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Insulin resistance (IR) is the principal pathophysiological change occurring in diabetes mellitus (DM). Baicalein, a bioactive flavonoid primarily extracted from the medicinal plant Scutellaria baicalensis Georgi, has been shown in our previous research to be a potential natural glucagon-like peptide-1 receptor (GLP-1R) agonist. However, the exact therapeutic effect of baicalein on DM and its underlying mechanisms remain elusive. In this study, we investigated the therapeutic effects of baicalein on diabetes and sought to clarify its underlying molecular mechanisms. Our results demonstrated that baicalein improves hyperglycemic, hyperinsulinemic, and glucometabolic disorders in mice with induced diabetes via GLP-1R. This was confirmed by the finding that baicalein's effects on improving IR were largely diminished in mice with whole-body Glp1r ablation. Complementarily, network pharmacology analysis highlighted the pivotal involvement of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) insulin signaling pathway in the therapeutic actions of baicalein on IR. Our mechanism research significantly confirmed that baicalein mitigates hepatic and muscular IR through the PI3K/AKT signal pathway, both in vitro and in vivo. Furthermore, we demonstrated that baicalein enhances glucose uptake in skeletal muscle cells under IR conditions through the Ca2+/calmodulin-dependent protein kinase II (CaMKII)-adenosine 5′-monophosphate-activated protein kinase (AMPK)-glucose transporter 4 (GLUT4) signaling pathway in a GLP-1R-dependent manner. In conclusion, our findings confirm the therapeutic effects of baicalein on IR and reveal that it improves IR in liver and muscle tissues through the PI3K/AKT insulin signaling pathway in a GLP-1R dependent manner. Moreover, we clarified that baicalein enhances the glucose uptake in skeletal muscle tissue through the Ca2+/CaMKII-AMPK-GLUT4 signal pathway. [ABSTRACT FROM AUTHOR]

Molybdenum disulfide has attracted significant research attention as a nanocatalyst for hydrogen evolution reaction. In this study, the effects of nanoribbons on the catalytic performance of molybdenum disulfide in the hydrogen evolution reaction are evaluated via the density functional theory. Co is considered to be an effective promoter of Mo-based catalysts. Thus, the promotion of the Mo-edge was studied here in a number of Co-substituted surface models. The results show that the electronic structure of the molybdenum disulfide nanoribbons changed after doping with Co atoms; this change significantly reduced the Gibbs free energy of the hydrogen evolution reaction and improved the reaction activity. In addition, the effects of stress regulation on the catalyst were analyzed. Tensile and compressive stresses were applied to the catalyst in the x direction. The results indicate that the distance between atoms changed owing to the effects of stress, and changes were also observed in the electronic properties. The insights obtained from this study will be helpful to further improve the activity of catalysts. [ABSTRACT FROM AUTHOR]

With practical electrocatalytic hydrogen production frequently involving the splitting of water in various pH media, there is an urgent need but still a technical challenge to develop low-cost, highly active, and stable electrocatalysts for pH-universal hydrogen evolution reaction (HER). We report herein the adoption of a hydrothermal reaction combined with a post gas-phase doping strategy to fabricate P-doped NiCo2Se4 hollow nanoneedle arrays on carbon fiber paper (i.e., P−NiCo2Se4/CFP). Notably, the optimal arrays (P8.71−NiCo2Se4/CFP) can afford an outstanding pH-universal HER performance, with an overpotential as low as 33, 57, and 69 mV at 10 mA·cm−2 and corresponding Tafel slopes down to 52, 61, and 72 mV·dec−1 in acidic, alkaline, and neutral media, respectively, outperforming most state-of-the-art nonprecious catalysts and even the commercial Pt/C catalyst in both neutral and alkaline media at large current densities. Impressively, P8.71−NiCo2Se4/CFP also displays good durability toward long-time stability testing in harsh acidic and alkaline electrolytes. Experimental and theoretical studies further reveal that the doping of P atoms into NiCo2Se4 can simultaneously optimize its H* adsorption/desorption energy, water adsorption energy, and water dissociation energy by adjusting the local electronic states of various active sites, thus accelerating the rate-determining step of HER in different pH media to endow P−NiCo2Se4 with an outstanding pH-universal HER performance. This work provides atomic-level insights into the roles of active sites in various electrolysis environments, thereby shedding new light on the rational design of highly efficient pH-universal nonprecious catalysts for HER and beyond. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are a kind of noncoding RNA, which plays an essential role in gene regulation by binding to messenger RNAs (mRNAs). Accurate and rapid identification of miRNA target genes is helpful to reveal the mechanism of transcriptome regulation, which is of great significance for the study of cancer and other diseases. Many bioinformatics methods have been proposed to solve this problem, but the previous research did not further study the encoding of the nucleotide sequence. In this paper, we developed a novel method combining word embedding and deep learning for human miRNA targets at the site-level prediction, which is inspired by the similarity between natural language and biological sequences. First, the word2vec model was used to mine the distribution representation of miRNAs and mRNAs. Then, the embedding is extracted automatically via the stacked bidirectional long short-term memory (BiLSTM) network. By testing, our method can effectively improve the accuracy, sensitivity, specificity, and F -measure of other methods. Through our research, it is proved that the distributed representation can improve the accuracy of the deep learning model and better solve the miRNA target site prediction problem. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN), one of the most detrimental microvascular complications of diabetes, is the leading cause of end-stage renal disease. The pathogenesis of DN is complicated, including hemodynamic changes, inflammatory response, oxidative stress, among others. Recently, many studies have demonstrated that mitophagy, especially PINK1/Parkin-mediated mitophagy, plays an important role in the pathogenesis of DN. Erythropoietin (EPO), a glycoprotein hormone mainly secreted by the kidney, regulates the production of erythrocytes. This research intends to explore the beneficial effects of EPO on DN and investigate related mechanisms. In in vitro experiments, we found that EPO promoted autophagic flux and alleviated mitochondrial dysfunction in terms of mitochondrial fragmentation, elevated mitochondrial ROS as well as the loss of mitochondrial potential, and lowered the apoptosis level in high-glucose-treated mesangial cells. Moreover, EPO increased protein expressions of PINK1 and Parkin, enhanced the co-localization of LC3 with mitochondria, Parkin with mitochondria as well as LC3 with Parkin, and increased the number of GFP-LC3 puncta, resulting in increased level of PINK1/Parkin-mediated mitophagy in mesangial cells. The knockdown of PINK1 abrogated the effect of EPO on mitophagy. In addition, in vivo experiments demonstrated that EPO attenuated renal injury, reduced oxidative stress, and promoted expressions of genes related to PINK1/Parkin-mediated mitophagy in the kidneys of DN mice. In summary, these results suggest that PINK1/Parkin-mediated mitophagy is involved in the development of DN and EPO mitigates DN by restoring PINK1/Parkin-mediated mitophagy. [ABSTRACT FROM AUTHOR]

• CUS induced down-regulation of RAGE and GLT-1 in hippocampus DG. • RAGE knockdown in hippocampus DG elicited depressive-like behaviors. • RAGE knockdown caused down-regulation of GLT-1, p-CREB and p-p65. • RAGE signaling in hippocampus involved in dysfunction of GLT-1 induced by CUS. A pivotal role of glutamatergic neurotransmission in the pathophysiology of major depressive disorder (MDD) has been supported in preclinical and clinical studies. Glutamate transporters are responsible for rapid uptake of glutamate to maintain glutamate homeostasis. Down-regulation of glutamate transporters has been reported in MDD patients and animal models. However, the mechanism for stress-induced modulation of glutamate transporter expression is poorly understood. Receptor for advanced glycosylation end products (RAGE), a member of immunoglobulin family, is found expressed widely in brain and play important roles in neuronal development, neurite growth, neurogenesis and neuroinflammation. Our study showed chronic unpredictable stress (CUS) induced depressive-like behaviors and reduced RAGE expression in hippocampus DG, CA1 and CA3 areas. The protein levels of GLT-1, p-CREB and p-p65 decreased in hippocampus DG as well. Knockdown of RAGE expression in hippocampus DG with RAGE shRNA lentivirus particles induced depressive-like behaviors. Meanwhile, the protein and mRNA levels of GLT-1 were significantly decreased as well as phosphorylation of CREB and p65. Neither CUS nor RAGE knockdown altered GLAST protein and mRNA levels. These findings suggested that RAGE/CREB-NF-κB signaling pathway in hippocampus DG involved in modulation of GLT-1 expression, which possibly contributed to the depressive-like behavior induced by CUS. [ABSTRACT FROM AUTHOR]

As compared to solar-blind ultraviolet (UV) photodetectors (PDs), far-UVC PDs not only show some irreplaceable advantages but also are more challenging to be developed. To solve this challenge, we report herein a soft template-assisted solvothermal route to synthesize ultrathin γ-Ga 2 O 3 quantum wires (UQWs) with diameters down to 1-2 nm. These UQWs all exhibit a cluster-like absorption feature with a strong peak located between 190 and 230 nm and an edge below 250 nm, allowing highly selective absorption to far-UVC light. Notably, their normalized absorption coefficients were experimentally and theoretically confirmed to increase obviously with decreasing their diameters. Self-powered photoelectrochemical-type PDs based on Ga 2 O 3 QWs of 1.7 nm diameter were therefore fabricated, exhibiting an excellent far-UVC detection performance with an unprecedented ultrahigh spectral selectivity ( R 210 nm / R 250 nm = 452). As a proof of concept, this paper offers a new idea for developing ultrawide bandgap semiconductor materials and devices by leveraging a strong quantum confinement effect.