Paternal sleep deprivation induces metabolic perturbations in male offspring via altered LRP5 DNA methylation of pancreatic islets.

Diabetes and metabolic perturbation are global health challenges. Sleep insufficiency may trigger metabolic dysregulation leading to diabetes. However, the intergenerational transmission of this environmental information is not clearly understood. The research objective was to determine the possible effect of paternal sleep deprivation on the metabolic phenotype of the offspring and to investigate the underlying mechanism of epigenetic inheritance. Male offspring of sleep-deprived fathers exhibit glucose intolerance, insulin resistance, and impaired insulin secretion. In these SD-F1 offspring, a reduction in beta cell mass and proliferation of beta cells were observed. Mechanistically, in pancreatic islets of SD-F1 offspring, we identified alterations in DNA methylation at the promoter region of the LRP5 (LDL receptor related protein 5) gene, a coreceptor of Wnt signaling, resulting in downregulation of downstream effectors cyclin D1, cyclin D2, and Ctnnb1. Restoration of Lrp5 in the pancreas of SD-F1 male mice could improve impaired glucose tolerance and expression of cyclin D1, cyclin D2, and Ctnnb1. This study might significantly contribute to our understanding of the effects of sleeplessness on health and metabolic disease risk from the perspective of the heritable epigenome.

Efficacy and safety analysis of angiotensin receptor neprilysin inhibition(ARNI)in patients with heart failure: a real-world retrospective study.

BACKGROUND: In a large randomized controlled trial (PARADIGM-HF), ARNI has been shown to significantly reduce cardiovascular mortality and hospitalization for patients with reduced ejection fraction in heart failure. This study analyzed the efficacy and safety of ARNI on the basis of various types of heart failure patients in southwestern Sichuan Province. METHODS: This study included patients with heart failure who were treated at the Affiliated Hospital of North Sichuan Medical College from July 2017 to June 2021. This study analyzed the efficacy and safety of ARNI in the treatment of heart failure, and analyzed the risk factors for readmission after ARNI treatment. RESULTS: After propensity score matching, a total of 778 patients were included in the study. The readmission rate for heart failure in patients treated with ARNI (8.7%) was significantly lower than that in the standard treatment group (14.5%) (P = 0.023). Both the proportion of patients with increased LVEF and with decreased LVEF were higher in the ARNI treatment group than in the conventional therapy group. Compared with receiving standard medical treatment, combined ARNI treatment resulted in a greater reduction in SBP (-10.00, 95%CI: -24.00-1.50 vs. -7.00, 95%CI: -20.00-4.14; P = 0.016) in HF patients. Combination ARNI therapy did not increase the risk of adverse events. The study found that age (> 65 vs. ≤65 years) (OR = 4.038, 95%CI: 1.360-13.641, P = 0.013) and HFrEF (OR = 3.162, 95%CI: 1.028-9.724, P = 0.045) were independent predictors of readmission in HF patients treated with ARNI. CONCLUSION: Patients with heart failure treated with ARNI can improve clinical symptoms and reduce the risk of readmitted hospital admission. Age > ~ 65 years and HFrEF were independent predictors of readmission in HF patients treated in ARNI group.

Thyroid stimulating hormone aggravates diabetic retinopathy through the mitochondrial apoptotic pathway.

Diabetic retinopathy (DR) is a common complication of diabetes mellitus. High glucose-induced mitochondrial apoptosis is involved in the loss of retinal pericytes (PCs), which is considered to be a predominant pathologic change of diabetic retinopathy (DR). A high thyroid stimulating hormone (TSH) serum level is associated with an increased prevalence of DR in diabetic patients. Here, we investigated whether TSH regulated glucose-induced PCs loss through TSH-receptor (TSHR)-dependent mitochondrial apoptosis. First, the serum TSH level was found to be an independent risk factor for DR in Type 2 diabetic study participants (odds ratio = 2.294; 95% confidence interval: 1.925-2.733; p ≤ 0.001). Second, human PCs were treated with different concentrations of glucose, with or without bovine TSH (b-TSH). Glucose induced mitochondrial apoptosis through various mechanisms, including through regulating the expression of apoptosis-related proteins and inducing mitochondrial dysfunction, which could be deteriorated by costimulation of glucose and b-TSH. Additionally, we detected functional TSHR in PCs; blocking TSHR significantly restricted TSH-induced apoptosis. Thus, the presence of functional TSHR in human retinal PCs may facilitate the effect of high TSH on high glucose-induced PCs loss through TSHR-dependent mitochondrial apoptosis.

Mst1 deletion reduces hyperglycemia-mediated vascular dysfunction via attenuating mitochondrial fission and modulating the JNK signaling pathway.

Diabetes is a leading cause of microvascular complications, such as nephropathy and retinopathy. Recent studies have proposed that hyperglycemia-induced endothelial cell dysfunction is modulated by mitochondrial stress. Therefore, our experiment was to detect the upstream mediator of mitochondrial stress in hyperglycemia-treated endothelial cells with a focus on macrophage-stimulating 1 (Mst1) and mitochondrial fission. Our data illuminated that hyperglycemia incubation reduced cell viability, as well as increased apoptosis ratio in endothelial cell, and this alteration seemed to be associated with Mst1 upregulation. Inhibition of Mst1 via transfection of Mst1 siRNA into an endothelial cell could sustain cell viability and maintain mitochondrial function. At the molecular levels, endothelial cell death was accompanied with the activation of mitochondrial oxidative stress, mitochondrial apoptosis, and mitochondrial fission. Genetic ablation of Mst1 could reduce mitochondrial oxidative injury, block mitochondrial apoptosis, and repress mitochondrial fission. Besides, we also found Mst1 triggered mitochondrial dysfunction as well as endothelial cell damage through augmenting JNK pathway. Suppression of JNK largely ameliorated the protective actions of Mst1 silencing on hyperglycemia-treated endothelial cells and sustain mitochondrial function. The present study identifies Mst1 as a primary key mediator for hyperglycemia-induced mitochondrial damage and endothelial cell dysfunction. Increased Mst1 impairs mitochondrial function and activates endothelial cell death via opening mitochondrial death pathway through JNK.

Multi-Physical Models of Bending Characteristics on the Double-Clamped Beam Switch for Flexible Electronic Devices Application.

In this paper, multi-physical models of bending characteristics, including the static, dynamic and microwave models, are firstly proposed for the double-clamped beam switch based on flexible substrate. Both simulated and experimental verification have been carried out to prove that the changing regularity of the driving voltage and time of the switch is inversely proportional with the increase in the bending curvature of the flexible substrate. The microwave performance of the switch at the ON state is found to get worse with the increase in the bending curvature. The measured results indicate that when the bending curvature increases from 0 m-1 to 28.6 m-1, the measured driving voltage decreases from 90.0 V to 72.6 V with the error of 5.9% compared with the calculated results. The measured driving time decreases from 52.4 µs to 35.6 µs with the error of 16.7% compared with the calculated results. When the substrate bending curvature increases from 0 m-1 to 28.6 m-1, the measured reflection loss S11 of the switch gradually deteriorates from -27.1 dB to -22.0 dB with the error of 1.3 dB corresponding to the calculated results at 10 GHz. All the simulated and experimental results are consistent with the theoretical calculated results.

Investigations of the local distortions and EPR parameters for Cu2+ in xNa2 O-(30-x)K2 O-70B2 O3 (5 ≤ x ≤ 25 mol%) glasses.

The local distortions and electron paramagnetic resonance parameters for Cu2+ in the mixed alkali borate glasses xNa2 O-(30-x)K2 O-70B2 O3 (5 ≤ x ≤ 25 mol%) are theoretically studied with distinct modifier Na2 O compositions x. Owing to the Jahn-Teller effect, the octahedral [CuO6 ]10- clusters show significant tetragonal elongation ratios p ~19% along the C4 axis. With the increase of composition x, the cubic field parameter Dq and the orbital reduction factor k exhibit linearly and quasi-linearly decreasing tendencies, respectively, whereas the relative tetragonal elongation ratio p has quasi-linearly increasing rule with some fluctuations, leading to the minima of g factors at x = 10 mol%. The composition dependences of the optical spectra and the electron paramagnetic resonance parameters are suitably reproduced by the linear or quasi-linear relationships of the relevant quantities (i.e., Dq, k, and p) with x. The above composition dependences are analyzed from mixed alkali effect, which brings forward the modifications of the local crystal-fields and the electronic cloud distribution around Cu2+ with the variation of the composition of Na2 O.

Quantitative proteomics study of protective effects of grape seed procyanidin B2 on diabetic cardiomyopathy in db/db mice.

Diabetic cardiomyopathy is one of the major complications of diabetes mellitus. Oxidative stress appears to play a substantial role in cardiomyopathy. Grape seed procyanidin B2 (GSPB2) has been known as an anti-oxidant in treating diabetes mellitus; however, little is known about its effects and underlying mechanisms on diabetic cardiomyopathy. The present study is to explore the molecular targets of GSPB2 responsible for the anti-oxidative effects in db/db mice by quantitative proteomics. GSPB2 (30 mg/kg body weight/day) were intragastric administrated to db/db mice for 10 weeks. Proteomics of the heart tissue extracts by isobaric tags for relative and absolute quantification analysis was obtained from db/db mice. Our study provides important evidence that GSPB2 protect against cardiomyopathy in diabetes mellitus, which are believed to result from regulating the expression of key proteins involving cardiac fibrosis and proliferation. GSPB2 could be expected to become novel clinical application in fighting against diabetic cardiomyopathy.

[Retracted] Sirt1 inhibits HG­induced endothelial injury: Role of Mff­based mitochondrial fission and F­actin homeostasis­mediated cellular migration.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the immunochemistry data shown in Figs. 4K and 7G were strikingly similar to data appearing in different form in other research articles written by different authors at different research institutes that had either already been published, or were submitted for publication at around the same time. Owing to the fact that contentious data in the above article had already been published elsewhere prior to its submission to International Journal of Molecular Medicine, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 44: 89­102, 2019; DOI: 10.3892/ijmm.2019.4185].

Sirt1 inhibits HG-induced endothelial injury: Role of Mff-based mitochondrial fission and F­actin homeostasis-mediated cellular migration.

Although sirtuin 1 (Sirt1) has been found to be involved in diabetic vasculopathy and high glucose (HG)­mediated endothelial injury, the underlying mechanisms remain to be fully elucidated. The aim of the present study was to investigate the role of Sirt1 in HG­induced endothelial injury and its potential mechanism. In the present study, it was demonstrated that HG triggers the downregulation of Sirt1 by activating microRNA­195 in human umbilical vein endothelial cells (HUVECs), as determined by western blot analysis in vivo and in vitro. Furthermore, a lower expression of Sirt1 was correlated with glucose metabolic abnormalities, aortic endothelial dysfunction and endothelial apoptosis as evidenced by western blot analysis and ELISA in mice. By contrast, the loss of Sirt1 evoked mitochondrial fission factor (Mff)­mediated mitochondrial fission through the c­Jun N­terminal kinase (JNK) pathway, which contributes to the apoptosis of HUVECs. In addition, Sirt1 deficiency downregulated the migration of HUVECs through F­actin dyshomeostasis. Collectively, the results identify Sirt1 as a protective factor, which inhibits the JNK/Mff/mitochondrial fission pathway and sustains F­actin homeostasis, and has potential implications for novel approaches to diabetic vasculopathy.