Adult neurogenesis continuously produces new neurons critical for cognitive plasticity in adult rodents.While it is known transforming growth factor-βsignaling is important in embryonic neurogenesis,its role in postn...Adult neurogenesis continuously produces new neurons critical for cognitive plasticity in adult rodents.While it is known transforming growth factor-βsignaling is important in embryonic neurogenesis,its role in postnatal neurogenesis remains unclear.In this study,to define the precise role of transforming growth factor-βsignaling in postnatal neurogenesis at distinct stages of the neurogenic cascade both in vitro and in vivo,we developed two novel inducible and cell type-specific mouse models to specifically silence transforming growth factor-βsignaling in neural stem cells in(mGFAPcre-ALK5fl/fl-Ai9)or immature neuroblasts in(DCXcreERT2-ALK5fl/fl-Ai9).Our data showed that exogenous transforming growth factor-βtreatment led to inhibition of the proliferation of primary neural stem cells while stimulating their migration.These effects were abolished in activin-like kinase 5(ALK5)knockout primary neural stem cells.Consistent with this,inhibition of transforming growth factor-βsignaling with SB-431542 in wild-type neural stem cells stimulated proliferation while inhibited the migration of neural stem cells.Interestingly,deletion of transforming growth factor-βreceptor in neural stem cells in vivo inhibited the migration of postnatal born neurons in mGFAPcre-ALK5fl/fl-Ai9 mice,while abolishment of transforming growth factor-βsignaling in immature neuroblasts in DCXcreERT2-ALK5fl/fl-Ai9 mice did not affect the migration of these cells in the hippocampus.In summary,our data supports a dual role of transforming growth factor-βsignaling in the proliferation and migration of neural stem cells in vitro.Moreover,our data provides novel insights on cell type-specific-dependent requirements of transforming growth factor-βsignaling on neural stem cell proliferation and migration in vivo.展开更多
Strokes include both ischemic stroke,which is mediated by a blockade or reduction in the blood supply to the brain,and hemorrhagic stroke,which comprises intracerebral hemorrhage and subarachnoid hemorrhage and is cha...Strokes include both ischemic stroke,which is mediated by a blockade or reduction in the blood supply to the brain,and hemorrhagic stroke,which comprises intracerebral hemorrhage and subarachnoid hemorrhage and is characterized by bleeding within the brain.Stroke is a lifethreatening cerebrovascular condition characterized by intricate pathophysiological mechanisms,including oxidative stress,inflammation,mitochondrial dysfunction,and neuronal injury.Critical transcription factors,such as nuclear factor erythroid 2-related factor 2 and nuclear factor kappa B,play central roles in the progression of stroke.Nuclear factor erythroid 2-related factor 2 is sensitive to changes in the cellular redox status and is crucial in protecting cells against oxidative damage,inflammatory responses,and cytotoxic agents.It plays a significant role in post-stroke neuroprotection and repair by influencing mitochondrial function,endoplasmic reticulum stress,and lysosomal activity and regulating metabolic pathways and cytokine expression.Conversely,nuclear factor-kappa B is closely associated with mitochondrial dysfunction,the generation of reactive oxygen species,oxidative stress exacerbation,and inflammation.Nuclear factor-kappa B contributes to neuronal injury,apoptosis,and immune responses following stroke by modulating cell adhesion molecules and inflammatory mediators.The interplay between these pathways,potentially involving crosstalk among various organelles,significantly influences stroke pathophysiology.Advancements in single-cell sequencing and spatial transcriptomics have greatly improved our understanding of stroke pathogenesis and offer new opportunities for the development of targeted,individualized,cell typespecific treatments.In this review,we discuss the mechanisms underlying the involvement of nuclear factor erythroid 2-related factor 2 and nuclear factor-kappa B in both ischemic and hemorrhagic stroke,with an emphasis on their roles in oxidative stress,inflammation,and neuroprotection.展开更多
The aging process is an inexorable fact throughout our lives and is considered a major factor in develo ping neurological dysfunctions associated with cognitive,emotional,and motor impairments.Aging-associated neurode...The aging process is an inexorable fact throughout our lives and is considered a major factor in develo ping neurological dysfunctions associated with cognitive,emotional,and motor impairments.Aging-associated neurodegenerative diseases are characterized by the progressive loss of neuronal structure and function.展开更多
Magnolol,a compound extracted from Magnolia officinalis,demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases.Its biological activities encompass anti-inflammatory,antioxidant...Magnolol,a compound extracted from Magnolia officinalis,demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases.Its biological activities encompass anti-inflammatory,antioxidant,anticoagulant,and anti-diabetic effects.Growth/differentiation factor-15(GDF-15),a member of the transforming growth factorβsuperfamily,is considered a potential therapeutic target for metabolic disorders.This study investigated the impact of magnolol on GDF-15 production and its underlying mechanism.The research examined the pharmacological effect of magnolol on GDF-15 expression in vitro and in vivo,and determined the involvement of endoplasmic reticulum(ER)stress signaling in this process.Luciferase reporter assays,chromatin immunoprecipitation,and in vitro DNA binding assays were employed to examine the regulation of GDF-15 by activating transcription factor 4(ATF4),CCAAT enhancer binding proteinγ(CEBPG),and CCCTC-binding factor(CTCF).The study also investigated the effect of magnolol and ATF4 on the activity of a putative enhancer located in the intron of the GDF-15 gene,as well as the influence of single nucleotide polymorphisms(SNPs)on magnolol and ATF4-induced transcription activity.Results demonstrated that magnolol triggers GDF-15 production in endothelial cells(ECs),hepatoma cell line G2(HepG2)and hepatoma cell line 3B(Hep3B)cell lines,and primary mouse hepatocytes.The cooperative binding of ATF4 and CEBPG upstream of the GDF-15 gene or the E1944285 enhancer located in the intron led to full-power transcription of the GDF-15 gene.SNP alleles were found to impact the magnolol and ATF4-induced transcription activity of GDF-15.In high-fat diet ApoE^(-/-)mice,administration of magnolol induced GDF-15 production and partially suppressed appetite through GDF-15.These findings suggest that magnolol regulates GDF-15 expression through priming of promoter and enhancer activity,indicating its potential as a drug for the treatment of metabolic disorders.展开更多
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
Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in s...Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in spinal cord injury.Previous studies have shown that microglia can promote neuronal survival by phagocytosing dead cells and debris and by releasing neuroprotective and anti-inflammatory factors.However,excessive activation of microglia can lead to persistent inflammation and contribute to the formation of glial scars,which hinder axonal regeneration.Despite this,the precise role and mechanisms of microglia during the acute phase of spinal cord injury remain controversial and poorly understood.To elucidate the role of microglia in spinal cord injury,we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia.We observed that sustained depletion of microglia resulted in an expansion of the lesion area,downregulation of brain-derived neurotrophic factor,and impaired functional recovery after spinal cord injury.Next,we generated a transgenic mouse line with conditional overexpression of brain-derived neurotrophic factor specifically in microglia.We found that brain-derived neurotrophic factor overexpression in microglia increased angiogenesis and blood flow following spinal cord injury and facilitated the recovery of hindlimb motor function.Additionally,brain-derived neurotrophic factor overexpression in microglia reduced inflammation and neuronal apoptosis during the acute phase of spinal cord injury.Furthermore,through using specific transgenic mouse lines,TMEM119,and the colony-stimulating factor 1 receptor inhibitor PLX73086,we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages.In conclusion,our findings suggest the critical role of microglia in the formation of protective glial scars.Depleting microglia is detrimental to recovery of spinal cord injury,whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury.展开更多
BACKGROUND Hypoxia-inducible factor 1α(HIF-1α)plays a crucial role in the prognosis of breast cancer,but the current evidence remains inconclusive.AIM To provide comprehensive evidence about the correlation of alter...BACKGROUND Hypoxia-inducible factor 1α(HIF-1α)plays a crucial role in the prognosis of breast cancer,but the current evidence remains inconclusive.AIM To provide comprehensive evidence about the correlation of altered HIF-1αexpression with overall survival(OS)and disease-free survival(DFS)in breast cancer patients.METHODS A systematic search was conducted in PubMed,Embase,and Web of Science databases to collect relevant articles that were published before April 8,2024.A meta-analysis was used to assess the impact of altered HIF-1αexpression on the OS and DFS of breast cancer patients.Subgroup and sensitivity analyses were also performed in this meta-analysis.RESULTS This meta-analysis included 40 studies.The average percentage of breast cancer patients with high HIF-1αexpression was 39.6%.The overall meta-analysis results demonstrated that high HIF-1αexpression is strongly linked to poor outcomes in patients of breast cancer.Compared with low HIF-1αexpression,the overall hazard ratio for OS in patients with high HIF-1αexpression was 1.47[95%confidence interval(CI):1.29-1.69],and the overall hazard ratio for DFS was 1.82(95%CI:1.56-2.12).Furthermore,both OS[1.18(95%CI:1.01-1.38)]and DFS[1.79(95%CI:1.03-3.11)]were markedly shorter in triple-negative breast cancer cases with high HIF-1αexpression.Subgroup analysis revealed that the antibody used to detect HIF-1αexpression affected only the correlation linking HIF-1αexpression to DFS in breast cancer patients(P=0.0004).Furthermore,the sensitivity analysis demonstrates that the overall conclusions of the meta-analysis were unaffected by the removal of individual studies.CONCLUSION Compared to patients with low HIF-1αexpression,those with high expression level had shorter OS and DFS.However,the prognostic significance of high HIF-1αexpression varies across molecularly stratified breast cancer cohorts needs to be further elucidated.展开更多
BACKGROUND Hypoxia in oral cancer promotes tumoral invasion by inducing epithelial-mesenchymal transition,leading to aggressive tumor progression.AIM To characterize the expression of hypoxia-inducible factor 1-alpha(...BACKGROUND Hypoxia in oral cancer promotes tumoral invasion by inducing epithelial-mesenchymal transition,leading to aggressive tumor progression.AIM To characterize the expression of hypoxia-inducible factor 1-alpha(HIF-1α)at the invasive tumor front(ITF)in comparison to tumor islands(TI)in oral squamous cell carcinoma(OSCC)and to explore its relationship with E-cadherin and Vimentin expression.METHODS Thirty-eight cases of OSCC and five cases of normal oral mucosa(NOM)were included in this study.The ITF was identified based on the region and immune expression of AE1/AE3.Immunohistochemistry was performed to assess the expression of HIF-1α,Vimentin,and E-cadherin.The immunostaining was analyzed using an immunoreactive score,and the results were illustrated using immunofluorescence.RESULTS HIF-1αexpression was significantly higher in the TI region compared to the ITF region(P=0.0134).Additionally,a significant difference was observed between TI and NOM(P=0.0115).In the ITF regions,HIF-1αexpression showed a significant correlation with Vimentin expression,with higher levels of HIF-1αassociated with increased Vimentin expression(P=0.017).CONCLUSION Based on the results of this study,HIF-1αappears to play a distinct role in OSCC tumor progression,underscoring the importance of exploring hypoxia-driven changes in cellular phenotype at the ITF of OSCC.Further research is needed to better understand their impact on OSCC prognosis.展开更多
BACKGROUND Hepatic ischemia reperfusion(HIR)injury is a major complication affecting various major liver surgeries,including liver transplantation.Aprepitant(APRE),a neurokinin-1 receptor antagonist,is commonly used a...BACKGROUND Hepatic ischemia reperfusion(HIR)injury is a major complication affecting various major liver surgeries,including liver transplantation.Aprepitant(APRE),a neurokinin-1 receptor antagonist,is commonly used as an antiemetic to prevent chemotherapy-induced nausea and vomiting.AIM To assess the potential protective effect of APRE against HIR-induced liver injury via targeting the nucleotide-binding oligomerization domain-,leucine-rich repeat-,and pyrin domain-containing receptor 3/interleukin(IL)-1beta signaling pathway.METHODS Six groups of adult male Wistar albino rats were divided as follows:Sham group,Sham/APRE10 group(APRE 10 mg/kg),HIR group,HIR/APRE5 group(APRE 5 mg/kg),HIR/APRE10 group(APRE 10 mg/kg),and HIR/APRE20 group(APRE 20 mg/kg).Serum alanine transaminase,aspartate transaminase,liver malondialdehyde,total antioxidant capacity levels,as well as IL-6,sirtuin 1(Sirt1),caspase-3,cleaved caspase-3,and tumor necrosis factor alpha biomarkers,were evaluated.Hepatic specimens were examined histopathologically and immunohistochemically for nuclear factor erythroid-2-related factor 2(Nrf2)immunoexpression.RESULTS HIR resulted in hepatic damage,as evidenced by histopathological changes and a significant increase in serum alanine transaminase,aspartate transaminase,hepatic malondialdehyde,caspase-3,and tumor necrosis factor alpha levels.Additionally,there were significant increases in hepatic total antioxidant capacity and reductions in IL-6 and cleaved caspase-3 protein levels,as demonstrated by Western blot analysis,along with enhanced immunoexpression of Sirt1 and Nrf2.APRE has significantly reduced various parameters of oxidative stress,inflammation,and apoptosis,and a significant increase in liver Nrf2 immunoexpression,leading to a significant improvement in the histopathological changes.CONCLUSION In conclusion,targeting the Sirt1/Nrf2 signaling pathway,as demonstrated by APRE in our model,could present a promising therapeutic target to protect against HIR-induced liver injury during major liver surgeries.展开更多
BACKGROUND Tumor necrosis factor-α(TNF-α)has been implicated in the development of diabetes following chronic pancreatitis.However,its role in abnormal glucose metabolism(AGM)after acute pancreatitis(AP)and post-pan...BACKGROUND Tumor necrosis factor-α(TNF-α)has been implicated in the development of diabetes following chronic pancreatitis.However,its role in abnormal glucose metabolism(AGM)after acute pancreatitis(AP)and post-pancreatitis diabetes mellitus remains unclear.AIM To investigate the role of TNF-αin AP-associated AGM and its effects on isletβ-cell apoptosis,focusing on the underlying molecular mechanisms.METHODS Clinical data were collected to assess AGM’s incidence and identify the characteristics in 369 AP patients.In vitro,AP models were established using lipopolysaccharide in 266-6 acinar cells and MIN-6β-cells.Cell proliferation,apoptosis,and protein expression were analyzed using the Cell Counting Kit-8 assay,terminal deoxynucleotidyl transferase dUTP nick-end labeling assay,and western blotting.The TNF-αand insulin concentration in co-culture medium was measured by enzyme-linked immunosorbent assay.In vivo,an AP mouse model was induced using sodium taurocholate,and pancreatic tissues were analyzed through hematoxylin and eosin staining,terminal deoxynucleotidyl transferase dUTP nick-end labeling,and western blotting.TNF-αlevels were assessed by enzyme-linked immunosorbent assay.A TNF-αinhibitor was applied to the AP cell model to reassess apoptosis and protein expression.RESULTS AGM occurred in 40.38%of AP patients.Body mass index,severity grade,recurrence frequency,and lung injury were significantly associated with AGM.AP models in 266-6 and MIN-6 cells showed reducedβ-cell proliferation,insulin secretion,and increased apoptosis,which correlated with inflammation severity.Similar findings ofβ-cell apoptosis were confirmed in the mouse model.TNF-αlevels were significantly elevated in AP models,with higher levels in severe inflammation.Increased Bax and caspase-3 expression and decreased Bcl-2 expression were observed in both in vitro and in vivo models.These changes intensified with increasing inflammation.TNF-αinhibition reduced apoptosis and altered protein expression patterns,decreasing Bax and caspase-3,while increasing Bcl-2 in MIN-6 cells.CONCLUSION TNF-αcontributes toβ-cell apoptosis and AGM in AP through the Bax/Bcl-2/caspase-3 signaling pathway,suggesting TNF-αas a potential therapeutic target for preventing AP-associated AGM.展开更多
Pulmonary arterial hypertension(PAH)is a progressive disease marked by degeneration of the lung’s blood vessels.As the disease progresses,the resistance to blood flow in the pulmonary arteries increases,putting a str...Pulmonary arterial hypertension(PAH)is a progressive disease marked by degeneration of the lung’s blood vessels.As the disease progresses,the resistance to blood flow in the pulmonary arteries increases,putting a strain on the right side of the heart as it pumps blood through the lungs.PAH is characterized by changes in the structure of blood vessels and excessive cell growth.Untreated PAH leads to irreversible right-sided heart failure,often despite medical intervention.Patients experience a gradual decline in function until they are unable to perform daily activities.Advances in treatment have improved the prognosis for many PAH patients.Currently approved therapies target the prostacyclin,endothelin,nitric oxide,or phosphodiesterase pathways to slow the progression of the disease.To address the unmet need for effective PAH therapies,research efforts are focused on identifying new targets and developing therapies that specifically address the underlying disease mechanisms and restore vascular wall homeostasis.Among these,sotatercept,a fusion protein that targets the transforming growth factor-βsuperfamily signaling pathway,has emerged as a promising therapeutic option.In this review,we examine the available evidence from clinical trials to assess the potential of sotatercept as a treatment for PAH.展开更多
OBJECTIVE:To investigate the impact of Shenhua tablet(肾华片,SHT)on renal macrophage polarization and renal injury in mice with diabetic kidney disease(DKD)and to explore the potential mechanism involving the hypoxia-...OBJECTIVE:To investigate the impact of Shenhua tablet(肾华片,SHT)on renal macrophage polarization and renal injury in mice with diabetic kidney disease(DKD)and to explore the potential mechanism involving the hypoxia-inducible factor-1α(HIF-1α)and pyruvate kinase M2(PKM2)signaling pathway,along with the glycolysis metabolism pathway.METHODS:The animals were divided into the following groups:Model,Control,dapagliflozin,SHT low-dose,SHT medium-dose,and SHT high-dose.We assessed 24-hour urine protein(24 h-UTP)levels,urinary albuminto-creatinine ratio,and regularly monitored fasting blood glucose during the treatment period.After treatment,we examined renal tissue structure,renal function(urea nitrogen,uric acid,creatinine,cystatin C,β2-microglobulin),and glycolysis in renal macrophages.Additionally,we observed macrophage polarization in renal tissue and measured inflammatory factors(tumor necrosis factor-α,interleukin-1β,interleukin-6,interleukin-10,monocyte chemoattractant protein-1)to assess the immunoinflammatory status of the renal tissue.Finally,we investigated the expression of the HIF-1α/PKM2 signaling pathway in macrophages to explore its role in the glycolysis process.RESULTS:SHT shows a beneficial effect in treating DKD by reducing 24 h-UTP,regulating blood glucose levels,improving renal tissue structure,protecting renal function,inhibiting macrophage glycolysis,reducing macrophage transformation to the M1 state,and suppressing the expression of the HIF-1α/PKM2 signaling pathway.CONCLUSION:SHT may exert renoprotective effects by inhibiting macrophage glycolysis via the HIF-1α/PKM2 signaling pathway.This inhibition decreases macrophage M1 polarization and reduces immunoinflammatory injury in the renal tissue of DKD mice.展开更多
Pulpitis is a common infective oral disease in clinical situations.The regulatory mechanisms of immune defense in pulpitis are still being investigated.Osteomodulin(OMD)is a small leucine-rich proteoglycan family memb...Pulpitis is a common infective oral disease in clinical situations.The regulatory mechanisms of immune defense in pulpitis are still being investigated.Osteomodulin(OMD)is a small leucine-rich proteoglycan family member distributed in bones and teeth.It is a bioactive protein that promotes osteogenesis and suppresses the apoptosis of human dental pulp stem cells(hDPSCs).In this study,the role of OMD in pulpitis and the OMD-induced regulatory mechanism were investigated.The OMD expression in normal and inflamed human pulp tissues was detected via immunofluorescence staining.Intriguingly,the OMD expression decreased in the inflammatory infiltration area of pulpitis specimens.The cellular experiments demonstrated that recombined human OMD could resist the detrimental effects of lipopolysaccharide(LPS)-induced inflammation.A conditional Omd knockout mouse model with pulpal inflammation was established.LPS-induced inflammatory impairment significantly increased in conditional Omd knockout mice,whereas OMD administration exhibited a protective effect against pulpitis.Mechanistically,the transcriptome alterations of OMD overexpression showed significant enrichment in the nuclear factor-κB(NF-κB)signaling pathway.Interleukin-1 receptor 1(IL1R1),a vital membrane receptor activating the NF-κB pathway,was significantly downregulated in OMD-overexpressing hDPSCs.Additionally,the interaction between OMD and IL1R1 was verified using co-immunoprecipitation and molecular docking.In vivo,excessive pulpal inflammation in Omd-deficient mice was rescued using an IL1R antagonist.Overall,OMD played a protective role in the inflammatory response via the IL1R1/NF-κB signaling pathway.OMD may optimize the immunomodulatory functions of hDPSCs and can be used for regenerative endodontics.展开更多
Objective MicroRNA-1(miR-1)aggravates myocardial ischemia–reperfusion(I/R)injury,whereas insulin-like growth factor-1(IGF-1)maintains cardiomyocyte homeostasis.In this study,the aim is to investigate whether miR-1 ca...Objective MicroRNA-1(miR-1)aggravates myocardial ischemia–reperfusion(I/R)injury,whereas insulin-like growth factor-1(IGF-1)maintains cardiomyocyte homeostasis.In this study,the aim is to investigate whether miR-1 can exacerbate I/R injury through the regulation of IGF-1.Methods The infarct area,lactate dehydrogenase,miR-1 level,and apoptosis level were examined in the Langendorff isolated rat I/R model.The hypoxia–reoxygenation model of rat cardiacmyocytes and H9c2 cells were developed to determine the levels of miR-1,IGF-1 mRNA,and IGF-1 protein.Furthermore,the dual-luciferase assay was used to verify the relationship between miR-1 and IGF-1.Results Overexpression of miR-1 increased the level of apoptosis and decreased the IGF-1 expression.However,inhibition of miR-1 expression decreased the level of apoptosis,alleviated the degree of injury,and increased the IGF-1 expression.Overexpression of IGF-1 also reduced the degree of cellular damage and level of apoptosis caused by the overexpression of miR-1.When IGF-1 was knocked down,myocardial cells displayed more severe damage and a higher apoptosis level,even with decreased levels of miR-1.Conclusion miR-1 promotes apoptosis and aggravates I/R injury by downregulating IGF-1.展开更多
BACKGROUND Pathological calcification is a common feature of many diseases.Calcifying nanoparticles(CNPs)are considered potential inducers of this abnormal calcification,but their specific effects on bone marrow mesen...BACKGROUND Pathological calcification is a common feature of many diseases.Calcifying nanoparticles(CNPs)are considered potential inducers of this abnormal calcification,but their specific effects on bone marrow mesenchymal stem cells(BMSCs)remain unclear.BMSCs are key cells in bone formation and repair,and their aberrant apoptosis and calcification are closely related to disease progression.AIM To explore whether CNPs can induce apoptosis and calcification in BMSCs and analyzed the relationship between these processes.The differential effects of CNPs and nanoscale hydroxyapatites(nHAPs)in inducing apoptosis and calcification in BMSCs were also compared.METHODS CNPs obtained in the early stage were identified by electron microscopy and particle size analysis.BMSCs were cultured with various treatments,including different concentrations of nHAPs,CNPs[2 McFarland(MCF)turbidity,4 MCF,6 MCF],and a transforming growth factor(TGF)-βinhibitor(SB431542)for 72 hours.The isolated CNPs exhibited the expected sizes and shapes.RESULTS Exposure to CNPs and nHAPs suppressed cell proliferation and promoted apoptosis in a concentration-dependent manner,with CNPs exhibiting significantly stronger effects.Alizarin Red staining indicated an increase in calcium deposition with exposure to increasing concentrations of nHAPs and CNPs.Quantitative reverse-transcription polymerase chain reaction results indicated that medium concentrations of nHAPs and CNPs significantly enhanced the expression of pro-apoptotic and pro-calcification markers,whereas the expression of anti-apoptotic Bcl-2 was reduced compared with untreated controls.Western blotting results showed that medium concentrations of CNPs and nHAPs increased the expression of osteopontin,bone morphogenetic protein-2,TGF-β/Smad,Bax,and caspase-3 and decreased Bcl-2 expression compared with controls.CONCLUSION CNPs and nHAPs induced apoptosis and calcification in BMSCs,with CNPs being the most potent.Additionally,the TGF-βinhibitor SB431542 significantly reduced the occurrence of apoptosis and calcification.A correlation was found between apoptosis and calcification,which is likely mediated through the TGF-β/Smad signaling pathway.展开更多
BACKGROUND Krüppel-like factor-5(KLF5)is a zinc-finger transcription factor related to tumor progression.However,the relationship between KLF5 and lung cancer remains to be identified.AIM To investigate the clini...BACKGROUND Krüppel-like factor-5(KLF5)is a zinc-finger transcription factor related to tumor progression.However,the relationship between KLF5 and lung cancer remains to be identified.AIM To investigate the clinical value of KLF5 and interference with KLF5 mRNA transcription on the effects of biological behaviors in lung squamous-cell carcinoma(LUSC).METHODS Lung KLF5 mRNA data were extracted from bioinformatics databases.Blood and tissues from a cohort of patients with benign or malignant lung diseases were collected with ethical committee consent to validate KLF5 expression via multiplex immunofluorescence and immunohistochemistry,Western blot,Enzyme Linked Immunosorbent Assay or quantitative polymerase chain reaction.Furthermore,KLF5 mRNA was silenced in lung A549 cells to validate biological behaviors in vitro and nude mouse xenograft growth in vivo,respectively.RESULTS A cohort of bioinformatics databases revealed high KLF5 mRNA expression in LUSC(P<0.001)but lower KLF5 mRNA expression in lung adenocarcinoma.Upregulated KLF5 in the lung or sera of patients with lung cancer(P<0.001)were confirmed that related to poor differentiation,lymph node or distant metastasis.Furthermore,the incidence of KLF5 levels greater than 500 ng/mL in LUSC patients was 86.7%,which was significantly greater(P<0.001)than that in cases with benign lung diseases(13.3%)or healthy controls.Functionally,silencing KLF5 mRNA with a specific shRNA significantly suppressed A549 cell proliferation,decreased cell migration,increased the ratio of G2 phase cells in vitro,and inhibited the growth of nude mouse xenografts in vivo.CONCLUSION KLF5 is a novel diagnostic biomarker or potential therapeutic target for LUSC.展开更多
The published article titled“MicroRNA-33b Inhibits the Proliferation andMigration of Osteosarcoma Cells via TargetingHypoxia-Inducible Factor-1α”has been retracted from Oncology Research,Vol.25,No.3,2017,pp.397–405.
BACKGROUND Diabetes and its associated microvascular complications,such as nephropathy and retinopathy,significantly impact global health.These complications often begin in the prediabetic stage,emphasizing the import...BACKGROUND Diabetes and its associated microvascular complications,such as nephropathy and retinopathy,significantly impact global health.These complications often begin in the prediabetic stage,emphasizing the importance of early detection and intervention.Inflammatory pathways are key contributors to these conditions,and recent research has identified members of the tumor necrosis factor(TNF)receptor superfamily as potential biomarkers.However,their association with renal and retinal dysfunction in individuals with intermediate hyperglycemia(IH)remains underexplored.The Early Prevention of Diabetes Complications(ePREDICE)trial provides a valuable cohort to investigate these associations and improve risk assessment strategies.AIM To identify inflammatory biomarkers associated with early renal and retinal dysfunction in individuals with IH.Specifically,we evaluate the diagnostic and prognostic potential of TNF receptor superfamily members[TNF receptor 1(TNF-R1),TNF receptor 2(TNF-R2)],T-cell immunoglobulin and mucin domain 3(TIM-3)/HAVCR2,galectin-3,and interleukin-6(IL-6)in detecting kidney dysfunction and retinopathy in this high-risk population.By understanding their roles,we seek to enhance early screening methods and inform personalized intervention strategies.METHODS A cross-sectional analysis of 967 individuals with IH from the ePREDICE trial was conducted.Participants underwent comprehensive anthropometric and biochemical assessments.Key inflammatory biomarkers,including TNF-R1,TNF-R2,TIM-3/HAVCR2,galectin-3,and IL-6,were quantified using immunoassays.Renal function was assessed using estimated glomerular filtration rate(eGFR)and albuminuria,while retinopathy was evaluated through fundoscopic examination.Statistical analyses included adjusted mean comparisons,correlation studies,and receiver operating characteristic curve analysis to assess biomarker diagnostic accuracy.RESULTS TNF-R1,TNF-R2,and TIM-3/HAVCR2 were significantly associated with reduced filtration function(eGFR<60 mL/minute/1.73 m^(2))and albuminuria,with area under the curve(AUC)values between 0.815 and 0.845.TIM-3/HAVCR2 emerged as the strongest predictor of retinopathy(AUC=0.737).Strong correlations(r>0.75)were observed among TNF-R1,TNF-R2,and TIM-3/HAVCR2,suggesting a coordinated role in inflammatory pathways.CONCLUSION Our findings highlight the potential of TNF receptor superfamily members as biomarkers for early-stage renal and retinal complications in individuals with IH.Their integration into clinical screening protocols could facilitate earlier detection,improving patient stratification and personalized management strategies.Further longitudinal studies are necessary to validate their predictive value and potential for guiding therapeutic interventions in IH and early diabetes management.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is a global health concern,representing the second most common cause of malignancy-related mortality in the world.The primary cause of HCC in the United States is chronic infect...BACKGROUND Hepatocellular carcinoma(HCC)is a global health concern,representing the second most common cause of malignancy-related mortality in the world.The primary cause of HCC in the United States is chronic infection with the hepatitis C virus(HCV).Clinical observations have established sex-based differences in HCV infection with the disease progressing more severely and more rapidly in males and postmenopausal females compared to premenopausal females,suggesting that estrogens and their receptors may play an important role in hepatic defenses and development of HCV-mediated HCC.However,the precise mechanism of estrogen protection and their effects on inflammation is poorly understood.AIM To determine whether estrogen receptor(ER)expression is correlated with the expression of tumor necrosis factor-alpha(TNF-α)in males and females with HCV-associated diseases.METHODS The role of ERs in modulating innate immune responses was investigated using human liver tissues with HCV/cirrhosis and HCV/HCC.Messenger RNA(mRNA)and protein(nuclear and cytoplasmic)expression were measured for all markers of interest and compared to normal human liver tissue samples.RESULTS ERβwas reported for the first time to have a greater mRNA expression than ERαin normal liver(P≤0.001).In addition,ERβmRNA expression was found to be decreased in diseased livers(P≤0.05),while TNF-αexpression was increased(P≤0.0001).Upon stratifying by sex within each disease group,ESR1 was found to be negatively correlated with ESR2 in females with HCV/cirrhosis(r=-0.84,P≤0.001),whereas males with HCV/cirrhosis were found to have a significant positive correlation(r=0.57,P≤0.05).ESR2 mRNA expression had a significant positive correlation with TNF-αin both HCV/cirrhosis(r=0.61,P≤0.001)and HCV/HCC patients(r=0.45,P≤0.05).CONCLUSION All together,these findings indicate that changes in ERβand TNF-αexpression are associated with worsening disease,and may be part of the sex-dependent factors in HCC pathogenesis.展开更多
This systematic review synthesizes empirical research on external risk factors for adolescent smartphone addiction.Scopus and Web of Science were searched for English peer-reviewed empirical articles from 2008 onward;...This systematic review synthesizes empirical research on external risk factors for adolescent smartphone addiction.Scopus and Web of Science were searched for English peer-reviewed empirical articles from 2008 onward;28 met inclusion criteria(excluding non-adolescents,generic internet addiction,non-empirical work,or non-English).Thematic synthesis organized findings into three external risk domains—family,school,and peers—considering cultural/contextual mechanisms.Family dynamics(parental phubbing,harsh parenting,dysfunction),school stressors,and adverse peer relationships were identified as accumulating,direct and indirect contributors to smartphone addiction.These operate within a techno-ecological framework,where digital technologies amplify vulnerabilities and create new pathways for maladaptive use.Evidence favors an ecological,multi-level perspective.Future research should use longitudinal designs,standardize measures across cultures,and examine understudied regions—especially Africa—to guide culturally sensitive interventions.展开更多
基金supported by NIH grants,Nos.R01NS125074,R01AG083164,R01NS107365,and R21NS127177(to YL),1F31NS129204-01A1(to KW)and Albert Ryan Fellowship(to KW).
文摘Adult neurogenesis continuously produces new neurons critical for cognitive plasticity in adult rodents.While it is known transforming growth factor-βsignaling is important in embryonic neurogenesis,its role in postnatal neurogenesis remains unclear.In this study,to define the precise role of transforming growth factor-βsignaling in postnatal neurogenesis at distinct stages of the neurogenic cascade both in vitro and in vivo,we developed two novel inducible and cell type-specific mouse models to specifically silence transforming growth factor-βsignaling in neural stem cells in(mGFAPcre-ALK5fl/fl-Ai9)or immature neuroblasts in(DCXcreERT2-ALK5fl/fl-Ai9).Our data showed that exogenous transforming growth factor-βtreatment led to inhibition of the proliferation of primary neural stem cells while stimulating their migration.These effects were abolished in activin-like kinase 5(ALK5)knockout primary neural stem cells.Consistent with this,inhibition of transforming growth factor-βsignaling with SB-431542 in wild-type neural stem cells stimulated proliferation while inhibited the migration of neural stem cells.Interestingly,deletion of transforming growth factor-βreceptor in neural stem cells in vivo inhibited the migration of postnatal born neurons in mGFAPcre-ALK5fl/fl-Ai9 mice,while abolishment of transforming growth factor-βsignaling in immature neuroblasts in DCXcreERT2-ALK5fl/fl-Ai9 mice did not affect the migration of these cells in the hippocampus.In summary,our data supports a dual role of transforming growth factor-βsignaling in the proliferation and migration of neural stem cells in vitro.Moreover,our data provides novel insights on cell type-specific-dependent requirements of transforming growth factor-βsignaling on neural stem cell proliferation and migration in vivo.
基金supported by grants from the Zhejiang Provincial TCM Science and Technology Plan Project,No.2023ZL156(to YH)Ningbo Top Medical and Health Research Program,No.2022020304(to XG)+1 种基金the Natural Science Foundation of Ningbo,No.2023J019(to YH)Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang Province,No.2022E10026(to YH)。
文摘Strokes include both ischemic stroke,which is mediated by a blockade or reduction in the blood supply to the brain,and hemorrhagic stroke,which comprises intracerebral hemorrhage and subarachnoid hemorrhage and is characterized by bleeding within the brain.Stroke is a lifethreatening cerebrovascular condition characterized by intricate pathophysiological mechanisms,including oxidative stress,inflammation,mitochondrial dysfunction,and neuronal injury.Critical transcription factors,such as nuclear factor erythroid 2-related factor 2 and nuclear factor kappa B,play central roles in the progression of stroke.Nuclear factor erythroid 2-related factor 2 is sensitive to changes in the cellular redox status and is crucial in protecting cells against oxidative damage,inflammatory responses,and cytotoxic agents.It plays a significant role in post-stroke neuroprotection and repair by influencing mitochondrial function,endoplasmic reticulum stress,and lysosomal activity and regulating metabolic pathways and cytokine expression.Conversely,nuclear factor-kappa B is closely associated with mitochondrial dysfunction,the generation of reactive oxygen species,oxidative stress exacerbation,and inflammation.Nuclear factor-kappa B contributes to neuronal injury,apoptosis,and immune responses following stroke by modulating cell adhesion molecules and inflammatory mediators.The interplay between these pathways,potentially involving crosstalk among various organelles,significantly influences stroke pathophysiology.Advancements in single-cell sequencing and spatial transcriptomics have greatly improved our understanding of stroke pathogenesis and offer new opportunities for the development of targeted,individualized,cell typespecific treatments.In this review,we discuss the mechanisms underlying the involvement of nuclear factor erythroid 2-related factor 2 and nuclear factor-kappa B in both ischemic and hemorrhagic stroke,with an emphasis on their roles in oxidative stress,inflammation,and neuroprotection.
文摘The aging process is an inexorable fact throughout our lives and is considered a major factor in develo ping neurological dysfunctions associated with cognitive,emotional,and motor impairments.Aging-associated neurodegenerative diseases are characterized by the progressive loss of neuronal structure and function.
基金supported by the National Natural Science Foundation of China(Nos.82171552 and 82170479)the Natural Science Foundation of Shanghai Ctiy(No.21ZR1457500)the Science and Technology Bureau of Shanghai Putuo District(No.ptkwws202102).
文摘Magnolol,a compound extracted from Magnolia officinalis,demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases.Its biological activities encompass anti-inflammatory,antioxidant,anticoagulant,and anti-diabetic effects.Growth/differentiation factor-15(GDF-15),a member of the transforming growth factorβsuperfamily,is considered a potential therapeutic target for metabolic disorders.This study investigated the impact of magnolol on GDF-15 production and its underlying mechanism.The research examined the pharmacological effect of magnolol on GDF-15 expression in vitro and in vivo,and determined the involvement of endoplasmic reticulum(ER)stress signaling in this process.Luciferase reporter assays,chromatin immunoprecipitation,and in vitro DNA binding assays were employed to examine the regulation of GDF-15 by activating transcription factor 4(ATF4),CCAAT enhancer binding proteinγ(CEBPG),and CCCTC-binding factor(CTCF).The study also investigated the effect of magnolol and ATF4 on the activity of a putative enhancer located in the intron of the GDF-15 gene,as well as the influence of single nucleotide polymorphisms(SNPs)on magnolol and ATF4-induced transcription activity.Results demonstrated that magnolol triggers GDF-15 production in endothelial cells(ECs),hepatoma cell line G2(HepG2)and hepatoma cell line 3B(Hep3B)cell lines,and primary mouse hepatocytes.The cooperative binding of ATF4 and CEBPG upstream of the GDF-15 gene or the E1944285 enhancer located in the intron led to full-power transcription of the GDF-15 gene.SNP alleles were found to impact the magnolol and ATF4-induced transcription activity of GDF-15.In high-fat diet ApoE^(-/-)mice,administration of magnolol induced GDF-15 production and partially suppressed appetite through GDF-15.These findings suggest that magnolol regulates GDF-15 expression through priming of promoter and enhancer activity,indicating its potential as a drug for the treatment of metabolic disorders.
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 National Natural Science Foundation of China,Nos.82072165 and 82272256(both to XM)the Key Project of Xiangyang Central Hospital,No.2023YZ03(to RM)。
文摘Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in spinal cord injury.Previous studies have shown that microglia can promote neuronal survival by phagocytosing dead cells and debris and by releasing neuroprotective and anti-inflammatory factors.However,excessive activation of microglia can lead to persistent inflammation and contribute to the formation of glial scars,which hinder axonal regeneration.Despite this,the precise role and mechanisms of microglia during the acute phase of spinal cord injury remain controversial and poorly understood.To elucidate the role of microglia in spinal cord injury,we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia.We observed that sustained depletion of microglia resulted in an expansion of the lesion area,downregulation of brain-derived neurotrophic factor,and impaired functional recovery after spinal cord injury.Next,we generated a transgenic mouse line with conditional overexpression of brain-derived neurotrophic factor specifically in microglia.We found that brain-derived neurotrophic factor overexpression in microglia increased angiogenesis and blood flow following spinal cord injury and facilitated the recovery of hindlimb motor function.Additionally,brain-derived neurotrophic factor overexpression in microglia reduced inflammation and neuronal apoptosis during the acute phase of spinal cord injury.Furthermore,through using specific transgenic mouse lines,TMEM119,and the colony-stimulating factor 1 receptor inhibitor PLX73086,we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages.In conclusion,our findings suggest the critical role of microglia in the formation of protective glial scars.Depleting microglia is detrimental to recovery of spinal cord injury,whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury.
基金Supported by the Henan Province Medical Science and Technology Tackling Plan Joint Construction Project,No.LHGJ20220684Zhengzhou University Tianjian Advanced Biomedical Laboratory Funding Project,No.BS20240101.
文摘BACKGROUND Hypoxia-inducible factor 1α(HIF-1α)plays a crucial role in the prognosis of breast cancer,but the current evidence remains inconclusive.AIM To provide comprehensive evidence about the correlation of altered HIF-1αexpression with overall survival(OS)and disease-free survival(DFS)in breast cancer patients.METHODS A systematic search was conducted in PubMed,Embase,and Web of Science databases to collect relevant articles that were published before April 8,2024.A meta-analysis was used to assess the impact of altered HIF-1αexpression on the OS and DFS of breast cancer patients.Subgroup and sensitivity analyses were also performed in this meta-analysis.RESULTS This meta-analysis included 40 studies.The average percentage of breast cancer patients with high HIF-1αexpression was 39.6%.The overall meta-analysis results demonstrated that high HIF-1αexpression is strongly linked to poor outcomes in patients of breast cancer.Compared with low HIF-1αexpression,the overall hazard ratio for OS in patients with high HIF-1αexpression was 1.47[95%confidence interval(CI):1.29-1.69],and the overall hazard ratio for DFS was 1.82(95%CI:1.56-2.12).Furthermore,both OS[1.18(95%CI:1.01-1.38)]and DFS[1.79(95%CI:1.03-3.11)]were markedly shorter in triple-negative breast cancer cases with high HIF-1αexpression.Subgroup analysis revealed that the antibody used to detect HIF-1αexpression affected only the correlation linking HIF-1αexpression to DFS in breast cancer patients(P=0.0004).Furthermore,the sensitivity analysis demonstrates that the overall conclusions of the meta-analysis were unaffected by the removal of individual studies.CONCLUSION Compared to patients with low HIF-1αexpression,those with high expression level had shorter OS and DFS.However,the prognostic significance of high HIF-1αexpression varies across molecularly stratified breast cancer cohorts needs to be further elucidated.
基金Supported by Comisión Sectorial de Investigación Científica(CSIC-Research Group 88180)The Agencia Nacional de Investigación e Innovación/Sistema Nacional de Investigadores(ANII/SNI)The Programa de Desarrollo de las Ciencias Básicas(PEDECIBA),Uruguay.
文摘BACKGROUND Hypoxia in oral cancer promotes tumoral invasion by inducing epithelial-mesenchymal transition,leading to aggressive tumor progression.AIM To characterize the expression of hypoxia-inducible factor 1-alpha(HIF-1α)at the invasive tumor front(ITF)in comparison to tumor islands(TI)in oral squamous cell carcinoma(OSCC)and to explore its relationship with E-cadherin and Vimentin expression.METHODS Thirty-eight cases of OSCC and five cases of normal oral mucosa(NOM)were included in this study.The ITF was identified based on the region and immune expression of AE1/AE3.Immunohistochemistry was performed to assess the expression of HIF-1α,Vimentin,and E-cadherin.The immunostaining was analyzed using an immunoreactive score,and the results were illustrated using immunofluorescence.RESULTS HIF-1αexpression was significantly higher in the TI region compared to the ITF region(P=0.0134).Additionally,a significant difference was observed between TI and NOM(P=0.0115).In the ITF regions,HIF-1αexpression showed a significant correlation with Vimentin expression,with higher levels of HIF-1αassociated with increased Vimentin expression(P=0.017).CONCLUSION Based on the results of this study,HIF-1αappears to play a distinct role in OSCC tumor progression,underscoring the importance of exploring hypoxia-driven changes in cellular phenotype at the ITF of OSCC.Further research is needed to better understand their impact on OSCC prognosis.
文摘BACKGROUND Hepatic ischemia reperfusion(HIR)injury is a major complication affecting various major liver surgeries,including liver transplantation.Aprepitant(APRE),a neurokinin-1 receptor antagonist,is commonly used as an antiemetic to prevent chemotherapy-induced nausea and vomiting.AIM To assess the potential protective effect of APRE against HIR-induced liver injury via targeting the nucleotide-binding oligomerization domain-,leucine-rich repeat-,and pyrin domain-containing receptor 3/interleukin(IL)-1beta signaling pathway.METHODS Six groups of adult male Wistar albino rats were divided as follows:Sham group,Sham/APRE10 group(APRE 10 mg/kg),HIR group,HIR/APRE5 group(APRE 5 mg/kg),HIR/APRE10 group(APRE 10 mg/kg),and HIR/APRE20 group(APRE 20 mg/kg).Serum alanine transaminase,aspartate transaminase,liver malondialdehyde,total antioxidant capacity levels,as well as IL-6,sirtuin 1(Sirt1),caspase-3,cleaved caspase-3,and tumor necrosis factor alpha biomarkers,were evaluated.Hepatic specimens were examined histopathologically and immunohistochemically for nuclear factor erythroid-2-related factor 2(Nrf2)immunoexpression.RESULTS HIR resulted in hepatic damage,as evidenced by histopathological changes and a significant increase in serum alanine transaminase,aspartate transaminase,hepatic malondialdehyde,caspase-3,and tumor necrosis factor alpha levels.Additionally,there were significant increases in hepatic total antioxidant capacity and reductions in IL-6 and cleaved caspase-3 protein levels,as demonstrated by Western blot analysis,along with enhanced immunoexpression of Sirt1 and Nrf2.APRE has significantly reduced various parameters of oxidative stress,inflammation,and apoptosis,and a significant increase in liver Nrf2 immunoexpression,leading to a significant improvement in the histopathological changes.CONCLUSION In conclusion,targeting the Sirt1/Nrf2 signaling pathway,as demonstrated by APRE in our model,could present a promising therapeutic target to protect against HIR-induced liver injury during major liver surgeries.
基金Supported by Taicang Science and Technology Program,No.TC2021JCYL21“National Tutor System”Training Program for Health Youth Key Talents in Suzhou,No.Qngg2023042Suzhou Science and Technology Bureau,No.SYW2024152.
文摘BACKGROUND Tumor necrosis factor-α(TNF-α)has been implicated in the development of diabetes following chronic pancreatitis.However,its role in abnormal glucose metabolism(AGM)after acute pancreatitis(AP)and post-pancreatitis diabetes mellitus remains unclear.AIM To investigate the role of TNF-αin AP-associated AGM and its effects on isletβ-cell apoptosis,focusing on the underlying molecular mechanisms.METHODS Clinical data were collected to assess AGM’s incidence and identify the characteristics in 369 AP patients.In vitro,AP models were established using lipopolysaccharide in 266-6 acinar cells and MIN-6β-cells.Cell proliferation,apoptosis,and protein expression were analyzed using the Cell Counting Kit-8 assay,terminal deoxynucleotidyl transferase dUTP nick-end labeling assay,and western blotting.The TNF-αand insulin concentration in co-culture medium was measured by enzyme-linked immunosorbent assay.In vivo,an AP mouse model was induced using sodium taurocholate,and pancreatic tissues were analyzed through hematoxylin and eosin staining,terminal deoxynucleotidyl transferase dUTP nick-end labeling,and western blotting.TNF-αlevels were assessed by enzyme-linked immunosorbent assay.A TNF-αinhibitor was applied to the AP cell model to reassess apoptosis and protein expression.RESULTS AGM occurred in 40.38%of AP patients.Body mass index,severity grade,recurrence frequency,and lung injury were significantly associated with AGM.AP models in 266-6 and MIN-6 cells showed reducedβ-cell proliferation,insulin secretion,and increased apoptosis,which correlated with inflammation severity.Similar findings ofβ-cell apoptosis were confirmed in the mouse model.TNF-αlevels were significantly elevated in AP models,with higher levels in severe inflammation.Increased Bax and caspase-3 expression and decreased Bcl-2 expression were observed in both in vitro and in vivo models.These changes intensified with increasing inflammation.TNF-αinhibition reduced apoptosis and altered protein expression patterns,decreasing Bax and caspase-3,while increasing Bcl-2 in MIN-6 cells.CONCLUSION TNF-αcontributes toβ-cell apoptosis and AGM in AP through the Bax/Bcl-2/caspase-3 signaling pathway,suggesting TNF-αas a potential therapeutic target for preventing AP-associated AGM.
文摘Pulmonary arterial hypertension(PAH)is a progressive disease marked by degeneration of the lung’s blood vessels.As the disease progresses,the resistance to blood flow in the pulmonary arteries increases,putting a strain on the right side of the heart as it pumps blood through the lungs.PAH is characterized by changes in the structure of blood vessels and excessive cell growth.Untreated PAH leads to irreversible right-sided heart failure,often despite medical intervention.Patients experience a gradual decline in function until they are unable to perform daily activities.Advances in treatment have improved the prognosis for many PAH patients.Currently approved therapies target the prostacyclin,endothelin,nitric oxide,or phosphodiesterase pathways to slow the progression of the disease.To address the unmet need for effective PAH therapies,research efforts are focused on identifying new targets and developing therapies that specifically address the underlying disease mechanisms and restore vascular wall homeostasis.Among these,sotatercept,a fusion protein that targets the transforming growth factor-βsuperfamily signaling pathway,has emerged as a promising therapeutic option.In this review,we examine the available evidence from clinical trials to assess the potential of sotatercept as a treatment for PAH.
基金National Natural Science Foundation of China:Basic Research on the Mechanism of Organ Immune Damage and the Diagnosis and Treatment of Integrated Traditional Chinese and Western Medicine(No.32141005)。
文摘OBJECTIVE:To investigate the impact of Shenhua tablet(肾华片,SHT)on renal macrophage polarization and renal injury in mice with diabetic kidney disease(DKD)and to explore the potential mechanism involving the hypoxia-inducible factor-1α(HIF-1α)and pyruvate kinase M2(PKM2)signaling pathway,along with the glycolysis metabolism pathway.METHODS:The animals were divided into the following groups:Model,Control,dapagliflozin,SHT low-dose,SHT medium-dose,and SHT high-dose.We assessed 24-hour urine protein(24 h-UTP)levels,urinary albuminto-creatinine ratio,and regularly monitored fasting blood glucose during the treatment period.After treatment,we examined renal tissue structure,renal function(urea nitrogen,uric acid,creatinine,cystatin C,β2-microglobulin),and glycolysis in renal macrophages.Additionally,we observed macrophage polarization in renal tissue and measured inflammatory factors(tumor necrosis factor-α,interleukin-1β,interleukin-6,interleukin-10,monocyte chemoattractant protein-1)to assess the immunoinflammatory status of the renal tissue.Finally,we investigated the expression of the HIF-1α/PKM2 signaling pathway in macrophages to explore its role in the glycolysis process.RESULTS:SHT shows a beneficial effect in treating DKD by reducing 24 h-UTP,regulating blood glucose levels,improving renal tissue structure,protecting renal function,inhibiting macrophage glycolysis,reducing macrophage transformation to the M1 state,and suppressing the expression of the HIF-1α/PKM2 signaling pathway.CONCLUSION:SHT may exert renoprotective effects by inhibiting macrophage glycolysis via the HIF-1α/PKM2 signaling pathway.This inhibition decreases macrophage M1 polarization and reduces immunoinflammatory injury in the renal tissue of DKD mice.
基金supported by grants from the National Natural Science Foundation of China (82071104)Science and Technology Commission of Shanghai Municipality (23XD1434200/22Y21901000)+9 种基金Shanghai Hospital Development Center(SHDC12022120)National Clinical Research Center for Oral Diseases (NCRCO2021-omics-07)Shanghai Clinical Research Center for Oral Diseases (19MC1910600)Major and Key Cultivation Projects of Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine (JYZP006)Shanghai’s Top Priority Research Center (2022ZZ01017)CAMS Innovation Fund for Medical Sciences (2019-I2M-5-037)Fundamental research program funding of Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine(JYZZ237)Eastern Talent Plan Leading Project (BJZH2024001)partly supported by the Shanghai Ninth People’s Hospital affiliated with Shanghai Jiao Tong University,School of Medicine(JYJC202223)Shanghai Key Laboratory of Translational Medicine on Ear and Nose diseases (14DZ2260300)
文摘Pulpitis is a common infective oral disease in clinical situations.The regulatory mechanisms of immune defense in pulpitis are still being investigated.Osteomodulin(OMD)is a small leucine-rich proteoglycan family member distributed in bones and teeth.It is a bioactive protein that promotes osteogenesis and suppresses the apoptosis of human dental pulp stem cells(hDPSCs).In this study,the role of OMD in pulpitis and the OMD-induced regulatory mechanism were investigated.The OMD expression in normal and inflamed human pulp tissues was detected via immunofluorescence staining.Intriguingly,the OMD expression decreased in the inflammatory infiltration area of pulpitis specimens.The cellular experiments demonstrated that recombined human OMD could resist the detrimental effects of lipopolysaccharide(LPS)-induced inflammation.A conditional Omd knockout mouse model with pulpal inflammation was established.LPS-induced inflammatory impairment significantly increased in conditional Omd knockout mice,whereas OMD administration exhibited a protective effect against pulpitis.Mechanistically,the transcriptome alterations of OMD overexpression showed significant enrichment in the nuclear factor-κB(NF-κB)signaling pathway.Interleukin-1 receptor 1(IL1R1),a vital membrane receptor activating the NF-κB pathway,was significantly downregulated in OMD-overexpressing hDPSCs.Additionally,the interaction between OMD and IL1R1 was verified using co-immunoprecipitation and molecular docking.In vivo,excessive pulpal inflammation in Omd-deficient mice was rescued using an IL1R antagonist.Overall,OMD played a protective role in the inflammatory response via the IL1R1/NF-κB signaling pathway.OMD may optimize the immunomodulatory functions of hDPSCs and can be used for regenerative endodontics.
基金supported by the National Natural Science Foundation of China(81473453,81673800)the Projects of International Science and Technology Cooperation in Henan(182102410084).
文摘Objective MicroRNA-1(miR-1)aggravates myocardial ischemia–reperfusion(I/R)injury,whereas insulin-like growth factor-1(IGF-1)maintains cardiomyocyte homeostasis.In this study,the aim is to investigate whether miR-1 can exacerbate I/R injury through the regulation of IGF-1.Methods The infarct area,lactate dehydrogenase,miR-1 level,and apoptosis level were examined in the Langendorff isolated rat I/R model.The hypoxia–reoxygenation model of rat cardiacmyocytes and H9c2 cells were developed to determine the levels of miR-1,IGF-1 mRNA,and IGF-1 protein.Furthermore,the dual-luciferase assay was used to verify the relationship between miR-1 and IGF-1.Results Overexpression of miR-1 increased the level of apoptosis and decreased the IGF-1 expression.However,inhibition of miR-1 expression decreased the level of apoptosis,alleviated the degree of injury,and increased the IGF-1 expression.Overexpression of IGF-1 also reduced the degree of cellular damage and level of apoptosis caused by the overexpression of miR-1.When IGF-1 was knocked down,myocardial cells displayed more severe damage and a higher apoptosis level,even with decreased levels of miR-1.Conclusion miR-1 promotes apoptosis and aggravates I/R injury by downregulating IGF-1.
基金Supported by the Project of Xinjiang Production and Construction Corps,No.2022ZD090the Project of Xinjiang Production and Construction Corps-Young Science and Technology Innovation Talents,No.2023CB008-31+2 种基金The First Affiliated Hospital of Shihezi University Medical College,Doctoral Fund Project,No.BS202207Talent Development Fund-Tianshan Talents,No.CZ0012192024 National Health Commission Central Asian High-Incidence Prevention and Control Key Laboratory,No.KF202405.
文摘BACKGROUND Pathological calcification is a common feature of many diseases.Calcifying nanoparticles(CNPs)are considered potential inducers of this abnormal calcification,but their specific effects on bone marrow mesenchymal stem cells(BMSCs)remain unclear.BMSCs are key cells in bone formation and repair,and their aberrant apoptosis and calcification are closely related to disease progression.AIM To explore whether CNPs can induce apoptosis and calcification in BMSCs and analyzed the relationship between these processes.The differential effects of CNPs and nanoscale hydroxyapatites(nHAPs)in inducing apoptosis and calcification in BMSCs were also compared.METHODS CNPs obtained in the early stage were identified by electron microscopy and particle size analysis.BMSCs were cultured with various treatments,including different concentrations of nHAPs,CNPs[2 McFarland(MCF)turbidity,4 MCF,6 MCF],and a transforming growth factor(TGF)-βinhibitor(SB431542)for 72 hours.The isolated CNPs exhibited the expected sizes and shapes.RESULTS Exposure to CNPs and nHAPs suppressed cell proliferation and promoted apoptosis in a concentration-dependent manner,with CNPs exhibiting significantly stronger effects.Alizarin Red staining indicated an increase in calcium deposition with exposure to increasing concentrations of nHAPs and CNPs.Quantitative reverse-transcription polymerase chain reaction results indicated that medium concentrations of nHAPs and CNPs significantly enhanced the expression of pro-apoptotic and pro-calcification markers,whereas the expression of anti-apoptotic Bcl-2 was reduced compared with untreated controls.Western blotting results showed that medium concentrations of CNPs and nHAPs increased the expression of osteopontin,bone morphogenetic protein-2,TGF-β/Smad,Bax,and caspase-3 and decreased Bcl-2 expression compared with controls.CONCLUSION CNPs and nHAPs induced apoptosis and calcification in BMSCs,with CNPs being the most potent.Additionally,the TGF-βinhibitor SB431542 significantly reduced the occurrence of apoptosis and calcification.A correlation was found between apoptosis and calcification,which is likely mediated through the TGF-β/Smad signaling pathway.
基金Supported by Jiangsu Commission of Health of China,No.M2020096.
文摘BACKGROUND Krüppel-like factor-5(KLF5)is a zinc-finger transcription factor related to tumor progression.However,the relationship between KLF5 and lung cancer remains to be identified.AIM To investigate the clinical value of KLF5 and interference with KLF5 mRNA transcription on the effects of biological behaviors in lung squamous-cell carcinoma(LUSC).METHODS Lung KLF5 mRNA data were extracted from bioinformatics databases.Blood and tissues from a cohort of patients with benign or malignant lung diseases were collected with ethical committee consent to validate KLF5 expression via multiplex immunofluorescence and immunohistochemistry,Western blot,Enzyme Linked Immunosorbent Assay or quantitative polymerase chain reaction.Furthermore,KLF5 mRNA was silenced in lung A549 cells to validate biological behaviors in vitro and nude mouse xenograft growth in vivo,respectively.RESULTS A cohort of bioinformatics databases revealed high KLF5 mRNA expression in LUSC(P<0.001)but lower KLF5 mRNA expression in lung adenocarcinoma.Upregulated KLF5 in the lung or sera of patients with lung cancer(P<0.001)were confirmed that related to poor differentiation,lymph node or distant metastasis.Furthermore,the incidence of KLF5 levels greater than 500 ng/mL in LUSC patients was 86.7%,which was significantly greater(P<0.001)than that in cases with benign lung diseases(13.3%)or healthy controls.Functionally,silencing KLF5 mRNA with a specific shRNA significantly suppressed A549 cell proliferation,decreased cell migration,increased the ratio of G2 phase cells in vitro,and inhibited the growth of nude mouse xenografts in vivo.CONCLUSION KLF5 is a novel diagnostic biomarker or potential therapeutic target for LUSC.
文摘The published article titled“MicroRNA-33b Inhibits the Proliferation andMigration of Osteosarcoma Cells via TargetingHypoxia-Inducible Factor-1α”has been retracted from Oncology Research,Vol.25,No.3,2017,pp.397–405.
基金Supported by the Instituto de Salud Carlos Ⅲ(ISCⅢ)Through the Project Co-Funded by the European Union,No.PI20-00487,No.PI23-00119 and No.PI24-01630.
文摘BACKGROUND Diabetes and its associated microvascular complications,such as nephropathy and retinopathy,significantly impact global health.These complications often begin in the prediabetic stage,emphasizing the importance of early detection and intervention.Inflammatory pathways are key contributors to these conditions,and recent research has identified members of the tumor necrosis factor(TNF)receptor superfamily as potential biomarkers.However,their association with renal and retinal dysfunction in individuals with intermediate hyperglycemia(IH)remains underexplored.The Early Prevention of Diabetes Complications(ePREDICE)trial provides a valuable cohort to investigate these associations and improve risk assessment strategies.AIM To identify inflammatory biomarkers associated with early renal and retinal dysfunction in individuals with IH.Specifically,we evaluate the diagnostic and prognostic potential of TNF receptor superfamily members[TNF receptor 1(TNF-R1),TNF receptor 2(TNF-R2)],T-cell immunoglobulin and mucin domain 3(TIM-3)/HAVCR2,galectin-3,and interleukin-6(IL-6)in detecting kidney dysfunction and retinopathy in this high-risk population.By understanding their roles,we seek to enhance early screening methods and inform personalized intervention strategies.METHODS A cross-sectional analysis of 967 individuals with IH from the ePREDICE trial was conducted.Participants underwent comprehensive anthropometric and biochemical assessments.Key inflammatory biomarkers,including TNF-R1,TNF-R2,TIM-3/HAVCR2,galectin-3,and IL-6,were quantified using immunoassays.Renal function was assessed using estimated glomerular filtration rate(eGFR)and albuminuria,while retinopathy was evaluated through fundoscopic examination.Statistical analyses included adjusted mean comparisons,correlation studies,and receiver operating characteristic curve analysis to assess biomarker diagnostic accuracy.RESULTS TNF-R1,TNF-R2,and TIM-3/HAVCR2 were significantly associated with reduced filtration function(eGFR<60 mL/minute/1.73 m^(2))and albuminuria,with area under the curve(AUC)values between 0.815 and 0.845.TIM-3/HAVCR2 emerged as the strongest predictor of retinopathy(AUC=0.737).Strong correlations(r>0.75)were observed among TNF-R1,TNF-R2,and TIM-3/HAVCR2,suggesting a coordinated role in inflammatory pathways.CONCLUSION Our findings highlight the potential of TNF receptor superfamily members as biomarkers for early-stage renal and retinal complications in individuals with IH.Their integration into clinical screening protocols could facilitate earlier detection,improving patient stratification and personalized management strategies.Further longitudinal studies are necessary to validate their predictive value and potential for guiding therapeutic interventions in IH and early diabetes management.
基金Supported by Cancer Sucks,Bixby,Oklahoma Research Grant.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is a global health concern,representing the second most common cause of malignancy-related mortality in the world.The primary cause of HCC in the United States is chronic infection with the hepatitis C virus(HCV).Clinical observations have established sex-based differences in HCV infection with the disease progressing more severely and more rapidly in males and postmenopausal females compared to premenopausal females,suggesting that estrogens and their receptors may play an important role in hepatic defenses and development of HCV-mediated HCC.However,the precise mechanism of estrogen protection and their effects on inflammation is poorly understood.AIM To determine whether estrogen receptor(ER)expression is correlated with the expression of tumor necrosis factor-alpha(TNF-α)in males and females with HCV-associated diseases.METHODS The role of ERs in modulating innate immune responses was investigated using human liver tissues with HCV/cirrhosis and HCV/HCC.Messenger RNA(mRNA)and protein(nuclear and cytoplasmic)expression were measured for all markers of interest and compared to normal human liver tissue samples.RESULTS ERβwas reported for the first time to have a greater mRNA expression than ERαin normal liver(P≤0.001).In addition,ERβmRNA expression was found to be decreased in diseased livers(P≤0.05),while TNF-αexpression was increased(P≤0.0001).Upon stratifying by sex within each disease group,ESR1 was found to be negatively correlated with ESR2 in females with HCV/cirrhosis(r=-0.84,P≤0.001),whereas males with HCV/cirrhosis were found to have a significant positive correlation(r=0.57,P≤0.05).ESR2 mRNA expression had a significant positive correlation with TNF-αin both HCV/cirrhosis(r=0.61,P≤0.001)and HCV/HCC patients(r=0.45,P≤0.05).CONCLUSION All together,these findings indicate that changes in ERβand TNF-αexpression are associated with worsening disease,and may be part of the sex-dependent factors in HCC pathogenesis.
基金supported by the 2025 Fujian Provincial Social Science Foundation Project(FJ2025C074).
文摘This systematic review synthesizes empirical research on external risk factors for adolescent smartphone addiction.Scopus and Web of Science were searched for English peer-reviewed empirical articles from 2008 onward;28 met inclusion criteria(excluding non-adolescents,generic internet addiction,non-empirical work,or non-English).Thematic synthesis organized findings into three external risk domains—family,school,and peers—considering cultural/contextual mechanisms.Family dynamics(parental phubbing,harsh parenting,dysfunction),school stressors,and adverse peer relationships were identified as accumulating,direct and indirect contributors to smartphone addiction.These operate within a techno-ecological framework,where digital technologies amplify vulnerabilities and create new pathways for maladaptive use.Evidence favors an ecological,multi-level perspective.Future research should use longitudinal designs,standardize measures across cultures,and examine understudied regions—especially Africa—to guide culturally sensitive interventions.
