OBJECTIVE To explore hypoglycemic effect of 95%ethanol fraction of Nitraria roborowskii Kom(NRK-C)and its possible mechanism evaluated in the type 2 diabetes mellitus(T2DM)mice.METHODS The body weight,organ indices,bl...OBJECTIVE To explore hypoglycemic effect of 95%ethanol fraction of Nitraria roborowskii Kom(NRK-C)and its possible mechanism evaluated in the type 2 diabetes mellitus(T2DM)mice.METHODS The body weight,organ indices,blood glucose levels,serum biochemical indexes,as well as HE/PAS histopathological section were all analyzed to assess the hypoglycemic effect of NRK-C in T2DM mice induced by a high-fat diet(HFD)combined with six intraperitoneal injections of 35 mg·kg^(-1)of streptozotocin(STZ).The Western blotting and immunofluorescence were further applied to determine the regulatory effect of NRK-C on key signaling proteins.RESULTS The fasting blood glucose levels were significantly reduced after 7 weeks of administration of NRK-C.In addition,NRK-C could also significantly improve glucose tolerance,hepatic glycogen levels,and lipid levels(total cholesterol,triglyceride,low density lipoprotein and high density lipoprotein),and significantly reduced insulin resistance of diabetic mice,which played an important role in the antidiabetic effects.Further mechanism research demonstrated that phosphorylated PI3K expression was up-regulated and p-GSK3βexpression was up-regulated after NRK-C intervention,indicating that NRK-C might exert a potential antidiabetic effect by modulating the PI3K/AKT signaling pathway.CONCLUSION All these results suggested that NRK-C might improve T2DM and had the potential to be used as an adjunctive therapy.展开更多
Objective:To investigate the influence and underlying mechanisms of imrecoxib on liver damage in rats with type 2 diabetes mellitus(T2DM).Methods:A rat model of T2DM was established by a high-fat diet and streptozotoc...Objective:To investigate the influence and underlying mechanisms of imrecoxib on liver damage in rats with type 2 diabetes mellitus(T2DM).Methods:A rat model of T2DM was established by a high-fat diet and streptozotocin administration.Rats were then treated with imrecoxib 10,20,or 40 mg/kg for 5 weeks.Body weight and fasting blood glucose levels were measured.The analysis included serum liver function,blood lipid profiles,and the levels of inflammatory factors in the rats.Liver tissue histology was evaluated using hematoxylin and eosin staining.Western blotting was conducted to measure the liver expression of proteins such as AKT,PI3K,NF-κB,p-AKT,p-PI3K,and p-NF-κB.Results:Rats treated with imrecoxib showed a greater weight gain compared to untreated diabetic rats.Compared to untreated diabetic rats,imrecoxib at all three doses reduced alanine aminotransferase,aspartate aminotransferase,triglycerides,cholesterol,tumor necrosis factor-α,interleukin(IL)-6,and IL-1β,and significantly increased the levels of IL-10 and IL-4.In imrecoxib-treated rats,the expression levels of AKT,PI3K,p-AKT,and p-PI3K were higher in comparison to the diabetes group,whereas the expression of p-NF-κB was lower.Conclusions:Imrecoxib could alleviate hepatic damage in T2DM rats by modulating PI3K/AKT/NF-κB signaling.展开更多
Epidemiological studies have indicated that branched-chain amino acids(BCAAs)increased and gut microbiota disordered in type 2 diabetes mellitus(T2DM).This study aimed to investigate the mechanism of Lactiplantibacill...Epidemiological studies have indicated that branched-chain amino acids(BCAAs)increased and gut microbiota disordered in type 2 diabetes mellitus(T2DM).This study aimed to investigate the mechanism of Lactiplantibacillus plantarum strain 84-3(Lp84-3)combined with Staphylococcus aureus bacteriophage on ameliorating T2DM.Here we perform a case-control study and identify that Staphylococcus_phage was inversely correlated with fasting blood glucose(FBG).It revealed that Lp84-3 could inhibit the growth of S.aureus,and Lp84-3 contains BCAAs degradation enzymes in its genome.Furthermore,Lp84-3 alone or combined with S.aureus bacteriophage interventions can improve blood glucose,insulin resistance,triglycerides,interleukin-1β,tumor necrosis factor-α(TNF-α),BCAAs,and acetyllactate synthase(ALS)in db/db mice.Lp84-3 and S.aureus bacteriophage decreased S.aureus,Malacoplasma iowae,and Oscillibacter sp.,and increased some beneficial such as L.plantarum and Muribaculaceae bacterium.Transcriptomic analyses revealed that Lp84-3 and S.aureus bacteriophage activated the PI3K/AKT/GLUT4 signaling pathway and upregulated key genes of Il22,Hgf,Col6a1,Gh,Itga10,Fgf23,and Prl involved in glucose metabolism in hypothalamus.Collectively,Lp84-3 and S.aureus bacteriophage alleviate T2DM by modulating gut microbiota and enhancing glucose metabolism in hypothalamus,supporting its potential use as a promising functional compound microecological agent for alleviating T2DM.展开更多
目的探讨弱氧化性低密度脂蛋白(minimally modified low density lipoprotein,mmLDL)上调在体小鼠肠系膜动脉ETA受体的作用(endothelin type A receptors,ETA)并考察自噬是否参与这一过程。方法小鼠尾静脉注射mmLDL,腹腔注射ClassⅢPI3...目的探讨弱氧化性低密度脂蛋白(minimally modified low density lipoprotein,mmLDL)上调在体小鼠肠系膜动脉ETA受体的作用(endothelin type A receptors,ETA)并考察自噬是否参与这一过程。方法小鼠尾静脉注射mmLDL,腹腔注射ClassⅢPI3K自噬通路抑制剂6-氨基-3-甲基嘌呤(3-methyladenine,3-MA),探究自噬在mmLDL给药处理小鼠中的作用,微血管张力描记仪观察内皮素-1(endothelin-1,ET-1)引起的小鼠肠系膜动脉收缩量效曲线的变化,RT-PCR定量ETA受体mRNA,Western blot检测ETA受体和ClassⅢPI3K、Beclin-1、LC3-Ⅱ/Ⅰ、p62及p-NF-κB、NF-κB的蛋白水平表达。结果mmLDL引起ET-1收缩量效曲线明显增强,表现为Emax值由生理盐水(NS)组的(184.87±7.46)%上升为(319.91±20.31)%(P<0.001),pEC50值由NS组的(8.05±0.05)上升为(9.11±0.09)(P<0.01)。mmLDL在上调ClassⅢPI3K、beclin-1、LC3-Ⅱ/Ⅰ和下调p62蛋白水平的同时,也引起ETA受体mRNA水平、蛋白表达明显增加,增加了p-NF-κB的蛋白水平;腹腔注射3-MA抑制了mmLDL的这些作用。结论mmLDL能通过ClassⅢPI3K/Beclin-1通路激活自噬及下游NF-κB通路上调ETA受体。展开更多
OBJECTIVE:To investigate the effects of Jiawei Huangqi Guizhi decoction(加味黄芪桂枝汤)on chronic atrophic gastritis(CAG)in rats and its modulation of the phosphatidylinositol 3-kinase/protein kinase B/mechanistic tar...OBJECTIVE:To investigate the effects of Jiawei Huangqi Guizhi decoction(加味黄芪桂枝汤)on chronic atrophic gastritis(CAG)in rats and its modulation of the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin complex 2(PI3K/Akt/m TORC2)signaling pathway.METHODS:CAG was induced in rats and treated with high-,medium-,or low-dose Jiawei Huangqi Guizhi decoction.Gastric histopathology was observed by hematoxylin and eosin staining.Serum levels of gastrin,PI3K,Akt,and m TORC2 were detected by enzyme-linked immunosorbent assay.Gene and protein expression levels were analyzed by reverse transcription polymerase chain reaction and western blot.RESULTS:The decoction alleviated gastric mucosal injury,reduced inflammation,and restored epithelial structure.It regulated PI3K,Akt,and m TORC2 expression at both m RNA and protein levels.CONCLUSION:Jiawei Huangqi Guizhi decoction may prevent CAG progression by improving gastric tissue and modulating the PI3K/Akt/m TORC2 signaling pathway.展开更多
BACKGROUND Type 2 diabetes mellitus(T2DM)is associated with significant metabolic and renal complications,including diabetic nephropathy(DN).AIM To investigate the role of ribonucleotide reductase regulatory subunit M...BACKGROUND Type 2 diabetes mellitus(T2DM)is associated with significant metabolic and renal complications,including diabetic nephropathy(DN).AIM To investigate the role of ribonucleotide reductase regulatory subunit M2(RRM2)in T2DM and its potential involvement in renal injury through oxidative stress,apoptosis,and ferroptosis.METHODS A cross-sectional study was conducted,comprising 194 patients with T2DM and 120 healthy controls at our hospital between January 2022 and December 2023.The data were analyzed to ascertain the correlation between RRM2 levels and DN onset in patients with T2DM.The apoptosis rate,reactive oxygen species(ROS)levels,oxidative stress,cystine uptake,and ferrous ion(Fe2+)levels were quantified using the HK-2 cell lysates.Reverse transcription quantitative PCR and western blotting were used to assess mRNA and protein expression,respectively.RESULTS Serum RRM2 levels were significantly higher in T2DM patients than in controls(P<0.05)but declined in the macroalbuminuria subgroup.Receiver operating characteristic analysis identified 30 pg/mL as the optimal cut-off(area under the curve=0.958;sensitivity=86%;specificity=95%).RRM2 was negatively correlated with age,diabetes duration,systolic blood pressure,fasting blood glucose,glycosylated hemoglobin,serum creatinine,neutrophil gelatinase-associated lipocalin,kidney injury molecule-1,and malondialdehyde,and positively correlated with estimated glomerular filtration rate,glutathione(GSH),solute carrier family 7 member 11(SLC7A11),and GSH peroxidase 4(GPX4).Logistic regression confirmed RRM2 as an independent protective factor against DN[odds ratio(OR)=0.820,95%confidence interval(95%CI)=0.712-0.945,P=0.006].In vitro,RRM2 overexpression enhanced HK-2 cell proliferation,activated PI3K/Akt signaling,and reduced apoptosis,ROS,oxidative stress,and ferroptosis,accompanied by the restoration of GSH,Nrf2,SLC7A11,and GPX4.These protective effects were abolished by PI3K/Akt inhibition,highlighting RRM2’s renoprotective,pathway-dependent role.CONCLUSION These findings suggest that RRM2 plays a crucial protective role against diabetic renal injury by mitigating oxidative stress,apoptosis,and ferroptosis via PI3K/Akt activation.Serum RRM2 may serve as a novel biomarker for early DN detection,and therapeutic strategies targeting RRM2 may offer potential benefits in preventing diabetic kidney disease progression.展开更多
Gualou-Xiebai-Banxia decoction has a long history of medical use for treating cardiovascular diseases in China.In this study,we investigated the protective effect and underlying mechanisms GXB in typeⅡdiabetes with a...Gualou-Xiebai-Banxia decoction has a long history of medical use for treating cardiovascular diseases in China.In this study,we investigated the protective effect and underlying mechanisms GXB in typeⅡdiabetes with acute myocardial ischemia(T2DM-AMI)rats.We hypothesized that GXB may display its protective effect on T2DM-AMI by reducing endothelial progenitor cells(EPCs)apoptosis via activating PI3K(phosphatidyl inositol 3-kinase)/Akt(serine/threonine protein kinase B)/e NOS(endothelial nitric oxide synthase)signaling.Rats were challenged with a high-fat diet and intraperitoneal injection of streptozotocin to induce a model of typeⅡdiabetes mellitus(T2DM)and coronary ligation to induce acute myocardial infarction(AMI).Changes in metabolites were assessed via enzyme-linked immunoassay and biochemical examination.The number and apoptosis rate of EPCs in peripheral blood were detected by flow cytometry.Target m RNAs and proteins in EPCs were analyzed by RT-PCR and Western blot analysis.The results demonstrated that GXB treatment decreased T2DM-AMI-associated changes in plasma fasting blood glucose,muscular enzymes,and blood lipids,and reduced oxidative stress.Furthermore,EPC apoptosis was increased in T2DM-AMI rats and was associated with decreased m RNA and protein levels of PI3K,Akt,and eNOS compared to the controls.Conversely,T2DM-AMI rats treated with GXB exhibited more circulating EPCs and downregulated levels of cell apoptosis,combined with increased m RNA and protein levels of PI3 K,Akt,and eNOS compared to those of untreated T2DM-AMI rats.Our study showed that GXB treatment mitigated EPC apoptosis and promoted PI3K/Akt/eNOS signaling in T2DM-AMI rats.展开更多
Objective:This study investigated the potential mechanisms behind the beneficial effects of Fructus Zanthoxyli(FZ)against type 2 diabetes mellitus(T2DM)based on network pharmacology and experimental validation.Methods...Objective:This study investigated the potential mechanisms behind the beneficial effects of Fructus Zanthoxyli(FZ)against type 2 diabetes mellitus(T2DM)based on network pharmacology and experimental validation.Methods:Ultra-high-performance liquid chromatography coupled with hybrid quadrupole-orbitrap high-resolution mass spectrometry,and gas chromatography-mass spectrometry were used to identify the constituents of FZ.Next,the differentially expressed genes linked to the treatment of diabetes with FZ were screened using online databases(including Gene Expression Omnibus database and Swiss Target Prediction online database),and the overlapping genes and their enrichment were analyzed by Kyoto Encyclopedia of Genes and Genomes(KEGG).Finally,the pathway was verified by in vitro experiments,and cell staining with oil red and Nile red showed that the extract of FZ had a therapeutic effect on T2DM.Results:A total of 43 components were identified from FZ,and 39 differentially expressed overlapping genes were screened as the possible targets of FZ in T2DM.The dug component-target network indicated that PPARA,PPARG,PIK3R3,JAK2 and GPR88 might be the core genes targeted by FZ in the treatment of T2DM.Interestingly,the enrichment analysis of KEGG showed that effects of FZ against T2DM were closely correlated with the adenosine monophosphate-activated protein kinase(AMPK)and phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt)signaling pathways.In vitro experiments further confirmed that FZ significantly inhibited palmitic acid-induced lipid formation in Hep G2 cells.Moreover,FZ treatment was able to promote the AMPK and PI3K/Akt expressions in Hep G2 cells.Conclusion:Network pharmacology combined with experimental validation revealed that FZ extract can improve the glycolipid metabolism disorder of T2DM via activation of the AMPK/PI3K/Akt pathway.展开更多
Type 2 diabetes mellitus(T2DM)is a complex metabolic disease threatening human health.We investigated the effects of Tegillarca granosa polysaccharide(TGP)and determined its potential mechanisms in a mouse model of T2...Type 2 diabetes mellitus(T2DM)is a complex metabolic disease threatening human health.We investigated the effects of Tegillarca granosa polysaccharide(TGP)and determined its potential mechanisms in a mouse model of T2DM established through a high-fat diet and streptozotocin.TGP(5.1×10^(3) Da)was composed of mannose,glucosamine,rhamnose,glucuronic acid,galactosamine,glucose,galactose,xylose,and fucose.It could significantly alleviate weight loss,reduce fasting blood glucose levels,reverse dyslipidemia,reduce liver damage from oxidative stress,and improve insulin sensitivity.RT-PCR and Western blotting indicated that TGP could activate the phosphatidylinositol-3-kinase/protein kinase B signaling pathway to regulate disorders in glucolipid metabolism and improve insulin resistance.TGP increased the abundance of Allobaculum,Akkermansia,and Bifidobacterium,restored the microbiota abundance in the intestinal tracts of mice with T2DM,and promoted short-chain fatty acid production.This study provides new insights into the antidiabetic effects of TGP and highlights its potential as a natural hypoglycemic nutraceutical.展开更多
BACKGROUND Gastric cancer(GC)is a common type of digestive cancer with high morbidity and mortality rates worldwide.Considerable effort has been expended in understanding the mechanism of GC development and metastasis...BACKGROUND Gastric cancer(GC)is a common type of digestive cancer with high morbidity and mortality rates worldwide.Considerable effort has been expended in understanding the mechanism of GC development and metastasis.The current study therefore explores the involvement of microRNAs in the regulation of GC progression.AIM To explore the expression and function of miR-30e-3p in GC development.METHODS MiR-30e-3p was found to be downregulated in GC,with low levels thereof predicting poor outcomes among patients with GC.Functionally,we revealed that miR-30e-3p suppressed cell growth and metastatic behaviors of GC cells.Bioinformatics analysis predicted that THO complex 2(THOC2)was a direct target of miR-30e-3p,and the interaction between miR-30e-3p and THOC2 was further validated by a luciferase reporter assay.RESULTS Our findings revealed that knockdown of THOC2 inhibited the growth and metastatic behaviors of GC cells.After investigating signaling pathways involved in miR-30e-3p regulation,we found that the miR-30e-3p/THOC2 axis regulated the PI3K/AKT/mTOR pathway in GC.CONCLUSION Our findings suggest the novel functional axis miR-30e-3p/THOC2 is involved in GC development and progression.The miR-30e-3p/THOC2 axis could be utilized to develop new therapies against GC.展开更多
Objective: Sarcopenia causes loss of skeletal muscle and function, thus seriously affecting the physical function and quality of life in the elderly. This article discusses the specific molecular mechanism and amelior...Objective: Sarcopenia causes loss of skeletal muscle and function, thus seriously affecting the physical function and quality of life in the elderly. This article discusses the specific molecular mechanism and ameliorating effects of Tudangshen(TDS) on sarcopenia in elderly rats with type 2 diabetes mellitus(T2DM).Methods: Elderly Sprague-Dawley(SD) rats were randomly selected and fed with a high-fat diet combined with an intraperitoneal injection of streptozotocin to establish T2DM model. The model rats were stratified and randomly divided into the model group,metformin group, TDS high-dose group, TDS medium-dose group, and TDS low-dose group according to blood glucose combined with body weight, and the same batch of old SD rats was set as the normal control group. The effects of TDS in an elderly T2DM sarcopenia rat model were evaluated by observing the body positions of the rats, analyzing blood biochemistry, testing exercise capacity, and pathologically staining sectioned gastrocnemius muscle tissues. The molecular mechanisms of the effects were analyzed using quantitative real-time polymerase chain reaction and western blotting.Results: TDS has no statistically significant effect on blood glucose, insulin and glycosylated serum protein in aged rats with T2DM, but it can reduce levels of glycosylated serum protein, total cholesterol, triglycerides, and low-density lipoprotein;it improves pathological changes in rat gastrocnemius muscle tissues, and increases muscle cell activity in elderly rats with T2DM and sarcopenia. TDS also promoted the upregulation of the expression of mammalian target of rapamycin(mTOR)/protein kinase B(PKB/AKT)/phosphatidylinositol 3-kinase(PI3K)/ribosomal protein S6 kinase/eukaryotic initiation factor 4 E binding rotein1 mRNA in rats and triggered an increase in corresponding protein levels.Conclusions: TDS alleviated muscle decline in elderly rats with T2DM by activating the PI3 K/AKT/mTOR signaling pathway and regulating the synthesis of corresponding proteins.展开更多
Type 2 diabetes mellitus(T2DM)is accompanied by insulin resistance in liver and peripheral tissue.Bacillus amyloliquefaciens fmb50 produces lipopeptide surfactin,which has a wide range of biological activities.However...Type 2 diabetes mellitus(T2DM)is accompanied by insulin resistance in liver and peripheral tissue.Bacillus amyloliquefaciens fmb50 produces lipopeptide surfactin,which has a wide range of biological activities.However,the effects of surfactin on insulin resistance in any mouse model have not been reported.Our previous research demonstrated that dietary supplementation with surfactin can alleviate high fat diet(HFD)/streptozotocin(STZ)-induced T2DM in mice by regulating intestinal microbiota.This study aims to explore the detailed mechanism of the effect of surfactin on liver and peripheral tissue.The results indicated that surfactin inhibited hepatic gluconeogenesis and promoted hepatic glycogen synthesis by activating the adenosine monophosphate-activated protein kinase and phosphatidylinositol-3 kinase(PI3K)/protein kinase B(Akt)signalling pathways.Similarly,surfactin also significantly increased muscle glycogen synthesis by activating the PI3K/Akt signalling pathway.The glucose transporter 4 levels of skeletal muscle and adipose tissue,which are insulin-mediated vital organs,was noticeably increased after surfactin treatment.In addition,our results indicate that decreased hepatic fat accumulation and suppressed inflammation and oxidative stress in liver,skeletal muscle and adipose tissue also play critical roles in ameliorating insulin resistance.These findings demonstrate that surfactin not only ameliorates liver dysfunction but also enhances insulin sensitivity in HFD/STZ-induced T2DM mice.Finally,using fasting blood glucose,oral glucose tolerance test and insulin tolerance test,we show that early surfactin intervention can mitigate T2DM in mice.The study results warrant future functional food studies which will provide insight into diet-host interactions.展开更多
Diabetes mellitus(DM)is a metabolic disorder characterized by persistent hyperglycemia and other symptoms,which pose significant challenges to individual health,life expectancy,and public healthcare systems.The escala...Diabetes mellitus(DM)is a metabolic disorder characterized by persistent hyperglycemia and other symptoms,which pose significant challenges to individual health,life expectancy,and public healthcare systems.The escalating global prevalence of diabetes underscores the need for innovative therapeutic interventions.In this article,we critically comment on the study by Wang et al,published in the World Journal of Diabetes,which elucidates the therapeutic potential of Plantamajoside(PMS)in type 2 DM(T2DM)management.The authors provide evidence for the mechanism of action of PMS in T2DM models,demonstrating prevention of endoplasmic reticulum stress and apoptosis of pancreaticβ-cells via activation of DNAJC1.This manuscript provides a brief review of the pathogenesis of T2DM,explores the various roles of PMS in disease therapy in addition to the DNAJC-related apoptotic and autophagic functions,critically evaluates the experimental approaches employed by Wang et al,and provides recommendations for advancing future research.展开更多
Objective:Type 2 diabetes mellitus(T2DM)is characterized by insufficient insulin secretion and insulin resistance.Gypenosides(GPs)are the major bioactive saponins extracted from Gynostemma pentaphyllum.Previous studie...Objective:Type 2 diabetes mellitus(T2DM)is characterized by insufficient insulin secretion and insulin resistance.Gypenosides(GPs)are the major bioactive saponins extracted from Gynostemma pentaphyllum.Previous studies suggest that GPs have beneficial effects on T2DM,but the underlying mechanisms remain unclear.This study aims to investigate whether GPs exert therapeutic effects by influencing RNA N^(6)-methyladenosine(m6A)methylation modification,thereby regulating the downstream phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway.Methods:Expression levels and methylation changes of METTL3,METTL14,and FTO in T2DM were analyzed using public databases,and related pathways were explored via gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses.The main active components of GPs were screened from pharmacological databases,followed by compound-target network construction,enrichment analyses,and prediction of potential targets and pathways.A T2DM model was induced in Sprague-Dawley rats using a high-fat/high-sugar diet combined with low-dose streptozotocin.Rats were randomly divided into 4 groups:GPs-treated group(GPG,400 mg/kg),positive control group(PCG,metformin 100 mg/kg),normal saline control group(CONTROL),and T2DM model group(MODEL).Fasting blood glucose(FBG),oral glucose tolerance test(OGTT)-area under the glucose curve from 0 to 120 min(AUC0-120),fasting insulin(FINS),homeostasis model assessment of insulin resistance(HOMA-IR),serum inflammatory factors,and tissue pathology of pancreas and liver hematoxylin and eosin(HE)staining were assessed.Real-time fluorescence quantitative PCR and Western blotting were used to detect RNA and protein expression levels of METTL3,METTL14,FTO,PI3K,and AKT in pancreatic tissues.Molecular docking was applied to evaluate interactions between GPs’main components and METTL3,METTL14,and FTO to infer potential binding modes.Results:Bioinformatic analyses showed downregulation of METTL3/14 and upregulation of FTO in T2DM samples(all P<0.05),with enrichment in pathways related to insulin signaling,PI3K/AKT activation,oxidative stress response,and hormone secretion.Network pharmacology indicated that GPs components may act on targets involved in RNA modification and insulin-related pathways.In diabetic rats,GPs significantly reduced FBG,improved glucose tolerance,decreased HOMA-IR,and decreased the serum tumor necrosis factor-α(TNF-α)and interleukin(IL)-6 levels compared with MODEL(all P<0.05).Pancreatic pathology showed alleviated islet injury and improved cell morphology.GPs treatment upregulated METTL3/14 mRNA and protein levels,and down-regulated FTO mRNA/protein levels in pancreatic tissue(all P<0.05).PI3K and AKT expression levels increased(both P<0.05),consistent with activation of downstream signals related to glucose uptake and improved insulin sensitivity.Metformin also improved metabolic indices but exhibited a different regulatory pattern on m6A-related enzymes compared with GPs.Molecular docking revealed stable interactions between core GPs saponin structures and methyltransferase-like 3(METTL3),methyltransferase-like 14(METTL14),or obesityassociated protein(FTO),suggesting that GPs may directly or indirectly modulate m6A regulatory proteins.Conclusion:GPs can effectively improve glucose-metabolism disorders,reduce inflammation,and protect pancreatic tissue in T2DM rats.The mechanisms may be associated with METTL3/14 up-regulation and FTO down-regulation,leading to enhanced m6A methylation and subsequent activation of the PI3K/AKT signaling pathway.These findings provide strong evidence for GPs regulation of epigenetic m6A RNA modification and insulin-related downstream pathways,and suggest that natural compounds targeting m6A regulation may be explored in the future for metabolic disease interventions.展开更多
文摘OBJECTIVE To explore hypoglycemic effect of 95%ethanol fraction of Nitraria roborowskii Kom(NRK-C)and its possible mechanism evaluated in the type 2 diabetes mellitus(T2DM)mice.METHODS The body weight,organ indices,blood glucose levels,serum biochemical indexes,as well as HE/PAS histopathological section were all analyzed to assess the hypoglycemic effect of NRK-C in T2DM mice induced by a high-fat diet(HFD)combined with six intraperitoneal injections of 35 mg·kg^(-1)of streptozotocin(STZ).The Western blotting and immunofluorescence were further applied to determine the regulatory effect of NRK-C on key signaling proteins.RESULTS The fasting blood glucose levels were significantly reduced after 7 weeks of administration of NRK-C.In addition,NRK-C could also significantly improve glucose tolerance,hepatic glycogen levels,and lipid levels(total cholesterol,triglyceride,low density lipoprotein and high density lipoprotein),and significantly reduced insulin resistance of diabetic mice,which played an important role in the antidiabetic effects.Further mechanism research demonstrated that phosphorylated PI3K expression was up-regulated and p-GSK3βexpression was up-regulated after NRK-C intervention,indicating that NRK-C might exert a potential antidiabetic effect by modulating the PI3K/AKT signaling pathway.CONCLUSION All these results suggested that NRK-C might improve T2DM and had the potential to be used as an adjunctive therapy.
基金funded by the“Hengrui-Tianqing Medical Education Fund”of the Second Affiliated Hospital of Wannan Medical College(grant no.HXKT2022026)Natural Science Research Program for Universities in Anhui Province(grant no.2023AH051739).
文摘Objective:To investigate the influence and underlying mechanisms of imrecoxib on liver damage in rats with type 2 diabetes mellitus(T2DM).Methods:A rat model of T2DM was established by a high-fat diet and streptozotocin administration.Rats were then treated with imrecoxib 10,20,or 40 mg/kg for 5 weeks.Body weight and fasting blood glucose levels were measured.The analysis included serum liver function,blood lipid profiles,and the levels of inflammatory factors in the rats.Liver tissue histology was evaluated using hematoxylin and eosin staining.Western blotting was conducted to measure the liver expression of proteins such as AKT,PI3K,NF-κB,p-AKT,p-PI3K,and p-NF-κB.Results:Rats treated with imrecoxib showed a greater weight gain compared to untreated diabetic rats.Compared to untreated diabetic rats,imrecoxib at all three doses reduced alanine aminotransferase,aspartate aminotransferase,triglycerides,cholesterol,tumor necrosis factor-α,interleukin(IL)-6,and IL-1β,and significantly increased the levels of IL-10 and IL-4.In imrecoxib-treated rats,the expression levels of AKT,PI3K,p-AKT,and p-PI3K were higher in comparison to the diabetes group,whereas the expression of p-NF-κB was lower.Conclusions:Imrecoxib could alleviate hepatic damage in T2DM rats by modulating PI3K/AKT/NF-κB signaling.
基金supported by research grants from the Guangdong Province Basic and Applied Basic Research Fund Project(2022A1515110447)Open Fund Project of the State Key Laboratory of Applied Microbiology in South China(SKLAM006-2022)+1 种基金74th batch of general funding from the China Postdoctoral Science Foundation(2023M740774)Guangdong Provincial People’s Hospital,Postdoctoral Research Launch Fund(BY012022017)。
文摘Epidemiological studies have indicated that branched-chain amino acids(BCAAs)increased and gut microbiota disordered in type 2 diabetes mellitus(T2DM).This study aimed to investigate the mechanism of Lactiplantibacillus plantarum strain 84-3(Lp84-3)combined with Staphylococcus aureus bacteriophage on ameliorating T2DM.Here we perform a case-control study and identify that Staphylococcus_phage was inversely correlated with fasting blood glucose(FBG).It revealed that Lp84-3 could inhibit the growth of S.aureus,and Lp84-3 contains BCAAs degradation enzymes in its genome.Furthermore,Lp84-3 alone or combined with S.aureus bacteriophage interventions can improve blood glucose,insulin resistance,triglycerides,interleukin-1β,tumor necrosis factor-α(TNF-α),BCAAs,and acetyllactate synthase(ALS)in db/db mice.Lp84-3 and S.aureus bacteriophage decreased S.aureus,Malacoplasma iowae,and Oscillibacter sp.,and increased some beneficial such as L.plantarum and Muribaculaceae bacterium.Transcriptomic analyses revealed that Lp84-3 and S.aureus bacteriophage activated the PI3K/AKT/GLUT4 signaling pathway and upregulated key genes of Il22,Hgf,Col6a1,Gh,Itga10,Fgf23,and Prl involved in glucose metabolism in hypothalamus.Collectively,Lp84-3 and S.aureus bacteriophage alleviate T2DM by modulating gut microbiota and enhancing glucose metabolism in hypothalamus,supporting its potential use as a promising functional compound microecological agent for alleviating T2DM.
文摘目的探讨弱氧化性低密度脂蛋白(minimally modified low density lipoprotein,mmLDL)上调在体小鼠肠系膜动脉ETA受体的作用(endothelin type A receptors,ETA)并考察自噬是否参与这一过程。方法小鼠尾静脉注射mmLDL,腹腔注射ClassⅢPI3K自噬通路抑制剂6-氨基-3-甲基嘌呤(3-methyladenine,3-MA),探究自噬在mmLDL给药处理小鼠中的作用,微血管张力描记仪观察内皮素-1(endothelin-1,ET-1)引起的小鼠肠系膜动脉收缩量效曲线的变化,RT-PCR定量ETA受体mRNA,Western blot检测ETA受体和ClassⅢPI3K、Beclin-1、LC3-Ⅱ/Ⅰ、p62及p-NF-κB、NF-κB的蛋白水平表达。结果mmLDL引起ET-1收缩量效曲线明显增强,表现为Emax值由生理盐水(NS)组的(184.87±7.46)%上升为(319.91±20.31)%(P<0.001),pEC50值由NS组的(8.05±0.05)上升为(9.11±0.09)(P<0.01)。mmLDL在上调ClassⅢPI3K、beclin-1、LC3-Ⅱ/Ⅰ和下调p62蛋白水平的同时,也引起ETA受体mRNA水平、蛋白表达明显增加,增加了p-NF-κB的蛋白水平;腹腔注射3-MA抑制了mmLDL的这些作用。结论mmLDL能通过ClassⅢPI3K/Beclin-1通路激活自噬及下游NF-κB通路上调ETA受体。
基金Supported by Guangzhou Science and Technology Bureau Research Fund:the Mechanism of Action of Huangqi Guizhi Decoction on Precancerous Lesions in Cag Rats was Studied based on the Phosphatidylinositol 3-Kinase-Protein Kinase B-Mechanistic Target of Rapamycin Complex 2 Pathway(No.202102080643)Guangzhou Traditional Chinese Medicine and Integrative Medicine Research Project:Observation on the Therapeutic Effect of Wenyang Jianpi Ointment on Chronic Atrophic Gastritis of Spleen and Stomach Weakness Type and Study on its Regulatory Effect on Transforming Growth Factor Beta 3(No.20222A010079)Panyu District Science and Technology Project:the Mechanism by which the Modified Huangqi Guizhi Decoction Regulates the Transforming Growth Factor-β3 Signaling Pathway to Improve Precancerous Lesions in Rats with Chronic Atrophic Gastritis(No.2020-Z04-025)。
文摘OBJECTIVE:To investigate the effects of Jiawei Huangqi Guizhi decoction(加味黄芪桂枝汤)on chronic atrophic gastritis(CAG)in rats and its modulation of the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin complex 2(PI3K/Akt/m TORC2)signaling pathway.METHODS:CAG was induced in rats and treated with high-,medium-,or low-dose Jiawei Huangqi Guizhi decoction.Gastric histopathology was observed by hematoxylin and eosin staining.Serum levels of gastrin,PI3K,Akt,and m TORC2 were detected by enzyme-linked immunosorbent assay.Gene and protein expression levels were analyzed by reverse transcription polymerase chain reaction and western blot.RESULTS:The decoction alleviated gastric mucosal injury,reduced inflammation,and restored epithelial structure.It regulated PI3K,Akt,and m TORC2 expression at both m RNA and protein levels.CONCLUSION:Jiawei Huangqi Guizhi decoction may prevent CAG progression by improving gastric tissue and modulating the PI3K/Akt/m TORC2 signaling pathway.
文摘BACKGROUND Type 2 diabetes mellitus(T2DM)is associated with significant metabolic and renal complications,including diabetic nephropathy(DN).AIM To investigate the role of ribonucleotide reductase regulatory subunit M2(RRM2)in T2DM and its potential involvement in renal injury through oxidative stress,apoptosis,and ferroptosis.METHODS A cross-sectional study was conducted,comprising 194 patients with T2DM and 120 healthy controls at our hospital between January 2022 and December 2023.The data were analyzed to ascertain the correlation between RRM2 levels and DN onset in patients with T2DM.The apoptosis rate,reactive oxygen species(ROS)levels,oxidative stress,cystine uptake,and ferrous ion(Fe2+)levels were quantified using the HK-2 cell lysates.Reverse transcription quantitative PCR and western blotting were used to assess mRNA and protein expression,respectively.RESULTS Serum RRM2 levels were significantly higher in T2DM patients than in controls(P<0.05)but declined in the macroalbuminuria subgroup.Receiver operating characteristic analysis identified 30 pg/mL as the optimal cut-off(area under the curve=0.958;sensitivity=86%;specificity=95%).RRM2 was negatively correlated with age,diabetes duration,systolic blood pressure,fasting blood glucose,glycosylated hemoglobin,serum creatinine,neutrophil gelatinase-associated lipocalin,kidney injury molecule-1,and malondialdehyde,and positively correlated with estimated glomerular filtration rate,glutathione(GSH),solute carrier family 7 member 11(SLC7A11),and GSH peroxidase 4(GPX4).Logistic regression confirmed RRM2 as an independent protective factor against DN[odds ratio(OR)=0.820,95%confidence interval(95%CI)=0.712-0.945,P=0.006].In vitro,RRM2 overexpression enhanced HK-2 cell proliferation,activated PI3K/Akt signaling,and reduced apoptosis,ROS,oxidative stress,and ferroptosis,accompanied by the restoration of GSH,Nrf2,SLC7A11,and GPX4.These protective effects were abolished by PI3K/Akt inhibition,highlighting RRM2’s renoprotective,pathway-dependent role.CONCLUSION These findings suggest that RRM2 plays a crucial protective role against diabetic renal injury by mitigating oxidative stress,apoptosis,and ferroptosis via PI3K/Akt activation.Serum RRM2 may serve as a novel biomarker for early DN detection,and therapeutic strategies targeting RRM2 may offer potential benefits in preventing diabetic kidney disease progression.
基金supported by the National Natural Science Foundation of China(Nos.81173164 and 81573852)the Public Service Key Project of Shandong Provincial Research and Development(No.2018GSF119009)。
文摘Gualou-Xiebai-Banxia decoction has a long history of medical use for treating cardiovascular diseases in China.In this study,we investigated the protective effect and underlying mechanisms GXB in typeⅡdiabetes with acute myocardial ischemia(T2DM-AMI)rats.We hypothesized that GXB may display its protective effect on T2DM-AMI by reducing endothelial progenitor cells(EPCs)apoptosis via activating PI3K(phosphatidyl inositol 3-kinase)/Akt(serine/threonine protein kinase B)/e NOS(endothelial nitric oxide synthase)signaling.Rats were challenged with a high-fat diet and intraperitoneal injection of streptozotocin to induce a model of typeⅡdiabetes mellitus(T2DM)and coronary ligation to induce acute myocardial infarction(AMI).Changes in metabolites were assessed via enzyme-linked immunoassay and biochemical examination.The number and apoptosis rate of EPCs in peripheral blood were detected by flow cytometry.Target m RNAs and proteins in EPCs were analyzed by RT-PCR and Western blot analysis.The results demonstrated that GXB treatment decreased T2DM-AMI-associated changes in plasma fasting blood glucose,muscular enzymes,and blood lipids,and reduced oxidative stress.Furthermore,EPC apoptosis was increased in T2DM-AMI rats and was associated with decreased m RNA and protein levels of PI3K,Akt,and eNOS compared to the controls.Conversely,T2DM-AMI rats treated with GXB exhibited more circulating EPCs and downregulated levels of cell apoptosis,combined with increased m RNA and protein levels of PI3 K,Akt,and eNOS compared to those of untreated T2DM-AMI rats.Our study showed that GXB treatment mitigated EPC apoptosis and promoted PI3K/Akt/eNOS signaling in T2DM-AMI rats.
基金supported by the Project of Sichuan Science and Technology Program(No.22NSFSC1510)the Project of State Administration of Traditional Chinese Medicine of Sichuan Province of China(No.2020HJZX001)。
文摘Objective:This study investigated the potential mechanisms behind the beneficial effects of Fructus Zanthoxyli(FZ)against type 2 diabetes mellitus(T2DM)based on network pharmacology and experimental validation.Methods:Ultra-high-performance liquid chromatography coupled with hybrid quadrupole-orbitrap high-resolution mass spectrometry,and gas chromatography-mass spectrometry were used to identify the constituents of FZ.Next,the differentially expressed genes linked to the treatment of diabetes with FZ were screened using online databases(including Gene Expression Omnibus database and Swiss Target Prediction online database),and the overlapping genes and their enrichment were analyzed by Kyoto Encyclopedia of Genes and Genomes(KEGG).Finally,the pathway was verified by in vitro experiments,and cell staining with oil red and Nile red showed that the extract of FZ had a therapeutic effect on T2DM.Results:A total of 43 components were identified from FZ,and 39 differentially expressed overlapping genes were screened as the possible targets of FZ in T2DM.The dug component-target network indicated that PPARA,PPARG,PIK3R3,JAK2 and GPR88 might be the core genes targeted by FZ in the treatment of T2DM.Interestingly,the enrichment analysis of KEGG showed that effects of FZ against T2DM were closely correlated with the adenosine monophosphate-activated protein kinase(AMPK)and phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt)signaling pathways.In vitro experiments further confirmed that FZ significantly inhibited palmitic acid-induced lipid formation in Hep G2 cells.Moreover,FZ treatment was able to promote the AMPK and PI3K/Akt expressions in Hep G2 cells.Conclusion:Network pharmacology combined with experimental validation revealed that FZ extract can improve the glycolipid metabolism disorder of T2DM via activation of the AMPK/PI3K/Akt pathway.
基金funded by the National Key Research and Development Program of China(2020YFD0900902)Zhejiang Province Public Welfare Technology Application Research Project(LGJ21C20001)Zhejiang Provincial Key Research and Development Project of China(2019C02076 and 2019C02075)。
文摘Type 2 diabetes mellitus(T2DM)is a complex metabolic disease threatening human health.We investigated the effects of Tegillarca granosa polysaccharide(TGP)and determined its potential mechanisms in a mouse model of T2DM established through a high-fat diet and streptozotocin.TGP(5.1×10^(3) Da)was composed of mannose,glucosamine,rhamnose,glucuronic acid,galactosamine,glucose,galactose,xylose,and fucose.It could significantly alleviate weight loss,reduce fasting blood glucose levels,reverse dyslipidemia,reduce liver damage from oxidative stress,and improve insulin sensitivity.RT-PCR and Western blotting indicated that TGP could activate the phosphatidylinositol-3-kinase/protein kinase B signaling pathway to regulate disorders in glucolipid metabolism and improve insulin resistance.TGP increased the abundance of Allobaculum,Akkermansia,and Bifidobacterium,restored the microbiota abundance in the intestinal tracts of mice with T2DM,and promoted short-chain fatty acid production.This study provides new insights into the antidiabetic effects of TGP and highlights its potential as a natural hypoglycemic nutraceutical.
基金Supported by National Natural Science Foundation of China,No.81860442Ningxia Natural Science Foundation Project,No.2022AAC03525.
文摘BACKGROUND Gastric cancer(GC)is a common type of digestive cancer with high morbidity and mortality rates worldwide.Considerable effort has been expended in understanding the mechanism of GC development and metastasis.The current study therefore explores the involvement of microRNAs in the regulation of GC progression.AIM To explore the expression and function of miR-30e-3p in GC development.METHODS MiR-30e-3p was found to be downregulated in GC,with low levels thereof predicting poor outcomes among patients with GC.Functionally,we revealed that miR-30e-3p suppressed cell growth and metastatic behaviors of GC cells.Bioinformatics analysis predicted that THO complex 2(THOC2)was a direct target of miR-30e-3p,and the interaction between miR-30e-3p and THOC2 was further validated by a luciferase reporter assay.RESULTS Our findings revealed that knockdown of THOC2 inhibited the growth and metastatic behaviors of GC cells.After investigating signaling pathways involved in miR-30e-3p regulation,we found that the miR-30e-3p/THOC2 axis regulated the PI3K/AKT/mTOR pathway in GC.CONCLUSION Our findings suggest the novel functional axis miR-30e-3p/THOC2 is involved in GC development and progression.The miR-30e-3p/THOC2 axis could be utilized to develop new therapies against GC.
基金supported by the National Natural Science Foundation of China(Grant No.:82074394)。
文摘Objective: Sarcopenia causes loss of skeletal muscle and function, thus seriously affecting the physical function and quality of life in the elderly. This article discusses the specific molecular mechanism and ameliorating effects of Tudangshen(TDS) on sarcopenia in elderly rats with type 2 diabetes mellitus(T2DM).Methods: Elderly Sprague-Dawley(SD) rats were randomly selected and fed with a high-fat diet combined with an intraperitoneal injection of streptozotocin to establish T2DM model. The model rats were stratified and randomly divided into the model group,metformin group, TDS high-dose group, TDS medium-dose group, and TDS low-dose group according to blood glucose combined with body weight, and the same batch of old SD rats was set as the normal control group. The effects of TDS in an elderly T2DM sarcopenia rat model were evaluated by observing the body positions of the rats, analyzing blood biochemistry, testing exercise capacity, and pathologically staining sectioned gastrocnemius muscle tissues. The molecular mechanisms of the effects were analyzed using quantitative real-time polymerase chain reaction and western blotting.Results: TDS has no statistically significant effect on blood glucose, insulin and glycosylated serum protein in aged rats with T2DM, but it can reduce levels of glycosylated serum protein, total cholesterol, triglycerides, and low-density lipoprotein;it improves pathological changes in rat gastrocnemius muscle tissues, and increases muscle cell activity in elderly rats with T2DM and sarcopenia. TDS also promoted the upregulation of the expression of mammalian target of rapamycin(mTOR)/protein kinase B(PKB/AKT)/phosphatidylinositol 3-kinase(PI3K)/ribosomal protein S6 kinase/eukaryotic initiation factor 4 E binding rotein1 mRNA in rats and triggered an increase in corresponding protein levels.Conclusions: TDS alleviated muscle decline in elderly rats with T2DM by activating the PI3 K/AKT/mTOR signaling pathway and regulating the synthesis of corresponding proteins.
基金supported by the National Natural Science Foundation of China(32072182).
文摘Type 2 diabetes mellitus(T2DM)is accompanied by insulin resistance in liver and peripheral tissue.Bacillus amyloliquefaciens fmb50 produces lipopeptide surfactin,which has a wide range of biological activities.However,the effects of surfactin on insulin resistance in any mouse model have not been reported.Our previous research demonstrated that dietary supplementation with surfactin can alleviate high fat diet(HFD)/streptozotocin(STZ)-induced T2DM in mice by regulating intestinal microbiota.This study aims to explore the detailed mechanism of the effect of surfactin on liver and peripheral tissue.The results indicated that surfactin inhibited hepatic gluconeogenesis and promoted hepatic glycogen synthesis by activating the adenosine monophosphate-activated protein kinase and phosphatidylinositol-3 kinase(PI3K)/protein kinase B(Akt)signalling pathways.Similarly,surfactin also significantly increased muscle glycogen synthesis by activating the PI3K/Akt signalling pathway.The glucose transporter 4 levels of skeletal muscle and adipose tissue,which are insulin-mediated vital organs,was noticeably increased after surfactin treatment.In addition,our results indicate that decreased hepatic fat accumulation and suppressed inflammation and oxidative stress in liver,skeletal muscle and adipose tissue also play critical roles in ameliorating insulin resistance.These findings demonstrate that surfactin not only ameliorates liver dysfunction but also enhances insulin sensitivity in HFD/STZ-induced T2DM mice.Finally,using fasting blood glucose,oral glucose tolerance test and insulin tolerance test,we show that early surfactin intervention can mitigate T2DM in mice.The study results warrant future functional food studies which will provide insight into diet-host interactions.
文摘Diabetes mellitus(DM)is a metabolic disorder characterized by persistent hyperglycemia and other symptoms,which pose significant challenges to individual health,life expectancy,and public healthcare systems.The escalating global prevalence of diabetes underscores the need for innovative therapeutic interventions.In this article,we critically comment on the study by Wang et al,published in the World Journal of Diabetes,which elucidates the therapeutic potential of Plantamajoside(PMS)in type 2 DM(T2DM)management.The authors provide evidence for the mechanism of action of PMS in T2DM models,demonstrating prevention of endoplasmic reticulum stress and apoptosis of pancreaticβ-cells via activation of DNAJC1.This manuscript provides a brief review of the pathogenesis of T2DM,explores the various roles of PMS in disease therapy in addition to the DNAJC-related apoptotic and autophagic functions,critically evaluates the experimental approaches employed by Wang et al,and provides recommendations for advancing future research.
基金supported by College Students’Innovative Entrepreneurial Training Plan Program of Guizhou Province,China(S202210660105,S202310660055)。
文摘Objective:Type 2 diabetes mellitus(T2DM)is characterized by insufficient insulin secretion and insulin resistance.Gypenosides(GPs)are the major bioactive saponins extracted from Gynostemma pentaphyllum.Previous studies suggest that GPs have beneficial effects on T2DM,but the underlying mechanisms remain unclear.This study aims to investigate whether GPs exert therapeutic effects by influencing RNA N^(6)-methyladenosine(m6A)methylation modification,thereby regulating the downstream phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway.Methods:Expression levels and methylation changes of METTL3,METTL14,and FTO in T2DM were analyzed using public databases,and related pathways were explored via gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses.The main active components of GPs were screened from pharmacological databases,followed by compound-target network construction,enrichment analyses,and prediction of potential targets and pathways.A T2DM model was induced in Sprague-Dawley rats using a high-fat/high-sugar diet combined with low-dose streptozotocin.Rats were randomly divided into 4 groups:GPs-treated group(GPG,400 mg/kg),positive control group(PCG,metformin 100 mg/kg),normal saline control group(CONTROL),and T2DM model group(MODEL).Fasting blood glucose(FBG),oral glucose tolerance test(OGTT)-area under the glucose curve from 0 to 120 min(AUC0-120),fasting insulin(FINS),homeostasis model assessment of insulin resistance(HOMA-IR),serum inflammatory factors,and tissue pathology of pancreas and liver hematoxylin and eosin(HE)staining were assessed.Real-time fluorescence quantitative PCR and Western blotting were used to detect RNA and protein expression levels of METTL3,METTL14,FTO,PI3K,and AKT in pancreatic tissues.Molecular docking was applied to evaluate interactions between GPs’main components and METTL3,METTL14,and FTO to infer potential binding modes.Results:Bioinformatic analyses showed downregulation of METTL3/14 and upregulation of FTO in T2DM samples(all P<0.05),with enrichment in pathways related to insulin signaling,PI3K/AKT activation,oxidative stress response,and hormone secretion.Network pharmacology indicated that GPs components may act on targets involved in RNA modification and insulin-related pathways.In diabetic rats,GPs significantly reduced FBG,improved glucose tolerance,decreased HOMA-IR,and decreased the serum tumor necrosis factor-α(TNF-α)and interleukin(IL)-6 levels compared with MODEL(all P<0.05).Pancreatic pathology showed alleviated islet injury and improved cell morphology.GPs treatment upregulated METTL3/14 mRNA and protein levels,and down-regulated FTO mRNA/protein levels in pancreatic tissue(all P<0.05).PI3K and AKT expression levels increased(both P<0.05),consistent with activation of downstream signals related to glucose uptake and improved insulin sensitivity.Metformin also improved metabolic indices but exhibited a different regulatory pattern on m6A-related enzymes compared with GPs.Molecular docking revealed stable interactions between core GPs saponin structures and methyltransferase-like 3(METTL3),methyltransferase-like 14(METTL14),or obesityassociated protein(FTO),suggesting that GPs may directly or indirectly modulate m6A regulatory proteins.Conclusion:GPs can effectively improve glucose-metabolism disorders,reduce inflammation,and protect pancreatic tissue in T2DM rats.The mechanisms may be associated with METTL3/14 up-regulation and FTO down-regulation,leading to enhanced m6A methylation and subsequent activation of the PI3K/AKT signaling pathway.These findings provide strong evidence for GPs regulation of epigenetic m6A RNA modification and insulin-related downstream pathways,and suggest that natural compounds targeting m6A regulation may be explored in the future for metabolic disease interventions.
