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Tangerine peel is a traditional Chinese herb and has been widely applied in foods and medicine for its multiple pharmacological effects. Erythropoietin receptor (EPOR), a member of the cytokine receptor family, is widely expressed in multiple tissues in especial kidney and plays protective effects in adverse physiological and pathological conditions. We hypothesized that it might be EPOR agonists existing in Tangerine peel bring such renal benefits. To test our hypothesis, an EPOR/cell membrane chromatography (CMC)-high performance liquid chromatography (HPLC)-mass spectrometry (MS) analytical system was developed to screen EPOR targeted compounds from tangerine peel extra out. A fraction was retained on the EPOR/CMC column, separated, and further identified as nobiletin. Frontal analysis, non-linear chromatography, and molecular docking assay were applied to determine the binding force and sites between nobiletin and EPOR. Intracellular Ca 2+ mobilization, cAMP accumulation, and phosphorylation of JAK2 and STAT5 were determined to confirm the EPOR activation effect of nobiletin. CoCl 2 was applied to construct a renal hypoxic cell model, and cell viability and apoptosis of human glomerular mesangial cells (HMC) were carried out to assess the pharmacological effect of nobiletin. Apoptosis-related proteins including Bcl-2, Bcl-xL, Bax, Cleaved caspase 3, caspase 3, caspase 9, and Cytochrome C were determined. SiRNA and lentivirus were used to silence or overexpress EPOR. Our results indicated that nobiletin is a potential EPOR agonist, reflected on its explicit binding force and downstream signal activating effects. Furthermore, EPOR-overexpressing enhanced the hypoxia-tolerance of renal cells. Our mechanism research indicated that the protective effect of nobiletin against hypoxia was depended on its pro-proliferation and anti-apoptosis effects. In conclusion, nobiletin, a potential small molecular agonist of EPOR, protects HMC against hypoxia through positively activating EPOR., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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 Ca 2+ /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 Ca 2+ /CaMKII-AMPK-GLUT4 signal pathway.

There is increasing evidence that the activation of glucagon-like peptide-1 receptor (GLP-1R) can be used as a therapeutic intervention for cognitive disorders. Here, we have screened GLP-1R targeted compounds from Scutellaria baicalensis , which revealed baicalein is a potential GLP-1R small-molecule agonist. Mitophagy, a selective autophagy pathway for mitochondrial quality control, plays a neuroprotective role in multiple cognitive impairment diseases. We noticed that Glp1r knock-out (KO) mice present cognitive impairment symptoms and appear worse in spatial learning memory and learning capacity in Morris water maze (MWM) test than their wide-type (WT) counterparts. Our mechanistic studies revealed that mitophagy is impaired in hippocampus tissue of diabetic mice and Glp1r KO mice. Finally, we verified that the cognitive improvement effects of baicalein on diabetic cognitive dysfunction occur through the enhancement of mitophagy in a GLP-1R-dependent manner. Our findings shed light on the importance of GLP-1R for cognitive function maintenance, and revealed the vital significance of GLP-1R for maintaining mitochondrial homeostasis. Furthermore, we identified the therapeutic potential of baicalein in the treatment of cognitive disorder associated with diabetes., Competing Interests: The authors declare that the Editor-in-Chief Prof. Langchong He and the Section Editor Weina Ma didn't give additional favor for the submittion and publication of this work. And we declare that no known competing financial interests or personal relationships could have appeared to influence the work., (© 2024 The Authors.)

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.

Diabetes mellitus is a metabolic disease that is characterized by elevated blood sugar. Although glucagon-like peptide-1 receptor agonists (GLP-1RA) lower blood glucose in a glucose-dependent manner, most of them are macromolecule polypeptides. Macromolecular peptides are relatively expensive and inconvenient compared with small molecules. Therefore, this study sought to identify the small molecules binding to GLP-1R via cell membrane chromatography (CMC), confirm their agonistic activity, and further study its beneficial effects in a mouse model of type 2 diabetes mellitus (T2DM) induced by a combination of high-fat diet and streptozotocin. We used CMC, calcium imaging and molecular docking techniques to screen and identify the potential small molecule Schisandrin B (Sch B), which exhibits a strong binding effect to GLP-1R, from the small molecule library of traditional Chinese medicine. Through in-vitro experiments, we found that Sch B stimulated insulin secretion in β-TC-6 cells, while GLP-1R antagonist Exendin9-39, adenylate cyclase inhibitor SQ22536, and protein kinase A (PKA) inhibitor H89 could significantly inhibit the insulin secretion induced by Sch B. In vivo, Sch B significantly improved fasting blood glucose levels, intraperitoneal glucose tolerance test damage, and the status of pancreatic tissue damage, and reduced serum insulin levels, total cholesterol, triglyceride and low density lipoprotein in T2DM mice. These results indicate that Sch B alleviates T2DM by promoting insulin release through the GLP-1R/cAMP/PKA signaling pathway, suggesting that Sch B may be a potential GLP-1RA, which is expected to provide a new therapeutic strategy for the prevention and treatment of T2DM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: The incidence of diabetic cognitive dysfunction is increasing year by year, and it has gradually become a research hot spot. Studies have shown that glucagon-like peptide-1 receptor (GLP-1R) agonists can improve cognitive dysfunction in diabetic patients. This study focuses on whether small molecule GLP-1R agonists from traditional Chinese medicine (TCM) can improve the diabetic cognitive dysfunction., Materials and Methods: The small molecules from TCM were screened by cell membrane chromatography (CMC) with GLP-1R-HEK293 cell membrane column. MTT assay, flow cytometry, immunofluorescence cytochemistry and other methods were used to determine the effects of mollugin on the apoptosis rate and reactive oxygen species (ROS) level of high glucose (HG)/hydrogen peroxide (H 2 O 2 ) induced PC12 cells. Real-Time PCR was used to detect mRNA expression in mouse cerebral cortex. Water maze test was further used to confirm the effect of mollugin on cognitive dysfunction in T2DM mice., Key Findings: Mollugin bound to GLP-1R, promoted Ca 2+ influx, increased insulin secretion and cAMP content in β-TC-6 cells. Mollugin enhanced the cell viability, ameliorated apoptosis, reduced intracellular ROS levels in HG/H 2 O 2 -injured PC12 cells. Mollugin reduced the T2DM mice's escape latency, improved neuronal cell damage, decreased the expression of Pik3ca, Akt1 and Mapk1 mRNA in the cerebral cortex tissue., Significance: The results suggest that mollugin could improve cognitive dysfunction in T2DM mice through activating GLP-1R/cAMP/PKA signal pathway., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Background: Non-alcoholic fatty liver disease (NAFLD) is one of the most common complications of type 2 diabetes mellitus (T2DM). The pathogenesis of NAFLD involves multiple biological changes, including insulin resistance, oxidative stress, inflammation, as well as genetic and environmental factors. Liraglutide has been used to control blood sugar. But the impact of liraglutide on T2DM-associated NAFLD remains unclear. In this study, we investigated the impact and potential molecular mechanisms of inhibiting ferroptosis for liraglutide improves T2DM-associated NAFLD., Methods: Mice were fed on high-fat-diet and injected with streptozotocin to mimic T2DM-associated NAFLD and gene expression in liver was analysed by RNA-seq. The fast blood glucose was measured during the period of liraglutide and ferrostatin-1 administration. Hematoxylin and eosin staining was used to evaluate the pathological changes in the liver. The occurrence of hepatic ferroptosis was measured by lipid peroxidation in vivo. The mechanism of liraglutide inhibition ferroptosis was investigated by in vitro cell culture., Results: Liraglutide not only improved glucose metabolism, but also ameliorated tissue damage in the livers. Transcriptomic analysis indicated that liraglutide regulates lipid metabolism related signaling including AMPK and ACC. Furthermore, ferroptosis inhibitor rather than other cell death inhibitors rescued liver cell viability in the presence of high glucose. Mechanistically, liraglutide-induced activation of AMPK phosphorylated ACC, while AMPK inhibitor compound C blocked the liraglutide-mediated suppression of ferroptosis. Moreover, ferroptosis inhibitor restored liver function in T2DM mice in vivo., Conclusions: These findings indicate that liraglutide ameliorates the T2DM-associated NAFLD, which possibly through the activation of AMPK/ACC pathway and inhibition of ferroptosis., (© 2023. The Feinstein Institute for Medical Research.)

Type 2 diabetes mellitus (T2DM) is strongly associated with an increased risk of developing cognitive dysfunction. Numerous studies have indicated that erythropoietin (EPO) has neurotrophic effects. Ferroptosis has been reported to be associated with diabetic cognitive dysfunction. However, the impact of EPO on T2DM-associated cognitive dysfunction and its protective mechanism remain unclear. To evaluate the effects of EPO on diabetes-associated cognitive dysfunction, we constructed a T2DM mouse model and found that EPO not only decreased fasting blood glucose but also ameliorated hippocampal damage in the brain. The Morris water maze test indicated that EPO improved cognitive impairments in diabetic mice. Moreover, a ferroptosis inhibitor improved cognitive dysfunction in mice with T2DM in vivo. Furthermore, a ferroptosis inhibitor, but not other cell death inhibitors, mostly rescued high-glucose damaged PC12 cell viability. EPO had a similar effect as the ferroptosis inhibitor, which increased cell viability in the presence of a ferroptosis inducer. In addition, EPO reduced lipid peroxidation, iron levels, and regulated ferroptosis-related expression of proteins in vivo and in vitro. These findings indicate that EPO ameliorates T2DM-associated cognitive dysfunction, which might be related to decreasing iron overload and inhibiting ferroptosis., Competing Interests: Declaration of Competing Interest The authors declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Recent studies have shown that erythropoietin (EPO) is an effective neuroprotective and neurotrophic agent for neurological disorders, such as traumatic brain injury and Alzheimer's disease. However, the effectiveness of EPO administration against diabetic cognitive impairments has rarely been examined. In this study, we investigated the effects of EPO on streptozotocin (STZ)-induced male C57BL/6 J mice. Then, we sought to clarify the mechanisms of EPO-mediated neuroprotection in high-glucose (HG)-stimulated HT22 cells. In vivo, we found that STZ-induced diabetic mice showed impaired spatial learning and memory, which was alleviated by EPO treatment. EPO also significantly lowered elevated fasting blood glucose levels, improved pancreatic and hippocampal damage, and restored oxidative stress in the STZ-induced diabetic mice. In vitro, EPO markedly increased cell viability, restrained the expression of pro-apoptotic Bax, enhanced the expression of pro-caspase 3, anti-apoptotic Bcl-2, brain-derived neurotrophic factor (BDNF) and postsynaptic density 95 (PSD-95), and attenuated the upregulation of N-methyl-d-aspartic acid (NMDA) receptor subunits NR1, NR2A and NR2B in HG-induced HT22 cells. The protective effects of EPO was obviously abolished by treatment with an NMDA receptor agonist. Our findings revealed that EPO impedes hippocampal and synaptic damage and neuronal apoptosis by regulating BDNF and PSD-95 expression through NMDA receptors, thereby ameliorating cognitive impairments in mice with T1DM., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., Competing Interests: There is no conflicts of interest., (Copyright © 2022 Yuzhuo Sun et al.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yi, Yan, Guo, Liu, Wang, Shang, Wei, Cui, Sun, Ren and Chen.)

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., (Copyright © 2020 Elsevier Inc. All rights reserved.)