OBJECTIVE:To evaluate the effect of Fuzi Lizhong decoction(附子理中汤)on intestinal flora,serum inflammatory factors,and hypoxia inducible factor-1α(HIF-1α)in patients with colorectal cancer associated with spleen a...OBJECTIVE:To evaluate the effect of Fuzi Lizhong decoction(附子理中汤)on intestinal flora,serum inflammatory factors,and hypoxia inducible factor-1α(HIF-1α)in patients with colorectal cancer associated with spleen and kidney Yang deficiency.METHODS:A total of 100 patients diagnosed with advanced colorectal cancer were randomly divided into two groups:a control group(CON,50)and a Traditional Chinese Medicine(TCM)group(n=50).The control group received treatment with the Capecitabine+Oxaliplatin(CAPEOX)regimen,while the TCM group received the same regimen along with Fuzi Lizhong decoction for six weeks.Changes in intestinal flora were assessed before and after six weeks in both groups.Serum markers,including HIF-1α,vascular endothelial growth factor(VEGF),interleukin-6(IL-6),and tumor necrosis factor-alpha(TNF-α),were measured using enzyme-linked immunosorbent assay.Adverse reactions,clinical efficacy,and TCM syndrome efficacy were also monitored.RESULTS:After six weeks,the levels of Lactobacillus and Bifidobacterium were significantly higher,while the levels of Enterobacter and Enterococcus were significantly lower in the TCM group compared to the control group(P<0.05).Serum levels of HIF-1α,VEGF,IL-6,and TNF-αwere also significantly reduced in the TCM group compared to the control group(P<0.05).Additionally,the incidence of adverse reactions was lower,and the clinical efficacy was higher in the TCM group compared to the control group(P<0.05).CONCLUSION:Fuzi Lizhong decoction effectively improves intestinal microbiota composition,reduces inflammatory factors and HIF-1αexpression,alleviates chemotherapy-related adverse reactions,enhances clinical efficacy,and may inhibit tumor growth in patients with colorectal cancer.展开更多
The activation of the sirtuin1(SIRT1)/nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase 1(HO-1)pathway has been shown to mitigate oxidative stress-induced apoptosis and mitochondrial damage by reducing ...The activation of the sirtuin1(SIRT1)/nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase 1(HO-1)pathway has been shown to mitigate oxidative stress-induced apoptosis and mitochondrial damage by reducing reactive oxygen species(ROS)levels.Clinical trials have demonstrated that Zhongfeng Xingnao Liquid(ZFXN)ameliorates post-stroke cognitive impairment(PSCI).However,the underlying mechanism,particularly whether it involves protecting mitochondria and inhibiting apoptosis through the SIRT1/Nrf2/HO-1 pathway,remains unclear.This study employed an oxygen-glucose deprivation(OGD)cell model using SHSY5Y cells and induced PSCI in rats through modified bilateral carotid artery ligation(2VO).The effects of ZFXN on learning and memory,neuroprotective activity,mitochondrial function,oxidative stress,and the SIRT1/Nrf2/HO-1 pathway were evaluated both in vivo and in vitro.Results indicated that ZFXN significantly increased the B-cell lymphoma 2(Bcl2)/Bcl2-associated X(Bax)ratio,reduced terminal deoxynucleotidyl transferase-mediated d UTP nickend-labeling(TUNEL)+cells,and markedly improved cognition,synaptic plasticity,and neuronal function in the hippocampus and cortex.Furthermore,ZFXN exhibited potent antioxidant activity,evidenced by decreased ROS and malondialdehyde(MDA)content and increased superoxide dismutase(SOD),catalase(CAT),and glutathione(GSH)levels.ZFXN also demonstrated considerable enhancement of mitochondrial membrane potential(MMP),Tom 20 fluorescence intensity,adenosine triphosphate(ATP)and energy charge(EC)levels,and mitochondrial complexⅠandⅢactivity,thereby inhibiting mitochondrial damage.Additionally,ZFXN significantly increased SIRT1 activity and elevated SIRT1,nuclear Nrf2,and HO-1 levels.Notably,these effects were substantially counteracted when SIRT1 was suppressed by the inhibitor EX-527 in vitro.In conclusion,ZFXN alleviates PSCI by activating the SIRT1/Nrf2/HO-1 pathway and preventing mitochondrial damage.展开更多
Prenatal caffeine exposure(PCE)leads to intrauterine growth retardation and altered glucose homeostasis after birth,but the underlying mechanism remains unclear.This study aims to investigate the alteration of pancrea...Prenatal caffeine exposure(PCE)leads to intrauterine growth retardation and altered glucose homeostasis after birth,but the underlying mechanism remains unclear.This study aims to investigate the alteration of pancreatic development and insulin biosynthesis in the PCE female offspring and explore the intrauterine programming mechanism.Pregnant rats were orally treated with 120 mg/(kg·day)of caffeine from gestational day(GD)9 to 20.Results showed that fetal pancreaticβ-cells in the PCE group exhibited reduced mass and impaired insulin synthesis function,as evidenced by decreased expression of developmental and functional genes and reduced pancreatic insulin content.At postnatal week(PW)12,the PCE offspring exhibited glucose intolerance,diminishedβ-cell mass,and lower blood insulin levels.However,by PW28,glucose tolerance showed some improvement.Both in vivo and in vitro findings collectively indicated that excessive serum corticosterone(CORT)levels of the PCE fetuses may act through the activation of the pancreatic glucocorticoid receptor(GR)and recruitment of histone deacetylase 9(HDAC9),leading to H3K9 deacetylation in promoter and downregulation of insulin-like growth factor 1(IGF1),thereby inhibiting pancreatic islet morphogenesis and insulin synthesis in fetal rats.Furthermore,the PCE offspring after birth exhibited decreased blood CORT levels,increased H3K9 acetylation in promoter and upregulated gene expression of the pancreatic IGF1 promoter region,accompanied by elevated insulin biosynthesis.However,when exposed to chronic stress,the above changes were totally reversed.Conclusively,“glucocorticoid-insulin like growth factor 1(GC-IGF1)axis”programming may be involved in pancreaticβ-cell dysplasia and dysfunction in the PCE female offspring.展开更多
Objective:Baicalein has been reported to have wide therapeutic effects that act through its antiinflammatory activity.This study examines the effect and mechanism of baicalein on sepsis-induced cardiomyopathy(SIC).Met...Objective:Baicalein has been reported to have wide therapeutic effects that act through its antiinflammatory activity.This study examines the effect and mechanism of baicalein on sepsis-induced cardiomyopathy(SIC).Methods:A thorough screening of a small library of natural products,comprising 100 diverse compounds,was conducted to identify the most effective drug against lipopolysaccharide(LPS)-treated H9C2 cardiomyocytes.The core target proteins and their associated signaling pathways involved in baicalein's efficacy against LPS-induced myocardial injury were predicted by network pharmacology.Results:Baicalein was identified as the most potent protective agent in LPS-exposed H9C2 cardiomyocytes.It exhibited a dose-dependent inhibitory effect on cell injury and inflammation.In the LPSinduced septic mouse model,baicalein demonstrated a significant capacity to mitigate LPS-triggered myocardial deficits,inflammatory responses,and ferroptosis.Network pharmacological analysis and experimental confirmation suggested that hypoxia-inducible factor 1 subunit a(HIF1-a)is likely to be the crucial factor in mediating the impact of baicalein against LPS-induced myocardial ferroptosis and injury.By combining microRNA(miRNA)screening in LPS-treated myocardium with miRNA prediction targeting HIF1-a,we found that miR-299b-5p may serve as a regulator of HIF1-a.The reduction in miR-299b-5p levels in LPS-treated myocardium,compared to the control group,was reversed by baicalein treatment.The reverse transcription quantitative polymerase chain reaction,Western blotting,and dual-luciferase reporter gene analyses together identified HIF1-a as the target of miR-299b-5p in cardiomyocytes.Conclusion:Baicalein mitigates SIC at the miRNA level,suggesting the therapeutic potential of it in treating SIC through the regulation of miR-299b-5p/HIF1-a/ferroptosis pathway.展开更多
BACKGROUND Esophageal squamous-cell carcinoma(ESCC)is a highly aggressive cancer,predominantly affecting populations in Eastern Asia and parts of Africa.Its pathogenesis is influenced by both genetic and environmental...BACKGROUND Esophageal squamous-cell carcinoma(ESCC)is a highly aggressive cancer,predominantly affecting populations in Eastern Asia and parts of Africa.Its pathogenesis is influenced by both genetic and environmental factors.Despite recent therapeutic advances,survival rates remain dismal,underscoring an urgent need for novel therapeutic targets.AIM To investigate the role of hypoxia-inducible factor 1-alpha(HIF1A)in the progression of ESCC and its impact on the metabolic enzyme lactate dehydrogenase A(LDHA),which is crucial for the glycolytic pathway in hypoxic tumor environments.METHODS Utilizing transcriptomic data from multiple public databases,we analyzed differential gene expression and conducted gene ontology and transcription factor network analyses.The regulatory impact of HIF1A on LDHA was specifically examined through integrative analysis with HIF1A ChIP-seq data and confirmed via siRNA-mediated knockdown experiments in ESCC cell lines.RESULTS Our findings reveal a significant upregulation of HIF1A in ESCC tissues,associated with poor prognosis.HIF1A directly regulates LDHA,enhancing glycolysis under hypoxic conditions and contributing to tumor aggressiveness.Knockdown of HIF1A in cell lines not only reduced LDHA expression but also altered key pathways related to cell cycle and apoptosis.CONCLUSION The critical role of the HIF1A-LDHA axis in ESCC highlights its potential as a therapeutic target,underscoring the need for future clinical trials to validate the efficacy of HIF1A inhibitors in enhancing treatment outcomes.展开更多
BACKGROUND Diabetes is characterized by insulin resistance as well as impaired insulin production,withβ-cell dysfunction playing a critical role in disease progression.Exercise is known to improve insulin sensitivity...BACKGROUND Diabetes is characterized by insulin resistance as well as impaired insulin production,withβ-cell dysfunction playing a critical role in disease progression.Exercise is known to improve insulin sensitivity,but its effects on pancreatic islet quality and function remain poorly understood.This work hypothesized that swimming training enhances glycemic control and insulin secretion by upregulating the insulin-like growth factor 1(IGF-1)/phosphatidylinositol 3-kinase/protein kinase B(PI3K/AKT)pathway in streptozotocin(STZ)-induced diabetic rats.AIM To investigate the effects of swimming on pancreatic islet quality and function in STZ-induced diabetic rats via the IGF-1/PI3K/AKT pathway.METHODS Twenty-six Sprague-Dawley rats were grouped into diabetic and control groups,with each group further split into exercise and sedentary subgroups.Diabetic rats were induced with STZ.The exercise groups underwent swimming training for 60 minutes/day,5 days/week,for 8 weeks.Body weight,food intake,blood glucose,insulin,lipids,and muscle glycogen were measured.Pancreatic islet morphology and the protein expression levels of IGF-1,PI3K,and AKT were analyzed.Data were analyzed using two-way repeated-measure ANOVA,followed by Tukey’s post-hoc test.RESULTS Exercise training significantly improved body weight[diabetic exercise group(D-Ex):390.66±50.14 g vs diabetic sedentary group(D-Sed):315.89±50.12 g,P<0.05],reduced blood glucose(D-Ex:12.21±4.43 mmol/L vs D-Sed:17.79±2.05 mmol/L,P<0.05),and increased insulin levels(D-Ex:53.50±15.31 pmol/L vs D-Sed:25.31±10.23 pmol/L,P<0.05)in diabetic rats.It also enhanced islet morphology,increased IGF-1 expression,and activated the PI3K/AKT pathway(P<0.05).In-vitro experiments confirmed that IGF-1 positively regulated insulin expression and inhibitedβ-cell apoptosis via the PI3K/AKT pathway.CONCLUSION Exercise training improves pancreatic islet quality and function in diabetic rats by modulating the IGF-1/PI3K/AKT pathway,highlighting its therapeutic potential for diabetes management.展开更多
High expression of pescadillo ribosomal biogenesis factor 1(PES1)has been re-ported across multiple cancer types and is significantly associated with poor prog-nosis.Hu et al in their recent paper described their inve...High expression of pescadillo ribosomal biogenesis factor 1(PES1)has been re-ported across multiple cancer types and is significantly associated with poor prog-nosis.Hu et al in their recent paper described their investigation of PES1 in gastric cancer and head and neck squamous cell carcinoma,demonstrating positive cor-relations between PES1 and programmed death-ligand 1(PD-L1)expression(51.72%for PES1 and 58.62%for PD-L1),as well as associations with lymph node metastasis and tumor invasion depth.However,the relationship between PES1 and PD-L1 remains incompletely defined.To further address this gap,we ana-lyzed The Cancer Genome Atlas gastric adenocarcinoma dataset and found a negative correlation between PES1 expression and CD8+T cell infiltration,along-side a positive correlation with PD-L1 expression.Based on prior findings,we hypothesize that PES1 may regulate PD-L1 through the phosphatidylinositol 3-kinase/protein kinase B pathway or cellular Myc-mediated mechanisms.While these pathways require experimental validation,our observations highlight PES1 as a potential regulator of immune evasion and a promising target for cancer immunotherapy.展开更多
BACKGROUND Gastric cancer(GC)and head and neck squamous cell carcinoma(HNSCC)are common malignancies with high morbidity and mortality rates.Traditional treatments often yield limited efficacy,especially in advanced c...BACKGROUND Gastric cancer(GC)and head and neck squamous cell carcinoma(HNSCC)are common malignancies with high morbidity and mortality rates.Traditional treatments often yield limited efficacy,especially in advanced cases.Recent advancements in immunotherapy,particularly immune checkpoint inhibitors targeting programmed death-ligand 1(PD-L1),have shown promise.However,the expression and interaction of pescadillo ribosomal biogenesis factor 1(PES1)and PD-L1 in these cancers remain unclear.Understanding their roles could provide new insights into tumor biology and improve therapeutic strategies.AIM To investigate the expression levels of PES1 and PD-L1 in tumor tissues of patients with GC and HNSCC.METHODS A total of 58 cases of GC and HNSCC undergoing surgical resection were selected from January 2022 to January 2024.Paraffin specimens of GC and HNSCC tissues were taken from the patients,and the sections were subjected to staining with immunohistochemistry and hematoxylin-eosin staining,and the protein expression of PES1 and PD-L1 was observed microscopically.RESULTS Among 58 GC and HNSCC tissues,30 cases were positive and 28 cases were negative for PES1 expression,and 34 cases were positive and 24 cases were negative for PD-L1 expression.The positive expression rates of PES1 and PDL1 were 51.72% and 58.62%,respectively.PES1 expression was correlated with the TNM stage,lymph node metastasis,and the depth of infiltration(P<0.05),and PD-L1 expression was correlated with the differentiation degree,lymph node metastasis,and infiltration depth(P<0.05).CONCLUSION PES1 and PD-L1 were positively expressed in GC and HNSCC tissues and correlated with clinical features.They may serve as potential biomarkers for immune-targeted therapies.展开更多
Myocardial infarction(MI)is characterized by focal necrosis resulting from prolonged myocardial ischemia due to coronary artery obstruction.Vascular reconstruction following MI is crucial for improving cardiac functio...Myocardial infarction(MI)is characterized by focal necrosis resulting from prolonged myocardial ischemia due to coronary artery obstruction.Vascular reconstruction following MI is crucial for improving cardiac function and preventing recurrent infarction.This study investigates the interaction between macrophages and endothelial cells in angiogenesis mediated by nicotinamide mononucleotide(NMN)-induced secretion of macrophage-derived exosomes.We focus on the role of U2 small nuclear RNA auxiliary factor 1(U2af1)gene,a member of the splicing factor serine and arginine(SR)gene family,in the regulation of angiogenesis.Through cardiac ultrasound,Masson staining,2,3,5-triphenyltetrazolium chloride(TTC)staining,Microfil vascular perfusion,and platelet and endothelial cell adhesion molecule 1(CD31)immunofluorescence staining,extracellular vesicles from NMN-stimulated macrophages were shown to exert a protective effect in MI,with proteomic analysis identifying U2AF1 as a candidate protein involved in MI protection.Plasma U2AF1 levels were measured in 70 MI patients,revealing significantly lower levels in individuals with poor coronary collateral vessel(CCV;Rentrop scores 0–1)than in those with good CCV(Rentrop scores 2–3).In both myocardial and hindlimb ischemia mouse models,overexpression of endothelial cell-specific adenoviral overexpression U2AF1 promoted angiogenesis in the heart and hindlimbs and improved cardiac function after MI.Mechanistic studies demonstrated that U2AF1 regulates the alternative splicing(AS)of Yes1-associated transcriptional regulator(Yap1)gene,influencing post-MI angiogenesis and cardiac function recovery.Collectively,our clinical findings suggest that U2AF1 may serve as a therapeutic target for coronary collateral angiogenesis following MI.Given the low immunogenicity and high biosafety of exosomes,this study provides a foundational basis and translational potential for exosome-based therapies in MI treatment.展开更多
Background:Expression of mRNA is widely regulated by N6-methyladenosine(m6A).An increasing number of studies have shown that m6A methylation,facilitated by methyltransferase 3(METTL3),is crucial in the progression of ...Background:Expression of mRNA is widely regulated by N6-methyladenosine(m6A).An increasing number of studies have shown that m6A methylation,facilitated by methyltransferase 3(METTL3),is crucial in the progression of tumors.Previous reports have indicated the involvement of both METTL3 and c-Src kinase in the evolution of liver cancer.However,the potential connection between c-Src and the METTL3-mediated mechanism in liver cancer progression remains elusive.Methods:The correlation expression between c-Src and METTL3 between liver cancer patients and the control group was analyzed using the TCGA database,and was further demonstrated by Western blot and RT-qPCR.The functional roles of c-Src in METTL3-regulated liver cancer progression were investigated by cell proliferation assays and colony formation assays.The regulatory mechanism of METTL3 in c-Src expression was accessed by RNA-immunoprecipitation(RIP)-qPCR.Results:We demonstrated that c-Src kinase promoted liver cancer development,and the expression of SRC(encodes c-Src kinase)was positively correlated with METTL3 in liver cancer cases.We showed that SRC mRNA could be m6A-modified,and METTL3 regulated the transcription of SRC mRNA through interferon regulatory factor 1(IRF1).We revealed that IRF1,the expression of which was positively regulated byMETTL3,was a novel transcription factor of c-Src.Lastly,The pro-proliferative effect of METTL3 on hepatocellular carcinoma was mechanistically linked to IRF1/c-Src axis activation,as evidenced by our experimental data.Conclusion:Results suggested that the METTL3/IRF1/c-Src axis played potential oncogenic roles in liver cancer development and the axis may be a promising therapeutic target in the disease.展开更多
Background:Clear cell renal carcinoma(ccRCC),the leading histological subtype of RCC,lacks any targeted therapy options.Although some studies have shown that early growth response factor 1(EGR1)has a significant role ...Background:Clear cell renal carcinoma(ccRCC),the leading histological subtype of RCC,lacks any targeted therapy options.Although some studies have shown that early growth response factor 1(EGR1)has a significant role in cancer development and progression,its role and underlying mechanisms in ccRCC remain poorly understood.Methods:The Cancer Genome Atlas(TCGA)database was utilized to examine the expression of EGR1 in ccRCC.The expression of EGR1 in 55 ccRCC tissues was evaluated using immunohistochemistry.The link between EGR1 expression and clinicopathological variables was examined through an analysis.Gain-of-function assays were employed to investigate EGR1’s biological functions in ccRCC cells,involving proliferation,colony formation,invasion assays,and tumorigenesis in nude mice.In order to assess the protein expression of mitogen-activated protein kinase 15(MAPK15),E-cadherin,matrix metalloproteinase-9/-2(MMP-9 and MMP-2),Western blot technique was applied.Results:The results revealed a decrease in EGR1 expression in ccRCC tissues.This decrease was strongly linked to TNM stage,lymphatic metastasis,tumor size,histological grade,and unfavorable prognosis in ccRCC patients.It has been demonstrated that overexpressing EGR1 inhibits the growth of xenograft tumors in vivo and inhibits cell colony formation,motility,and invasion in vitro.Furthermore,EGR1 can prevent the development and movement of ccRCC cells by controlling the expression of MMP-2,MMP-9,E-cadherin,and MAPK15.Conclusions:The EGR1/MAPK15 axis may represent a promising target for drug development,with EGR1 serving as a possible target for ccRCC therapy.展开更多
OBJECTIVE:To explore the role and mechanism of Qufeng Jiejing(祛风解痉,QFJJ)formula in the asthma progression.METHODS:The Bagg Albino/c mice treated with Ovalbumin and AL(OH)3,and airway smooth muscle cells(ASMCs)trea...OBJECTIVE:To explore the role and mechanism of Qufeng Jiejing(祛风解痉,QFJJ)formula in the asthma progression.METHODS:The Bagg Albino/c mice treated with Ovalbumin and AL(OH)3,and airway smooth muscle cells(ASMCs)treated with platelet-derived growth factor(PDGF)-BB to establish a asthma model in vivo and in vitro.The cell morphology was observed with microscope and immunofluorescence staining.The cell viability was assessed with methyl thiazolyl tetrazolium assay.The tumor necrosis factor-αlpha(TNF-α),interleukin-1beta(IL-1β),laminin,fibronectin and collagen IV levels in the ASMCs were detected with corresponding enzyme linked immunosorbent assay kits.Transwell and wound healing assays were conducted to test the cell migration.The TGF-β1,Smad2 and Smad3 levels were measured with Western blot.RESULTS:We found that QFJJ formula treatment dramatically decreased the cell viability,TNF-α,IL-1β,laminin,fibronectin and collagen IV levels in the PDGFBB stimulated ASMCs.Additionally,the protein levels of TGF-β1,Smad2 and Smad3 in the PDGF-BB stimulated ASMCs were prominently depleted after QFJJ formula treatment.Besides,SRI treatment neutralized the role of QFJJ formula in the PDGF-BB stimulated ASMCs.CONCLUSION:QFJJ formula effectively relieved the asthma progression through ameliorate the ASMCs function,which was achieved through suppressing the TGF-β1/Smads signaling pathway.展开更多
BACKGROUND Diabetic macular edema(DME)is the most common cause of vision loss in people with diabetes.Tight junction disruption of the retinal pigment epithelium(RPE)cells has been reported to induce DME development.S...BACKGROUND Diabetic macular edema(DME)is the most common cause of vision loss in people with diabetes.Tight junction disruption of the retinal pigment epithelium(RPE)cells has been reported to induce DME development.SMAD-specific E3 ubiquitin protein ligase(SMURF)1 was associated with the tight junctions of cells.However,the mechanism of SMURF1 in the DME process remains unclear.AIM To investigate the role of SMURF1 in RPE cell tight junction during DME.METHODS ARPE-19 cells treated with high glucose(HG)and desferrioxamine mesylate(DFX)for establishment of the DME cell model.DME mice models were constructed by streptozotocin induction.The trans-epithelial electrical resistance and permeability of RPE cells were analyzed.The expressions of tight junction-related and autophagy-related proteins were determined.The interaction between insulin like growth factor 2 mRNA binding protein 2(IGF2BP2)and SMURF1 mRNA was verified by RNA immunoprecipitation(RIP).SMURF1 N6-methyladenosine(m6A)level was detected by methylated RIP.RESULTS SMURF1 and vascular endothelial growth factor(VEGF)were upregulated in DME.SMURF1 knockdown reduced HG/DFX-induced autophagy,which protected RPE cell tight junctions and ameliorated retinal damage in DME mice.SMURF1 activated the Wnt/β-catenin-VEGF signaling pathway by promoting WNT inhibitory factor(WIF)1 ubiquitination and degradation.IGF2BP2 upregulated SMURF1 expression in an m6A modification-dependent manner.CONCLUSION M6A-modified SMURF1 promoted WIF1 ubiquitination and degradation,which activated autophagy to inhibit RPE cell tight junctions,ultimately promoting DME progression.展开更多
The flower of Syringa pubescens Turcz.(SP),was used as both medicine and food in China,exhibited various biological activities.However,it remains unknown whether SP affects ameliorative nonalcoholic steatohepatitis(NA...The flower of Syringa pubescens Turcz.(SP),was used as both medicine and food in China,exhibited various biological activities.However,it remains unknown whether SP affects ameliorative nonalcoholic steatohepatitis(NASH).In this study,the improvement of SP ethyl acetate extract(SPE)on NASH was evaluated and the potential mechanisms were explored.The glycosides of SPE were determined by HPLC method.Hep G2 cell lines were treated with free fatty acid to clarify the improvement effect and mechanisms of SPE on NASH in vitro.C57BL/6J mice were treated by 60%kcal high-fat diet(HFD)combined with carbon tetrachloride(CCl_4)to establish the NASH model in vivo.The results showed SPE could inhibit the hepatic injury and lipid steatosis by decreasing the levels of alanine aminotransferase,aspartate aminotransferase,triglyceride and total cholesterol in vitro and in vivo.The SPE suppressed the oxidative stress and inflammation by restraining the generation of reactive oxygen species,malondialdehyde,interleukin(IL)-1β,IL-6 and tumor necrosis factor-α(TNF-α)and enhancing the activity of antioxidant enzymes including superoxide dismutase,catalase and glutathione peroxidase in NASH model.Moreover,SPE declined the level of fibrosis markers including hydroxyproline,type I collagen andα-smooth muscle actin(α-SMA)in HFD combined CCl_4-induced mice.Mechanically,SPE inhibited hepatocellular Kelch like ECH associated protein 1 expression and promoted nuclear erythroid 2-related factor 2(Nrf2)nuclear translocation,which suppressed the phosphorylation of IκBα/NF-κB.In addition,SPE down-regulated the level of transforming growth factorβ1(TGF-β1)and phosphorylation of Smad2 to mitigate fibrosis.In brief,SPE could significantly alleviate lipid accumulation,oxidative stress,inflammation and fibrosis via regulating Nrf2/HO-1,IκBα/NF-κB and TGF-β1/Smad2 pathways in the progression of NASH,which indicated that SPE had the potential to be a novel and effective drug or food supplements for the improvement of NASH.展开更多
Coronavirus disease 2019(COVID-19)is a multi-system disease that can lead to various severe complications.Acute limb ischemia(ALI)has been increasingly recognized as a COVID-19-associated complication that often predi...Coronavirus disease 2019(COVID-19)is a multi-system disease that can lead to various severe complications.Acute limb ischemia(ALI)has been increasingly recognized as a COVID-19-associated complication that often predicts a poor prognosis.However,the pathophysiology and molecular mechanisms underlying COVID-19-associated ALI remain poorly understood.Hypercoagulability and thrombosis are considered important mechanisms,but we also emphasize the roles of vasospasm,hypoxia,and acidosis in the pathogenesis of the disease.The angiotensin-converting enzyme 2(ACE2)pathway,inflammation,and platelet activation may be important molecular mechanisms underlying these pathological changes induced by COVID-19.Furthermore,we discuss the hypotheses of risk factors for COVID-19-associated ALI from genetic,age,and gender perspectives based on our analysis of molecular mechanisms.Additionally,we summarize therapeutic approaches such as use of the interleukin-6(IL-6)blocker tocilizumab,calcium channel blockers,and angiotensin-converting enzyme inhibitors,providing insights for the future treatment of coronavirus-associated limb ischemic diseases.展开更多
BACKGROUND Diabetic retinopathy(DR)is a major microvascular complication of diabetes mellitus,leading to significant visual impairment and blindness among adults.Current treatment options are limited,making it essenti...BACKGROUND Diabetic retinopathy(DR)is a major microvascular complication of diabetes mellitus,leading to significant visual impairment and blindness among adults.Current treatment options are limited,making it essential to explore novel therapeutic strategies.Curcumol,a sesquiterpenoid derived from traditional Chinese medicine,has shown anti-inflammatory and anti-cancer properties,but its potential role in DR remains unclear.AIM To investigate the therapeutic effects of curcumol on the progression of DR and to elucidate the underlying molecular mechanisms,particularly its impact on the fat mass and obesity-associated(FTO)protein and the long non-coding RNA(lncRNA)MAF transcription factor G antisense RNA 1(MAFG-AS1).METHODS A streptozotocin-induced mouse model of DR was established,followed by treatment with curcumol.Retinal damage and inflammation were evaluated through histological analysis and molecular assays.Human retinal vascular endothelial cells were exposed to high glucose conditions to simulate diabetic environments in vitro.Cell proliferation,migration,and inflammation markers were assessed in curcumoltreated cells.LncRNA microarray analysis identified key molecules regulated by curcumol,and further experiments were conducted to confirm the involvement of FTO and MAFG-AS1 in the progression of DR.RESULTS Curcumol treatment significantly reduced blood glucose levels and alleviated retinal damage in streptozotocininduced DR mouse models.In high-glucose-treated human retinal vascular endothelial cells,curcumol inhibited cell proliferation,migration,and inflammatory responses.LncRNA microarray analysis identified MAFG-AS1 as the most upregulated lncRNA following curcumol treatment.Mechanistically,FTO demethylated MAFG-AS1,stabilizing its expression.Rescue experiments demonstrated that the protective effects of curcumol against DR were mediated through the FTO/MAFG-AS1 signaling pathway.CONCLUSION Curcumol ameliorates the progression of DR by modulating the FTO/MAFG-AS1 axis,providing a novel therapeutic pathway for the treatment of DR.These findings suggest that curcumol-based therapies could offer a promising alternative for managing this debilitating complication of diabetes.展开更多
Background:VPS37A(VPS37A subunit of ESCRT-I),a component of the ESCRT-I(endosomal sorting complex required for transport I)complex,mediates vesicular trafficking through sorting endocytic ubiquitinated cargos into mul...Background:VPS37A(VPS37A subunit of ESCRT-I),a component of the ESCRT-I(endosomal sorting complex required for transport I)complex,mediates vesicular trafficking through sorting endocytic ubiquitinated cargos into multivesicular bodies(MVBs).Although accumulating evidence indicates that VPS37A deficiency occurs in numerous malignancies and exerts tumor-suppressive effects during cancer progression,its functional significance in colorectal cancer(CRC)pathogenesis remains poorly characterized.Therefore,this study aims to further investigate the functional and molecular mechanisms by which VPS37A downregulation contributes to malignant biological phenotypes in CRC,with a specific focus on how its dysregulation affects cell death pathways.Methods:Multi-omics analysis of TCGA,GEO,and CPTAC cohorts identified VPS37A as a downregulated tumor suppressor gene in CRC.The prognostic relevance of VPS37A was validated in two clinical cohorts(Cohorts 1 and 2)using immunohistochemistry.Functional assays in VPS37A-overexpressing CRC cells and xenografts assessed proliferation,cell cycle progression,and stress-induced cell death.RNA sequencing,nuclear factor kappa-B(NF-κB)luciferase reporter assays,and lysosomal inhibition experiments elucidated the mechanisms underlying tumor necrosis factor receptor 1(TNFR1)degradation.Results:VPS37A is significantly downregulated in advanced-stage CRC and independently predicts poor survival.Functionally,VPS37A overexpression suppresses proliferation and induces G2/M arrest in vitro,while reducing xenograft growth.Under metabolic stress(glucose deprivation/galactose adaptation),VPS37A triggers cell death via apoptosis,necroptosis,and ferroptosis.Mechanistically,VPS37A redirects TNFR1 to lysosomal degradation,suppressing NF-κB nuclear translocation and transcriptional activity.Conclusion:VPS37A deficiency drives CRC progression by sustaining TNFR1/NF-κB signaling under metabolic stress.Restoring VPS37A activity promotes TNFR1 degradation,offering a therapeutic strategy to counteract NF-κB-mediated treatment resistance in CRC.展开更多
A broad spectrum of liver disorders and their associated complications most notably hepatic encephalopathy impact millions of individuals worldwide,including conditions such as non-alcoholic fatty liver disease,alcoho...A broad spectrum of liver disorders and their associated complications most notably hepatic encephalopathy impact millions of individuals worldwide,including conditions such as non-alcoholic fatty liver disease,alcoholic liver injury,viral hepatitis,hepatic fibrosis,cirrhosis,and hepatocellular carcinoma.The underlying pathogenic mechanisms are multifactorial,encompassing oxidative stress,inflammatory cascades,mitochondrial impairment,and disturbances in immune homeostasis.Hepatic encephalopathy patients experience cognitive impairment,mood disturbances,and psychomotor dysfunction,significantly reducing quality of life through mechanisms including oxidative stress,neuroinflammation,and neurotransmitter imbalances.The nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)signaling pathway serves as a critical antioxidative defense mechanism in these conditions.Nrf2 regulates the expression of protective enzymes,while HO-1 exerts anti-inflammatory,anti-apoptotic,and antifibrotic effects through heme degradation products.Natural herbal monomers as Nrf2 activators offer advantages of low toxicity,multi-target actions,and extensive traditional use.Various herbal monomers demonstrate specific effects against different liver diseases:In fatty liver,baicalin alleviates lipid accumulation and inflammation;In alcoholic liver disease,curcumin enhances Nrf2 activity reducing oxidative damage;In drug-induced liver injury,dihydromyricetin mitigates oxidative stress;In viral hepatitis,andrographolide inhibits hepatitis C virus replication;In liver fibrosis,multiple compounds inhibit stellate cell activation.These natural compounds simultaneously alleviate hepatic dysfunction and neuropsychiatric symptoms by modulating the Nrf2/HO-1 pathway,though clinical application still faces challenges such as low bioavailability,requiring further research.展开更多
Objectives:Ovarian cancer(OC)is a highly heterogeneous disease characterized by high metastatic potential and frequent recurrence.3β-hydroxysterolΔ24-reductase(DHCR24)is closely associated with the progression of va...Objectives:Ovarian cancer(OC)is a highly heterogeneous disease characterized by high metastatic potential and frequent recurrence.3β-hydroxysterolΔ24-reductase(DHCR24)is closely associated with the progression of various malignant tumors,but its role in OC remains unexplored.This study is the first to systematically investigate the function of DHCR24 in OC and elucidate its mechanism in promoting OC progression,providing novel theoretical insights for targeted therapy.Methods:The expression of DHCR24 was evaluated in tissues using bioinformatics and clinical data;the impact of DHCR24 on the malignant behavior of OC was assessed through in vivo and in vitro experiments;and the mechanism by which DHCR24 functions in OC was preliminarily explored using sequencing and rescue experiments.Statistical analysis was conducted using the chi-square test,t-test,and oneway ANOVA.Results:Database,clinical data,and immunohistochemical(IHC)analyses demonstrated that DHCR24 is upregulated in OC and correlates with poor outcomes.In vitro experiments indicated that DHCR24 promotes proliferation,migration,invasion,and epithelial-mesenchymal transition in OC cells.The addition of a DHCR24 inhibitor suppressed the malignant behavior of OC cells.The nude mouse tumor formation experiment demonstrated that inhibiting DHCR24 suppresses the in vivo growth of OC cells.Further experiments showed that DHCR24 promotes the malignant behavior of OC cells,correlating with the regulation of the transforming growth factor beta(TGF-β)signaling pathway.All the above experiments showed statistical significance.Conclusion:DHCR24 contributes to ovarian cancer progression by upregulating the TGF-β1 pathway,highlighting its potential as a therapeutic target in ovarian cancer.展开更多
BACKGROUND Bletilla striata polysaccharides(BSP)have antioxidant,immune regulation,and anti-fibrotic activities.However,the therapeutic effect and mechanisms underlying the action of BSP in metabolic dysfunction-assoc...BACKGROUND Bletilla striata polysaccharides(BSP)have antioxidant,immune regulation,and anti-fibrotic activities.However,the therapeutic effect and mechanisms underlying the action of BSP in metabolic dysfunction-associated steatotic liver disease(MASLD)have not been fully understood.AIMTo investigate the therapeutic effects and mechanisms of BSP on MASLD by centering on the hepatocyte nuclearfactor kappa B p65(RelA)/hepatocyte nuclear factor-1 alpha(HNF1α)signaling.METHODSA mouse model of MASLD was induced by feeding with a high-fat-diet(HFD)and a hepatocyte model of steatosiswas induced by treatment with sodium oleate(SO)and sodium palmitate(SP).The therapeutic effects of BSP onMASLD were examined in vivo and in vitro.The mechanisms underlying the action of BSP were analyzed for theireffect on lipid metabolism disorder,endoplasmic reticulum(ER)stress,and the RelA/HNF1αsignaling.RESULTSHFD feeding reduced hepatocyte RelA and HNF1αexpression,induced ER stress,lipid metabolism disorder,andnecroptosis in mice,which were significantly mitigated by treatment with BSP.Furthermore,treatment with BSP orBSP-containing conditional rat serum significantly attenuated the sodium oleate/sodium palmitate(SO/SP)-induced hepatocyte steatosis by decreasing lipid accumulation,and lipid peroxidation,and enhancing theexpression of RelA,and HNF1α.The therapeutic effects of BSP on MASLD were partially abrogated by RELAsilencing in mice and RELA knockout in hepatocytes.RELA silencing or knockout significantly down-regulatedHNF1αexpression,and remodeled ER stress and oxidative stress responses during hepatic steatosis.CONCLUSIONTreatment with BSP ameliorates MASLD,associated with enhancing the RelA/HNF1αsignaling,remodeling ERstress and oxidative stress responses in hepatocytes.展开更多
基金Supported by the Guangxi Natural Science Foundation“Controllable Synthesis of Ordered Mesoporous Seafoam-Loaded g-C3N4 Gomposites and Their Mechanism of Adsorption-Photocatalytic Degradation of Antidepressants in Water Bodies”(2017GXNSFBA198216)the Open Fund for the Director of Guangxi Key Laboratory of Spatial Information and Geographic Information“Geographic Spatial Analysis of Regional Urinary Tract Stone Disease”(19-185-10-04)。
文摘OBJECTIVE:To evaluate the effect of Fuzi Lizhong decoction(附子理中汤)on intestinal flora,serum inflammatory factors,and hypoxia inducible factor-1α(HIF-1α)in patients with colorectal cancer associated with spleen and kidney Yang deficiency.METHODS:A total of 100 patients diagnosed with advanced colorectal cancer were randomly divided into two groups:a control group(CON,50)and a Traditional Chinese Medicine(TCM)group(n=50).The control group received treatment with the Capecitabine+Oxaliplatin(CAPEOX)regimen,while the TCM group received the same regimen along with Fuzi Lizhong decoction for six weeks.Changes in intestinal flora were assessed before and after six weeks in both groups.Serum markers,including HIF-1α,vascular endothelial growth factor(VEGF),interleukin-6(IL-6),and tumor necrosis factor-alpha(TNF-α),were measured using enzyme-linked immunosorbent assay.Adverse reactions,clinical efficacy,and TCM syndrome efficacy were also monitored.RESULTS:After six weeks,the levels of Lactobacillus and Bifidobacterium were significantly higher,while the levels of Enterobacter and Enterococcus were significantly lower in the TCM group compared to the control group(P<0.05).Serum levels of HIF-1α,VEGF,IL-6,and TNF-αwere also significantly reduced in the TCM group compared to the control group(P<0.05).Additionally,the incidence of adverse reactions was lower,and the clinical efficacy was higher in the TCM group compared to the control group(P<0.05).CONCLUSION:Fuzi Lizhong decoction effectively improves intestinal microbiota composition,reduces inflammatory factors and HIF-1αexpression,alleviates chemotherapy-related adverse reactions,enhances clinical efficacy,and may inhibit tumor growth in patients with colorectal cancer.
基金supported by the Science&Technology Department of Sichuan Province(No.2019YFS0040)the Improvement Plan of“Xinglin Scholar”Scientific Research Talent,Chengdu University of Traditional Chinese Medicine(No.XKTD2022002)。
文摘The activation of the sirtuin1(SIRT1)/nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase 1(HO-1)pathway has been shown to mitigate oxidative stress-induced apoptosis and mitochondrial damage by reducing reactive oxygen species(ROS)levels.Clinical trials have demonstrated that Zhongfeng Xingnao Liquid(ZFXN)ameliorates post-stroke cognitive impairment(PSCI).However,the underlying mechanism,particularly whether it involves protecting mitochondria and inhibiting apoptosis through the SIRT1/Nrf2/HO-1 pathway,remains unclear.This study employed an oxygen-glucose deprivation(OGD)cell model using SHSY5Y cells and induced PSCI in rats through modified bilateral carotid artery ligation(2VO).The effects of ZFXN on learning and memory,neuroprotective activity,mitochondrial function,oxidative stress,and the SIRT1/Nrf2/HO-1 pathway were evaluated both in vivo and in vitro.Results indicated that ZFXN significantly increased the B-cell lymphoma 2(Bcl2)/Bcl2-associated X(Bax)ratio,reduced terminal deoxynucleotidyl transferase-mediated d UTP nickend-labeling(TUNEL)+cells,and markedly improved cognition,synaptic plasticity,and neuronal function in the hippocampus and cortex.Furthermore,ZFXN exhibited potent antioxidant activity,evidenced by decreased ROS and malondialdehyde(MDA)content and increased superoxide dismutase(SOD),catalase(CAT),and glutathione(GSH)levels.ZFXN also demonstrated considerable enhancement of mitochondrial membrane potential(MMP),Tom 20 fluorescence intensity,adenosine triphosphate(ATP)and energy charge(EC)levels,and mitochondrial complexⅠandⅢactivity,thereby inhibiting mitochondrial damage.Additionally,ZFXN significantly increased SIRT1 activity and elevated SIRT1,nuclear Nrf2,and HO-1 levels.Notably,these effects were substantially counteracted when SIRT1 was suppressed by the inhibitor EX-527 in vitro.In conclusion,ZFXN alleviates PSCI by activating the SIRT1/Nrf2/HO-1 pathway and preventing mitochondrial damage.
基金supported by grants from the National Key Research and Development Program of China(2020YFA0803900)the National Natural Science Foundation of China(U23A20407,82414020,81703631)the Hubei Provincial Natural Science Foundation of China(2024AFB742)。
文摘Prenatal caffeine exposure(PCE)leads to intrauterine growth retardation and altered glucose homeostasis after birth,but the underlying mechanism remains unclear.This study aims to investigate the alteration of pancreatic development and insulin biosynthesis in the PCE female offspring and explore the intrauterine programming mechanism.Pregnant rats were orally treated with 120 mg/(kg·day)of caffeine from gestational day(GD)9 to 20.Results showed that fetal pancreaticβ-cells in the PCE group exhibited reduced mass and impaired insulin synthesis function,as evidenced by decreased expression of developmental and functional genes and reduced pancreatic insulin content.At postnatal week(PW)12,the PCE offspring exhibited glucose intolerance,diminishedβ-cell mass,and lower blood insulin levels.However,by PW28,glucose tolerance showed some improvement.Both in vivo and in vitro findings collectively indicated that excessive serum corticosterone(CORT)levels of the PCE fetuses may act through the activation of the pancreatic glucocorticoid receptor(GR)and recruitment of histone deacetylase 9(HDAC9),leading to H3K9 deacetylation in promoter and downregulation of insulin-like growth factor 1(IGF1),thereby inhibiting pancreatic islet morphogenesis and insulin synthesis in fetal rats.Furthermore,the PCE offspring after birth exhibited decreased blood CORT levels,increased H3K9 acetylation in promoter and upregulated gene expression of the pancreatic IGF1 promoter region,accompanied by elevated insulin biosynthesis.However,when exposed to chronic stress,the above changes were totally reversed.Conclusively,“glucocorticoid-insulin like growth factor 1(GC-IGF1)axis”programming may be involved in pancreaticβ-cell dysplasia and dysfunction in the PCE female offspring.
基金supported by Natural Science Foundation Project of Ningxia Hui Autonomous Region(No.2021AAC03327)Hunan Provincial Natural Science Foundation(No.2021JJ31058)+2 种基金Shanghai Pujiang Program(No.23PJ1403300)Shanghai Science and Technology Commission(No.23ZR1440700)National Natural Science Foundation of China(No.82000797,82102244,31971077,and 82070255)。
文摘Objective:Baicalein has been reported to have wide therapeutic effects that act through its antiinflammatory activity.This study examines the effect and mechanism of baicalein on sepsis-induced cardiomyopathy(SIC).Methods:A thorough screening of a small library of natural products,comprising 100 diverse compounds,was conducted to identify the most effective drug against lipopolysaccharide(LPS)-treated H9C2 cardiomyocytes.The core target proteins and their associated signaling pathways involved in baicalein's efficacy against LPS-induced myocardial injury were predicted by network pharmacology.Results:Baicalein was identified as the most potent protective agent in LPS-exposed H9C2 cardiomyocytes.It exhibited a dose-dependent inhibitory effect on cell injury and inflammation.In the LPSinduced septic mouse model,baicalein demonstrated a significant capacity to mitigate LPS-triggered myocardial deficits,inflammatory responses,and ferroptosis.Network pharmacological analysis and experimental confirmation suggested that hypoxia-inducible factor 1 subunit a(HIF1-a)is likely to be the crucial factor in mediating the impact of baicalein against LPS-induced myocardial ferroptosis and injury.By combining microRNA(miRNA)screening in LPS-treated myocardium with miRNA prediction targeting HIF1-a,we found that miR-299b-5p may serve as a regulator of HIF1-a.The reduction in miR-299b-5p levels in LPS-treated myocardium,compared to the control group,was reversed by baicalein treatment.The reverse transcription quantitative polymerase chain reaction,Western blotting,and dual-luciferase reporter gene analyses together identified HIF1-a as the target of miR-299b-5p in cardiomyocytes.Conclusion:Baicalein mitigates SIC at the miRNA level,suggesting the therapeutic potential of it in treating SIC through the regulation of miR-299b-5p/HIF1-a/ferroptosis pathway.
文摘BACKGROUND Esophageal squamous-cell carcinoma(ESCC)is a highly aggressive cancer,predominantly affecting populations in Eastern Asia and parts of Africa.Its pathogenesis is influenced by both genetic and environmental factors.Despite recent therapeutic advances,survival rates remain dismal,underscoring an urgent need for novel therapeutic targets.AIM To investigate the role of hypoxia-inducible factor 1-alpha(HIF1A)in the progression of ESCC and its impact on the metabolic enzyme lactate dehydrogenase A(LDHA),which is crucial for the glycolytic pathway in hypoxic tumor environments.METHODS Utilizing transcriptomic data from multiple public databases,we analyzed differential gene expression and conducted gene ontology and transcription factor network analyses.The regulatory impact of HIF1A on LDHA was specifically examined through integrative analysis with HIF1A ChIP-seq data and confirmed via siRNA-mediated knockdown experiments in ESCC cell lines.RESULTS Our findings reveal a significant upregulation of HIF1A in ESCC tissues,associated with poor prognosis.HIF1A directly regulates LDHA,enhancing glycolysis under hypoxic conditions and contributing to tumor aggressiveness.Knockdown of HIF1A in cell lines not only reduced LDHA expression but also altered key pathways related to cell cycle and apoptosis.CONCLUSION The critical role of the HIF1A-LDHA axis in ESCC highlights its potential as a therapeutic target,underscoring the need for future clinical trials to validate the efficacy of HIF1A inhibitors in enhancing treatment outcomes.
文摘BACKGROUND Diabetes is characterized by insulin resistance as well as impaired insulin production,withβ-cell dysfunction playing a critical role in disease progression.Exercise is known to improve insulin sensitivity,but its effects on pancreatic islet quality and function remain poorly understood.This work hypothesized that swimming training enhances glycemic control and insulin secretion by upregulating the insulin-like growth factor 1(IGF-1)/phosphatidylinositol 3-kinase/protein kinase B(PI3K/AKT)pathway in streptozotocin(STZ)-induced diabetic rats.AIM To investigate the effects of swimming on pancreatic islet quality and function in STZ-induced diabetic rats via the IGF-1/PI3K/AKT pathway.METHODS Twenty-six Sprague-Dawley rats were grouped into diabetic and control groups,with each group further split into exercise and sedentary subgroups.Diabetic rats were induced with STZ.The exercise groups underwent swimming training for 60 minutes/day,5 days/week,for 8 weeks.Body weight,food intake,blood glucose,insulin,lipids,and muscle glycogen were measured.Pancreatic islet morphology and the protein expression levels of IGF-1,PI3K,and AKT were analyzed.Data were analyzed using two-way repeated-measure ANOVA,followed by Tukey’s post-hoc test.RESULTS Exercise training significantly improved body weight[diabetic exercise group(D-Ex):390.66±50.14 g vs diabetic sedentary group(D-Sed):315.89±50.12 g,P<0.05],reduced blood glucose(D-Ex:12.21±4.43 mmol/L vs D-Sed:17.79±2.05 mmol/L,P<0.05),and increased insulin levels(D-Ex:53.50±15.31 pmol/L vs D-Sed:25.31±10.23 pmol/L,P<0.05)in diabetic rats.It also enhanced islet morphology,increased IGF-1 expression,and activated the PI3K/AKT pathway(P<0.05).In-vitro experiments confirmed that IGF-1 positively regulated insulin expression and inhibitedβ-cell apoptosis via the PI3K/AKT pathway.CONCLUSION Exercise training improves pancreatic islet quality and function in diabetic rats by modulating the IGF-1/PI3K/AKT pathway,highlighting its therapeutic potential for diabetes management.
文摘High expression of pescadillo ribosomal biogenesis factor 1(PES1)has been re-ported across multiple cancer types and is significantly associated with poor prog-nosis.Hu et al in their recent paper described their investigation of PES1 in gastric cancer and head and neck squamous cell carcinoma,demonstrating positive cor-relations between PES1 and programmed death-ligand 1(PD-L1)expression(51.72%for PES1 and 58.62%for PD-L1),as well as associations with lymph node metastasis and tumor invasion depth.However,the relationship between PES1 and PD-L1 remains incompletely defined.To further address this gap,we ana-lyzed The Cancer Genome Atlas gastric adenocarcinoma dataset and found a negative correlation between PES1 expression and CD8+T cell infiltration,along-side a positive correlation with PD-L1 expression.Based on prior findings,we hypothesize that PES1 may regulate PD-L1 through the phosphatidylinositol 3-kinase/protein kinase B pathway or cellular Myc-mediated mechanisms.While these pathways require experimental validation,our observations highlight PES1 as a potential regulator of immune evasion and a promising target for cancer immunotherapy.
文摘BACKGROUND Gastric cancer(GC)and head and neck squamous cell carcinoma(HNSCC)are common malignancies with high morbidity and mortality rates.Traditional treatments often yield limited efficacy,especially in advanced cases.Recent advancements in immunotherapy,particularly immune checkpoint inhibitors targeting programmed death-ligand 1(PD-L1),have shown promise.However,the expression and interaction of pescadillo ribosomal biogenesis factor 1(PES1)and PD-L1 in these cancers remain unclear.Understanding their roles could provide new insights into tumor biology and improve therapeutic strategies.AIM To investigate the expression levels of PES1 and PD-L1 in tumor tissues of patients with GC and HNSCC.METHODS A total of 58 cases of GC and HNSCC undergoing surgical resection were selected from January 2022 to January 2024.Paraffin specimens of GC and HNSCC tissues were taken from the patients,and the sections were subjected to staining with immunohistochemistry and hematoxylin-eosin staining,and the protein expression of PES1 and PD-L1 was observed microscopically.RESULTS Among 58 GC and HNSCC tissues,30 cases were positive and 28 cases were negative for PES1 expression,and 34 cases were positive and 24 cases were negative for PD-L1 expression.The positive expression rates of PES1 and PDL1 were 51.72% and 58.62%,respectively.PES1 expression was correlated with the TNM stage,lymph node metastasis,and the depth of infiltration(P<0.05),and PD-L1 expression was correlated with the differentiation degree,lymph node metastasis,and infiltration depth(P<0.05).CONCLUSION PES1 and PD-L1 were positively expressed in GC and HNSCC tissues and correlated with clinical features.They may serve as potential biomarkers for immune-targeted therapies.
基金supported by the National Natural Science Founda-tion of China(82370417,82330011,and U21A20339)the Science Fund for Distinguished Young Scholars of Heilongjiang Province(JQ2024H001)the Heilongjiang Provincial Postdoctoral Science Foundation(LBH-Z23212).
文摘Myocardial infarction(MI)is characterized by focal necrosis resulting from prolonged myocardial ischemia due to coronary artery obstruction.Vascular reconstruction following MI is crucial for improving cardiac function and preventing recurrent infarction.This study investigates the interaction between macrophages and endothelial cells in angiogenesis mediated by nicotinamide mononucleotide(NMN)-induced secretion of macrophage-derived exosomes.We focus on the role of U2 small nuclear RNA auxiliary factor 1(U2af1)gene,a member of the splicing factor serine and arginine(SR)gene family,in the regulation of angiogenesis.Through cardiac ultrasound,Masson staining,2,3,5-triphenyltetrazolium chloride(TTC)staining,Microfil vascular perfusion,and platelet and endothelial cell adhesion molecule 1(CD31)immunofluorescence staining,extracellular vesicles from NMN-stimulated macrophages were shown to exert a protective effect in MI,with proteomic analysis identifying U2AF1 as a candidate protein involved in MI protection.Plasma U2AF1 levels were measured in 70 MI patients,revealing significantly lower levels in individuals with poor coronary collateral vessel(CCV;Rentrop scores 0–1)than in those with good CCV(Rentrop scores 2–3).In both myocardial and hindlimb ischemia mouse models,overexpression of endothelial cell-specific adenoviral overexpression U2AF1 promoted angiogenesis in the heart and hindlimbs and improved cardiac function after MI.Mechanistic studies demonstrated that U2AF1 regulates the alternative splicing(AS)of Yes1-associated transcriptional regulator(Yap1)gene,influencing post-MI angiogenesis and cardiac function recovery.Collectively,our clinical findings suggest that U2AF1 may serve as a therapeutic target for coronary collateral angiogenesis following MI.Given the low immunogenicity and high biosafety of exosomes,this study provides a foundational basis and translational potential for exosome-based therapies in MI treatment.
基金supported by Natural Science Foundation of Hunan Province of China(project No.2022JJ40413)Outstanding Youth Project of Hunan Provincial Department of Education(project No.22B0814)+1 种基金Regional Consolidated Foundation ofHunan Province of China(project No.2023JJ50065)Natural Science Foundation of Hunan Province of China(project No.2023JJ50412).
文摘Background:Expression of mRNA is widely regulated by N6-methyladenosine(m6A).An increasing number of studies have shown that m6A methylation,facilitated by methyltransferase 3(METTL3),is crucial in the progression of tumors.Previous reports have indicated the involvement of both METTL3 and c-Src kinase in the evolution of liver cancer.However,the potential connection between c-Src and the METTL3-mediated mechanism in liver cancer progression remains elusive.Methods:The correlation expression between c-Src and METTL3 between liver cancer patients and the control group was analyzed using the TCGA database,and was further demonstrated by Western blot and RT-qPCR.The functional roles of c-Src in METTL3-regulated liver cancer progression were investigated by cell proliferation assays and colony formation assays.The regulatory mechanism of METTL3 in c-Src expression was accessed by RNA-immunoprecipitation(RIP)-qPCR.Results:We demonstrated that c-Src kinase promoted liver cancer development,and the expression of SRC(encodes c-Src kinase)was positively correlated with METTL3 in liver cancer cases.We showed that SRC mRNA could be m6A-modified,and METTL3 regulated the transcription of SRC mRNA through interferon regulatory factor 1(IRF1).We revealed that IRF1,the expression of which was positively regulated byMETTL3,was a novel transcription factor of c-Src.Lastly,The pro-proliferative effect of METTL3 on hepatocellular carcinoma was mechanistically linked to IRF1/c-Src axis activation,as evidenced by our experimental data.Conclusion:Results suggested that the METTL3/IRF1/c-Src axis played potential oncogenic roles in liver cancer development and the axis may be a promising therapeutic target in the disease.
基金supported by grants from the Shenzhen Basic Research Project(JCYJ20210324125803008)the Shenzhen Longhua District Science and Innovation Bureau Fund for Medical Institutions(2022143).
文摘Background:Clear cell renal carcinoma(ccRCC),the leading histological subtype of RCC,lacks any targeted therapy options.Although some studies have shown that early growth response factor 1(EGR1)has a significant role in cancer development and progression,its role and underlying mechanisms in ccRCC remain poorly understood.Methods:The Cancer Genome Atlas(TCGA)database was utilized to examine the expression of EGR1 in ccRCC.The expression of EGR1 in 55 ccRCC tissues was evaluated using immunohistochemistry.The link between EGR1 expression and clinicopathological variables was examined through an analysis.Gain-of-function assays were employed to investigate EGR1’s biological functions in ccRCC cells,involving proliferation,colony formation,invasion assays,and tumorigenesis in nude mice.In order to assess the protein expression of mitogen-activated protein kinase 15(MAPK15),E-cadherin,matrix metalloproteinase-9/-2(MMP-9 and MMP-2),Western blot technique was applied.Results:The results revealed a decrease in EGR1 expression in ccRCC tissues.This decrease was strongly linked to TNM stage,lymphatic metastasis,tumor size,histological grade,and unfavorable prognosis in ccRCC patients.It has been demonstrated that overexpressing EGR1 inhibits the growth of xenograft tumors in vivo and inhibits cell colony formation,motility,and invasion in vitro.Furthermore,EGR1 can prevent the development and movement of ccRCC cells by controlling the expression of MMP-2,MMP-9,E-cadherin,and MAPK15.Conclusions:The EGR1/MAPK15 axis may represent a promising target for drug development,with EGR1 serving as a possible target for ccRCC therapy.
基金Supported by Science and Technology Innovation Project of China Academy of Chinese Medical Sciences of Study on the Mechanism of Qufeng Jiejing Formula in Regulating Mitogen-activated Protein Kinase Signaling Pathway to Inhibit Phenotypic Transformation of Airway Smooth Muscle Cells in Asthma(No.CI2021A01108)Cultivation Project of The National Natural Science Foundation of China of Xiyuan Hospital,China Academy of Chinese Medical Sciences of Research on the Role of Traditional Chinese Medicines-Qufeng Jiejing in the Proliferation,Migration and Phenotypic Transformation of Airway Smooth Muscle Cells in Asthma(No.XY20-17)。
文摘OBJECTIVE:To explore the role and mechanism of Qufeng Jiejing(祛风解痉,QFJJ)formula in the asthma progression.METHODS:The Bagg Albino/c mice treated with Ovalbumin and AL(OH)3,and airway smooth muscle cells(ASMCs)treated with platelet-derived growth factor(PDGF)-BB to establish a asthma model in vivo and in vitro.The cell morphology was observed with microscope and immunofluorescence staining.The cell viability was assessed with methyl thiazolyl tetrazolium assay.The tumor necrosis factor-αlpha(TNF-α),interleukin-1beta(IL-1β),laminin,fibronectin and collagen IV levels in the ASMCs were detected with corresponding enzyme linked immunosorbent assay kits.Transwell and wound healing assays were conducted to test the cell migration.The TGF-β1,Smad2 and Smad3 levels were measured with Western blot.RESULTS:We found that QFJJ formula treatment dramatically decreased the cell viability,TNF-α,IL-1β,laminin,fibronectin and collagen IV levels in the PDGFBB stimulated ASMCs.Additionally,the protein levels of TGF-β1,Smad2 and Smad3 in the PDGF-BB stimulated ASMCs were prominently depleted after QFJJ formula treatment.Besides,SRI treatment neutralized the role of QFJJ formula in the PDGF-BB stimulated ASMCs.CONCLUSION:QFJJ formula effectively relieved the asthma progression through ameliorate the ASMCs function,which was achieved through suppressing the TGF-β1/Smads signaling pathway.
基金Supported by Natural Science Foundation of Guangdong Province,No.2022A1515012346.
文摘BACKGROUND Diabetic macular edema(DME)is the most common cause of vision loss in people with diabetes.Tight junction disruption of the retinal pigment epithelium(RPE)cells has been reported to induce DME development.SMAD-specific E3 ubiquitin protein ligase(SMURF)1 was associated with the tight junctions of cells.However,the mechanism of SMURF1 in the DME process remains unclear.AIM To investigate the role of SMURF1 in RPE cell tight junction during DME.METHODS ARPE-19 cells treated with high glucose(HG)and desferrioxamine mesylate(DFX)for establishment of the DME cell model.DME mice models were constructed by streptozotocin induction.The trans-epithelial electrical resistance and permeability of RPE cells were analyzed.The expressions of tight junction-related and autophagy-related proteins were determined.The interaction between insulin like growth factor 2 mRNA binding protein 2(IGF2BP2)and SMURF1 mRNA was verified by RNA immunoprecipitation(RIP).SMURF1 N6-methyladenosine(m6A)level was detected by methylated RIP.RESULTS SMURF1 and vascular endothelial growth factor(VEGF)were upregulated in DME.SMURF1 knockdown reduced HG/DFX-induced autophagy,which protected RPE cell tight junctions and ameliorated retinal damage in DME mice.SMURF1 activated the Wnt/β-catenin-VEGF signaling pathway by promoting WNT inhibitory factor(WIF)1 ubiquitination and degradation.IGF2BP2 upregulated SMURF1 expression in an m6A modification-dependent manner.CONCLUSION M6A-modified SMURF1 promoted WIF1 ubiquitination and degradation,which activated autophagy to inhibit RPE cell tight junctions,ultimately promoting DME progression.
基金supported by grants from the National Natural Science Foundation of China(U1804175,32270418)the Joint Fund of Provincial Science and Technology Research and Development plan of Henan Province(232103810055,232301420100)。
文摘The flower of Syringa pubescens Turcz.(SP),was used as both medicine and food in China,exhibited various biological activities.However,it remains unknown whether SP affects ameliorative nonalcoholic steatohepatitis(NASH).In this study,the improvement of SP ethyl acetate extract(SPE)on NASH was evaluated and the potential mechanisms were explored.The glycosides of SPE were determined by HPLC method.Hep G2 cell lines were treated with free fatty acid to clarify the improvement effect and mechanisms of SPE on NASH in vitro.C57BL/6J mice were treated by 60%kcal high-fat diet(HFD)combined with carbon tetrachloride(CCl_4)to establish the NASH model in vivo.The results showed SPE could inhibit the hepatic injury and lipid steatosis by decreasing the levels of alanine aminotransferase,aspartate aminotransferase,triglyceride and total cholesterol in vitro and in vivo.The SPE suppressed the oxidative stress and inflammation by restraining the generation of reactive oxygen species,malondialdehyde,interleukin(IL)-1β,IL-6 and tumor necrosis factor-α(TNF-α)and enhancing the activity of antioxidant enzymes including superoxide dismutase,catalase and glutathione peroxidase in NASH model.Moreover,SPE declined the level of fibrosis markers including hydroxyproline,type I collagen andα-smooth muscle actin(α-SMA)in HFD combined CCl_4-induced mice.Mechanically,SPE inhibited hepatocellular Kelch like ECH associated protein 1 expression and promoted nuclear erythroid 2-related factor 2(Nrf2)nuclear translocation,which suppressed the phosphorylation of IκBα/NF-κB.In addition,SPE down-regulated the level of transforming growth factorβ1(TGF-β1)and phosphorylation of Smad2 to mitigate fibrosis.In brief,SPE could significantly alleviate lipid accumulation,oxidative stress,inflammation and fibrosis via regulating Nrf2/HO-1,IκBα/NF-κB and TGF-β1/Smad2 pathways in the progression of NASH,which indicated that SPE had the potential to be a novel and effective drug or food supplements for the improvement of NASH.
基金supported by the Zhejiang Provincial Medical Scientific Research Program(No.2022RC136),China.
文摘Coronavirus disease 2019(COVID-19)is a multi-system disease that can lead to various severe complications.Acute limb ischemia(ALI)has been increasingly recognized as a COVID-19-associated complication that often predicts a poor prognosis.However,the pathophysiology and molecular mechanisms underlying COVID-19-associated ALI remain poorly understood.Hypercoagulability and thrombosis are considered important mechanisms,but we also emphasize the roles of vasospasm,hypoxia,and acidosis in the pathogenesis of the disease.The angiotensin-converting enzyme 2(ACE2)pathway,inflammation,and platelet activation may be important molecular mechanisms underlying these pathological changes induced by COVID-19.Furthermore,we discuss the hypotheses of risk factors for COVID-19-associated ALI from genetic,age,and gender perspectives based on our analysis of molecular mechanisms.Additionally,we summarize therapeutic approaches such as use of the interleukin-6(IL-6)blocker tocilizumab,calcium channel blockers,and angiotensin-converting enzyme inhibitors,providing insights for the future treatment of coronavirus-associated limb ischemic diseases.
文摘BACKGROUND Diabetic retinopathy(DR)is a major microvascular complication of diabetes mellitus,leading to significant visual impairment and blindness among adults.Current treatment options are limited,making it essential to explore novel therapeutic strategies.Curcumol,a sesquiterpenoid derived from traditional Chinese medicine,has shown anti-inflammatory and anti-cancer properties,but its potential role in DR remains unclear.AIM To investigate the therapeutic effects of curcumol on the progression of DR and to elucidate the underlying molecular mechanisms,particularly its impact on the fat mass and obesity-associated(FTO)protein and the long non-coding RNA(lncRNA)MAF transcription factor G antisense RNA 1(MAFG-AS1).METHODS A streptozotocin-induced mouse model of DR was established,followed by treatment with curcumol.Retinal damage and inflammation were evaluated through histological analysis and molecular assays.Human retinal vascular endothelial cells were exposed to high glucose conditions to simulate diabetic environments in vitro.Cell proliferation,migration,and inflammation markers were assessed in curcumoltreated cells.LncRNA microarray analysis identified key molecules regulated by curcumol,and further experiments were conducted to confirm the involvement of FTO and MAFG-AS1 in the progression of DR.RESULTS Curcumol treatment significantly reduced blood glucose levels and alleviated retinal damage in streptozotocininduced DR mouse models.In high-glucose-treated human retinal vascular endothelial cells,curcumol inhibited cell proliferation,migration,and inflammatory responses.LncRNA microarray analysis identified MAFG-AS1 as the most upregulated lncRNA following curcumol treatment.Mechanistically,FTO demethylated MAFG-AS1,stabilizing its expression.Rescue experiments demonstrated that the protective effects of curcumol against DR were mediated through the FTO/MAFG-AS1 signaling pathway.CONCLUSION Curcumol ameliorates the progression of DR by modulating the FTO/MAFG-AS1 axis,providing a novel therapeutic pathway for the treatment of DR.These findings suggest that curcumol-based therapies could offer a promising alternative for managing this debilitating complication of diabetes.
基金funded by the National Natural Science Foundation of China(81902815,81802786)the Natural Science Foundation of Shandong Province(ZR2023MH011,ZR2019BH044,ZR2018BH025).
文摘Background:VPS37A(VPS37A subunit of ESCRT-I),a component of the ESCRT-I(endosomal sorting complex required for transport I)complex,mediates vesicular trafficking through sorting endocytic ubiquitinated cargos into multivesicular bodies(MVBs).Although accumulating evidence indicates that VPS37A deficiency occurs in numerous malignancies and exerts tumor-suppressive effects during cancer progression,its functional significance in colorectal cancer(CRC)pathogenesis remains poorly characterized.Therefore,this study aims to further investigate the functional and molecular mechanisms by which VPS37A downregulation contributes to malignant biological phenotypes in CRC,with a specific focus on how its dysregulation affects cell death pathways.Methods:Multi-omics analysis of TCGA,GEO,and CPTAC cohorts identified VPS37A as a downregulated tumor suppressor gene in CRC.The prognostic relevance of VPS37A was validated in two clinical cohorts(Cohorts 1 and 2)using immunohistochemistry.Functional assays in VPS37A-overexpressing CRC cells and xenografts assessed proliferation,cell cycle progression,and stress-induced cell death.RNA sequencing,nuclear factor kappa-B(NF-κB)luciferase reporter assays,and lysosomal inhibition experiments elucidated the mechanisms underlying tumor necrosis factor receptor 1(TNFR1)degradation.Results:VPS37A is significantly downregulated in advanced-stage CRC and independently predicts poor survival.Functionally,VPS37A overexpression suppresses proliferation and induces G2/M arrest in vitro,while reducing xenograft growth.Under metabolic stress(glucose deprivation/galactose adaptation),VPS37A triggers cell death via apoptosis,necroptosis,and ferroptosis.Mechanistically,VPS37A redirects TNFR1 to lysosomal degradation,suppressing NF-κB nuclear translocation and transcriptional activity.Conclusion:VPS37A deficiency drives CRC progression by sustaining TNFR1/NF-κB signaling under metabolic stress.Restoring VPS37A activity promotes TNFR1 degradation,offering a therapeutic strategy to counteract NF-κB-mediated treatment resistance in CRC.
文摘Objectives:Ovarian cancer(OC)is a highly heterogeneous disease characterized by high metastatic potential and frequent recurrence.3β-hydroxysterolΔ24-reductase(DHCR24)is closely associated with the progression of various malignant tumors,but its role in OC remains unexplored.This study is the first to systematically investigate the function of DHCR24 in OC and elucidate its mechanism in promoting OC progression,providing novel theoretical insights for targeted therapy.Methods:The expression of DHCR24 was evaluated in tissues using bioinformatics and clinical data;the impact of DHCR24 on the malignant behavior of OC was assessed through in vivo and in vitro experiments;and the mechanism by which DHCR24 functions in OC was preliminarily explored using sequencing and rescue experiments.Statistical analysis was conducted using the chi-square test,t-test,and oneway ANOVA.Results:Database,clinical data,and immunohistochemical(IHC)analyses demonstrated that DHCR24 is upregulated in OC and correlates with poor outcomes.In vitro experiments indicated that DHCR24 promotes proliferation,migration,invasion,and epithelial-mesenchymal transition in OC cells.The addition of a DHCR24 inhibitor suppressed the malignant behavior of OC cells.The nude mouse tumor formation experiment demonstrated that inhibiting DHCR24 suppresses the in vivo growth of OC cells.Further experiments showed that DHCR24 promotes the malignant behavior of OC cells,correlating with the regulation of the transforming growth factor beta(TGF-β)signaling pathway.All the above experiments showed statistical significance.Conclusion:DHCR24 contributes to ovarian cancer progression by upregulating the TGF-β1 pathway,highlighting its potential as a therapeutic target in ovarian cancer.
基金National Natural Science Foundation of China,No.32260089Science and Technology Research Foundation of Guizhou Province,No.QKHJC-ZK(2022)YB642+3 种基金Science and Technology Research Foundation of Hubei Province,No.2022BCE030Science and Technology Research Foundation of Changzhou City,No.CE20225040Science and Technology Research Foundation of Zunyi City,No.ZSKHHZ(2022)344 and No.ZSKHHZ(2022)360WBE Liver Fibrosis Foundation,No.CFHPC2025028.
文摘BACKGROUND Bletilla striata polysaccharides(BSP)have antioxidant,immune regulation,and anti-fibrotic activities.However,the therapeutic effect and mechanisms underlying the action of BSP in metabolic dysfunction-associated steatotic liver disease(MASLD)have not been fully understood.AIMTo investigate the therapeutic effects and mechanisms of BSP on MASLD by centering on the hepatocyte nuclearfactor kappa B p65(RelA)/hepatocyte nuclear factor-1 alpha(HNF1α)signaling.METHODSA mouse model of MASLD was induced by feeding with a high-fat-diet(HFD)and a hepatocyte model of steatosiswas induced by treatment with sodium oleate(SO)and sodium palmitate(SP).The therapeutic effects of BSP onMASLD were examined in vivo and in vitro.The mechanisms underlying the action of BSP were analyzed for theireffect on lipid metabolism disorder,endoplasmic reticulum(ER)stress,and the RelA/HNF1αsignaling.RESULTSHFD feeding reduced hepatocyte RelA and HNF1αexpression,induced ER stress,lipid metabolism disorder,andnecroptosis in mice,which were significantly mitigated by treatment with BSP.Furthermore,treatment with BSP orBSP-containing conditional rat serum significantly attenuated the sodium oleate/sodium palmitate(SO/SP)-induced hepatocyte steatosis by decreasing lipid accumulation,and lipid peroxidation,and enhancing theexpression of RelA,and HNF1α.The therapeutic effects of BSP on MASLD were partially abrogated by RELAsilencing in mice and RELA knockout in hepatocytes.RELA silencing or knockout significantly down-regulatedHNF1αexpression,and remodeled ER stress and oxidative stress responses during hepatic steatosis.CONCLUSIONTreatment with BSP ameliorates MASLD,associated with enhancing the RelA/HNF1αsignaling,remodeling ERstress and oxidative stress responses in hepatocytes.
