Objective:Panax notoginseng saponins (PNS),extracted from rhizome of the herb Radix et Rhizoma Notoginseng (Panax notoginseng (Burk.) F.H.Chen),was recently discovered to have beneficial effects against neurological d...Objective:Panax notoginseng saponins (PNS),extracted from rhizome of the herb Radix et Rhizoma Notoginseng (Panax notoginseng (Burk.) F.H.Chen),was recently discovered to have beneficial effects against neurological damage.This study investigated the effects of PNS on cerebral ischemia and elucidated the molecular mechanisms underlying these effects.Methods:Middle cerebral artery occlusion rats were treated with PNS (3.6 mg/100 g or 7.2 mg/100 g per day) for 7 days,the gene of LINGO-1 was measured and the expression of protein synaptophysin,postsynaptic density protein 95,LINGO-1 and p-EGFR/p-PI3K/p-AKT were investigated.The weight and mNSS score of Sprague-Dawley rats in each group were recorded every day during the 7 days.Results:PNS promoted middle cerebral artery occlusion rats' weight and the recovery of neural function.PNS significantly decreased ischemia-induced LINGO-1 protein expression.PNS also elevated EGFR/PI3K/AKT phosphorylation levels.Conclusion:PNS promoted cerebral recovery from ischemic injury by accelerating synapse reconstruction and inhibiting the neuron growth negative regulatory protein LINGO-1 and activating the epidermal growth factor receptor (EGFR)/PI3K/AKT signaling pathway in vivo.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
Preclinical and clinical studies have shown that microglia and macrophages participate in a multiphasic brain damage repair process following intracerebral hemorrhage.The E26 transformation-specific sequence-related t...Preclinical and clinical studies have shown that microglia and macrophages participate in a multiphasic brain damage repair process following intracerebral hemorrhage.The E26 transformation-specific sequence-related transcription factor Spi1 regulates microglial/macrophage commitment and maturation.However,the effect of Spi1 on intracerebral hemorrhage remains unclear.In this study,we found that Spi1 may regulate recovery from the neuroinflammation and neurofunctional damage caused by intracerebral hemorrhage by modulating the microglial/macrophage transcriptome.We showed that high Spi1expression in microglia/macrophages after intracerebral hemorrhage is associated with the activation of many pathways that promote phagocytosis,glycolysis,and autophagy,as well as debris clearance and sustained remyelination.Notably,microglia with higher levels of Soil expression were chara cterized by activation of pathways associated with a variety of hemorrhage-related cellular processes,such as complement activation,angiogenesis,and coagulation.In conclusion,our results suggest that Spi1 plays a vital role in the microglial/macrophage inflammatory response following intracerebral hemorrhage.This new insight into the regulation of Spi1 and its target genes may advance our understanding of neuroinflammation in intracerebral hemorrhage and provide therapeutic targets for patients with intracerebral hemorrhage.展开更多
Background:The aberrant intraellular expression of a mitochondrial aspartyl tRNA synthetase 2(DARS2)has been reported in human cancers.Nevertheless its critical role and detailed mechanism in lung adenocarcinoma(LUAD)...Background:The aberrant intraellular expression of a mitochondrial aspartyl tRNA synthetase 2(DARS2)has been reported in human cancers.Nevertheless its critical role and detailed mechanism in lung adenocarcinoma(LUAD)remain unexplored.Methods:Initially,The Cancer Genome Atlas(TCGA)based Gene Expression Profiling Interactive Analysis(GEPIA)database (http:/gepia.cancer-pku.cn/)was used to analyze the prognostic relevance of DARS2 expression in LUAD.Further,cell counting kit(CCK)8,immunostaining,and transwell invasion assays in LUAD cell lines in vitro,as well as DARS2 silence on LUAD by tumorigenicity experiments in wivo in nude mice,were performed.Besides,we analyzed the expression levels of p-PI3K(phosphorylated Phosphotylinosital3 kinase),PI3K,AKT(Protein Kinase B),p-AKT(phosphorylated Protein Kinase B),PCNA(proliferating cell nudear antigen),cleaved-caspase 3,E cadherin,and N-cadherin proteins using the Westem blot analysis.Results:LUAD tissues showed higher DARS2 expression compared to normal tissues.Upregulation of DARS2 could be related to Tumor-Node-Metastasis(TNM)stage,high lymph node metastasis,and inferior prognosis.DARS2 silence decreased the proliferation,migration,and invasion abilities of LUAD cells.In addition,the DARS2 downregulation decreased the PCNA and N-cadherin expression and increased cleaved:caspase 3 and E cadherin expressions in LUAD cells,coupled with the inactivation of the PI3K/AKT signaling pathway.Moreover,DARS2 silence impaired the tumonigenicity of LUAD in vivo.Interestingly,let:7b-5p could recognize DARS2 through a complementary sequence.Mechanistically,the increased let 7b 5p expression attenuated the promo oncogenic action of DARS2 during LUAD progression,which were inversely correlated to each other in the LUAD tssues Conclusion:In summary,let 7b-5p,downregulated DARS2 expression,regulating the progression of LUAD cells by the PI3K/AKT signaling pathway.展开更多
Background:Melanoma is a deadly skin tumor resulting from the malignant transformation of melanocytes.It is highly malignant and invasive,with the highest mortality rate among skin cancers.Acalypha australis L.(AAL),a...Background:Melanoma is a deadly skin tumor resulting from the malignant transformation of melanocytes.It is highly malignant and invasive,with the highest mortality rate among skin cancers.Acalypha australis L.(AAL),a plant with dual medicinal and culinary purposes,is commonly regarded as an edible wild vegetable in southern China.Additionally,AAL has a long history of medicinal use in China,often employed for its hemostatic,anti-diarrheal,and anti-inflammatory properties.Modern pharmacology has demonstrated that AAL possesses functions such as weight loss,antimicrobial activity,antiviral effects,and treatment for ulcerative colitis.However,there is currently no research available regarding its effectiveness and mechanisms of action on melanoma.Methods:In this investigation,we used methyl thiazolyl tetrazolium assay to detect cell viability,transwell assay to detect cell migration and invasion ability,and Western blot assay to detect relevant signaling pathways.Results:The present study reveals that 2 mg/mL AAL effectively suppresses the metastasis of B16 cells,while simultaneously triggering the expression of key apoptosis-related proteins,including Bcl-2,Bax,and cleaved caspased 3.Subsequent investigations demonstrate that AAL exerts this inhibitory effect via the PI3K/AKT signal transduction pathway,as evidenced by the observed deficits in Ras,AKT,p-AKT,and PI3K expression levels.Conclusion:These findings indicated that AAL could be a valuable therapeutic option for reducing the metastatic potential of B16 melanoma cells.展开更多
Autism spectrum disorders are a group of neurodevelopmental disorders involving more than 1100 genes,including Ctnnd2 as a candidate gene.Ctnnd2knockout mice,serving as an animal model of autis m,have been demonstrate...Autism spectrum disorders are a group of neurodevelopmental disorders involving more than 1100 genes,including Ctnnd2 as a candidate gene.Ctnnd2knockout mice,serving as an animal model of autis m,have been demonstrated to exhibit decreased density of dendritic spines.The role of melatonin,as a neuro hormone capable of effectively alleviating social interaction deficits and regulating the development of dendritic spines,in Ctnnd2 deletion-induced nerve injury remains unclea r.In the present study,we discove red that the deletion of exon 2 of the Ctnnd2 gene was linked to social interaction deficits,spine loss,impaired inhibitory neurons,and suppressed phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt) signal pathway in the prefrontal cortex.Our findings demonstrated that the long-term oral administration of melatonin for 28 days effectively alleviated the aforementioned abnormalities in Ctnnd2 gene-knockout mice.Furthermore,the administration of melatonin in the prefro ntal cortex was found to improve synaptic function and activate the PI3K/Akt signal pathway in this region.The pharmacological blockade of the PI3K/Akt signal pathway with a PI3K/Akt inhibitor,wo rtmannin,and melatonin receptor antagonists,luzindole and 4-phenyl-2-propionamidotetralin,prevented the melatonin-induced enhancement of GABAergic synaptic function.These findings suggest that melatonin treatment can ameliorate GABAe rgic synaptic function by activating the PI3K/Akt signal pathway,which may contribute to the improvement of dendritic spine abnormalities in autism spectrum disorders.展开更多
BACKGROUND Development of end-stage renal disease is predominantly attributed to diabetic nephropathy(DN).Previous studies have indicated that myricetin possesses the potential to mitigate the pathological alterations...BACKGROUND Development of end-stage renal disease is predominantly attributed to diabetic nephropathy(DN).Previous studies have indicated that myricetin possesses the potential to mitigate the pathological alterations observed in renal tissue.Never-theless,the precise molecular mechanism through which myricetin influences the progression of DN remains uncertain.AIM To investigate the effects of myricetin on DN and explore its potential therapeutic mechanism.METHODS Db/db mice were administered myricetin intragastrically on a daily basis at doses of 50 mg/kg or 100 mg/kg for a duration of 12 wk.Subsequently,blood and urine indexes were assessed,along with examination of renal tissue pathology.Kidney morphology and fibrosis were evaluated using various staining techniques including hematoxylin and eosin,periodic acid–Schiff,Masson’s trichrome,and Sirius-red.Additionally,high-glucose culturing was conducted on the RAW 264.7 cell line,treated with 25 mM myricetin or co-administered with the PI3K/Akt inhibitor LY294002 for a period of 24 h.In both in vivo and in vitro settings,quantification of inflammation factor levels was conducted using western blotting,real-time qPCR and ELISA.RESULTS In db/db mice,administration of myricetin led to a mitigating effect on DN-induced renal dysfunction and fibrosis.Notably,we observed a significant reduction in expressions of the kidney injury markers kidney injury molecule-1 and neutrophil gelatinase associated lipocalin,along with a decrease in expressions of inflammatory cytokine-related factors.Furthermore,myricetin treatment effectively inhibited the up-regulation of tumor necrosis factor-alpha,interleukin-6,and interluekin-1βinduced by high glucose in RAW 264.7 cells.Additionally,myricetin modulated the M1-type polarization of the RAW 264.7 cells.Molecular docking and bioinformatic analyses revealed Akt as the target of myricetin.The protective effect of myricetin was nullified upon blocking the polarization of RAW 264.7 via inhibition of PI3K/Akt activation using LY294002.CONCLUSION This study demonstrated that myricetin effectively mitigates kidney injury in DN mice through the regulation of macrophage polarization via the PI3K/Akt signaling pathway.展开更多
Background:Liqi Huoxue dripping pill(LQHXDP),a traditional Chinese drug for coronary heart disease,has a protective effect on the heart of rats with myocardial ischemia-reperfusion injury(MIRI)in previous studies;howe...Background:Liqi Huoxue dripping pill(LQHXDP),a traditional Chinese drug for coronary heart disease,has a protective effect on the heart of rats with myocardial ischemia-reperfusion injury(MIRI)in previous studies;however,its mechanism of action remains unclear.The purpose of this study was to investigate the protective mechanism of LQHXDP on MIRI in rats and its relationship with the PI3K/Akt signaling pathway.Methods:In this study,Sprague-Dawley rats were pre-infused with LQHXDP(175 mg/kg/d)for 10 days.PI3K inhibitor LY294002(0.3 mg/kg)was intravenously injected 15 minutes before ischemia.The rat model of MIRI was established by ligating the left anterior descending coronary artery.Subsequently,cardiac hemodynamics,serum myocardial injury markers,inflammatory factors,myocardial infarct size,antioxidant indexes,myocardial histopathology,and phosphorylation levels of key proteins of PI3K/Akt signaling pathway were assessed in rats.Results:LQHXDP was found to improve cardiac hemodynamic indexes,reduce serum creatine kinase MB isoenzyme activity and cardiac troponin and heart-type fatty acid binding protein levels,lower serum interleukin-1 beta,interleukin-6 and tumour necrosis factorαlevels,reduce the myocardial infarct size and enhance the antioxidant capacity of myocardial tissue in MIRI rats.Pathological analysis revealed that LQHXDP attenuated the extent of myocardial injury and protected mitochondria from damage in MIRI rats.Immunoblot analysis revealed that LQHXDP increased the expression levels of p-Akt and p-GSK-3βin MIRI rat cardiomyocytes.PI3K inhibitor LY294002 could impair these effects of LQHXDP.Conclusion:LQHXDP attenuated myocardial injury,attenuated oxidative stress injury and reduced inflammatory response in MIRI rats,and its protective effects were mediated by activating of PI3K/Akt/GSK-3βsignaling pathway.展开更多
Objective Osteogenesis is vitally important for bone defect repair,and Zuo Gui Wan(ZGW)is a classic prescription in traditional Chinese medicine(TCM)for strengthening bones.However,the specific mechanism by which ZGW ...Objective Osteogenesis is vitally important for bone defect repair,and Zuo Gui Wan(ZGW)is a classic prescription in traditional Chinese medicine(TCM)for strengthening bones.However,the specific mechanism by which ZGW regulates osteogenesis is still unclear.The current study is based on a network pharmacology analysis to explore the potential mechanism of ZGW in promoting osteogenesis.Methods A network pharmacology analysis followed by experimental validation was applied to explore the potential mechanisms of ZGW in promoting the osteogenesis of bone marrow mesenchymal stem cells(BMSCs).Results In total,487 no-repeat targets corresponding to the bioactive components of ZGW were screened,and 175 target genes in the intersection of ZGW and osteogenesis were obtained.And 28 core target genes were then obtained from a PPI network analysis.A GO functional enrichment analysis showed that the relevant biological processes mainly involve the cellular response to chemical stress,metal ions,and lipopolysaccharide.Additionally,KEGG pathway enrichment analysis revealed that multiple signaling pathways,including the phosphatidylinositol-3-kinase/protein kinase B(PI3K/AKT)signaling pathway,were associated with ZGW-promoted osteogensis.Further experimental validation showed that ZGW could increase alkaline phosphatase(ALP)activity as well as the mRNA and protein levels of ALP,osteocalcin(OCN),and runt related transcription factor 2(Runx 2).What’s more,Western blot analysis results showed that ZGW significantly increased the protein levels of p-PI3K and p-AKT,and the increases of these protein levels significantly receded after the addition of the PI3K inhibitor LY294002.Finally,the upregulated osteogenic-related indicators were also suppressed by the addition of LY294002.Conclusion ZGW promotes the osteogenesis of BMSCs via PI3K/AKT signaling pathway.展开更多
Objective This study investigated the impact of occupational mercury(Hg) exposure on human gene transcription and expression, and its potential biological mechanisms.Methods Differentially expressed genes related to H...Objective This study investigated the impact of occupational mercury(Hg) exposure on human gene transcription and expression, and its potential biological mechanisms.Methods Differentially expressed genes related to Hg exposure were identified and validated using gene expression microarray analysis and extended validation. Hg-exposed cell models and PTEN lowexpression models were established in vitro using 293T cells. PTEN gene expression was assessed using qRT-PCR, and Western blotting was used to measure PTEN, AKT, and PI3K protein levels. IL-6 expression was determined by ELISA.Results Combined findings from gene expression microarray analysis, bioinformatics, and population expansion validation indicated significant downregulation of the PTEN gene in the high-concentration Hg exposure group. In the Hg-exposed cell model(25 and 10 μmol/L), a significant decrease in PTEN expression was observed, accompanied by a significant increase in PI3K, AKT, and IL-6 expression.Similarly, a low-expression cell model demonstrated that PTEN gene knockdown led to a significant decrease in PTEN protein expression and a substantial increase in PI3K, AKT, and IL-6 levels.Conclusion This is the first study to report that Hg exposure downregulates the PTEN gene, activates the PI3K/AKT regulatory pathway, and increases the expression of inflammatory factors, ultimately resulting in kidney inflammation.展开更多
We evaluated the effect of isoquercetin(quercetin-O-3-glucoside-quercetin,IQ)as a functional component of Abeliophyllum disistichum Nakai ethanol extract(ADLE)on prostate cell proliferation and apoptosis and its effec...We evaluated the effect of isoquercetin(quercetin-O-3-glucoside-quercetin,IQ)as a functional component of Abeliophyllum disistichum Nakai ethanol extract(ADLE)on prostate cell proliferation and apoptosis and its effects on the IGF-1/PI3K/Akt/mTOR pathway in benign prostatic hyperplasia(BPH).Metabolites in ADLE were analyzed using UHPLC-qTOF-MS and HPLC.IQ was orally administered(1 or 10 mg/kg)to a testosterone propionate-induced BPH rat model,and its effects on the prostate weight were evaluated.The effect of IQ on androgen receptor(AR)signaling was analyzed in LNCaP cells.Whether IGF-1 and IQ affect the IGF-1/PI3K/Akt/mTOR pathway in BPH-1 cells was also examined.The metabolites in ADLE were identified and quantified,which confirmed that ADLE contained abundant IQ(20.88 mg/g).IQ significantly reduced the prostate size in a concentration-dependent manner in a BPH rat model,and significantly decreased the expression of AR signaling factors in the rat prostate tissue and LNCaP cells in a concentration-dependent manner.IQ also inhibited the PI3K/AKT/mTOR pathway activated by IGF-1 treatment in BPH-1 cells.In BPH-1 cells,IQ led to G0/G1 arrest and suppressed the expression of proliferation factors while inducing apoptosis.Thus,IQ shows potential for use as a pharmaceutical and nutraceutical for BPH.展开更多
The key to managing fracture is to achieve stable internal fixation,and currently,biologically and mechanically appropriate internal fixation devices are urgently needed.With excellent biocompatibility and corrosion r...The key to managing fracture is to achieve stable internal fixation,and currently,biologically and mechanically appropriate internal fixation devices are urgently needed.With excellent biocompatibility and corrosion resistance,titanium–niobium alloys have the potential to become a new generation of internal fixation materials for fractures.However,the role and mechanism of titanium–niobium alloys on promoting fracture healing are still undefined.Therefore,in this study,we systematically evaluated the bone-enabling properties of Ti45Nb via in vivo and in vitro experiments.In vitro,we found that Ti45Nb has an excellent ability to promote MC3T3-E1 cell adhesion and proliferation without obvious cytotoxicity.Alkaline phosphatase(ALP)activity and alizarin red staining and semiquantitative analysis showed that Ti45Nb enhanced the osteogenic differentiation of MC3T3-E1 cells compared to the Ti6Al4V control.In the polymerase chain reaction experiment,the expression of osteogenic genes in the Ti45Nb group,such as ALP,osteopontin(OPN),osteocalcin(OCN),type 1 collagen(Col-1)and runt-related transcription factor-2(Runx2),was significantly higher than that in the control group.Meanwhile,in the western blot experiment,the expression of osteogenic-related proteins in the Ti45Nb group was significantly increased,and the expression of PI3K–Akt-related proteins was also higher,which indicated that Ti45Nb might promote fracture healing by activating the PI3K–Akt signaling pathway.In vivo,we found that Ti45Nb implants accelerated fracture healing compared to Ti6Al4V,and the biosafety of Ti45Nb was confirmed by histological evaluation.Furthermore,immunohistochemical staining confirmed that Ti45Nb may promote osteogenesis by upregulating the PI3K/Akt signaling pathway.Our study demonstrated that Ti45Nb exerts an excellent ability to promote fracture healing as well as enhance osteoblast differentiation by activating the PI3K/Akt signaling pathway,and its good biosafety has been confirmed,which indicates its clinical translation potential.展开更多
Background:The purpose of the study was to investigatethe active ingredients and potential biochemicalmechanisms of Simiao Wan(SMW)in obesity-associated insulin resistance.Methods:An integrated network pharmacology me...Background:The purpose of the study was to investigatethe active ingredients and potential biochemicalmechanisms of Simiao Wan(SMW)in obesity-associated insulin resistance.Methods:An integrated network pharmacology method to screen the active compoundsand candidate targets,construct the protein-protein-interaction network,and ingredients-targets-pathways network was constructed for topological analysis to identify core targets and main ingredients.To find the possible signaling pathways,enrichment analysis was performed.Further,a model of insulin resistance in HL-7702 cells was established to verify the impact of SMW and the regulatory processes.Results:An overall of 63 active components and 151 candidate targets were obtained,in which flavonoids were the main ingredients.Enrichment analysis indicated that the PI3K-Akt signaling pathway was the potential pathway regulated by SMW in obesity-associated insulin resistance treatment.The result showed that SMW could significantly ameliorate insulin sensitivity,increase glucose synthesis and glucose utilization and reduce intracellular lipids accumulation in hepatocytes.Also,SMW inhibited diacylglycerols accumulation-induced PKCεactivity and decreased its translocation to the membrane.Conclusion:SMW ameliorated obesity-associated insulin resistance through PKCε/IRS-1/PI3K/Akt signaling axis in hepatocytes,providing a new strategy for metabolic disease treatment.展开更多
Objective:This study aimed to elucidate the differences in effects and mechanisms of action of electric-needle therapy at Tian Shu(ST25),Da Chang Shu(BL25),Zu San Li(ST36)and Shang Ju Xu(ST37)acupoints on chronic expe...Objective:This study aimed to elucidate the differences in effects and mechanisms of action of electric-needle therapy at Tian Shu(ST25),Da Chang Shu(BL25),Zu San Li(ST36)and Shang Ju Xu(ST37)acupoints on chronic experimental colitis in rats through the PI3K/AKT/mTOR signaling pathway.Methods:Sixty pathogen-free SD rats were randomly assigned to six groups:the normal,model,Tian Shu(ST25),Da Chang Shu(BL25),Zu San Li(ST36)and Shang Ju Xu(ST37)groups,each with 10 rats.Chronic colitis was induced in rats by combining immunization and local stimulation.After model establishment,electrical needle intervention combined with dispersing wave of 2 Hz/50 Hz with a current intensity of 2 mA once daily for 20 min was applied on acupoints of each group.Subsequently,the inflammation of colonic mucosa and serum levels of inflammatory factors(IL-23,IL-17,IL-10)were observed;ELISA was used to detect mRNA expressions of PI3K,Akt and mTOR in colitic tissues by RT-PCR as well as protein content of p-PI3k/PI3K,p-Akt/Akt,and p-mTOR/mTOR in colitic tissues by Western blotting.Result:Compared with the normal group,the model rats showed a poor general condition,serious damage to the colonic mucosa with a large number of inflammatory cells infiltration.The serum IL-23 and IL-17 expressions were significantly increased(P<0.01),while the serum IL-10 expression was significantly decreased(P<0.01);the mRNA and protein expressions of PI3K,Akt,mTOR and p-PI3K,p-Akt and p-mTOR were significantly increased(P<0.05,P<0.01).Compared with the model group,the pathological slices of rats in each acupoints intervention group showed obvious improvement of colitis inflammatory reaction and tissue damage;the serological levels of IL-23 and IL-17 were significantly reduced(P<0.01),while the serology level of IL-10 was significantly increased(P<0.01);the expressions of PI3K,Akt,mTOR mRNA and p-PI3K,p-Akt,p-mTOR proteins were significantly decreased(P<0.05,P<0.01).Compared with Tian Shu(ST25),Da Chang Shu(BL25),Zu San Li(ST36)groups,the recovery degree of mucosa layers in Shang Ju Xu(ST37)group was closer to that of normal group,and the curative effect was relatively the best;in terms of serological levels of IL-23 and IL-17,the Shang Ju Xu(ST37)group was significantly lower(P<0.05),while the level of IL-10 was significantly higher(P<0.01);the expressions of PI3K,Akt,mTOR mRNA and p-PI3K,p-Akt,p-mTOR proteins were significantly decreased(P<0.05,P<0.01).Conclusion:Results indicate that electrical acupuncture at Tian Shu(ST25),Da Chang Shu(BL25),Zu San Li(ST36)and Shang Ju Xu(ST37)show similar effects in relieving the colitis-induced damage in the mucosa of chronic colitis rats,as well as inflammatory response.Among them,Shang Ju Xu(ST25)has a superior overall effect in treating chronic colitis compared to Tian Shu(ST25),Da Chang Shu(BL25)and Zu San Li(ST36).The mechanism may be related to inhibition of PI3K/Akt/mTOR signaling pathway.展开更多
Non-traumatic osteonecrosis of the femoral head(NONFH)is one of the most common orthopedic diseases,influenced by multiple signaling pathways and inflammatory factors.The PI3K/AKT signaling pathway is closely related ...Non-traumatic osteonecrosis of the femoral head(NONFH)is one of the most common orthopedic diseases,influenced by multiple signaling pathways and inflammatory factors.The PI3K/AKT signaling pathway is closely related to various biological processes such as apoptosis,autophagy,and metabolism in cells.Increasing evidence suggests that it plays an important role in the development of femoral head necrosis.This paper aims to explore the mechanism of the PI3K/AKT signaling pathway in the pathogenesis of NONFH by analyzing its regulation of lipid metabolism,cell apoptosis and autophagy,and intravascular coagulation.This study provides new insights for the research of NONFH.展开更多
Background:To investigate the role of fibroblast growth factor 2(FGF2)in chemotherapy resistance of colon cancer.Methods:An HCT116/5-fluorouracil(5-FU)-resistant cell line was established,and FGF2 levels were detected...Background:To investigate the role of fibroblast growth factor 2(FGF2)in chemotherapy resistance of colon cancer.Methods:An HCT116/5-fluorouracil(5-FU)-resistant cell line was established,and FGF2 levels were detected in a sensitive cell group(HCT116)and a resistant cell group(HCT1116-R)using different methods.Fibroblast growth factor 2 levels in the medium were determined by enzyme-linked immunoassay.The protein expressions of FGF2,fibroblast growth factor receptor 1(FGFR1),and phospho-FGFR1 were assessed by Western blotting,and FGF2 mRNA levels were detected by quantitative real-time polymerase chain reaction.Fibroblast growth factor 2 recombinant protein was added to sensitive cells,and FGFR inhibitor AZD4547 was added to resistant cells,and the cell survival rate was determined using the cell counting kit-8 method and the protein expressions of PI3K(phosphatidylinositol 3 kinase),p-PI3K(phospho-PI3K),Akt(protein kinase B),p-Akt(phospho-Akt),mammalian target of rapamycin(mTOR),p-mTOR(phospho-mTOR),Bad(Bcl-xL/Bcl-2-associated death promoter),NF-κB(nuclear factorκB),GSK-3(glycogen synthase kinase-3),FKHR(forkhead box protein O1),and PTEN(phosphatase and tensin homolog deleted on chromosome ten)were detected by Western blotting.Results:Fibroblast growth factor 2 protein and mRNA expression levels in the HCT116-R group were significantly higher than those in the HCT116 group.Fibroblast growth factor 2 increased the survival rate of HCT116 cells;improved tolerance to 5-FU;upregulated p-PI3K,p-Akt,and p-mTOR;and downregulated Bad.The FGFR inhibitor AZD4547 decreased cell survival rate and tolerance to 5-FU;downregulated p-PI3K,p-Akt,and p-mTOR expression;and upregulated Bad.Conclusions:Fibroblast growth factor 2 promotes chemotherapy tolerance in colon cancer cells by activating the Akt/mTOR and Akt/Bad signaling pathways downstream of PI3K.展开更多
The phosphoinositide-3-kinase/Akt(PI3K/AKT)signaling pathway is crucial for Sertoli cell development and completing spermatogenesis.Its main role is to promote proliferation and inhibit apoptosis.Many factors activate...The phosphoinositide-3-kinase/Akt(PI3K/AKT)signaling pathway is crucial for Sertoli cell development and completing spermatogenesis.Its main role is to promote proliferation and inhibit apoptosis.Many factors activate the PI3K/AKT pathway,like hormones,such as follicle stimulating hormone(FSH),androgen,estrogen,insulin to name a few.Many of these factors have receptors inside or on the surface of Sertoli cells(SCs).This review summarizes how these hormones directly regulate the PI3K/AKT signaling pathway in SCs,which in turn affects SC proliferation and differentiation.Further,hormone-mediated PI3K/AKT signaling also stimulates SC secretion,which is essential for germ cell development,suggesting an indirect role of PI3K/AKT signaling during spermatogenesis.These functions include promoting spermatogonia proliferation and differentiation,meiosis of spermatocytes,sperm maturation,and their release.This review also provides potential hints for clinically treating male infertility issues like cryptorchidism and Sertoli cell-only syndrome.展开更多
BACKGROUND Diabetic skin ulcers,a significant global healthcare burden,are mainly caused by the inhibition of cell proliferation and impaired angiogenesis.XB130 is an adaptor protein that regulates cell proliferation ...BACKGROUND Diabetic skin ulcers,a significant global healthcare burden,are mainly caused by the inhibition of cell proliferation and impaired angiogenesis.XB130 is an adaptor protein that regulates cell proliferation and migration.However,the role of XB130 in the development of diabetic skin ulcers remains unclear.AIM To investigate whether XB130 can regulate the inhibition of proliferation and vascular damage induced by high glucose.Additionally,we aim to determine whether XB130 is involved in the healing process of diabetic skin ulcers,along with its molecular mechanisms.METHODS We conducted RNA-sequencing analysis to identify the key genes involved in diabetic skin ulcers.We investigated the effects of XB130 on wound healing using histological analyses.In addition,we used reverse transcription-quantitative polymerase chain reaction,Western blot,terminal deoxynucleotidyl transferasemediated dUTP nick end labeling staining,immunofluorescence,wound healing,and tubule formation experiments to investigate their effects on cellular processes in human umbilical vein endothelial cells(HUVECs)stimulated with high glucose.Finally,we performed functional analysis to elucidate the molecular mechanisms underlying diabetic skin ulcers.RESULTS RNA-sequencing analysis showed that the expression of XB130 was up-regulated in the tissues of diabetic skin ulcers.Knockdown of XB130 promoted the healing of skin wounds in mice,leading to an accelerated wound healing process and shortened wound healing time.At the cellular level,knockdown of XB130 alleviated high glucose-induced inhibition of cell proliferation and angiogenic impairment in HUVECs.Inhibition of the PI3K/Akt pathway removed the proliferative effects and endothelial protection mediated by XB130.CONCLUSION The findings of this study indicated that the expression of XB130 is up-regulated in high glucose-stimulated diabetic skin ulcers and HUVECs.Knockdown of XB130 promotes cell proliferation and angiogenesis via the PI3K/Akt signalling pathway,which accelerates the healing of diabetic skin ulcers.展开更多
基金funding from the National Natural Science Foundation of China(Grant Nos.81573926 and 81173235).
文摘Objective:Panax notoginseng saponins (PNS),extracted from rhizome of the herb Radix et Rhizoma Notoginseng (Panax notoginseng (Burk.) F.H.Chen),was recently discovered to have beneficial effects against neurological damage.This study investigated the effects of PNS on cerebral ischemia and elucidated the molecular mechanisms underlying these effects.Methods:Middle cerebral artery occlusion rats were treated with PNS (3.6 mg/100 g or 7.2 mg/100 g per day) for 7 days,the gene of LINGO-1 was measured and the expression of protein synaptophysin,postsynaptic density protein 95,LINGO-1 and p-EGFR/p-PI3K/p-AKT were investigated.The weight and mNSS score of Sprague-Dawley rats in each group were recorded every day during the 7 days.Results:PNS promoted middle cerebral artery occlusion rats' weight and the recovery of neural function.PNS significantly decreased ischemia-induced LINGO-1 protein expression.PNS also elevated EGFR/PI3K/AKT phosphorylation levels.Conclusion:PNS promoted cerebral recovery from ischemic injury by accelerating synapse reconstruction and inhibiting the neuron growth negative regulatory protein LINGO-1 and activating the epidermal growth factor receptor (EGFR)/PI3K/AKT signaling pathway in vivo.
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 the National Natural Science Foundation of China,No.81971097(to JY)。
文摘Preclinical and clinical studies have shown that microglia and macrophages participate in a multiphasic brain damage repair process following intracerebral hemorrhage.The E26 transformation-specific sequence-related transcription factor Spi1 regulates microglial/macrophage commitment and maturation.However,the effect of Spi1 on intracerebral hemorrhage remains unclear.In this study,we found that Spi1 may regulate recovery from the neuroinflammation and neurofunctional damage caused by intracerebral hemorrhage by modulating the microglial/macrophage transcriptome.We showed that high Spi1expression in microglia/macrophages after intracerebral hemorrhage is associated with the activation of many pathways that promote phagocytosis,glycolysis,and autophagy,as well as debris clearance and sustained remyelination.Notably,microglia with higher levels of Soil expression were chara cterized by activation of pathways associated with a variety of hemorrhage-related cellular processes,such as complement activation,angiogenesis,and coagulation.In conclusion,our results suggest that Spi1 plays a vital role in the microglial/macrophage inflammatory response following intracerebral hemorrhage.This new insight into the regulation of Spi1 and its target genes may advance our understanding of neuroinflammation in intracerebral hemorrhage and provide therapeutic targets for patients with intracerebral hemorrhage.
文摘Background:The aberrant intraellular expression of a mitochondrial aspartyl tRNA synthetase 2(DARS2)has been reported in human cancers.Nevertheless its critical role and detailed mechanism in lung adenocarcinoma(LUAD)remain unexplored.Methods:Initially,The Cancer Genome Atlas(TCGA)based Gene Expression Profiling Interactive Analysis(GEPIA)database (http:/gepia.cancer-pku.cn/)was used to analyze the prognostic relevance of DARS2 expression in LUAD.Further,cell counting kit(CCK)8,immunostaining,and transwell invasion assays in LUAD cell lines in vitro,as well as DARS2 silence on LUAD by tumorigenicity experiments in wivo in nude mice,were performed.Besides,we analyzed the expression levels of p-PI3K(phosphorylated Phosphotylinosital3 kinase),PI3K,AKT(Protein Kinase B),p-AKT(phosphorylated Protein Kinase B),PCNA(proliferating cell nudear antigen),cleaved-caspase 3,E cadherin,and N-cadherin proteins using the Westem blot analysis.Results:LUAD tissues showed higher DARS2 expression compared to normal tissues.Upregulation of DARS2 could be related to Tumor-Node-Metastasis(TNM)stage,high lymph node metastasis,and inferior prognosis.DARS2 silence decreased the proliferation,migration,and invasion abilities of LUAD cells.In addition,the DARS2 downregulation decreased the PCNA and N-cadherin expression and increased cleaved:caspase 3 and E cadherin expressions in LUAD cells,coupled with the inactivation of the PI3K/AKT signaling pathway.Moreover,DARS2 silence impaired the tumonigenicity of LUAD in vivo.Interestingly,let:7b-5p could recognize DARS2 through a complementary sequence.Mechanistically,the increased let 7b 5p expression attenuated the promo oncogenic action of DARS2 during LUAD progression,which were inversely correlated to each other in the LUAD tssues Conclusion:In summary,let 7b-5p,downregulated DARS2 expression,regulating the progression of LUAD cells by the PI3K/AKT signaling pathway.
基金This work was supported by the Hunan Education Department Project(NO.20A390)National Innovation and Entrepreneurship Training Program(S202010548007).
文摘Background:Melanoma is a deadly skin tumor resulting from the malignant transformation of melanocytes.It is highly malignant and invasive,with the highest mortality rate among skin cancers.Acalypha australis L.(AAL),a plant with dual medicinal and culinary purposes,is commonly regarded as an edible wild vegetable in southern China.Additionally,AAL has a long history of medicinal use in China,often employed for its hemostatic,anti-diarrheal,and anti-inflammatory properties.Modern pharmacology has demonstrated that AAL possesses functions such as weight loss,antimicrobial activity,antiviral effects,and treatment for ulcerative colitis.However,there is currently no research available regarding its effectiveness and mechanisms of action on melanoma.Methods:In this investigation,we used methyl thiazolyl tetrazolium assay to detect cell viability,transwell assay to detect cell migration and invasion ability,and Western blot assay to detect relevant signaling pathways.Results:The present study reveals that 2 mg/mL AAL effectively suppresses the metastasis of B16 cells,while simultaneously triggering the expression of key apoptosis-related proteins,including Bcl-2,Bax,and cleaved caspased 3.Subsequent investigations demonstrate that AAL exerts this inhibitory effect via the PI3K/AKT signal transduction pathway,as evidenced by the observed deficits in Ras,AKT,p-AKT,and PI3K expression levels.Conclusion:These findings indicated that AAL could be a valuable therapeutic option for reducing the metastatic potential of B16 melanoma cells.
基金supported by the Chongqing Science and Technology CommitteeNatural Science Foundation of Chongqing,No.cstc2021jcyj-msxmX0065 (to YL)。
文摘Autism spectrum disorders are a group of neurodevelopmental disorders involving more than 1100 genes,including Ctnnd2 as a candidate gene.Ctnnd2knockout mice,serving as an animal model of autis m,have been demonstrated to exhibit decreased density of dendritic spines.The role of melatonin,as a neuro hormone capable of effectively alleviating social interaction deficits and regulating the development of dendritic spines,in Ctnnd2 deletion-induced nerve injury remains unclea r.In the present study,we discove red that the deletion of exon 2 of the Ctnnd2 gene was linked to social interaction deficits,spine loss,impaired inhibitory neurons,and suppressed phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt) signal pathway in the prefrontal cortex.Our findings demonstrated that the long-term oral administration of melatonin for 28 days effectively alleviated the aforementioned abnormalities in Ctnnd2 gene-knockout mice.Furthermore,the administration of melatonin in the prefro ntal cortex was found to improve synaptic function and activate the PI3K/Akt signal pathway in this region.The pharmacological blockade of the PI3K/Akt signal pathway with a PI3K/Akt inhibitor,wo rtmannin,and melatonin receptor antagonists,luzindole and 4-phenyl-2-propionamidotetralin,prevented the melatonin-induced enhancement of GABAergic synaptic function.These findings suggest that melatonin treatment can ameliorate GABAe rgic synaptic function by activating the PI3K/Akt signal pathway,which may contribute to the improvement of dendritic spine abnormalities in autism spectrum disorders.
基金Supported by National Natural Science Foundation of China,No.82205025,No.82374355 and No.82174293Subject of Jiangsu Province Hospital of Chinese Medicine,No.Y21023Forth Batch of Construction Program for Inheritance Office of Jiangsu Province Famous TCM Experts,No.[2021]7.
文摘BACKGROUND Development of end-stage renal disease is predominantly attributed to diabetic nephropathy(DN).Previous studies have indicated that myricetin possesses the potential to mitigate the pathological alterations observed in renal tissue.Never-theless,the precise molecular mechanism through which myricetin influences the progression of DN remains uncertain.AIM To investigate the effects of myricetin on DN and explore its potential therapeutic mechanism.METHODS Db/db mice were administered myricetin intragastrically on a daily basis at doses of 50 mg/kg or 100 mg/kg for a duration of 12 wk.Subsequently,blood and urine indexes were assessed,along with examination of renal tissue pathology.Kidney morphology and fibrosis were evaluated using various staining techniques including hematoxylin and eosin,periodic acid–Schiff,Masson’s trichrome,and Sirius-red.Additionally,high-glucose culturing was conducted on the RAW 264.7 cell line,treated with 25 mM myricetin or co-administered with the PI3K/Akt inhibitor LY294002 for a period of 24 h.In both in vivo and in vitro settings,quantification of inflammation factor levels was conducted using western blotting,real-time qPCR and ELISA.RESULTS In db/db mice,administration of myricetin led to a mitigating effect on DN-induced renal dysfunction and fibrosis.Notably,we observed a significant reduction in expressions of the kidney injury markers kidney injury molecule-1 and neutrophil gelatinase associated lipocalin,along with a decrease in expressions of inflammatory cytokine-related factors.Furthermore,myricetin treatment effectively inhibited the up-regulation of tumor necrosis factor-alpha,interleukin-6,and interluekin-1βinduced by high glucose in RAW 264.7 cells.Additionally,myricetin modulated the M1-type polarization of the RAW 264.7 cells.Molecular docking and bioinformatic analyses revealed Akt as the target of myricetin.The protective effect of myricetin was nullified upon blocking the polarization of RAW 264.7 via inhibition of PI3K/Akt activation using LY294002.CONCLUSION This study demonstrated that myricetin effectively mitigates kidney injury in DN mice through the regulation of macrophage polarization via the PI3K/Akt signaling pathway.
基金supported by National Natural Science Foundation of China(Grant No.81860873 and 81960864)the Scientific and Technological Projects of Guizhou Province(Qian Kehe Jichu(2016)1401)High-level Talents Project of Guizhou Province(GUTCM(ZQ2018005)).
文摘Background:Liqi Huoxue dripping pill(LQHXDP),a traditional Chinese drug for coronary heart disease,has a protective effect on the heart of rats with myocardial ischemia-reperfusion injury(MIRI)in previous studies;however,its mechanism of action remains unclear.The purpose of this study was to investigate the protective mechanism of LQHXDP on MIRI in rats and its relationship with the PI3K/Akt signaling pathway.Methods:In this study,Sprague-Dawley rats were pre-infused with LQHXDP(175 mg/kg/d)for 10 days.PI3K inhibitor LY294002(0.3 mg/kg)was intravenously injected 15 minutes before ischemia.The rat model of MIRI was established by ligating the left anterior descending coronary artery.Subsequently,cardiac hemodynamics,serum myocardial injury markers,inflammatory factors,myocardial infarct size,antioxidant indexes,myocardial histopathology,and phosphorylation levels of key proteins of PI3K/Akt signaling pathway were assessed in rats.Results:LQHXDP was found to improve cardiac hemodynamic indexes,reduce serum creatine kinase MB isoenzyme activity and cardiac troponin and heart-type fatty acid binding protein levels,lower serum interleukin-1 beta,interleukin-6 and tumour necrosis factorαlevels,reduce the myocardial infarct size and enhance the antioxidant capacity of myocardial tissue in MIRI rats.Pathological analysis revealed that LQHXDP attenuated the extent of myocardial injury and protected mitochondria from damage in MIRI rats.Immunoblot analysis revealed that LQHXDP increased the expression levels of p-Akt and p-GSK-3βin MIRI rat cardiomyocytes.PI3K inhibitor LY294002 could impair these effects of LQHXDP.Conclusion:LQHXDP attenuated myocardial injury,attenuated oxidative stress injury and reduced inflammatory response in MIRI rats,and its protective effects were mediated by activating of PI3K/Akt/GSK-3βsignaling pathway.
文摘Objective Osteogenesis is vitally important for bone defect repair,and Zuo Gui Wan(ZGW)is a classic prescription in traditional Chinese medicine(TCM)for strengthening bones.However,the specific mechanism by which ZGW regulates osteogenesis is still unclear.The current study is based on a network pharmacology analysis to explore the potential mechanism of ZGW in promoting osteogenesis.Methods A network pharmacology analysis followed by experimental validation was applied to explore the potential mechanisms of ZGW in promoting the osteogenesis of bone marrow mesenchymal stem cells(BMSCs).Results In total,487 no-repeat targets corresponding to the bioactive components of ZGW were screened,and 175 target genes in the intersection of ZGW and osteogenesis were obtained.And 28 core target genes were then obtained from a PPI network analysis.A GO functional enrichment analysis showed that the relevant biological processes mainly involve the cellular response to chemical stress,metal ions,and lipopolysaccharide.Additionally,KEGG pathway enrichment analysis revealed that multiple signaling pathways,including the phosphatidylinositol-3-kinase/protein kinase B(PI3K/AKT)signaling pathway,were associated with ZGW-promoted osteogensis.Further experimental validation showed that ZGW could increase alkaline phosphatase(ALP)activity as well as the mRNA and protein levels of ALP,osteocalcin(OCN),and runt related transcription factor 2(Runx 2).What’s more,Western blot analysis results showed that ZGW significantly increased the protein levels of p-PI3K and p-AKT,and the increases of these protein levels significantly receded after the addition of the PI3K inhibitor LY294002.Finally,the upregulated osteogenic-related indicators were also suppressed by the addition of LY294002.Conclusion ZGW promotes the osteogenesis of BMSCs via PI3K/AKT signaling pathway.
基金supported by the Jiangsu Province’s Outstanding Medical Academic Leader Program [CXTDA2017029]the Jiangsu Provincial Key Medical Discipline [ZDXK202249].
文摘Objective This study investigated the impact of occupational mercury(Hg) exposure on human gene transcription and expression, and its potential biological mechanisms.Methods Differentially expressed genes related to Hg exposure were identified and validated using gene expression microarray analysis and extended validation. Hg-exposed cell models and PTEN lowexpression models were established in vitro using 293T cells. PTEN gene expression was assessed using qRT-PCR, and Western blotting was used to measure PTEN, AKT, and PI3K protein levels. IL-6 expression was determined by ELISA.Results Combined findings from gene expression microarray analysis, bioinformatics, and population expansion validation indicated significant downregulation of the PTEN gene in the high-concentration Hg exposure group. In the Hg-exposed cell model(25 and 10 μmol/L), a significant decrease in PTEN expression was observed, accompanied by a significant increase in PI3K, AKT, and IL-6 expression.Similarly, a low-expression cell model demonstrated that PTEN gene knockdown led to a significant decrease in PTEN protein expression and a substantial increase in PI3K, AKT, and IL-6 levels.Conclusion This is the first study to report that Hg exposure downregulates the PTEN gene, activates the PI3K/AKT regulatory pathway, and increases the expression of inflammatory factors, ultimately resulting in kidney inflammation.
基金supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF)funded by the Ministry of Education,Science and Technology (NRF2020R1A2C1014798 to E-K Kim)。
文摘We evaluated the effect of isoquercetin(quercetin-O-3-glucoside-quercetin,IQ)as a functional component of Abeliophyllum disistichum Nakai ethanol extract(ADLE)on prostate cell proliferation and apoptosis and its effects on the IGF-1/PI3K/Akt/mTOR pathway in benign prostatic hyperplasia(BPH).Metabolites in ADLE were analyzed using UHPLC-qTOF-MS and HPLC.IQ was orally administered(1 or 10 mg/kg)to a testosterone propionate-induced BPH rat model,and its effects on the prostate weight were evaluated.The effect of IQ on androgen receptor(AR)signaling was analyzed in LNCaP cells.Whether IGF-1 and IQ affect the IGF-1/PI3K/Akt/mTOR pathway in BPH-1 cells was also examined.The metabolites in ADLE were identified and quantified,which confirmed that ADLE contained abundant IQ(20.88 mg/g).IQ significantly reduced the prostate size in a concentration-dependent manner in a BPH rat model,and significantly decreased the expression of AR signaling factors in the rat prostate tissue and LNCaP cells in a concentration-dependent manner.IQ also inhibited the PI3K/AKT/mTOR pathway activated by IGF-1 treatment in BPH-1 cells.In BPH-1 cells,IQ led to G0/G1 arrest and suppressed the expression of proliferation factors while inducing apoptosis.Thus,IQ shows potential for use as a pharmaceutical and nutraceutical for BPH.
基金This work was supported by the National Natural Science Foundation of China(Nos.81972058,81902194 and 82202680)the Science and Technology Commission of Shanghai Municipality(No.22YF1422900)+3 种基金the Shanghai Municipal Key Clinical Specialty,China(No.shslczdzk06701)the National Facility for Translational Medicine(Shanghai),China(No.TMSZ-2020-207)the Shanghai Engineering Research Center of Orthopedic Innovative Instruments and Personalized Medicine Instruments and Personalized Medicine(No.19DZ2250200)the Key R&D Program of Ningxia,China(Nos.2020BCH01001 and 2021BEG02037).
文摘The key to managing fracture is to achieve stable internal fixation,and currently,biologically and mechanically appropriate internal fixation devices are urgently needed.With excellent biocompatibility and corrosion resistance,titanium–niobium alloys have the potential to become a new generation of internal fixation materials for fractures.However,the role and mechanism of titanium–niobium alloys on promoting fracture healing are still undefined.Therefore,in this study,we systematically evaluated the bone-enabling properties of Ti45Nb via in vivo and in vitro experiments.In vitro,we found that Ti45Nb has an excellent ability to promote MC3T3-E1 cell adhesion and proliferation without obvious cytotoxicity.Alkaline phosphatase(ALP)activity and alizarin red staining and semiquantitative analysis showed that Ti45Nb enhanced the osteogenic differentiation of MC3T3-E1 cells compared to the Ti6Al4V control.In the polymerase chain reaction experiment,the expression of osteogenic genes in the Ti45Nb group,such as ALP,osteopontin(OPN),osteocalcin(OCN),type 1 collagen(Col-1)and runt-related transcription factor-2(Runx2),was significantly higher than that in the control group.Meanwhile,in the western blot experiment,the expression of osteogenic-related proteins in the Ti45Nb group was significantly increased,and the expression of PI3K–Akt-related proteins was also higher,which indicated that Ti45Nb might promote fracture healing by activating the PI3K–Akt signaling pathway.In vivo,we found that Ti45Nb implants accelerated fracture healing compared to Ti6Al4V,and the biosafety of Ti45Nb was confirmed by histological evaluation.Furthermore,immunohistochemical staining confirmed that Ti45Nb may promote osteogenesis by upregulating the PI3K/Akt signaling pathway.Our study demonstrated that Ti45Nb exerts an excellent ability to promote fracture healing as well as enhance osteoblast differentiation by activating the PI3K/Akt signaling pathway,and its good biosafety has been confirmed,which indicates its clinical translation potential.
基金supported by the National Natural Science Foundation of China(81903871)Natural Science Foundation of Jiangsu Province(BK20190565)+1 种基金Fundamental Research Funds for the Central Universities(2632021ZD16)Zhenjiang City 2022 Science and Technology Innovation Fund(SH2022084).
文摘Background:The purpose of the study was to investigatethe active ingredients and potential biochemicalmechanisms of Simiao Wan(SMW)in obesity-associated insulin resistance.Methods:An integrated network pharmacology method to screen the active compoundsand candidate targets,construct the protein-protein-interaction network,and ingredients-targets-pathways network was constructed for topological analysis to identify core targets and main ingredients.To find the possible signaling pathways,enrichment analysis was performed.Further,a model of insulin resistance in HL-7702 cells was established to verify the impact of SMW and the regulatory processes.Results:An overall of 63 active components and 151 candidate targets were obtained,in which flavonoids were the main ingredients.Enrichment analysis indicated that the PI3K-Akt signaling pathway was the potential pathway regulated by SMW in obesity-associated insulin resistance treatment.The result showed that SMW could significantly ameliorate insulin sensitivity,increase glucose synthesis and glucose utilization and reduce intracellular lipids accumulation in hepatocytes.Also,SMW inhibited diacylglycerols accumulation-induced PKCεactivity and decreased its translocation to the membrane.Conclusion:SMW ameliorated obesity-associated insulin resistance through PKCε/IRS-1/PI3K/Akt signaling axis in hepatocytes,providing a new strategy for metabolic disease treatment.
基金Shanxi Province Applied Basic Research Project(No.201801D121358)。
文摘Objective:This study aimed to elucidate the differences in effects and mechanisms of action of electric-needle therapy at Tian Shu(ST25),Da Chang Shu(BL25),Zu San Li(ST36)and Shang Ju Xu(ST37)acupoints on chronic experimental colitis in rats through the PI3K/AKT/mTOR signaling pathway.Methods:Sixty pathogen-free SD rats were randomly assigned to six groups:the normal,model,Tian Shu(ST25),Da Chang Shu(BL25),Zu San Li(ST36)and Shang Ju Xu(ST37)groups,each with 10 rats.Chronic colitis was induced in rats by combining immunization and local stimulation.After model establishment,electrical needle intervention combined with dispersing wave of 2 Hz/50 Hz with a current intensity of 2 mA once daily for 20 min was applied on acupoints of each group.Subsequently,the inflammation of colonic mucosa and serum levels of inflammatory factors(IL-23,IL-17,IL-10)were observed;ELISA was used to detect mRNA expressions of PI3K,Akt and mTOR in colitic tissues by RT-PCR as well as protein content of p-PI3k/PI3K,p-Akt/Akt,and p-mTOR/mTOR in colitic tissues by Western blotting.Result:Compared with the normal group,the model rats showed a poor general condition,serious damage to the colonic mucosa with a large number of inflammatory cells infiltration.The serum IL-23 and IL-17 expressions were significantly increased(P<0.01),while the serum IL-10 expression was significantly decreased(P<0.01);the mRNA and protein expressions of PI3K,Akt,mTOR and p-PI3K,p-Akt and p-mTOR were significantly increased(P<0.05,P<0.01).Compared with the model group,the pathological slices of rats in each acupoints intervention group showed obvious improvement of colitis inflammatory reaction and tissue damage;the serological levels of IL-23 and IL-17 were significantly reduced(P<0.01),while the serology level of IL-10 was significantly increased(P<0.01);the expressions of PI3K,Akt,mTOR mRNA and p-PI3K,p-Akt,p-mTOR proteins were significantly decreased(P<0.05,P<0.01).Compared with Tian Shu(ST25),Da Chang Shu(BL25),Zu San Li(ST36)groups,the recovery degree of mucosa layers in Shang Ju Xu(ST37)group was closer to that of normal group,and the curative effect was relatively the best;in terms of serological levels of IL-23 and IL-17,the Shang Ju Xu(ST37)group was significantly lower(P<0.05),while the level of IL-10 was significantly higher(P<0.01);the expressions of PI3K,Akt,mTOR mRNA and p-PI3K,p-Akt,p-mTOR proteins were significantly decreased(P<0.05,P<0.01).Conclusion:Results indicate that electrical acupuncture at Tian Shu(ST25),Da Chang Shu(BL25),Zu San Li(ST36)and Shang Ju Xu(ST37)show similar effects in relieving the colitis-induced damage in the mucosa of chronic colitis rats,as well as inflammatory response.Among them,Shang Ju Xu(ST25)has a superior overall effect in treating chronic colitis compared to Tian Shu(ST25),Da Chang Shu(BL25)and Zu San Li(ST36).The mechanism may be related to inhibition of PI3K/Akt/mTOR signaling pathway.
文摘Non-traumatic osteonecrosis of the femoral head(NONFH)is one of the most common orthopedic diseases,influenced by multiple signaling pathways and inflammatory factors.The PI3K/AKT signaling pathway is closely related to various biological processes such as apoptosis,autophagy,and metabolism in cells.Increasing evidence suggests that it plays an important role in the development of femoral head necrosis.This paper aims to explore the mechanism of the PI3K/AKT signaling pathway in the pathogenesis of NONFH by analyzing its regulation of lipid metabolism,cell apoptosis and autophagy,and intravascular coagulation.This study provides new insights for the research of NONFH.
基金supported by the National Natural Science Foundation of China (no. 81904109)the Natural Science Project of Hunan Provincial Department of Science and Technology (no.2023JJ30361, no. 2019JJ50344).
文摘Background:To investigate the role of fibroblast growth factor 2(FGF2)in chemotherapy resistance of colon cancer.Methods:An HCT116/5-fluorouracil(5-FU)-resistant cell line was established,and FGF2 levels were detected in a sensitive cell group(HCT116)and a resistant cell group(HCT1116-R)using different methods.Fibroblast growth factor 2 levels in the medium were determined by enzyme-linked immunoassay.The protein expressions of FGF2,fibroblast growth factor receptor 1(FGFR1),and phospho-FGFR1 were assessed by Western blotting,and FGF2 mRNA levels were detected by quantitative real-time polymerase chain reaction.Fibroblast growth factor 2 recombinant protein was added to sensitive cells,and FGFR inhibitor AZD4547 was added to resistant cells,and the cell survival rate was determined using the cell counting kit-8 method and the protein expressions of PI3K(phosphatidylinositol 3 kinase),p-PI3K(phospho-PI3K),Akt(protein kinase B),p-Akt(phospho-Akt),mammalian target of rapamycin(mTOR),p-mTOR(phospho-mTOR),Bad(Bcl-xL/Bcl-2-associated death promoter),NF-κB(nuclear factorκB),GSK-3(glycogen synthase kinase-3),FKHR(forkhead box protein O1),and PTEN(phosphatase and tensin homolog deleted on chromosome ten)were detected by Western blotting.Results:Fibroblast growth factor 2 protein and mRNA expression levels in the HCT116-R group were significantly higher than those in the HCT116 group.Fibroblast growth factor 2 increased the survival rate of HCT116 cells;improved tolerance to 5-FU;upregulated p-PI3K,p-Akt,and p-mTOR;and downregulated Bad.The FGFR inhibitor AZD4547 decreased cell survival rate and tolerance to 5-FU;downregulated p-PI3K,p-Akt,and p-mTOR expression;and upregulated Bad.Conclusions:Fibroblast growth factor 2 promotes chemotherapy tolerance in colon cancer cells by activating the Akt/mTOR and Akt/Bad signaling pathways downstream of PI3K.
基金supported in part by the National Natural Science Foundation of China(Nos.32270555 and 32072954).
文摘The phosphoinositide-3-kinase/Akt(PI3K/AKT)signaling pathway is crucial for Sertoli cell development and completing spermatogenesis.Its main role is to promote proliferation and inhibit apoptosis.Many factors activate the PI3K/AKT pathway,like hormones,such as follicle stimulating hormone(FSH),androgen,estrogen,insulin to name a few.Many of these factors have receptors inside or on the surface of Sertoli cells(SCs).This review summarizes how these hormones directly regulate the PI3K/AKT signaling pathway in SCs,which in turn affects SC proliferation and differentiation.Further,hormone-mediated PI3K/AKT signaling also stimulates SC secretion,which is essential for germ cell development,suggesting an indirect role of PI3K/AKT signaling during spermatogenesis.These functions include promoting spermatogonia proliferation and differentiation,meiosis of spermatocytes,sperm maturation,and their release.This review also provides potential hints for clinically treating male infertility issues like cryptorchidism and Sertoli cell-only syndrome.
基金the National Natural Science Foundation of China,No.82272355Shanghai Science and Technology Committee,No.21410750500.
文摘BACKGROUND Diabetic skin ulcers,a significant global healthcare burden,are mainly caused by the inhibition of cell proliferation and impaired angiogenesis.XB130 is an adaptor protein that regulates cell proliferation and migration.However,the role of XB130 in the development of diabetic skin ulcers remains unclear.AIM To investigate whether XB130 can regulate the inhibition of proliferation and vascular damage induced by high glucose.Additionally,we aim to determine whether XB130 is involved in the healing process of diabetic skin ulcers,along with its molecular mechanisms.METHODS We conducted RNA-sequencing analysis to identify the key genes involved in diabetic skin ulcers.We investigated the effects of XB130 on wound healing using histological analyses.In addition,we used reverse transcription-quantitative polymerase chain reaction,Western blot,terminal deoxynucleotidyl transferasemediated dUTP nick end labeling staining,immunofluorescence,wound healing,and tubule formation experiments to investigate their effects on cellular processes in human umbilical vein endothelial cells(HUVECs)stimulated with high glucose.Finally,we performed functional analysis to elucidate the molecular mechanisms underlying diabetic skin ulcers.RESULTS RNA-sequencing analysis showed that the expression of XB130 was up-regulated in the tissues of diabetic skin ulcers.Knockdown of XB130 promoted the healing of skin wounds in mice,leading to an accelerated wound healing process and shortened wound healing time.At the cellular level,knockdown of XB130 alleviated high glucose-induced inhibition of cell proliferation and angiogenic impairment in HUVECs.Inhibition of the PI3K/Akt pathway removed the proliferative effects and endothelial protection mediated by XB130.CONCLUSION The findings of this study indicated that the expression of XB130 is up-regulated in high glucose-stimulated diabetic skin ulcers and HUVECs.Knockdown of XB130 promotes cell proliferation and angiogenesis via the PI3K/Akt signalling pathway,which accelerates the healing of diabetic skin ulcers.