in vivo studies, diabetic rats were given Dap (1 mg/ kg/ day) by gavage for eight weeks. Dap treatment obviously ameliorated cardiac dysfunction, and improved myocardial fibrosis, apoptosis and oxidase stress. In in vitro studies, Dap also attenuated the enhanced levels of reactive oxygen species and cell death in H9C2 cells incubated with high glucose. Mechanically, Dap administration remarkably reduced the expression of membrane-bound nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits gp91phox and p22phox, suppressed the p67phox subunit translocation to membrane, and decreased the compensatory elevated copper, zinc superoxide dismutase (Cu/Zn-SOD) protein expression and total SOD activity both in vivo and in vitro. Collectively, our results indicated that Dap protects cardiac myocytes from damage caused by hyperglycemia through suppressing NADPH oxidase-mediated oxidative stress.

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Methylglyoxal, a major precursor of advanced glycation end products, is elevated in the plasma of patients with type 2 diabetes mellitus. Islet β-cell function was recently shown to be regulated by N6-methyladenosine (m6A), an RNA modification consisting of methylation at the N6 position of adenosine. However, the role of m6A methylation modification in methylglyoxal-induced impairment of insulin secretion in pancreatic β cells has not been clarified. In this study, we showed that treatment of two β-cell lines, NIT-1 and β-TC-6, with methylglyoxal reduced m6A RNA content and methyltransferase-like 3 (METTL3) expression levels. We also showed that silencing of METTL3 inhibited glucose-stimulated insulin secretion (GSIS) from NIT-1 cells, whereas upregulation of METTL3 significantly reversed the methylglyoxal-induced decrease in GSIS. The methylglyoxal-induced decreases in m6A RNA levels and METTL3 expression were not altered by knockdown of the receptor for the advanced glycation end product but were further decreased by silencing of glyoxalase 1. Mechanistic investigations revealed that silencing of METTL3 reduced m6A levels, mRNA stability, and the mRNA and protein expression levels of musculoaponeurotic fibrosarcoma oncogene family A (MafA). Overexpression of MafA greatly improved the decrease in GSIS induced by METTL3 silencing; silencing of MafA blocked the reversal of the MG-induced decrease in GSIS caused by METTL3 overexpression. The current study demonstrated that METTL3 ameliorates MG-induced impairment of insulin secretion in pancreatic β cells by regulating MafA.

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