Objective:To identify chromatin regulators(CRs)-based molecular subtypes and risk scores for accurately predicting biochemical recurrence(BCR)after radical prostatectomy(RAP)in prostate cancer(PCa)patients.Methods:Dif...Objective:To identify chromatin regulators(CRs)-based molecular subtypes and risk scores for accurately predicting biochemical recurrence(BCR)after radical prostatectomy(RAP)in prostate cancer(PCa)patients.Methods:Differentially expressed genes(DEGs)between tumor and normal samples from The Cancer Genome Atlas(TCGA)and gene expression omnibus(GEO)databases were intersected with CR-related and prognostic genes.Consensus clustering,risk score analysis,functional analysis,immune microenvironment,m6A,and heterogeneity assessments were performed using R software.In vitro validation used DU145 and C42B PCa cell lines.Topoisomerase II alpha(TOP2A)was knocked down via si RNA.Assays included CCK-8 proliferation,colony formation,transwell migration/invasion,wound healing,and western blotting(WB)for pathway validation.Results:TOP2A and peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PPARGC1A)defined molecular subtypes and a risk score in TCGA,validated in a GEO dataset.Cluster 2 exhibited significantly shorter BCR-free survival vs.cluster 1 in TCGA[hazard ratio(HR):2.21;95%confidence interval(95%CI):1.32-3.73;P=0.003],GEO(HR:2.05;95%CI:1.05-4.02;P=0.010),and MSKCC2010(HR:5.93;95%CI:1.96-17.87;P<0.001).Similar survival differences were observed between high-and low-risk groups(defined by the median risk score).Cluster 2 showed greater tumor heterogeneity and higher m6A gene expression.Gene set variation analysis(GSVA)revealed downregulated cell-cycle pathways in cluster 2,alongside suppressed tumor-infiltrating immune cells.TOP2A knockdown significantly impaired PCa cell proliferation,colony formation,migration,and invasion.Mechanistically,it suppressed phosphoinositide 3-kinase(PI3K)/AKT serine/threonine kinase(AKT)pathway activation,reducing phosphorylated PI3K and AKT levels without altering total protein.Conclusions:TOP2A and PPARGC1A effectively stratify PCa subtypes for RAP patients.TOP2A drives malignant progression via the PI3K/AKT pathway.展开更多
This study aimed to investigate the effects of infant feces-derived Bifidobacterium breve CCFM1078 on rheumatoid cachexia(RC).Twenty-four female Wistar rats were assigned to 3 groups:CON group(normal saline by gavage)...This study aimed to investigate the effects of infant feces-derived Bifidobacterium breve CCFM1078 on rheumatoid cachexia(RC).Twenty-four female Wistar rats were assigned to 3 groups:CON group(normal saline by gavage),CIA group(collagen-induced arthritis(CIA),normal saline by gavage),and CCFM1078 group(CIA,3×10^(9)CFU/(rat·day)B.breve CCFM1078 gavage).The results demonstrated that B.breve CCFM1078 not only improved skeletal muscle function in CIA rats,but also modulated the gut microbiota,skeletal muscle metabolism and hormone levels,reduced inflammation in the knee joint and skeletal muscles,decreased activity of the nuclear factor κB(NF-κB)inflammatory signaling pathway,enhanced the insulin receptor substrate 1(IRS1)/phosphatidylinositol 3-kinase/protein kinase(PI3K/Akt)signaling pathway,promoted skeletal muscle differentiation,and maintained skeletal muscle fiber diameter,consequently slowing down the progression of RC.These findings suggested that B.breve CCFM1078 may have a beneficial role as part of a dietary intervention for RC,enhancing overall therapeutic effects.展开更多
Objective:To investigate the anti-atherosclerosis effect of chikusetsusaponinⅣ(CSⅣ)against high-fat diet-induced atherosclerosis in rats.Methods:A high-fat diet was used for the induction of atherosclerosis in rats,...Objective:To investigate the anti-atherosclerosis effect of chikusetsusaponinⅣ(CSⅣ)against high-fat diet-induced atherosclerosis in rats.Methods:A high-fat diet was used for the induction of atherosclerosis in rats,and the rats received oral CSⅣor atorvastatin.The body weight,organ weights,food intake,calorie intake,lipid parameters,3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA)/mevalonate ratio,collagen,free fatty acid,cardiac parameters,apolipoprotein(A and B),antioxidant parameters,inflammatory cytokines,and inflammatory parameters were assessed.The mRNA expressions of interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α),IL-6,IL-17,PI3K,AKT,and mTOR were estimated.Results:CSⅣsignificantly modulated food intake,body weight,organ weight(liver,kidney,and heart),and calories(P<0.05).Total cholesterol,triglycerides,very low-density lipoprotein cholesterol,low-density lipoprotein cholesterol,cardiovascular risk index-1,and cardiovascular risk index-2 were decreased,while high-density lipoprotein cholesterol and anti-atherogenic index were increased significantly in the CSⅣgroup(P<0.05).Besides,CSⅣsignificantly restored the level of HMG-CoA/mevalonate ratio,collagen,free fatty acid,cardiac parameters(creatinine kinase-MB,lactate dehydrogenase,cTnT,cTnI),apolipoprotein(apolipoprotein A and apolipoprotein B),antioxidant parameters(MDA,CAT,GPx,GSH,SOD),inflammatory cytokines(TNF-α,IL-1β,IL-6,IL-10),inflammatory parameters(COX-2,TGF-β,NF-κB),intercellular adhesion molecule-1,vascular cell adhesion molecule-1,and monocyte chemoattractant protein-1.CSⅣalso decreased the mRNA expression of IL-1β,TNF-α,IL-6,IL-17,PI3K,AKT,and mTOR.Conclusions:This study showed the anti-atherosclerosis effect of CSⅣagainst high-fat diet-induced atherosclerosis in rats via alteration of NF-κB/COX-2 and PI3K/AKT/mTOR signaling pathway.展开更多
Muscle atrophy can be induced by high doses or prolonged use of glucocorticoids.Kaempferol(Kae)is a naturally occurring flavonoid with a variety of biological activities and the effect of Kae on dexamethasone(Dex)indu...Muscle atrophy can be induced by high doses or prolonged use of glucocorticoids.Kaempferol(Kae)is a naturally occurring flavonoid with a variety of biological activities and the effect of Kae on dexamethasone(Dex)induced muscle atrophy in animals has not been elucidated.To explore this issue,the present experiments used a computationally assisted drug design scheme combining network pharmacology,molecular docking and in vivo experiments to investigate the mechanism of Kae against muscle atrophy.Network pharmacological analyses revealed 275 potential targets for Kae and 12294 potential targets for muscle atrophy,with a total of 228 crosstargets for Kae and muscle atrophy.GO and KEGG analyses were performed based on the protein-protein interaction(PPI)network of muscle atrophy and Kae component targets.The GO results showed that the biological processes were mainly related to the metabolic process of reactive oxygen species,and the response to oxidative stress;the cellular components were mainly focused on membrane microdomains,and membrane regions;the molecular functions mainly worked on phosphatase binding;and the KEGG pathway enrichment analyses identified the pathways of interaction between Kae and muscle atrophy.Finally,as verified by in vivo experiments,Kae may reduce the onset of muscle atrophy by activating the PI3K/AKT/m TOR/signalling pathway,inhibiting Foxo1/Foxo3 activity,and inhibiting downstream production of the ubiquitination 3 ligases Atrogin1 and Mu RF1;Kae also promotes the expression of NRF2/HO-1/KEAP1 signalling pathway,enhances muscle antioxidant capacity,inhibits the release of COX-2 and TNF-αinflammatory factors,and reduces the damage caused by oxidative stress and inflammatory factors to muscles.Therefore,there may be a synergistic effect of PI3K/AKT/m TOR and NRF2/HO-1/KEAP1 in Kae working together to prevent muscle atrophy.The binding energy and stability of Kae to potential targets were examined by molecular docking and molecular dynamics simulations,implying that Kae could be used for the prevention and treatment of muscle atrophy in patients.展开更多
Objective:To establish a mouse model of homocysteine(Hcy)-induced coronary microvascular dysfunction(CMD),and to evaluate the therapeutic efficacy of Shexiang Tongxin dropping pill(STDP)and elucidate its underlying me...Objective:To establish a mouse model of homocysteine(Hcy)-induced coronary microvascular dysfunction(CMD),and to evaluate the therapeutic efficacy of Shexiang Tongxin dropping pill(STDP)and elucidate its underlying mechanisms.Methods:The chemical composition and quality of STDP were characterized using ultra-high performance liquid chromatography,and its absorbed components were identified using ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry.CMD was induced in C57BL/6J mice by feeding a 3%methionine diet for four weeks.STDP efficacy was evaluated using laser speckle perfusion imaging,tomato lectin staining,and quantification of plasma nitric oxide(NO),reactive oxygen species(ROS),and endothelial adhesion molecules(intercellular cell adhesion molecule-1[ICAM-1],vascular cell adhesion molecule-1[VCAM-1]).Network pharmacology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to identify potential targets and regulatory pathways.An in vitro Hcy-induced endothelial injury model was used to validate the effects of STDP on cell viability,NO production,and activation of phosphatidylinositol 3-kinase/protein kinase B/endothelial nitric oxide synthase(PI3K/Akt/eNOS)pathway.Results:STDP was stable,with 180 constituents identified in the preparation and 30 absorbed components in plasma.STDP treatment restored perfusion,increased plasma NO,decreased ROS,and downregulated ICAM-1 and VCAM-1.Network analysis identified 152 putative targets,highlighting the PI3K/Akt pathway as the central,with PIK3CA,AKT1,and NOS3 as key nodes.In vitro,STDP enhanced cell viability,NO production,and PI3K/Akt/eNOS phosphorylation,these effects were abolished by pharmacological inhibition of PI3K and eNOS.Conclusion:A 3%methionine diet for four weeks effectively induces CMD in C57BL/6J mice.STDP,rich in bioactive components,alleviates Hcy-induced CMD by activating the PI3K/Akt/eNOS pathway,thereby improving endothelial function and microvascular perfusion.These findings support STDP as a promising therapeutic candidate for CMD management.展开更多
AIM:To highlight the importance of microRNA(miRNA)-21-5p in directing the phosphatase and tensin homolog(PTEN)gene to control the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/Akt/mTOR)...AIM:To highlight the importance of microRNA(miRNA)-21-5p in directing the phosphatase and tensin homolog(PTEN)gene to control the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/Akt/mTOR)pathway in retinal pigment epithelial(RPE)cells in humans subjected to photodamage.METHODS:Human adult RPE cell line-19(ARPE-19)was cultured in vitro and randomly divided into control,damage,overexpression,negative,and PI3K/Akt blocker groups to establish a photodamage model of ARPE-19 cells.The models were subjected to 24h of light exposure,after which the corresponding indices were detected.The cell counting kit-8 assay quantified cell viability,while flow cytometry determined apoptosis rates.The miRNA-21 mimics and miRNA mimic NC were transfected into ARPE-19 cells using a transient transfection technique.Quantitative reverse transcription polymerase chain reaction(SYBR Green)and Western blotting analyzed expression levels of miRNA-21-5p,PTEN,p-PI3K/PI3K,p-mTOR/mTOR,and p-Akt/Akt.Statistical analyses comprised one-way analysis of variance and the Student-Newman-Keuls test for multiple group comparisons.RESULTS:The photodamage group demonstrated reduced cell survival rates than the control group(P<0.01).The overexpression group exhibited higher cell survival rates than the injury group(P<0.01).The negative group showed no difference in viability(P>0.05).The PI3K/Akt blocker group demonstrated lower cell viability,compared with the overexpression group(P<0.01).CONCLUSION:miRNA-21-5p significantly increases ARPE-19 cell survival after photodamage and inhibits lightinduced ARPE-19 cell apoptosis,suggesting that it may play a protective role in RPE by activating the PI3K/Akt/mTOR pathway while downregulating PTEN expression.展开更多
Cancer represents a significant disease that profoundly impacts human health and longevity.Projections indicate a 47%increase in the global cancer burden by 2040 compared to 2020,accompanied by a further rise in the a...Cancer represents a significant disease that profoundly impacts human health and longevity.Projections indicate a 47%increase in the global cancer burden by 2040 compared to 2020,accompanied by a further rise in the associated economic burden.Consequently,there is an urgent need to discover and develop new alternative drugs to mitigate the global impact of cancer.Natural products(NPs)play a crucial role in the identification and development of anticancer therapeutics.This study identified ustusolate E(UE)and its analog 11α-hydroxy-ustusolate E(HUE)from strain Aspergillus calidoustus TJ403-EL05,and examined their antitumor activities and mechanisms of action.The findings demonstrate that both compounds significantly inhibited the proliferation and colony formation of AGS(human gastric cancer cells)and 786-O(human renal clear cell carcinoma cells),induced irreversible DNA damage,blocked the cell cycle at the G_(2)/M phase,and further induced apoptosis in tumor cells.To the best of the authors’knowledge,this is the first report on the anticancer effects of UE and HUE and their underlying mechanisms.The present study suggests that HUE and UE could serve as lead compounds for the development of novel anticancer drugs.展开更多
Objective:To investigate the biological functions and molecular regulatory mechanisms of kinesin family member 11(KIF11)in colorectal cancer(CRC).Methods:The expression of KIF11 in CRC was examined by qRT⁃PCR and publ...Objective:To investigate the biological functions and molecular regulatory mechanisms of kinesin family member 11(KIF11)in colorectal cancer(CRC).Methods:The expression of KIF11 in CRC was examined by qRT⁃PCR and public databases.Functional assays(CCK⁃8,colony formation,EdU,and Transwell)were employed to evaluate KIF11’s roles in CRC progression.Western blot,RIP⁃qPCR,MeRIP⁃qPCR,and RNA stability assays were performed to elucidate the molecular mechanism of N6⁃methyladenosine(m6A)modification for KIF11.RNA sequencing(RNA⁃seq)and correlation analysis were used to examine the downstream mechanism of KIF11 regulation.Results:KIF11 was highly expressed in CRC and promoted CRC proliferation and migration.Mechanistically,methyltransferase⁃like 3(METTL3)/insulin like growth factor 2 mRNA binding protein 2(IGF2BP2)enhanced KIF11 mRNA stability and expression in an m6A⁃dependent way.Furthermore,by means of the PROM1/PI3K/AKT pathway,KIF11 facilitated the progression of CRC.Conclusion:The m6A modification of KIF11 by METTL3/IGF2BP2 contributes to CRC progression via the PI3K/AKT signaling pathway,highlighting its potential as a prognostic biomarker and therapeutic target.展开更多
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
Silicosis is an occupational lung disease caused by prolonged exposure to silica dust in the workplace.It has a complex pathogenesis and currently lacks effective treatments.Homoharringtonine(HHT)is a natural compound...Silicosis is an occupational lung disease caused by prolonged exposure to silica dust in the workplace.It has a complex pathogenesis and currently lacks effective treatments.Homoharringtonine(HHT)is a natural compound approved for the treatment of acute myeloid leukemia,but its effects on silicosis remain unclear.In the present study,we constructed a mouse model of silica(SiO_(2))-induced pulmonary fibrosis and evaluated the preventive and therapeutic effects of HHT.The results showed that HHT significantly attenuated the progression of SiO_(2)-induced pulmonary fibrosis in mice.We then used MRC-5,a human lung fibroblast cell line,to explore the mechanisms underlying HHT's inhibitory effects in vitro and found that HHT significantly inhibited the activation and migratory capacity of MRC-5 cells.Mechanistically,these effects were mediated by enhanced ubiquitination and degradation of the CCR1 protein.Furthermore,HHT exhibited favorable biocompatibility in vivo,and its preventive and therapeutic effects were validated in SiO_(2)-treated mice.Collectively,the current study demonstrates that HHT shows significant potential as a therapeutic agent for silicosis by targeting CCR1 and the PI3K/AKT/m TOR signaling pathway,highlighting it as a promising candidate for clinical translation for silicosis treatment.展开更多
Objective To investigate the effect of electroacupuncture(EA)on microRNA(miRNA)expression spectrum and PI3K/Akt/mTOR signaling pathway in uterine tissue of rats with primary dysmenorrhea(PDM),and to explore the potent...Objective To investigate the effect of electroacupuncture(EA)on microRNA(miRNA)expression spectrum and PI3K/Akt/mTOR signaling pathway in uterine tissue of rats with primary dysmenorrhea(PDM),and to explore the potential mechanism of EA in the treatment of PDM.Methods Thirty female SD rats,weighted(200±20)g were randomly divided into control group,model group and EA group,10 rats in each group.By using subcutaneous injection of estradiol diphenhydrate combined with intraperitoneal injection of oxytocin,PDM models were established.Rats in the EA group received EA at“Sanyinjiao”(SP6)and“Guanyuan”(CV4)at dense waves and a frequency of 50 Hz,once a day,20 min each time,for 10 consecutive days.After the 10-day intervention,samples were collected and transmission electron microscopy was used to observe the ultrastructural changes of the cells in uterine tissue in each group.With RNA-seq method,the changes of miRNA expression spectrum in rat uterine tissue were detected.Bioinformatics analysis such as GO functional annotation and KEGG pathway was performed according to differentially expressed miRNAs.Differentially expressed miRNAs were verified by qRT-PCR.Endometrial stromal cells were selected as the target cells and transfected;and they were divided into control group,NC mimics group,mimic miR-144–3p group,NC inhibitor group and inhibitor miR-144–3p group.The apoptosis was determined by using flow cytometrydetect apoptosis,the miRNA and protein expression of PI3K/Akt/mTOR signaling pathway were detected by qRT-PCR and Western blot in each group separately.Results 1.Transmission electron microscope.(1)Control group:no obvious morphological changes in the uterine tissue.(2)Model group:fibroblasts in uterine tissue were irregular,the edema was presented in cellular cytoplasm,the nuclei were irregular and mitochondria swollen seriously;the rough endoplasmic reticulum was expanded moderately.(3)EA group:fibroblasts were spindle-shaped and pyknotic,the cytoplasm increased in electron density,the nuclei were slightly irregular and pyknotic,mitochondria were oval in shape,with little swelling and vacuolation;the rough endoplasmic reticulum was expanded slightly and retained,with a small amount of degranulation.2.Compared with the control group,there were 26 differentially expressed miRNAs in the uterine tissue of rats with PDM.After EA intervention,the expression of miR-144–3p was significantly up-regulated.GO functional analysis of differentially expressed miRNAs in PDM rats after EA showed that the biological functions involved calcium transmembrane transporter activity,mitogen-activated protein kinase binding,epithelial cell migration,tissue migration,etc.3.KEGG pathway analysis showed that PI3K/Akt signaling pathway,MAPK signaling pathway and calcium signaling pathway were enriched.Mimic miR-144-3p increased the apotosis of endometrial stromal cells,and decreased the mRNA and protein expression of PI3K,Akt,and mTOR(P<0.01).Conclusion EA can optimize the cell morphology in the uterine tissue of rats with PDM and affect the miRNA expression spectrum,which may be associated with the effect of EA for up-regulating miR-144–3p expression in endometrial stromal cells,suppressing PI3K/Akt/mTOR signaling pathway and causing apoptosis.展开更多
PI3K/AKT/mTOR signaling pathway is a key pathway of myocardial ischemia-reperfusion injury(MIRI).The mechanism of action is mainly oxidative stress,inflammatory response,calcium overload,ferroptosis,autophagy,and apop...PI3K/AKT/mTOR signaling pathway is a key pathway of myocardial ischemia-reperfusion injury(MIRI).The mechanism of action is mainly oxidative stress,inflammatory response,calcium overload,ferroptosis,autophagy,and apoptosis.MIRI belongs to the category of chest obstruction in traditional Chinese medicine,and its etiology and pathogenesis are mainly“Yang Wei Yin Xian.”Traditional Chinese medicine has the effect of multi-target and multi-component effect,and has played a significant role in the treatment of MIRI in recent years.At present,the monomers of traditional Chinese medicine mainly include saponins,flavonoids,alkaloids,terpenoids,and phenols,and the compounds mainly include Zhigancao Decoction,Zhenyuan Capsule,Jiawei Shenqibai Powder,Qili Qiangxin Capsule,Tongmai Yangxin Pill,Zhilong Huoxue Tongyu Capsule,Guizhi Tongluo Tablets,etc.This paper reviews the research on the improvement of MIRI by regulating PI3K/AKT/mTOR signaling pathway in recent years,and expounds the mechanism and advantages of traditional Chinese medicine in the treatment of MIRI.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
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
BACKGROUND Gastric cancer(GC)is a widespread malignancy and associated with high rates of morbidity and mortality worldwide.AIM To examine the functional role of long non-coding RNAs small nucleolar RNA host gene 5(SN...BACKGROUND Gastric cancer(GC)is a widespread malignancy and associated with high rates of morbidity and mortality worldwide.AIM To examine the functional role of long non-coding RNAs small nucleolar RNA host gene 5(SNHG5)and its regulation of miR-92a-3p and B-cell translocation gene 2(BTG2)in GC progression.METHODS Quantitative reverse transcription PCR and western blot analysis determined the expression of SNHG5,miR-92a-3p,and BTG2 in GC and adjacent non-neoplastic mucosa.Dual-luciferase assays demonstrated interactions of SNHG5 with miR-92a-3p and BTG2.AGS cells were transfected with SNHG5 overexpression and miR-92a-3p knockdown models.Various assays,including CCK-8,colony formation,scratch wound healing,and Transwell assays,were used to determine cell proliferation and migration.An experimental model of a xenograft mouse was used to determine in vivo tumor growth.At the same time histological changes were evaluated by hematoxylin and eosin staining,with western blot analysis used to evaluate signaling pathway protein expression.RESULTS BTG2 and SNHG5 were downregulated in GC tissues,and miR-92a-3p was upregulated.Overexpression of SNHG5 or knockdown of miR-92a-3p reduced GC cell proliferation and migration,and increased BTG2 expression while decreasing PI3K/AKT signaling activity.The dual-luciferase assays demonstrated direct binding of miR-92a-3p to SNHG5 and BTG2.Tumor volume and weight were significantly reduced in mice transplanted with AGS cells treated with miR-92a-3p inhibitor or SNHG5 overexpression compared with control AGS cells.Hematoxylin and eosin staining revealed that treated tumors exhibited degenerative characteristics,including irregular morphology and nucleolysis.CONCLUSION LncRNA SNHG5 inhibited GC cell growth and migration by modulating the PI3K/AKT pathway via the miR-92a-3p/BTG2 axis.展开更多
Andrographolide sulfonate(AS)is a sulfonated derivative of andrographolide extracted from Andrographis paniculata(Burm.f.)Nees,and has been approved for several decades in China.The present study aimed to investigate ...Andrographolide sulfonate(AS)is a sulfonated derivative of andrographolide extracted from Andrographis paniculata(Burm.f.)Nees,and has been approved for several decades in China.The present study aimed to investigate the novel therapeutic application and possible mechanisms of AS in the treatment of rheumatoid arthritis.Results indicated that administration of AS by injection or gavage significantly reduced the paw swelling,improved body weights,and attenuated pathological changes in joints of rats with adjuvant-induced arthritis.Additionally,the levels of tumor necrosis factor-alpha(TNF-α),interleukin-6(IL-6),and IL-1β in the serum and ankle joints were reduced.Bioinformatics analysis,along with the spleen index and measurements of IL-17 and IL-10 levels,suggested a potential relationship between AS and Th17 cells under arthritic conditions.In vitro,AS was shown to block Th17 cell differentiation,as evidenced by the reduced percentages of CD4^(+)IL-17A^(+)T cells and decreased expression levels of RORγt,IL-17A,IL-17F,IL-21,and IL-22,without affecting the cell viability and apoptosis.This effect was attributed to the limited glycolysis,as indicated by metabolomics analysis,reduced glucose uptake,and p H measurements.Further investigation revealed that AS might bind to hexokinase2(HK2)to down-regulate the protein levels of HK2 but not glyceraldehyde-3-phosphate dehydrogenase(GAPDH)or pyruvate kinase M2(PKM2),and overexpression of HK2 reversed the inhibition of AS on Th17 cell differentiation.Furthermore,AS impaired the activation of phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)signals in vivo and in vitro,which was abolished by the addition of lactate.In conclusion,AS significantly improved adjuvant-induced arthritis(AIA)in rats by inhibiting glycolysis-mediated activation of PI3K/AKT to restrain Th17 cell differentiation.展开更多
Epilepsy is a chronic and severe neurological disorder that has negative effects on the autonomous activities of patients. Functionally, Trem2(triggering receptor expressed on myeloid cells-2) is an immunoglobulin rec...Epilepsy is a chronic and severe neurological disorder that has negative effects on the autonomous activities of patients. Functionally, Trem2(triggering receptor expressed on myeloid cells-2) is an immunoglobulin receptor that affects neurological and psychiatric genetic diseases. Based on this rationale, we aimed to assess the potential role of Trem2 integration with the PI3 K/Akt pathway in epilepsy. We used microarray-based gene expression profiling to identify epilepsy-related differentially-expressed genes. In a mouse hippocampal neuron model of epilepsy, neurons were treated with lowMg^2+ extracellular fluid, and the protein and mRNA expression of Trem2 were determined. Using a gain-offunction approach with Trem2, neuronal apoptosis and its related factors were assessed by flow cytometry, RT-qPCR,and Western blot analysis. In a pilocarpine-induced epileptic mouse model, the malondialdehyde(MDA) and8-hydroxy-20-deoxyguanosine(8-OHdG) content and superoxide dismutase(SOD) and glutathione-peroxidase(GSH-Px) activity in the hippocampus were determined,and the protein expression of Trem2 was measured. In addition, the regulatory effect of Trem2 on the PI3 K/Akt pathway was analyzed by inhibiting this pathway in both the cell and mouse models of epilepsy. Trem2 was found to occupy a core position and was correlated with epilepsy.Trem2 was decreased in the hippocampus of epileptic miceand epileptic hippocampal neurons. Of crucial importance,overexpression of Trem2 activated the PI3 K/Akt pathway to inhibit neuronal apoptosis. Moreover, activation of the PI3 K/Akt pathway through over-expression of Trem2 alleviated oxidative stress, as shown by the increased expression of SOD and GSH-Px and the decreased expression of MDA and 8-OHdG. The current study defines the potential role of Trem2 in inhibiting the development of epilepsy, indicating that Trem2 up-regulation alleviates hippocampal neuronal injury and oxidative stress, and inhibits neuronal apoptosis in epilepsy by activating the PI3 K/Akt pathway.展开更多
Objectives:PI3K plays a pivotal role in the inflammatory response by modulating the production and release of inflammatory factors.Pik3cb is one of the subunits of PI3K,and its specific role in myocardium inflammation...Objectives:PI3K plays a pivotal role in the inflammatory response by modulating the production and release of inflammatory factors.Pik3cb is one of the subunits of PI3K,and its specific role in myocardium inflammation remains unelucidated.This study aimed to investigate the role of Pik3cb in the inflammatory response and to elucidate the underlying mechanism.Methods:An inflammation model was established using H9c2 cells treated with LPS and ATP,and Pik3cb expression was evaluated in this model system.Subsequently,an overexpression model was constructed by transfecting cells with a Pik3cb overexpression plasmid,after which the effects of Pik3cb overexpression on the PI3K/AKT and NF-κB/NLRP3 inflammatory signaling pathways were assessed.Results:These analyses revealed that the expression and distribution of Pik3cb were significantly reduced in the LPS/ATP-induced cellular inflammation model group,whereas plasmid-mediated overexpression of Pik3cb significantly inhibited the activation of the PI3K/AKT signaling pathway in response to LPS/ATP stimulation.Additionally,the LPS/ATP-induced activation of the NF-κB/NLRP3 axis was significantly inhibited following Pik3cb overexpression.Conclusion:This study demonstrates that Pik3cb acts as a negative regulator of LPS/ATP-induced inflammation in cardiomyocytes,exerting anti-inflammatory effects by inhibiting the PI3K/AKT/NF-κB/NLRP3 signaling axis.These findings provide a potential therapeutic target for the treatment of myocardial inflammation.展开更多
BACKGROUND Liver cancer has a high incidence and mortality worldwide,especially in China.Herein,we investigated the therapeutic effect and mechanism of tetrahydrocurcumin against hepatocellular carcinoma(HCC),with a f...BACKGROUND Liver cancer has a high incidence and mortality worldwide,especially in China.Herein,we investigated the therapeutic effect and mechanism of tetrahydrocurcumin against hepatocellular carcinoma(HCC),with a focus on the of phosphoinositide 3-kinases(PI3K)/AKT signaling pathway.AIM To investigate the effects and mechanism of tetrahydrocurcumin in HCC cell lines HepG2 and Huh7.METHODS Using Metascape,we analyzed the potential targets of tetrahydrocurcumin in HCC.Molecular docking validation was performed using SYBYL2.0.Cell Counting Kit-8,wound healing,and transwell assays were performed to evaluate the effects of tetrahydrocurcumin on HepG2 and Huh7 cell migration,invasion,and apoptosis.The expression of PI3K/AKT signaling pathway-related proteins was detected by western blotting.RESULTS Network pharmacology and molecular docking showed that tetrahydrocurcumin has high binding affinity for phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha.In vitro experiments demonstrated that tetrahydrocurcumin suppressed the migration and invasion of liver cancer cells,promoted their apoptosis,and downregulated the expression of p-PI3K,p-AKT,and B cell leukemia/lymphoma 2,while upregulating caspase-3,p53,and B cell leukemia/lymphoma 2 associated X.CONCLUSION In summary,tetrahydrocurcumin suppresses PI3K/AKT signaling,promotes apoptosis,and prevents the migration and invasion of liver cancer cells.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
基金supported by the funding of Chinese Scholarship Council(No.202206240086)。
文摘Objective:To identify chromatin regulators(CRs)-based molecular subtypes and risk scores for accurately predicting biochemical recurrence(BCR)after radical prostatectomy(RAP)in prostate cancer(PCa)patients.Methods:Differentially expressed genes(DEGs)between tumor and normal samples from The Cancer Genome Atlas(TCGA)and gene expression omnibus(GEO)databases were intersected with CR-related and prognostic genes.Consensus clustering,risk score analysis,functional analysis,immune microenvironment,m6A,and heterogeneity assessments were performed using R software.In vitro validation used DU145 and C42B PCa cell lines.Topoisomerase II alpha(TOP2A)was knocked down via si RNA.Assays included CCK-8 proliferation,colony formation,transwell migration/invasion,wound healing,and western blotting(WB)for pathway validation.Results:TOP2A and peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PPARGC1A)defined molecular subtypes and a risk score in TCGA,validated in a GEO dataset.Cluster 2 exhibited significantly shorter BCR-free survival vs.cluster 1 in TCGA[hazard ratio(HR):2.21;95%confidence interval(95%CI):1.32-3.73;P=0.003],GEO(HR:2.05;95%CI:1.05-4.02;P=0.010),and MSKCC2010(HR:5.93;95%CI:1.96-17.87;P<0.001).Similar survival differences were observed between high-and low-risk groups(defined by the median risk score).Cluster 2 showed greater tumor heterogeneity and higher m6A gene expression.Gene set variation analysis(GSVA)revealed downregulated cell-cycle pathways in cluster 2,alongside suppressed tumor-infiltrating immune cells.TOP2A knockdown significantly impaired PCa cell proliferation,colony formation,migration,and invasion.Mechanistically,it suppressed phosphoinositide 3-kinase(PI3K)/AKT serine/threonine kinase(AKT)pathway activation,reducing phosphorylated PI3K and AKT levels without altering total protein.Conclusions:TOP2A and PPARGC1A effectively stratify PCa subtypes for RAP patients.TOP2A drives malignant progression via the PI3K/AKT pathway.
基金supported by the National Natural Science Foundation of China(32021005)111 project(BP0719028)the Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province.
文摘This study aimed to investigate the effects of infant feces-derived Bifidobacterium breve CCFM1078 on rheumatoid cachexia(RC).Twenty-four female Wistar rats were assigned to 3 groups:CON group(normal saline by gavage),CIA group(collagen-induced arthritis(CIA),normal saline by gavage),and CCFM1078 group(CIA,3×10^(9)CFU/(rat·day)B.breve CCFM1078 gavage).The results demonstrated that B.breve CCFM1078 not only improved skeletal muscle function in CIA rats,but also modulated the gut microbiota,skeletal muscle metabolism and hormone levels,reduced inflammation in the knee joint and skeletal muscles,decreased activity of the nuclear factor κB(NF-κB)inflammatory signaling pathway,enhanced the insulin receptor substrate 1(IRS1)/phosphatidylinositol 3-kinase/protein kinase(PI3K/Akt)signaling pathway,promoted skeletal muscle differentiation,and maintained skeletal muscle fiber diameter,consequently slowing down the progression of RC.These findings suggested that B.breve CCFM1078 may have a beneficial role as part of a dietary intervention for RC,enhancing overall therapeutic effects.
基金funded by the Yancheng Municipal Health Commission 2024 Medical Research Project(YK2024166).
文摘Objective:To investigate the anti-atherosclerosis effect of chikusetsusaponinⅣ(CSⅣ)against high-fat diet-induced atherosclerosis in rats.Methods:A high-fat diet was used for the induction of atherosclerosis in rats,and the rats received oral CSⅣor atorvastatin.The body weight,organ weights,food intake,calorie intake,lipid parameters,3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA)/mevalonate ratio,collagen,free fatty acid,cardiac parameters,apolipoprotein(A and B),antioxidant parameters,inflammatory cytokines,and inflammatory parameters were assessed.The mRNA expressions of interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α),IL-6,IL-17,PI3K,AKT,and mTOR were estimated.Results:CSⅣsignificantly modulated food intake,body weight,organ weight(liver,kidney,and heart),and calories(P<0.05).Total cholesterol,triglycerides,very low-density lipoprotein cholesterol,low-density lipoprotein cholesterol,cardiovascular risk index-1,and cardiovascular risk index-2 were decreased,while high-density lipoprotein cholesterol and anti-atherogenic index were increased significantly in the CSⅣgroup(P<0.05).Besides,CSⅣsignificantly restored the level of HMG-CoA/mevalonate ratio,collagen,free fatty acid,cardiac parameters(creatinine kinase-MB,lactate dehydrogenase,cTnT,cTnI),apolipoprotein(apolipoprotein A and apolipoprotein B),antioxidant parameters(MDA,CAT,GPx,GSH,SOD),inflammatory cytokines(TNF-α,IL-1β,IL-6,IL-10),inflammatory parameters(COX-2,TGF-β,NF-κB),intercellular adhesion molecule-1,vascular cell adhesion molecule-1,and monocyte chemoattractant protein-1.CSⅣalso decreased the mRNA expression of IL-1β,TNF-α,IL-6,IL-17,PI3K,AKT,and mTOR.Conclusions:This study showed the anti-atherosclerosis effect of CSⅣagainst high-fat diet-induced atherosclerosis in rats via alteration of NF-κB/COX-2 and PI3K/AKT/mTOR signaling pathway.
基金funded by Yunnan Youth Top-notch Talent Support Program(YNWR-QNBJ2018-173)Agricultural Joint project of Yunnan Provincial S&T Programs(202301BD070001-195)+2 种基金S&T project of Yunnan provincial finance(K212020001-01)supported by Yunnan Province Education Department’s Engineering Research Center of Eco-friendly Products from Yunnan Characteristic Edible FungiYunnan Province Yongsheng County Farmer Academician Technology service station.
文摘Muscle atrophy can be induced by high doses or prolonged use of glucocorticoids.Kaempferol(Kae)is a naturally occurring flavonoid with a variety of biological activities and the effect of Kae on dexamethasone(Dex)induced muscle atrophy in animals has not been elucidated.To explore this issue,the present experiments used a computationally assisted drug design scheme combining network pharmacology,molecular docking and in vivo experiments to investigate the mechanism of Kae against muscle atrophy.Network pharmacological analyses revealed 275 potential targets for Kae and 12294 potential targets for muscle atrophy,with a total of 228 crosstargets for Kae and muscle atrophy.GO and KEGG analyses were performed based on the protein-protein interaction(PPI)network of muscle atrophy and Kae component targets.The GO results showed that the biological processes were mainly related to the metabolic process of reactive oxygen species,and the response to oxidative stress;the cellular components were mainly focused on membrane microdomains,and membrane regions;the molecular functions mainly worked on phosphatase binding;and the KEGG pathway enrichment analyses identified the pathways of interaction between Kae and muscle atrophy.Finally,as verified by in vivo experiments,Kae may reduce the onset of muscle atrophy by activating the PI3K/AKT/m TOR/signalling pathway,inhibiting Foxo1/Foxo3 activity,and inhibiting downstream production of the ubiquitination 3 ligases Atrogin1 and Mu RF1;Kae also promotes the expression of NRF2/HO-1/KEAP1 signalling pathway,enhances muscle antioxidant capacity,inhibits the release of COX-2 and TNF-αinflammatory factors,and reduces the damage caused by oxidative stress and inflammatory factors to muscles.Therefore,there may be a synergistic effect of PI3K/AKT/m TOR and NRF2/HO-1/KEAP1 in Kae working together to prevent muscle atrophy.The binding energy and stability of Kae to potential targets were examined by molecular docking and molecular dynamics simulations,implying that Kae could be used for the prevention and treatment of muscle atrophy in patients.
基金supported by the National Key Research and Development Program of China(2022YFC3500100)the National Natural Science Foundation of China(82230126 and U24A20800)+2 种基金the National Science and Technology Major Project of the Ministry of Science and Technology of China(2023ZD0502600)National Science Fund for Excellent Young Scholars(82222075)the Incubation Program for the Science and Technology Development of Chinese Medicine Guangdong Laboratory(Project HQL2024PZ045 and HQCML).
文摘Objective:To establish a mouse model of homocysteine(Hcy)-induced coronary microvascular dysfunction(CMD),and to evaluate the therapeutic efficacy of Shexiang Tongxin dropping pill(STDP)and elucidate its underlying mechanisms.Methods:The chemical composition and quality of STDP were characterized using ultra-high performance liquid chromatography,and its absorbed components were identified using ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry.CMD was induced in C57BL/6J mice by feeding a 3%methionine diet for four weeks.STDP efficacy was evaluated using laser speckle perfusion imaging,tomato lectin staining,and quantification of plasma nitric oxide(NO),reactive oxygen species(ROS),and endothelial adhesion molecules(intercellular cell adhesion molecule-1[ICAM-1],vascular cell adhesion molecule-1[VCAM-1]).Network pharmacology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to identify potential targets and regulatory pathways.An in vitro Hcy-induced endothelial injury model was used to validate the effects of STDP on cell viability,NO production,and activation of phosphatidylinositol 3-kinase/protein kinase B/endothelial nitric oxide synthase(PI3K/Akt/eNOS)pathway.Results:STDP was stable,with 180 constituents identified in the preparation and 30 absorbed components in plasma.STDP treatment restored perfusion,increased plasma NO,decreased ROS,and downregulated ICAM-1 and VCAM-1.Network analysis identified 152 putative targets,highlighting the PI3K/Akt pathway as the central,with PIK3CA,AKT1,and NOS3 as key nodes.In vitro,STDP enhanced cell viability,NO production,and PI3K/Akt/eNOS phosphorylation,these effects were abolished by pharmacological inhibition of PI3K and eNOS.Conclusion:A 3%methionine diet for four weeks effectively induces CMD in C57BL/6J mice.STDP,rich in bioactive components,alleviates Hcy-induced CMD by activating the PI3K/Akt/eNOS pathway,thereby improving endothelial function and microvascular perfusion.These findings support STDP as a promising therapeutic candidate for CMD management.
文摘AIM:To highlight the importance of microRNA(miRNA)-21-5p in directing the phosphatase and tensin homolog(PTEN)gene to control the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/Akt/mTOR)pathway in retinal pigment epithelial(RPE)cells in humans subjected to photodamage.METHODS:Human adult RPE cell line-19(ARPE-19)was cultured in vitro and randomly divided into control,damage,overexpression,negative,and PI3K/Akt blocker groups to establish a photodamage model of ARPE-19 cells.The models were subjected to 24h of light exposure,after which the corresponding indices were detected.The cell counting kit-8 assay quantified cell viability,while flow cytometry determined apoptosis rates.The miRNA-21 mimics and miRNA mimic NC were transfected into ARPE-19 cells using a transient transfection technique.Quantitative reverse transcription polymerase chain reaction(SYBR Green)and Western blotting analyzed expression levels of miRNA-21-5p,PTEN,p-PI3K/PI3K,p-mTOR/mTOR,and p-Akt/Akt.Statistical analyses comprised one-way analysis of variance and the Student-Newman-Keuls test for multiple group comparisons.RESULTS:The photodamage group demonstrated reduced cell survival rates than the control group(P<0.01).The overexpression group exhibited higher cell survival rates than the injury group(P<0.01).The negative group showed no difference in viability(P>0.05).The PI3K/Akt blocker group demonstrated lower cell viability,compared with the overexpression group(P<0.01).CONCLUSION:miRNA-21-5p significantly increases ARPE-19 cell survival after photodamage and inhibits lightinduced ARPE-19 cell apoptosis,suggesting that it may play a protective role in RPE by activating the PI3K/Akt/mTOR pathway while downregulating PTEN expression.
基金supported by the Program for Changjiang Scholars of the Ministry of Education of the People’s Republic of China (No. T2016088)the National Natural Science Foundation for Distinguished Young Scholars (No. 81725021)+4 种基金the National Key R&D Program of China (No. 2021YFA0910500)the Science and Technology Major Project of Hubei Province (No.2021ACA012)the Innovative Research Groups of the National Natural Science Foundation of China (No. 81721005)the Academic Frontier Youth Team of HUST (No. 2017QYTD19)the Fundamental Research Funds for the Central Universities (No.2172019kfy XJJS166)
文摘Cancer represents a significant disease that profoundly impacts human health and longevity.Projections indicate a 47%increase in the global cancer burden by 2040 compared to 2020,accompanied by a further rise in the associated economic burden.Consequently,there is an urgent need to discover and develop new alternative drugs to mitigate the global impact of cancer.Natural products(NPs)play a crucial role in the identification and development of anticancer therapeutics.This study identified ustusolate E(UE)and its analog 11α-hydroxy-ustusolate E(HUE)from strain Aspergillus calidoustus TJ403-EL05,and examined their antitumor activities and mechanisms of action.The findings demonstrate that both compounds significantly inhibited the proliferation and colony formation of AGS(human gastric cancer cells)and 786-O(human renal clear cell carcinoma cells),induced irreversible DNA damage,blocked the cell cycle at the G_(2)/M phase,and further induced apoptosis in tumor cells.To the best of the authors’knowledge,this is the first report on the anticancer effects of UE and HUE and their underlying mechanisms.The present study suggests that HUE and UE could serve as lead compounds for the development of novel anticancer drugs.
基金江苏省卫生健康委员会医学科研重点项目(K2023024)789 Outstanding Talent Program of SAHNMU(789ZYRC202090147)。
文摘Objective:To investigate the biological functions and molecular regulatory mechanisms of kinesin family member 11(KIF11)in colorectal cancer(CRC).Methods:The expression of KIF11 in CRC was examined by qRT⁃PCR and public databases.Functional assays(CCK⁃8,colony formation,EdU,and Transwell)were employed to evaluate KIF11’s roles in CRC progression.Western blot,RIP⁃qPCR,MeRIP⁃qPCR,and RNA stability assays were performed to elucidate the molecular mechanism of N6⁃methyladenosine(m6A)modification for KIF11.RNA sequencing(RNA⁃seq)and correlation analysis were used to examine the downstream mechanism of KIF11 regulation.Results:KIF11 was highly expressed in CRC and promoted CRC proliferation and migration.Mechanistically,methyltransferase⁃like 3(METTL3)/insulin like growth factor 2 mRNA binding protein 2(IGF2BP2)enhanced KIF11 mRNA stability and expression in an m6A⁃dependent way.Furthermore,by means of the PROM1/PI3K/AKT pathway,KIF11 facilitated the progression of CRC.Conclusion:The m6A modification of KIF11 by METTL3/IGF2BP2 contributes to CRC progression via the PI3K/AKT signaling pathway,highlighting its potential as a prognostic biomarker and therapeutic target.
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supported by grants from the National Natural Science Foundation of China(Grant Nos.82473601 to Y.L.,82404234 to W.S.,and 82073518 to C.N.)the Foundation of Chongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and Poisoning(Grant No.2022-2023ZYBKF04 to C.N.)。
文摘Silicosis is an occupational lung disease caused by prolonged exposure to silica dust in the workplace.It has a complex pathogenesis and currently lacks effective treatments.Homoharringtonine(HHT)is a natural compound approved for the treatment of acute myeloid leukemia,but its effects on silicosis remain unclear.In the present study,we constructed a mouse model of silica(SiO_(2))-induced pulmonary fibrosis and evaluated the preventive and therapeutic effects of HHT.The results showed that HHT significantly attenuated the progression of SiO_(2)-induced pulmonary fibrosis in mice.We then used MRC-5,a human lung fibroblast cell line,to explore the mechanisms underlying HHT's inhibitory effects in vitro and found that HHT significantly inhibited the activation and migratory capacity of MRC-5 cells.Mechanistically,these effects were mediated by enhanced ubiquitination and degradation of the CCR1 protein.Furthermore,HHT exhibited favorable biocompatibility in vivo,and its preventive and therapeutic effects were validated in SiO_(2)-treated mice.Collectively,the current study demonstrates that HHT shows significant potential as a therapeutic agent for silicosis by targeting CCR1 and the PI3K/AKT/m TOR signaling pathway,highlighting it as a promising candidate for clinical translation for silicosis treatment.
基金supported by the National Natural Science Foundation of China(no.82004490)Hunan Natural Science Foundation Youth Project:2021JJ40402the Innovation Platform Open Fund project of the Hunan Education Department(no.20K091).
文摘Objective To investigate the effect of electroacupuncture(EA)on microRNA(miRNA)expression spectrum and PI3K/Akt/mTOR signaling pathway in uterine tissue of rats with primary dysmenorrhea(PDM),and to explore the potential mechanism of EA in the treatment of PDM.Methods Thirty female SD rats,weighted(200±20)g were randomly divided into control group,model group and EA group,10 rats in each group.By using subcutaneous injection of estradiol diphenhydrate combined with intraperitoneal injection of oxytocin,PDM models were established.Rats in the EA group received EA at“Sanyinjiao”(SP6)and“Guanyuan”(CV4)at dense waves and a frequency of 50 Hz,once a day,20 min each time,for 10 consecutive days.After the 10-day intervention,samples were collected and transmission electron microscopy was used to observe the ultrastructural changes of the cells in uterine tissue in each group.With RNA-seq method,the changes of miRNA expression spectrum in rat uterine tissue were detected.Bioinformatics analysis such as GO functional annotation and KEGG pathway was performed according to differentially expressed miRNAs.Differentially expressed miRNAs were verified by qRT-PCR.Endometrial stromal cells were selected as the target cells and transfected;and they were divided into control group,NC mimics group,mimic miR-144–3p group,NC inhibitor group and inhibitor miR-144–3p group.The apoptosis was determined by using flow cytometrydetect apoptosis,the miRNA and protein expression of PI3K/Akt/mTOR signaling pathway were detected by qRT-PCR and Western blot in each group separately.Results 1.Transmission electron microscope.(1)Control group:no obvious morphological changes in the uterine tissue.(2)Model group:fibroblasts in uterine tissue were irregular,the edema was presented in cellular cytoplasm,the nuclei were irregular and mitochondria swollen seriously;the rough endoplasmic reticulum was expanded moderately.(3)EA group:fibroblasts were spindle-shaped and pyknotic,the cytoplasm increased in electron density,the nuclei were slightly irregular and pyknotic,mitochondria were oval in shape,with little swelling and vacuolation;the rough endoplasmic reticulum was expanded slightly and retained,with a small amount of degranulation.2.Compared with the control group,there were 26 differentially expressed miRNAs in the uterine tissue of rats with PDM.After EA intervention,the expression of miR-144–3p was significantly up-regulated.GO functional analysis of differentially expressed miRNAs in PDM rats after EA showed that the biological functions involved calcium transmembrane transporter activity,mitogen-activated protein kinase binding,epithelial cell migration,tissue migration,etc.3.KEGG pathway analysis showed that PI3K/Akt signaling pathway,MAPK signaling pathway and calcium signaling pathway were enriched.Mimic miR-144-3p increased the apotosis of endometrial stromal cells,and decreased the mRNA and protein expression of PI3K,Akt,and mTOR(P<0.01).Conclusion EA can optimize the cell morphology in the uterine tissue of rats with PDM and affect the miRNA expression spectrum,which may be associated with the effect of EA for up-regulating miR-144–3p expression in endometrial stromal cells,suppressing PI3K/Akt/mTOR signaling pathway and causing apoptosis.
基金Natural Science Foundation of Guangxi(Grant No.2021JJD140147)。
文摘PI3K/AKT/mTOR signaling pathway is a key pathway of myocardial ischemia-reperfusion injury(MIRI).The mechanism of action is mainly oxidative stress,inflammatory response,calcium overload,ferroptosis,autophagy,and apoptosis.MIRI belongs to the category of chest obstruction in traditional Chinese medicine,and its etiology and pathogenesis are mainly“Yang Wei Yin Xian.”Traditional Chinese medicine has the effect of multi-target and multi-component effect,and has played a significant role in the treatment of MIRI in recent years.At present,the monomers of traditional Chinese medicine mainly include saponins,flavonoids,alkaloids,terpenoids,and phenols,and the compounds mainly include Zhigancao Decoction,Zhenyuan Capsule,Jiawei Shenqibai Powder,Qili Qiangxin Capsule,Tongmai Yangxin Pill,Zhilong Huoxue Tongyu Capsule,Guizhi Tongluo Tablets,etc.This paper reviews the research on the improvement of MIRI by regulating PI3K/AKT/mTOR signaling pathway in recent years,and expounds the mechanism and advantages of traditional Chinese medicine in the treatment of MIRI.
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 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BACKGROUND Gastric cancer(GC)is a widespread malignancy and associated with high rates of morbidity and mortality worldwide.AIM To examine the functional role of long non-coding RNAs small nucleolar RNA host gene 5(SNHG5)and its regulation of miR-92a-3p and B-cell translocation gene 2(BTG2)in GC progression.METHODS Quantitative reverse transcription PCR and western blot analysis determined the expression of SNHG5,miR-92a-3p,and BTG2 in GC and adjacent non-neoplastic mucosa.Dual-luciferase assays demonstrated interactions of SNHG5 with miR-92a-3p and BTG2.AGS cells were transfected with SNHG5 overexpression and miR-92a-3p knockdown models.Various assays,including CCK-8,colony formation,scratch wound healing,and Transwell assays,were used to determine cell proliferation and migration.An experimental model of a xenograft mouse was used to determine in vivo tumor growth.At the same time histological changes were evaluated by hematoxylin and eosin staining,with western blot analysis used to evaluate signaling pathway protein expression.RESULTS BTG2 and SNHG5 were downregulated in GC tissues,and miR-92a-3p was upregulated.Overexpression of SNHG5 or knockdown of miR-92a-3p reduced GC cell proliferation and migration,and increased BTG2 expression while decreasing PI3K/AKT signaling activity.The dual-luciferase assays demonstrated direct binding of miR-92a-3p to SNHG5 and BTG2.Tumor volume and weight were significantly reduced in mice transplanted with AGS cells treated with miR-92a-3p inhibitor or SNHG5 overexpression compared with control AGS cells.Hematoxylin and eosin staining revealed that treated tumors exhibited degenerative characteristics,including irregular morphology and nucleolysis.CONCLUSION LncRNA SNHG5 inhibited GC cell growth and migration by modulating the PI3K/AKT pathway via the miR-92a-3p/BTG2 axis.
基金supported by the project of Central Funds Guiding the Local Science and Technology Development(No.20212ZDD02010)。
文摘Andrographolide sulfonate(AS)is a sulfonated derivative of andrographolide extracted from Andrographis paniculata(Burm.f.)Nees,and has been approved for several decades in China.The present study aimed to investigate the novel therapeutic application and possible mechanisms of AS in the treatment of rheumatoid arthritis.Results indicated that administration of AS by injection or gavage significantly reduced the paw swelling,improved body weights,and attenuated pathological changes in joints of rats with adjuvant-induced arthritis.Additionally,the levels of tumor necrosis factor-alpha(TNF-α),interleukin-6(IL-6),and IL-1β in the serum and ankle joints were reduced.Bioinformatics analysis,along with the spleen index and measurements of IL-17 and IL-10 levels,suggested a potential relationship between AS and Th17 cells under arthritic conditions.In vitro,AS was shown to block Th17 cell differentiation,as evidenced by the reduced percentages of CD4^(+)IL-17A^(+)T cells and decreased expression levels of RORγt,IL-17A,IL-17F,IL-21,and IL-22,without affecting the cell viability and apoptosis.This effect was attributed to the limited glycolysis,as indicated by metabolomics analysis,reduced glucose uptake,and p H measurements.Further investigation revealed that AS might bind to hexokinase2(HK2)to down-regulate the protein levels of HK2 but not glyceraldehyde-3-phosphate dehydrogenase(GAPDH)or pyruvate kinase M2(PKM2),and overexpression of HK2 reversed the inhibition of AS on Th17 cell differentiation.Furthermore,AS impaired the activation of phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)signals in vivo and in vitro,which was abolished by the addition of lactate.In conclusion,AS significantly improved adjuvant-induced arthritis(AIA)in rats by inhibiting glycolysis-mediated activation of PI3K/AKT to restrain Th17 cell differentiation.
基金supported by Beijing Key Laboratory of Neuromodulation(BZ0098)the Precision Medicine Project of the Ministry of Science and Technology of China(2016YFC0904400)
文摘Epilepsy is a chronic and severe neurological disorder that has negative effects on the autonomous activities of patients. Functionally, Trem2(triggering receptor expressed on myeloid cells-2) is an immunoglobulin receptor that affects neurological and psychiatric genetic diseases. Based on this rationale, we aimed to assess the potential role of Trem2 integration with the PI3 K/Akt pathway in epilepsy. We used microarray-based gene expression profiling to identify epilepsy-related differentially-expressed genes. In a mouse hippocampal neuron model of epilepsy, neurons were treated with lowMg^2+ extracellular fluid, and the protein and mRNA expression of Trem2 were determined. Using a gain-offunction approach with Trem2, neuronal apoptosis and its related factors were assessed by flow cytometry, RT-qPCR,and Western blot analysis. In a pilocarpine-induced epileptic mouse model, the malondialdehyde(MDA) and8-hydroxy-20-deoxyguanosine(8-OHdG) content and superoxide dismutase(SOD) and glutathione-peroxidase(GSH-Px) activity in the hippocampus were determined,and the protein expression of Trem2 was measured. In addition, the regulatory effect of Trem2 on the PI3 K/Akt pathway was analyzed by inhibiting this pathway in both the cell and mouse models of epilepsy. Trem2 was found to occupy a core position and was correlated with epilepsy.Trem2 was decreased in the hippocampus of epileptic miceand epileptic hippocampal neurons. Of crucial importance,overexpression of Trem2 activated the PI3 K/Akt pathway to inhibit neuronal apoptosis. Moreover, activation of the PI3 K/Akt pathway through over-expression of Trem2 alleviated oxidative stress, as shown by the increased expression of SOD and GSH-Px and the decreased expression of MDA and 8-OHdG. The current study defines the potential role of Trem2 in inhibiting the development of epilepsy, indicating that Trem2 up-regulation alleviates hippocampal neuronal injury and oxidative stress, and inhibits neuronal apoptosis in epilepsy by activating the PI3 K/Akt pathway.
基金supported by Medical and Health Technology Project of Shandong Province(202402020509)20 New Universities Funding Project of Jinan(202228121).
文摘Objectives:PI3K plays a pivotal role in the inflammatory response by modulating the production and release of inflammatory factors.Pik3cb is one of the subunits of PI3K,and its specific role in myocardium inflammation remains unelucidated.This study aimed to investigate the role of Pik3cb in the inflammatory response and to elucidate the underlying mechanism.Methods:An inflammation model was established using H9c2 cells treated with LPS and ATP,and Pik3cb expression was evaluated in this model system.Subsequently,an overexpression model was constructed by transfecting cells with a Pik3cb overexpression plasmid,after which the effects of Pik3cb overexpression on the PI3K/AKT and NF-κB/NLRP3 inflammatory signaling pathways were assessed.Results:These analyses revealed that the expression and distribution of Pik3cb were significantly reduced in the LPS/ATP-induced cellular inflammation model group,whereas plasmid-mediated overexpression of Pik3cb significantly inhibited the activation of the PI3K/AKT signaling pathway in response to LPS/ATP stimulation.Additionally,the LPS/ATP-induced activation of the NF-κB/NLRP3 axis was significantly inhibited following Pik3cb overexpression.Conclusion:This study demonstrates that Pik3cb acts as a negative regulator of LPS/ATP-induced inflammation in cardiomyocytes,exerting anti-inflammatory effects by inhibiting the PI3K/AKT/NF-κB/NLRP3 signaling axis.These findings provide a potential therapeutic target for the treatment of myocardial inflammation.
基金the Central Government Guidance Local Science and Technology Development Fund,No.2023JH6/100100021Liaoning Province Education Department Foundation of China,No.JYTMS20231393+2 种基金Scientific Research Project of Liaoning Province Education Department,No.SYYX2019015Science and Technology Fund of Shenyang Medical College,No.20171004,Shenyang Medical College Master’s Science and Technology Innovation Fund,No.Y20220509Liaoning Provincial Department of Education Scientific Research Project,No.LJ212410164032.
文摘BACKGROUND Liver cancer has a high incidence and mortality worldwide,especially in China.Herein,we investigated the therapeutic effect and mechanism of tetrahydrocurcumin against hepatocellular carcinoma(HCC),with a focus on the of phosphoinositide 3-kinases(PI3K)/AKT signaling pathway.AIM To investigate the effects and mechanism of tetrahydrocurcumin in HCC cell lines HepG2 and Huh7.METHODS Using Metascape,we analyzed the potential targets of tetrahydrocurcumin in HCC.Molecular docking validation was performed using SYBYL2.0.Cell Counting Kit-8,wound healing,and transwell assays were performed to evaluate the effects of tetrahydrocurcumin on HepG2 and Huh7 cell migration,invasion,and apoptosis.The expression of PI3K/AKT signaling pathway-related proteins was detected by western blotting.RESULTS Network pharmacology and molecular docking showed that tetrahydrocurcumin has high binding affinity for phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha.In vitro experiments demonstrated that tetrahydrocurcumin suppressed the migration and invasion of liver cancer cells,promoted their apoptosis,and downregulated the expression of p-PI3K,p-AKT,and B cell leukemia/lymphoma 2,while upregulating caspase-3,p53,and B cell leukemia/lymphoma 2 associated X.CONCLUSION In summary,tetrahydrocurcumin suppresses PI3K/AKT signaling,promotes apoptosis,and prevents the migration and invasion of liver cancer cells.
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.
