Glycogen synthase 1 (GYS1) is the rate-limiting enzyme responsible for glycogen synthesis in skeletal muscle, heart, brain, and other extrahepatic tissues, playing a central role in systemic energy homeostasis. The human GYS1 gene maps to chromosome 19q13.33, comprises 16 exons, and encodes a 737-amino-acid polypeptide that is highly conserved across mammals. GYS1 activity is subject to multilayered and precisely coordinated regulation. At the transcriptional level, the GYS1 promoter contains a hypoxia response element (HRE) that mediates HIF-1α-dependent induction under low-oxygen conditions, as well as a muscle-specific enhancer harboring MEF2 and MyoD binding sites that confers tissue-restricted expression. At the post-translational level, a hierarchical phosphorylation cascade serves as the primary activity switch: glycogen synthase kinase 3β (GSK3β) sequentially phosphorylates four C-terminal serine residues following casein kinase II priming, while protein kinase A (PKA) and AMP-activated protein kinase (AMPK) provide parallel inhibitory inputs at both N- and C-terminal sites. Dephosphorylation and reactivation are mediated by protein phosphatase 1 (PP1) through tissue-specific glycogen-targeting regulatory subunits such as PPP1R3A and PPP1R3B, which anchor PP1 to glycogen particles and direct its activity toward GYS1. The allosteric activator glucose-6-phosphate (G6P) binds at the dimer interface, simultaneously enhancing catalytic efficiency and promoting dephosphorylation susceptibility, thereby establishing a feed-forward activation loop that couples substrate availability to glycogen synthesis. Beyond phosphorylation, GYS1 is regulated by ubiquitination (mediated by the E3 ligase PJA1), acetylation, O-linked β-N-acetylglucosamine (O-GlcNAc) modification, and SUMOylation, which collectively modulate protein stability, subcellular localization, and protein-protein interactions. Epigenetic mechanisms, including CpG island methylation and histone acetylation dynamics, govern chromatin accessibility at the GYS1 locus, while muscle-specific microRNAs such as miR-1 and miR-206 fine-tune GYS1 expression at the post-transcriptional level. Dysregulation of GYS1 has been identified as a central pathogenic driver in a spectrum of human diseases. In inherited glycogen storage disorders—including Lafora disease, adult polyglucosan body disease (APBD), and Pompe disease—loss of upstream regulatory control leads to GYS1 hyperactivation and the accumulation of structurally abnormal or excessive glycogen, resulting in progressive neurodegeneration, myopathy, and multiorgan dysfunction. In type 2 diabetes mellitus (T2DM), impaired insulin signaling through the PI3K-AKT-GSK3β axis maintains GYS1 in a hyperphosphorylated inactive state in skeletal muscle, compromising postprandial glucose disposal and exacerbating hyperglycemia. In oncology, GYS1 exhibits context-dependent roles across multiple cancer types. In hepatocellular carcinoma, FMO2⁺ cancer-associated fibroblasts stabilize GYS1 by competitively inhibiting PJA1-mediated ubiquitination, and stabilized GYS1 subsequently activates NF‑κB/CCL19 signaling to promote tertiary lymphoid structure formation and enhance anti-PD-1 immunotherapy responsiveness. In clear cell renal cell carcinoma, GYS1 promotes tumor progression through non-canonical NF‑κB pathway activation via the scaffold protein RPS27A. In triple-negative breast cancer, GYS1 has been identified as a trigger of disulfidptosis and an activator of NF-κB signaling through non-enzymatic facilitation of IκBα degradation. In colorectal cancer, mitochondrial fission deficiency drives AMPK-dependent GYS1 upregulation and glycogen accumulation as a compensatory survival mechanism, while in cervical cancer, GYS1-maintained glycogen reserves fuel the pentose phosphate pathway to generate NADPH for ROS clearance, thereby conferring cisplatin resistance in cancer stem cells. Therapeutic strategies targeting GYS1 have gained substantial momentum across these disease contexts. For glycogen storage disorders, antisense oligonucleotides, small interfering RNAs (e.g., ABX1100), and small-molecule inhibitors (e.g., MZ-101) have demonstrated preclinical and early clinical efficacy in reducing pathological glycogen accumulation. For T2DM, pharmacological activation of GYS1 through GSK3β inhibition or enhancement of PP1-mediated dephosphorylation is being explored to restore insulin-stimulated glycogen synthesis. In cancer, GYS1-directed interventions—including targeted silencing to sensitize tumors to chemotherapy and immune microenvironment modulation to enhance immunotherapy—represent emerging precision oncology approaches. This review provides a comprehensive and integrated account of GYS1 gene structure, tissue-specific distribution, regulatory networks, and pathogenic roles in metabolic disorders and malignancies, with the aim of establishing a theoretical framework for the development of GYS1-targeted precision therapies.

AIM To investigate effects of petroleum ether fraction from Derris eriocarpa How on glucose and lipid metabolism in a mouse model of metabolic syndrome(MS).METHODS KM mice were fed a high-fat diet and administered streptozotocin intraperitoneally to establish MS models.The MS mice were then randomly assigned to the model group,the metformin hydrochloride group,the lovastatin group,the ursolic acid group,and the high-,medium-and low-dose D.eriocarpa petroleum ether fraction groups,with 10 mice in each group.Ten additional mice maitained on a normal diet served as the normal control group.After 4 weeks of intragastric administration,glucose and lipid metabolism indicators were measured.Hepatic pathological changes were assessed using HE staining and oil red O staining.Liver tissue mRNA expressions of ATF3,PEPCK,FXR,CYP7A1,HNF4ɑ,CYP8B1 and SRB1 were quantified by RT-qPCR.Hepatic protein expressions of ATF3,HNF4ɑ,PEPCK,FXR and CYP7A1 was analyzed by Western blot in MS mice.RESULTS Compared to the model group,the high-dose D.eriocarpa petroleum ether fraction group exhibited significant glucose tolerance improvement(reduced OGTT-AUC,P＜0.01);favorable serum lipid modulation in terms of increased HDL-C levels(P＜0.01)and decreased TG,TC,LDL-C(P＜0.01);reduced renal biomarkers(BUN,SCR)and hepatotoxic indicators of TBA,AST and ALT activities(P＜0.01);alleviated hepatic lipid accumulation and histopathological damage;downregulated mRNA and protein expressions of ATF3,HNF4ɑ and PEPCK,as well as CYP8B1 mRNA expression(P＜0.01);and upregulated mRNA and protein expressions of FXR and CYP7A1,along with SRB1 mRNA expression(P＜0.01).CONCLUSION D.eriocarpa petroleum ether fraction ameliorates glucose and lipid metabolism dysregulation in MS mice by modulating the ATF3/HNF4ɑ/CYP7A1 signaling pathway,consequently eliciting hypoglycemic,hypolipidemic,hepatoprotective and nephroprotective effects.

Aim To investigate the effects of circ_0071653 targeting miR-197-3p on the proliferation and metastasis of esophageal squamous cell carcinoma(ES-CC)cells.Methods The circular structure of circ_0071653 was confirmed by Sanger sequencing and ribo-nuclease R tolerance experiments.Real-time quantita-tive polymerase chain reaction(RT-qPCR)and tissue fluorescence in situ hybridization assay were performed to detect the circ_0071653 expression levels and ana-lyze its clinical relevance.Cell fluorescence in situ hy-bridization and nuclear cytoplasmic separation assays were used to verify the subcellular localization of circ_0071653 and miR-197-3p.Bioinformatics analysis,dual luciferase reporter gene and RT-qPCR assays were conducted to validate the interactions between circ_0071653 and miR-197-3p.Moreover,the cell counting Kit-8(CCK-8),colony formation,scratch,Transwell invasion and subcutaneous tumor formation in nude mice assays were used to evaluate the effects of circ_0071653 and miR-197-3p on cell viability,prolifera-tion,migration,and invasion and in vivo tumorigenesi-sability.Results Circ_0071653 was a circular RNA,which showed high expression in ESCC cell lines and tissues.The expression of circ_0071653 was signifi-cantly correlated with lymph node metastasis and clini-cal stage of ESCC patients.Circ_0071653 and miR-197-3p were mainly localized in the cytoplasm.The databases predict that circ_0071653 had complementa-ry binding sites with miR-197-3p,and their binding were confirmed by dual luciferase reporter geneand RT-qPCR assays.Moreover,the activity,proliferation,migration,invasion and in vivo tumorigenesis abilities of ESCC cells were significantly reduced after knocking down circ_0071653,and this effect could be reversed by downregulating the expression of miR-197-3p.Con-clusions Circ_0071653 promotes the malignant pro-gression of ESCC through targeted regulation of miR-197-3p.

OBJECTIVE: This study aimed to explore the association between body mass index (BMI) and mortality based on the 10-year population-based multicenter prospective study. METHODS: A general population-based multicenter prospective study was conducted at four sites in rural China between 2013 and 2023. Multivariate Cox proportional hazards models and restricted cubic spline analyses were used to assess the association between BMI and mortality. Stratified analyses were performed based on the individual characteristics of the participants. RESULTS: Overall, 19,107 participants with a sum of 163,095 person-years were included and 1,910 participants died. The underweight (< 18.5 kg/m ²) presented an increase in all-cause mortality (adjusted hazards ratio [ aHR] = 2.00, 95% confidence interval [ CI]: 1.66-2.41), while overweight (≥ 24.0 to < 28.0 kg/m ²) and obesity (≥ 28.0 kg/m ²) presented a decrease with an aHR of 0.61 (95% CI: 0.52-0.73) and 0.51 (95% CI: 0.37-0.70), respectively. Overweight ( aHR = 0.76, 95% CI: 0.67-0.86) and mild obesity ( aHR = 0.72, 95% CI: 0.59-0.87) had a positive impact on mortality in people older than 60 years. All-cause mortality decreased rapidly until reaching a BMI of 25.7 kg/m ² ( aHR = 0.95, 95% CI: 0.92-0.98) and increased slightly above that value, indicating a U-shaped association. The beneficial impact of being overweight on mortality was robust in most subgroups and sensitivity analyses. CONCLUSION This study provides additional evidence that overweight and mild obesity may be inversely related to the risk of death in individuals older than 60 years. Therefore, it is essential to consider age differences when formulating health and weight management strategies.
Humans ; Body Mass Index ; China/epidemiology* ; Male ; Female ; Middle Aged ; Prospective Studies ; Rural Population/statistics & numerical data* ; Aged ; Follow-Up Studies ; Adult ; Mortality ; Cause of Death ; Obesity/mortality* ; Overweight/mortality*

Aim To investigate the effects of circ_0071653 targeting miR-197-3p on the proliferation and metastasis of esophageal squamous cell carcinoma(ES-CC)cells.Methods The circular structure of circ_0071653 was confirmed by Sanger sequencing and ribo-nuclease R tolerance experiments.Real-time quantita-tive polymerase chain reaction(RT-qPCR)and tissue fluorescence in situ hybridization assay were performed to detect the circ_0071653 expression levels and ana-lyze its clinical relevance.Cell fluorescence in situ hy-bridization and nuclear cytoplasmic separation assays were used to verify the subcellular localization of circ_0071653 and miR-197-3p.Bioinformatics analysis,dual luciferase reporter gene and RT-qPCR assays were conducted to validate the interactions between circ_0071653 and miR-197-3p.Moreover,the cell counting Kit-8(CCK-8),colony formation,scratch,Transwell invasion and subcutaneous tumor formation in nude mice assays were used to evaluate the effects of circ_0071653 and miR-197-3p on cell viability,prolifera-tion,migration,and invasion and in vivo tumorigenesi-sability.Results Circ_0071653 was a circular RNA,which showed high expression in ESCC cell lines and tissues.The expression of circ_0071653 was signifi-cantly correlated with lymph node metastasis and clini-cal stage of ESCC patients.Circ_0071653 and miR-197-3p were mainly localized in the cytoplasm.The databases predict that circ_0071653 had complementa-ry binding sites with miR-197-3p,and their binding were confirmed by dual luciferase reporter geneand RT-qPCR assays.Moreover,the activity,proliferation,migration,invasion and in vivo tumorigenesis abilities of ESCC cells were significantly reduced after knocking down circ_0071653,and this effect could be reversed by downregulating the expression of miR-197-3p.Con-clusions Circ_0071653 promotes the malignant pro-gression of ESCC through targeted regulation of miR-197-3p.

AIM To investigate effects of petroleum ether fraction from Derris eriocarpa How on glucose and lipid metabolism in a mouse model of metabolic syndrome(MS).METHODS KM mice were fed a high-fat diet and administered streptozotocin intraperitoneally to establish MS models.The MS mice were then randomly assigned to the model group,the metformin hydrochloride group,the lovastatin group,the ursolic acid group,and the high-,medium-and low-dose D.eriocarpa petroleum ether fraction groups,with 10 mice in each group.Ten additional mice maitained on a normal diet served as the normal control group.After 4 weeks of intragastric administration,glucose and lipid metabolism indicators were measured.Hepatic pathological changes were assessed using HE staining and oil red O staining.Liver tissue mRNA expressions of ATF3,PEPCK,FXR,CYP7A1,HNF4ɑ,CYP8B1 and SRB1 were quantified by RT-qPCR.Hepatic protein expressions of ATF3,HNF4ɑ,PEPCK,FXR and CYP7A1 was analyzed by Western blot in MS mice.RESULTS Compared to the model group,the high-dose D.eriocarpa petroleum ether fraction group exhibited significant glucose tolerance improvement(reduced OGTT-AUC,P＜0.01);favorable serum lipid modulation in terms of increased HDL-C levels(P＜0.01)and decreased TG,TC,LDL-C(P＜0.01);reduced renal biomarkers(BUN,SCR)and hepatotoxic indicators of TBA,AST and ALT activities(P＜0.01);alleviated hepatic lipid accumulation and histopathological damage;downregulated mRNA and protein expressions of ATF3,HNF4ɑ and PEPCK,as well as CYP8B1 mRNA expression(P＜0.01);and upregulated mRNA and protein expressions of FXR and CYP7A1,along with SRB1 mRNA expression(P＜0.01).CONCLUSION D.eriocarpa petroleum ether fraction ameliorates glucose and lipid metabolism dysregulation in MS mice by modulating the ATF3/HNF4ɑ/CYP7A1 signaling pathway,consequently eliciting hypoglycemic,hypolipidemic,hepatoprotective and nephroprotective effects.

Objective:To systematically evaluate the clinical efficacy and safety of Tonifying kidney and activating blood thera-py for the treatment of diabetic mellitus erectile dysfunction.Methods:China National Knowledge Infrastructure(CNKI),Wanfang Data,VIP,Chinese Biomedical Database(CBM),PubMed,Cochrane Library,Embase and Web of Science were searched from incep-tion until October 20th of 2024,for randomized controlled trials of Tonifying kidney and activating blood therapy for the treatment of dia-betic erectile dysfunction.Literature screening,quality evaluation,and data extraction were carried out in accordance with relevant standards.The software of RevMan5.4 was used for the analysis of publication bias.And meta-analysis was conducted to assess the im-pact of this therapy on IIEF-5,total effective rate,adverse reactions.The evidence levels according to the analysis results were evalua-ted.Results:Totally 19 RCTs were included,involving 1 612 patients.The result of meta-analysis indicated that Tonifying kidney and activating blood therapy had advantages on the improvement of IIEF-5 scores(MD=3.59,95％CI[2.14,5.03],P＜0.01),total effective rate(OR=4.30,95％CI[3.29,5.32],P＜0.000 01).However,there was no statistically significant difference in the inci-dence of adverse reactions(OR=0.98,95％CI[0.48,2.01],P=0.96)between the two groups.Conclusions:Tonifying kidney and activating blood therapy can improve the clinical efficacy and IIEF-5 score for the patients with diabetic erectile dysfunction.But considering the limited quantity of included studies,more high-quality studies still be needed to validate the therapeutic effect.

[Purpose]To investigate the acceptance and willingness-to-pay(WTP)of combined can-cer screening among rural residents in Shandong Province,and to analyze its influencing factors.[Methods]A face-to-face questionnaire survey was conducted among rural residents aged 40～70 in villages setected by cluster sampling from three counties(county level city or district)in Shan-dong Province.The questionnaire was developed using the method of double-bound dichotomous choice combined with open-ended questions in contingent valuation.The factors influencing inten-sity of WTP was analyzed with using single-factor and ordinary least squares regression models.[Results]A total of 962 subjects were surveyed.89.19％of the respondents were willing to accept cancer combined screening,and 62.00％were willing to pay part of the costs.The average of WTP was 963.67 CNY,which accounted for 32.12％of the total cost.The proportion of respon-dents who were willing to pay between 0～1 500 CNY was the highest(76.49％).In the multivariate analysis,age,sex and income had significant effects on the maximum payment of multi-cancer screening.[Conclusion]The acceptance of multi-cancer screening among rural residents in the study sites is high,but the willingness-to-pay is limited.The out-of-pocket payment for multi-can-cer screening should be controlled,and a co-payment mechanism among government,enterprises,social organizations and individuals should be explored.

Aim To investigate the therapeutic effects of corylifol A(CYA)on Lewis lung carcinoma(LLC)cachexia mice and its ameliorating effects on myotube atrophy induced by LLC cell-conditioned medium(LLC CM)in vitro,and to explore the mechanisms.Methods The cancer cachexia was induced by subcu-taneous inoculation of LLC cells to C57BL/6J mice.The effects of CYA(10,20 mg·kg-1·d-1,i.p.)on the cachexia symptoms and survival time of cachexia mice were observed.The effects of 2.5 or 5 μmol·L-1 CYA on myotube atrophy of C2C12 induced by LLC CM were observed.The effects of CYA on its pos-sible target the serine/threonine-protein kinase TAO1(TAOK1)and downstream signaling pathways were detected using Western blot.The influence of TAOK1 knockout on the ameliorating effects of CYA on myo-tube atrophy was observed.Results CYA could sig-nificantly prolong the survival time of tumor-bearing mice and ameliorate the muscle atrophy associated with LLC.The effects of CYA on myotube atrophy are relat-ed to its regulation of TAOK1.The effects of CYA could be reduced by knockout of TAOK1.Conclusions CYA improves the survival of LLC cachexia mice and ameliorates the related skeletal muscle atrophy.The mechanism of CYA is related to its inhibition on TAOK1 and downstream signaling pathways.