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
Long-term exposure to ambient fine particulate matter(PM2.5)may increase the risk of neurotoxicity in human populations.However,research studies on the underlying mechanisms of chronic PM2.5-induced depression-like be...Long-term exposure to ambient fine particulate matter(PM2.5)may increase the risk of neurotoxicity in human populations.However,research studies on the underlying mechanisms of chronic PM2.5-induced depression-like behaviors,and potential therapeutical strategies,remain scarce.In the present study,after long-term exposure to real-world PM2.5 for 15 weeks,male mice displayed depression-like behaviors,which were revealed using the open field and sucrose preference tests.Mechanistically,chronic PM2.5 exposure promoted astrocytic A1 polarization and disrupted reduction-oxidation balance in the mouse hippocampus.Furthermore,PM2.5-exposed mice displayed pathological damage to hippocampal neurons as well as the inhibition of nuclear factor erythroid 2-related factor 2 signaling.Astrocytic ablation of nuclear factor erythroid 2-related factor 2 exacerbated PM2.5-induced hippocampal neuronal injury in mice via the disruption of astrocyte-to-microglia communication;this finding was confirmed in mice with bilateral and unilateral hippocampal astrocytic Nfe2l2 knockdown.Importantly,the upregulation of nuclear factor erythroid 2-related factor 2 activation by procyanidin significantly ameliorated PM2.5-induced depression-like behaviors through the remodeling of astrocyte-to-microglia communication.Together,our findings shed light on the important role of hippocampal astrocytic nuclear factor erythroid 2-related factor 2 activation for maintaining astrocyte-to-microglia communication,and indicate potential research avenues for therapeutic strategies against PM2.5-induced depresson-like behaviors.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
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
BACKGROUND Rosmarinic acid(RA)is a natural polyphenol carboxylic acid known for its role in chemoprevention.Given its widespread use as a food additive,we are interested in whether RA affects the development of colore...BACKGROUND Rosmarinic acid(RA)is a natural polyphenol carboxylic acid known for its role in chemoprevention.Given its widespread use as a food additive,we are interested in whether RA affects the development of colorectal cancer(CRC).AIM To examine the anti-tumor effects of RA on various CRC cell lines,and to further investigate the possible mechanisms.METHODS Cell Counting Kit-8 assay and optical microscopy imaging were used to evaluate the viability of CRC cell lines.Western blot,quantitative real-time polymerase chain reaction,and flow cytometry analyses were performed to assess cell viability and activation of nuclear factor-kappa B(NF-κB)signaling.Molecular modeling was used to assess the interaction between RA and inhibitory kappa B kinase beta.Luciferase assay was used to examine the activity of NF-κB-driven transcription.The combinations of RA with 5-fluorouracil or oxaliplatin were utilized to evaluate the potential synergistic action of RA with the chemotherapeutics.RESULTS RA exerted potent cytotoxic actions on all six CRC cell lines examined.RA was docked nicely into the binding pocket of inhibitory kappa B kinase beta by molecular modeling.The activity of NF-κB-driven luciferase and the phosphorylation of NF-κB p65 were decreased after exposure to the compound.Lipopolysaccharide-induced NF-κB activation was effectively inhibited by RA,too.Further,RA downregulated the expression of cell proliferationrelated cyclin D1 and MYC,which are target genes of NF-κB.Of note,the cytotoxic actions of 5-fluorouracil and oxaliplatin were markedly enhanced by RA in those CRC cells.CONCLUSION Our results indicate that RA inhibits NF-κB signaling and induces apoptosis in CRC cells.It enhances the cytotoxic actions of chemotherapeutics and might help to improve the chemotherapy of CRC.展开更多
Objectives Dysregulated osteoclast function contributes to skeletal diseases.However,the specific ubiquitination regulators of the osteoclastogenesis repressor MafB,particularly at the post-translational level,remain ...Objectives Dysregulated osteoclast function contributes to skeletal diseases.However,the specific ubiquitination regulators of the osteoclastogenesis repressor MafB,particularly at the post-translational level,remain undefined.This study aims to identify ubiquitin-specific proteases(USPs)that deubiquitinate MafB and enhance its stability.Methods We constructed a MafB-conjugated luciferase and overexpressed 40 individual USPs,measuring changes in luciferase activity.The identified USP was overexpressed in human CD14^(+) peripheral blood mononuclear cells(PBMCs)to evaluate its effect.Osteoclast differentiation was assessed through osteoclast marker Integrin alpha-V(CD51)staining and Western blot analysis.Co-immunoprecipitation(co-IP)was performed to assess the interplay.The influence on MafB ubiquitination and degradation was evaluated via immunoprecipitation and Western blot.Finally,MafB was knocked down in the USP-overexpressing PBMCs to analyze its effect on osteoclast differentiation.Results Overexpression of ubiquitin-specific protease 29(USP29)significantly increased MafB expression by approximately 75%(p<0.0001).Elevated USP29 levels strongly inhibited osteoclastic differentiation in CD14^(+) PBMCs(p<0.0001).USP29 was found to interact with MafB,markedly reducing its ubiquitination and subsequent degradation in PBMCs(p<0.001).Knocking down MafB in USP29-overexpressing PBMCs alleviated the inhibitory effect of USP29 on osteoclastogenesis.Conclusion USP29 acts as a potent stabilizer of MafB,inhibiting osteoclastogenesis in human CD14^(+) PBMCs,at least in part,by enhancing MafB stability.These findings expand our understanding of USP29’s role and the post-translational regulation of MafB.Furthermore,USP29 serves as a vital factor that controls osteoclast differentiation,and its regulatory function is at least partially mediated by deubiquitinating and stabilizing MafB.展开更多
BACKGROUND Radiation induced pulmonary fibrosis(RIPF)is a long-term lung condition with a bleak outlook and few treatment possibilities.Mesenchymal stem cells(MSCs)-derived exosomes(MSCs-exosomes)possess tissue repair...BACKGROUND Radiation induced pulmonary fibrosis(RIPF)is a long-term lung condition with a bleak outlook and few treatment possibilities.Mesenchymal stem cells(MSCs)-derived exosomes(MSCs-exosomes)possess tissue repair and regenerative pro-perties,but their exact mechanisms in RIPF remain unclear.This study explores whether MSCs-exosomes can alleviate RIPF by modulating inflammation,ex-tracellular matrix(ECM)accumulation,and epithelial-mesenchymal transition(EMT)via the protein kinase B(Akt)/nuclear factor kappa B(NF-κB)pathway.Sprague-Dawley rats were received 30 Gy X-ray radiation on the right chest to induce RIPF,while RLE-6TN and BEAS-2B cell lines were exposed to 10 Gy X-rays.Using differential centrifugation,MSCs-exosomes were isolated,and their protective effects were examined both in vivo and in vitro.Inflammatory cytokine concentrations were measured using Luminex liquid chip detection and enzyme linked immunosorbent assay.ECM and EMT-related proteins were analyzed using immunohistochemistry,western blotting,and real-time quantitative polymerase chain reaction.Western blotting and immunohistochemistry were also used to investigate the mechanisms underlying MSCs-exosomes’effects in RIPF.RESULTS Administration of MSCs-exosomes significantly mitigated RIPF,reduced collagen deposition,and decreased levels of various inflammatory cytokines.Additionally,MSCs-exosomes prevented radiation-induced ECM accumulation and EMT.Treatment with MSCs-exosomes notably promoted cell proliferation,suppressed inflammation,and reversed ECM deposition and EMT in radiation-exposed alveolar epithelial cells.Mechanistic analysis further revealed that MSCs-exosomes exerted their anti-RIPF effects by inhibiting the Akt/NF-κB pathway,as shown in both in vivo and in vitro models.CONCLUSION MSCs-exosomes mitigate RIPF by suppressing inflammation,ECM deposition,and EMT through Akt/NF-κB inhibition,highlighting their potential as a therapeutic strategy.展开更多
BACKGROUND Mesenchymal stromal cells(MSCs)are renowned for their immunosuppressive properties,which make them widely used in managing excessive inflammation.Although CD146+and CD146-MSCs exhibit similar morphological ...BACKGROUND Mesenchymal stromal cells(MSCs)are renowned for their immunosuppressive properties,which make them widely used in managing excessive inflammation.Although CD146+and CD146-MSCs exhibit similar morphological traits and surface marker expression levels,the specific characteristics and differential regulatory mechanisms of these two subtypes remain poorly understood.This knowledge gap has limited the precise application of MSCs in targeted thera-peutic strategies.AIM To compare the functional differences between CD146+and CD146-MSCs and investigate the underlying mechanisms.METHODS In this study,magnetic beads were used to sort umbilical cord-derived MSCs into CD146+and CD146-subsets.The pro-angiogenic factors(hepatocyte growth factor,prostaglandin E2,vascular endothelial growth factor,angiopoietin-1)production and immunomodulatory effects on T lymphocyte subsets were evaluated in vitro.The therapeutic efficacy was assessed in an acute respiratory distress syndrome(ARDS)mouse model via tail vein injection.RESULTS Cytokine secretion and angiogenesis:CD146+MSCs significantly increased the production of hepatocyte growth factor,prostaglandin E2,vascular endothelial growth factor,and angiopoietin-1 and exhibited increased pro-angiogenic activity in vitro.Immunomodulatory effects:CD146+MSCs potently inhibited the differentiation and proliferation of pro-inflammatory T helper type 1/T helper type 17 cells while promoting the expansion of regulatory T cells during T lymphocyte activation.ARDS therapy:In a mouse ARDS model,compared with CD146-MSCs,CD146+MSCs demonstrated superior therapeutic efficacy,as evidenced by improved clinical scores.Mechanistically,CD146+MSCs activated the nuclear factor kappa B pathway,upregulated cyclooxygenase 2 expression,and facilitated damaged epithelial cell repair.CONCLUSION CD146+MSCs show stronger ARDS therapeutic potential than CD146-MSCs via pro-angiogenic/immunomodulatory traits.Nuclear factor kappa B/cyclooxygenase 2 activation aids epithelial repair,highlighting CD146+MSCs as promising targets.展开更多
BACKGROUND Erianin is a natural bibenzyl compound extracted from Dendrobium chrysotoxum and is known for its anti-inflammatory and antioxidant properties.AIM To explore the possible therapeutic mechanisms of erianin a...BACKGROUND Erianin is a natural bibenzyl compound extracted from Dendrobium chrysotoxum and is known for its anti-inflammatory and antioxidant properties.AIM To explore the possible therapeutic mechanisms of erianin and determine if it can reduce cardiac damage in mice with type 2 diabetes.METHODS High-fat diet and intraperitoneal injections of streptozotocin were used to induce type 2 diabetes mellitus in C57BL/6 mice.Mice were divided into different groups including control,model,and treatment with various doses of erianin(10,20,and 40 mg/kg)as well as ML-385+erianin group.RESULTS Erianin reduced oxidative stress and inflammation and alleviated diabetic cardiomyopathy through the activation of the adenosine monophosphate-acti-vated protein kinase(AMPK)-nuclear factor erythroid 2-related factor 2(Nrf2)-heme oxygenase-1(HO-1)pathway.Treatments with erianin-M and erianin-H promoted weight stabilization and normalized fasting glucose levels relative to diabetic controls.Echocardiographic assessment demonstrated that erianin dose-dependently enhanced left ventricular systolic function(left ventricular ejection fraction,left ventricular fractional shortening)and mitigated ventricular remodeling(left ventricular internal diameter at end-diastole,left ventricular internal diameter at end-systole;P<0.05 vs model group).No significant differences were observed between the ML-385+erianin and placebo-treated groups.Histopathological examination through hematoxylin-eosin staining indicated that erianin ameliorated myocardial fiber fragmentation,structural disorganization,inflammatory cell infiltration,and cytolytic damage.Furthermore,it significantly reduced the serum levels of cardiac troponin I,creatine kinase,and its MB isoenzyme.However,the ML-385+erianin co-treatment failed to alleviate myocardial injury.Metabolic profiling revealed erianin-mediated improvements in glycemic regulation(glycated hemoglobin:P<0.001),plasma insulin homeostasis,and lipid metabolism(total cholesterol,triglycerides,low-density lipo-protein cholesterol reduction,and high-density lipoprotein cholesterol restoration;P<0.05 vs model group).Pro-inflammatory cytokines including tumor necrosis factor-α,interleukin(IL)-1β,and IL-6 were markedly suppressed in the erianin-M and erianin-H groups compared with the model group,whereas no significant differences were detected between the model and ML-385+erianin groups.Oxidative stress parameters showed decreased malondialdehyde levels accompanied by elevated superoxide dismutase and catalase activities in erianin-treated groups,with the most pronounced effects in the erianin-H group(P<0.05).Western blot analysis confirmed the significant upregulation of proteins associated with the AMPK/Nrf2/HO-1 pathway in erianin-M and erianin-H groups.These protective effects were abolished in the ML-385+erianin co-treatment group,which showed no statistical differences from the model group.CONCLUSION Erianin can effectively alleviate myocardial injury in type 2 diabetic mice by activating the AMPK-Nrf2-HO-1 pathway.展开更多
BACKGROUND Excessive oxidative stress plays a key role in the development of diabetic complications,including impaired ulcer healing.Previous studies have shown that fish scale ointment can promote wound healing.AIM T...BACKGROUND Excessive oxidative stress plays a key role in the development of diabetic complications,including impaired ulcer healing.Previous studies have shown that fish scale ointment can promote wound healing.AIM To preliminarily investigate the effect of fish scale ointment on wound healing in a diabetic foot ulcer(DFU)rat model by examining its regulation of the nuclear factor E2-related factor 2(Nrf2)pathway and induction of ferroptosis.METHODS Fish scale ointment(collagen product)was prepared from 500 g of silver carp scales.A diabetic rat model was induced by high-fat and high-sugar feeding combined with intraperitoneal streptozotocin injections.For the DFU rat model,ulcer wounds were created by removing dorsal foot hair and cutting the skin to the fascia.The diabetic rats were randomized into five groups:Model,fish scale collagen(FSC),control+liproxstatin-1(Lip-1),model+Lip-1,and FSC+Lip-1.In each group,treatments were administered once daily by topical application and intraperitoneal injection for 14 days.Wound healing was evaluated on days 7 and 14 after treatment.Hematoxylin and eosin staining was used to assess wound injury and capillary formation.Basic fibroblast growth factor(bFGF)and CD31 levels in wound tissue were measured by immunohistochemistry.Additionally,malondialdehyde(MDA),glutathione(GSH),ferroptosis-associated genes,and iron ion concentrations were quantified using assay kits.Protein levels of Nrf2,heme oxygenase-1(HO-1),and glutathione peroxidase 4(GPX4)were determined using Western blotting.RESULTS Compared with the control group,the model group showed slower wound healing,reduced angiogenesis,decreased bFGF and CD31 levels,increased iron ion concentration and MDA levels,reduced GSH levels,and decreased Nrf2,HO-1,and GPX4 protein expression(all P<0.05).The FSC,model+Lip-1,and FSC+Lip-1 groups showed increased wound healing and angiogenesis,elevated bFGF and CD31 expression,lowered iron ion concentration and MDA levels,increased GSH levels,and enhanced Nrf2,HO-1,and GPX4 protein levels compared with the model group(P<0.05).Improvements were more pronounced in the FSC+Lip-1 group compared with the FSC group(P<0.05).CONCLUSION Fish scale ointment promotes angiogenesis and wound healing in DFU rat models by inhibiting ferroptosis,possibly through the activation of the Nrf2 pathway.展开更多
BACKGROUND Negative pressure wound therapy(NPWT)is a potential treatment for diabetic foot ulcers(DFUs),although the mechanisms underlying its effectiveness remain unclear.This study posits that NPWT may improve wound...BACKGROUND Negative pressure wound therapy(NPWT)is a potential treatment for diabetic foot ulcers(DFUs),although the mechanisms underlying its effectiveness remain unclear.This study posits that NPWT may improve wound healing by promoting angiogenesis and activating the nuclear factor erythroid 2-related factor 2(Nrf2)/Kelch-like epichlorohydrin-associated protein 1(Keap1)signaling pathway,which is crucial for the body’s defense against oxidative stress.The hypothesis indicates that enhancing antioxidant defenses through NPWT may positively affect the healing process.There are still limited data on the roles of Nrf2,its downstream signaling molecules,and angiogenesis markers in patients undergoing NPWT.AIM To study the mechanism of NPWT in DFUs.METHODS This study included a total of 40 hospitalized patients with DFUs from Xuzhou Central Hospital,who were divided into Control group(n=21)and NPWT group(n=19).The levels of Nrf2 and Keap1 were analyzed in the granulation tissue 7 days after treatment.The wound condition,erythrocyte sedimentation rate(ESR),procalcitonin(PCT),interleukin 6(IL-6),tumor necrosis factor alpha(TNF-α),vascular endothelial growth factor(VEGF),basic fibroblast growth factor(b-FGF),cluster of differentiation 31(CD31),and levels of oxidative stress[malondialdehyde(MDA),superoxide dismutase(SOD),catalase(CAT),and total antioxidant capacity(T-AOC)]were analyzed before and 7 days after treatment by the Mann-Whitney U test.RESULTS The NPWT group demonstrated significant improvements in wound healing compared to the control group after 7 days of treatment.The levels of ESR,PCT,IL-6,and TNF-αwere significantly reduced in the NPWT group compared to the control group(P<0.05),while the levels of CD31,VEGF,and b-FGF showed significant increases(P<0.05).The NPWT group exhibited notable elevations in the levels of Nrf2 and its downstream targets(SOD,CAT,and T-AOC),accompanied by decreases in the levels of Keap1 and MDA(P<0.05).CONCLUSION NPWT may contribute to the healing of DFUs by potentially reducing levels of oxidative stress.Its effects could possibly be enhanced through the action of Nrf2.展开更多
Colorectal cancer(CRC)is the third most common malignancy.However,the efficacy of current treatment strategies remains limited.In recent years,monomeric compounds from traditional Chinese medicine have received extens...Colorectal cancer(CRC)is the third most common malignancy.However,the efficacy of current treatment strategies remains limited.In recent years,monomeric compounds from traditional Chinese medicine have received extensive attention in cancer therapy.Rosmarinic acid(RA),a natural phenolic acid,has multiple biological activities and exhibits anti-oncogenic effects in several cancers.Liu et al previously uncovered that RA could serve as a dual-action therapeutic agent in CRC.By suppressing nuclear factor-kappa B signaling via direct inhibition of inhibitory kappa B kinase beta,RA not only impedes tumor progression but also synergizes with first-line chemotherapeutics(5-fluorouracil/oxaliplatin)to reverse drug resistance.The authors demonstrate RA’s capacity to downregulate nuclear factor-kappa B-driven oncogenes and enhance chemotherapeutic cytotoxicity in vitro through integrative approaches,including molecular docking,luciferase assays,and functional validation.While these findings position RA as a cost-effective adjuvant in precision oncology,critical clinical translational gaps remain,including optimizing RA’s in vivo bioavailability,validating systemic safety in combinatorial regimens,and elucidating its immunomodulatory effects within the tumor microenvironment.This underscores the urgency of bridging phytochemistry and clinical oncology,advocating for biomarker-driven animal studies and phase I trials to translate RA’s potential into actionable CRC therapies.By addressing these hurdles,RA could emerge as a paradigm-shifting agent,harmonizing natural product efficacy with modern therapeutic precision.展开更多
Metabolic dysfunction-associated steatotic liver disease,characterized by pathological intracellular triglyceride(TG)accumulation,is mechanistically associated with the disrupted spatiotemporal regulation of hepatocyt...Metabolic dysfunction-associated steatotic liver disease,characterized by pathological intracellular triglyceride(TG)accumulation,is mechanistically associated with the disrupted spatiotemporal regulation of hepatocyte nuclear factor(HNF)-dependent transcriptional programs.HNFs,including key members such as HNF-1α,HNF-4α,and HNF-6,constitute a liver-enriched family of transcription factors that govern hepatic lipid metabolism through hierarchical transcriptional regulatory networks.These networks critically regulate the dynamic equilibrium of TG metabolism,encompassing TG synthesis,storage,lipolysis,and lipoprotein-mediated export.This review comprehensively deciphers the molecular cascades through which HNF dysfunction exacerbates TG metabolic disorder in metabolic dysfunction-associated steatotic liver disease.Additionally,we evaluate emerging translational strategies targeting key HNF regulatory nodes and discuss current clinical challenges as well as potential solutions.展开更多
BACKGROUND Metabolic dysfunction-associated steatotic liver disease(MASLD)has emerged as a prominent and pervasive global health challenge.Bicuculline(BIC),which is a key active component of the anti-MASLD prescriptio...BACKGROUND Metabolic dysfunction-associated steatotic liver disease(MASLD)has emerged as a prominent and pervasive global health challenge.Bicuculline(BIC),which is a key active component of the anti-MASLD prescription"Eight Zhes Decoction",has been preliminarily shown by our research team to have significant potential in treating MASLD.AIM To determine BIC's efficacy in treating MASLD by regulating lipid metabolism and suppressing hepatic inflammation via nuclear factor-kappa B(NF-κB)pathway,identifying it as a therapeutic candidate.METHODS This study explored the potential of BIC in preventing and treating MASLD using zebrafish,cellular(HepG2 and AML12),and mouse models.RESULTS Our results indicate that BIC significantly reduces lipid accumulation and inflammation both in vivo and in vitro.Transcriptomic analysis suggested that the anti-MASLD effects of BIC are linked to the inhibition of the NF-κB pathway,which plays a critical role in mitigating inflammation and lipid deposition.CONCLUSION This study is the first to demonstrate that BIC specifically alleviates lipid accumulation and hepatic steatosis in MASLD models via the NF-κB signaling pathway.Overall,BIC has emerged as a promising candidate for treating MASLD.展开更多
OBJECTIVE:To investigate the mechanism by which An's anorectal fumigation lotion(AAFL)treats inflammatory mixed hemorrhoids.METHODS:Eighty Sprague-Dawley rats,with an equal number of males and females,were randoml...OBJECTIVE:To investigate the mechanism by which An's anorectal fumigation lotion(AAFL)treats inflammatory mixed hemorrhoids.METHODS:Eighty Sprague-Dawley rats,with an equal number of males and females,were randomly assigned to the following four groups:control,model,AAFL,and positive groups.Following hemorrhoid induction,hemorrhoidal tissues were collected from the rats for analysis.Pathological alterations in these tissues were examined via hematoxylin-eosin staining.Immunohistochemistry was used to detect inflammatory markers.The ultrastructural pathological changes in these tissues were observed by transmission electron microscopy.Reverse transcription-polymerase chain reaction and Western blotting were used to analyze the gene and protein expression of nuclear factor kappa-B(NF-κB)p65,inhibitor of kappa-B(IκB),inhibitor of NF-κB kinase(IκK-β),interleukin-1 beta(IL-1β),interleukin-6(IL-6),and tumor necrosis factor-alpha(TNF-α).RESULTS:Compared with the control group,the rats in each treatment group showed general improvements in hemorrhoidal tissue pathology.The AAFL group showed increased IκB expression and decreased IL-1β,IL-6,TNF-α,NF-κB,p65,and IκK-βexpressions.CONCLUSION:AAFL can decrease the production of inflammatory markers by targeting the NF-κB pathway,resulting in improved pathological conditions in mixed hemorrhoids.Our findings will aid in the treatment of mixed hemorrhoids.展开更多
BACKGROUND In vivo degradation of bone scaffolds is significantly influenced by osteoclast(OC)activity,which is orchestrated by the interplay between receptor activator of nuclear factor-kappa B ligand(RANKL)and osteo...BACKGROUND In vivo degradation of bone scaffolds is significantly influenced by osteoclast(OC)activity,which is orchestrated by the interplay between receptor activator of nuclear factor-kappa B ligand(RANKL)and osteoprotegerin(OPG).The ratio of RANKL/OPG is a crucial determinant of OC-mediated bone resorption,which plays an integral role in bone remodeling and scaffold degradation.Elevated levels of RANKL relative to OPG enhance osteoclastogenesis,thereby accelerating the degradation process essential for integrating bone scaffolds into the host tissue.AIM To elucidate the effects of OPG gene silencing on osteoclastogenesis within rat bone marrow-derived mesenchymal stem cells(BMSCs).By investigating these effects,the study aimed to provide deeper insights into the regulatory mechanisms that influence bone scaffold degradation,potentially leading to improved bone repair and regeneration strategies.METHODS We employed recombinant lentiviral plasmids to silence the OPG gene in rat BMSCs to achieve the aims.The efficacy of gene silencing was assessed using quantitative reverse transcription polymerase chain reaction and western blot analysis to measure the expression levels of OPG and RANKL.Tartrate-resistant acid phosphatase staining was utilized to evaluate the formation of OCs.Additionally,co-immunoprecipitation assays were conducted to explore the interactions between RANKL and OPG proteins,further assessing the biochemical pathways involved in osteoclastogenesis.RESULTS The silencing of the OPG gene in BMSCs resulted in a significant increase in the RANKL/OPG ratio,evidenced by decreased expression levels of OPG and increased levels of RANKL.Enhanced osteoclastogenesis was observed through tartrate-resistant acid phosphatase staining,which indicated a substantial rise in OC formation in response to the altered RANKL/OPG balance.The co-immunoprecipitation assays provided concrete evidence of the direct interaction between RANKL and OPG proteins,substantiating their pivotal roles in regulating OC activity.CONCLUSION The findings from this study underscore the critical role of the RANKL/OPG axis in osteoclastogenesis.Silencing of the OPG gene in BMSCs effectively increases the RANKL/OPG ratio,promoting OC activity and potentially enhancing bone scaffold degradation.This regulatory mechanism offers a promising avenue for modulating bone remodeling processes,which is essential for effective bone repair and the successful integration of bone scaffolds into damaged sites.Future research might focus on optimizing the control of this axis to better facilitate bone tissue engineering and regenerative therapies.展开更多
Objective To investigate the mechanisms of catgut implantation at acupoints on ulcerative colitis. Methods Eighteen SD rats were randomly divided into a normal control group （NC）, a model group （MO） and a catgut i...Objective To investigate the mechanisms of catgut implantation at acupoints on ulcerative colitis. Methods Eighteen SD rats were randomly divided into a normal control group （NC）, a model group （MO） and a catgut implantation group （CI） with 6 rats in each group. Animals in group MO and group CI were treated by trinitro-benzene-sulfonic acid （TNBS） to establish model with colitis. No other treatment was given to the rats in group MO, but catgut was implanted at ＂Shàngjùxū＂ （上 巨虚 ST 37）, ＂Tiānshū＂ （天枢 ST 25） and ＂Dàchángshū＂ （大肠俞 BL 25） in the rats in group CI. The symptoms of diarrhea and bloody stool, and changes in histopathology were detected 15 days after the treatment. Expressions of splenic lymphocyte nuclear factor κB p65（NF-κB p65）and correlated signaling molecules（β2AR）were detected by the western blot method. Results Diarrhea and mucus bloody purulent stool were soon controlled, and mucous injures were obviously improved in group CI. The NF-κB p65 value of splenic lymphocytes was signifi cantly increased （P0.01） and expression of β2AR remarkably reduced in group MO （P0.01）, compared with group NC. But, the NF-κB p65 value was significantly decreased （P0.01） and expression of β2AR remarkably increased in group CI （P 0.01） , compared with group MO. Conclusion Catgut implantation at acupoints is obviously effective in treating experimental colitis. Modulation of NF-κB p65 and the correlated signaling molecules β2AR may be involved in the mechanisms.展开更多
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.
基金National Basic Research Plan Project of China,No.2023YFC3708303the National Natural Science Foundation of China,No.82241084the High-level Talent in Public Health of Beijing,No.Discipline Leaders-03-29(all to XL).
文摘Long-term exposure to ambient fine particulate matter(PM2.5)may increase the risk of neurotoxicity in human populations.However,research studies on the underlying mechanisms of chronic PM2.5-induced depression-like behaviors,and potential therapeutical strategies,remain scarce.In the present study,after long-term exposure to real-world PM2.5 for 15 weeks,male mice displayed depression-like behaviors,which were revealed using the open field and sucrose preference tests.Mechanistically,chronic PM2.5 exposure promoted astrocytic A1 polarization and disrupted reduction-oxidation balance in the mouse hippocampus.Furthermore,PM2.5-exposed mice displayed pathological damage to hippocampal neurons as well as the inhibition of nuclear factor erythroid 2-related factor 2 signaling.Astrocytic ablation of nuclear factor erythroid 2-related factor 2 exacerbated PM2.5-induced hippocampal neuronal injury in mice via the disruption of astrocyte-to-microglia communication;this finding was confirmed in mice with bilateral and unilateral hippocampal astrocytic Nfe2l2 knockdown.Importantly,the upregulation of nuclear factor erythroid 2-related factor 2 activation by procyanidin significantly ameliorated PM2.5-induced depression-like behaviors through the remodeling of astrocyte-to-microglia communication.Together,our findings shed light on the important role of hippocampal astrocytic nuclear factor erythroid 2-related factor 2 activation for maintaining astrocyte-to-microglia communication,and indicate potential research avenues for therapeutic strategies against PM2.5-induced depresson-like behaviors.
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 Natural Science Foundation of Heilongjiang Province of China Under Grant,No.PL2024H020High-Quality Innovation Platform of Science and Education Innovation Zone in Suzhou Industrial Park-Key Platform Project,No.YZCXPT2023104.
文摘BACKGROUND Rosmarinic acid(RA)is a natural polyphenol carboxylic acid known for its role in chemoprevention.Given its widespread use as a food additive,we are interested in whether RA affects the development of colorectal cancer(CRC).AIM To examine the anti-tumor effects of RA on various CRC cell lines,and to further investigate the possible mechanisms.METHODS Cell Counting Kit-8 assay and optical microscopy imaging were used to evaluate the viability of CRC cell lines.Western blot,quantitative real-time polymerase chain reaction,and flow cytometry analyses were performed to assess cell viability and activation of nuclear factor-kappa B(NF-κB)signaling.Molecular modeling was used to assess the interaction between RA and inhibitory kappa B kinase beta.Luciferase assay was used to examine the activity of NF-κB-driven transcription.The combinations of RA with 5-fluorouracil or oxaliplatin were utilized to evaluate the potential synergistic action of RA with the chemotherapeutics.RESULTS RA exerted potent cytotoxic actions on all six CRC cell lines examined.RA was docked nicely into the binding pocket of inhibitory kappa B kinase beta by molecular modeling.The activity of NF-κB-driven luciferase and the phosphorylation of NF-κB p65 were decreased after exposure to the compound.Lipopolysaccharide-induced NF-κB activation was effectively inhibited by RA,too.Further,RA downregulated the expression of cell proliferationrelated cyclin D1 and MYC,which are target genes of NF-κB.Of note,the cytotoxic actions of 5-fluorouracil and oxaliplatin were markedly enhanced by RA in those CRC cells.CONCLUSION Our results indicate that RA inhibits NF-κB signaling and induces apoptosis in CRC cells.It enhances the cytotoxic actions of chemotherapeutics and might help to improve the chemotherapy of CRC.
文摘Objectives Dysregulated osteoclast function contributes to skeletal diseases.However,the specific ubiquitination regulators of the osteoclastogenesis repressor MafB,particularly at the post-translational level,remain undefined.This study aims to identify ubiquitin-specific proteases(USPs)that deubiquitinate MafB and enhance its stability.Methods We constructed a MafB-conjugated luciferase and overexpressed 40 individual USPs,measuring changes in luciferase activity.The identified USP was overexpressed in human CD14^(+) peripheral blood mononuclear cells(PBMCs)to evaluate its effect.Osteoclast differentiation was assessed through osteoclast marker Integrin alpha-V(CD51)staining and Western blot analysis.Co-immunoprecipitation(co-IP)was performed to assess the interplay.The influence on MafB ubiquitination and degradation was evaluated via immunoprecipitation and Western blot.Finally,MafB was knocked down in the USP-overexpressing PBMCs to analyze its effect on osteoclast differentiation.Results Overexpression of ubiquitin-specific protease 29(USP29)significantly increased MafB expression by approximately 75%(p<0.0001).Elevated USP29 levels strongly inhibited osteoclastic differentiation in CD14^(+) PBMCs(p<0.0001).USP29 was found to interact with MafB,markedly reducing its ubiquitination and subsequent degradation in PBMCs(p<0.001).Knocking down MafB in USP29-overexpressing PBMCs alleviated the inhibitory effect of USP29 on osteoclastogenesis.Conclusion USP29 acts as a potent stabilizer of MafB,inhibiting osteoclastogenesis in human CD14^(+) PBMCs,at least in part,by enhancing MafB stability.These findings expand our understanding of USP29’s role and the post-translational regulation of MafB.Furthermore,USP29 serves as a vital factor that controls osteoclast differentiation,and its regulatory function is at least partially mediated by deubiquitinating and stabilizing MafB.
基金Supported by Natural Science Foundation of Liaoning Province,No.2024-MS-250.
文摘BACKGROUND Radiation induced pulmonary fibrosis(RIPF)is a long-term lung condition with a bleak outlook and few treatment possibilities.Mesenchymal stem cells(MSCs)-derived exosomes(MSCs-exosomes)possess tissue repair and regenerative pro-perties,but their exact mechanisms in RIPF remain unclear.This study explores whether MSCs-exosomes can alleviate RIPF by modulating inflammation,ex-tracellular matrix(ECM)accumulation,and epithelial-mesenchymal transition(EMT)via the protein kinase B(Akt)/nuclear factor kappa B(NF-κB)pathway.Sprague-Dawley rats were received 30 Gy X-ray radiation on the right chest to induce RIPF,while RLE-6TN and BEAS-2B cell lines were exposed to 10 Gy X-rays.Using differential centrifugation,MSCs-exosomes were isolated,and their protective effects were examined both in vivo and in vitro.Inflammatory cytokine concentrations were measured using Luminex liquid chip detection and enzyme linked immunosorbent assay.ECM and EMT-related proteins were analyzed using immunohistochemistry,western blotting,and real-time quantitative polymerase chain reaction.Western blotting and immunohistochemistry were also used to investigate the mechanisms underlying MSCs-exosomes’effects in RIPF.RESULTS Administration of MSCs-exosomes significantly mitigated RIPF,reduced collagen deposition,and decreased levels of various inflammatory cytokines.Additionally,MSCs-exosomes prevented radiation-induced ECM accumulation and EMT.Treatment with MSCs-exosomes notably promoted cell proliferation,suppressed inflammation,and reversed ECM deposition and EMT in radiation-exposed alveolar epithelial cells.Mechanistic analysis further revealed that MSCs-exosomes exerted their anti-RIPF effects by inhibiting the Akt/NF-κB pathway,as shown in both in vivo and in vitro models.CONCLUSION MSCs-exosomes mitigate RIPF by suppressing inflammation,ECM deposition,and EMT through Akt/NF-κB inhibition,highlighting their potential as a therapeutic strategy.
基金Supported by the Science and Technology SMEs Innovation Capacity Improvement Project of Shandong Province,No.2022TSGC1004National Key R&D Program of China,No.2021YFA1101502。
文摘BACKGROUND Mesenchymal stromal cells(MSCs)are renowned for their immunosuppressive properties,which make them widely used in managing excessive inflammation.Although CD146+and CD146-MSCs exhibit similar morphological traits and surface marker expression levels,the specific characteristics and differential regulatory mechanisms of these two subtypes remain poorly understood.This knowledge gap has limited the precise application of MSCs in targeted thera-peutic strategies.AIM To compare the functional differences between CD146+and CD146-MSCs and investigate the underlying mechanisms.METHODS In this study,magnetic beads were used to sort umbilical cord-derived MSCs into CD146+and CD146-subsets.The pro-angiogenic factors(hepatocyte growth factor,prostaglandin E2,vascular endothelial growth factor,angiopoietin-1)production and immunomodulatory effects on T lymphocyte subsets were evaluated in vitro.The therapeutic efficacy was assessed in an acute respiratory distress syndrome(ARDS)mouse model via tail vein injection.RESULTS Cytokine secretion and angiogenesis:CD146+MSCs significantly increased the production of hepatocyte growth factor,prostaglandin E2,vascular endothelial growth factor,and angiopoietin-1 and exhibited increased pro-angiogenic activity in vitro.Immunomodulatory effects:CD146+MSCs potently inhibited the differentiation and proliferation of pro-inflammatory T helper type 1/T helper type 17 cells while promoting the expansion of regulatory T cells during T lymphocyte activation.ARDS therapy:In a mouse ARDS model,compared with CD146-MSCs,CD146+MSCs demonstrated superior therapeutic efficacy,as evidenced by improved clinical scores.Mechanistically,CD146+MSCs activated the nuclear factor kappa B pathway,upregulated cyclooxygenase 2 expression,and facilitated damaged epithelial cell repair.CONCLUSION CD146+MSCs show stronger ARDS therapeutic potential than CD146-MSCs via pro-angiogenic/immunomodulatory traits.Nuclear factor kappa B/cyclooxygenase 2 activation aids epithelial repair,highlighting CD146+MSCs as promising targets.
文摘BACKGROUND Erianin is a natural bibenzyl compound extracted from Dendrobium chrysotoxum and is known for its anti-inflammatory and antioxidant properties.AIM To explore the possible therapeutic mechanisms of erianin and determine if it can reduce cardiac damage in mice with type 2 diabetes.METHODS High-fat diet and intraperitoneal injections of streptozotocin were used to induce type 2 diabetes mellitus in C57BL/6 mice.Mice were divided into different groups including control,model,and treatment with various doses of erianin(10,20,and 40 mg/kg)as well as ML-385+erianin group.RESULTS Erianin reduced oxidative stress and inflammation and alleviated diabetic cardiomyopathy through the activation of the adenosine monophosphate-acti-vated protein kinase(AMPK)-nuclear factor erythroid 2-related factor 2(Nrf2)-heme oxygenase-1(HO-1)pathway.Treatments with erianin-M and erianin-H promoted weight stabilization and normalized fasting glucose levels relative to diabetic controls.Echocardiographic assessment demonstrated that erianin dose-dependently enhanced left ventricular systolic function(left ventricular ejection fraction,left ventricular fractional shortening)and mitigated ventricular remodeling(left ventricular internal diameter at end-diastole,left ventricular internal diameter at end-systole;P<0.05 vs model group).No significant differences were observed between the ML-385+erianin and placebo-treated groups.Histopathological examination through hematoxylin-eosin staining indicated that erianin ameliorated myocardial fiber fragmentation,structural disorganization,inflammatory cell infiltration,and cytolytic damage.Furthermore,it significantly reduced the serum levels of cardiac troponin I,creatine kinase,and its MB isoenzyme.However,the ML-385+erianin co-treatment failed to alleviate myocardial injury.Metabolic profiling revealed erianin-mediated improvements in glycemic regulation(glycated hemoglobin:P<0.001),plasma insulin homeostasis,and lipid metabolism(total cholesterol,triglycerides,low-density lipo-protein cholesterol reduction,and high-density lipoprotein cholesterol restoration;P<0.05 vs model group).Pro-inflammatory cytokines including tumor necrosis factor-α,interleukin(IL)-1β,and IL-6 were markedly suppressed in the erianin-M and erianin-H groups compared with the model group,whereas no significant differences were detected between the model and ML-385+erianin groups.Oxidative stress parameters showed decreased malondialdehyde levels accompanied by elevated superoxide dismutase and catalase activities in erianin-treated groups,with the most pronounced effects in the erianin-H group(P<0.05).Western blot analysis confirmed the significant upregulation of proteins associated with the AMPK/Nrf2/HO-1 pathway in erianin-M and erianin-H groups.These protective effects were abolished in the ML-385+erianin co-treatment group,which showed no statistical differences from the model group.CONCLUSION Erianin can effectively alleviate myocardial injury in type 2 diabetic mice by activating the AMPK-Nrf2-HO-1 pathway.
基金Supported by the National Natural Science Foundation of China,No.82172095Qingdao Municipal Traditional Chinese Medicine Science and Technology Project,No.2022-zyym03.
文摘BACKGROUND Excessive oxidative stress plays a key role in the development of diabetic complications,including impaired ulcer healing.Previous studies have shown that fish scale ointment can promote wound healing.AIM To preliminarily investigate the effect of fish scale ointment on wound healing in a diabetic foot ulcer(DFU)rat model by examining its regulation of the nuclear factor E2-related factor 2(Nrf2)pathway and induction of ferroptosis.METHODS Fish scale ointment(collagen product)was prepared from 500 g of silver carp scales.A diabetic rat model was induced by high-fat and high-sugar feeding combined with intraperitoneal streptozotocin injections.For the DFU rat model,ulcer wounds were created by removing dorsal foot hair and cutting the skin to the fascia.The diabetic rats were randomized into five groups:Model,fish scale collagen(FSC),control+liproxstatin-1(Lip-1),model+Lip-1,and FSC+Lip-1.In each group,treatments were administered once daily by topical application and intraperitoneal injection for 14 days.Wound healing was evaluated on days 7 and 14 after treatment.Hematoxylin and eosin staining was used to assess wound injury and capillary formation.Basic fibroblast growth factor(bFGF)and CD31 levels in wound tissue were measured by immunohistochemistry.Additionally,malondialdehyde(MDA),glutathione(GSH),ferroptosis-associated genes,and iron ion concentrations were quantified using assay kits.Protein levels of Nrf2,heme oxygenase-1(HO-1),and glutathione peroxidase 4(GPX4)were determined using Western blotting.RESULTS Compared with the control group,the model group showed slower wound healing,reduced angiogenesis,decreased bFGF and CD31 levels,increased iron ion concentration and MDA levels,reduced GSH levels,and decreased Nrf2,HO-1,and GPX4 protein expression(all P<0.05).The FSC,model+Lip-1,and FSC+Lip-1 groups showed increased wound healing and angiogenesis,elevated bFGF and CD31 expression,lowered iron ion concentration and MDA levels,increased GSH levels,and enhanced Nrf2,HO-1,and GPX4 protein levels compared with the model group(P<0.05).Improvements were more pronounced in the FSC+Lip-1 group compared with the FSC group(P<0.05).CONCLUSION Fish scale ointment promotes angiogenesis and wound healing in DFU rat models by inhibiting ferroptosis,possibly through the activation of the Nrf2 pathway.
文摘BACKGROUND Negative pressure wound therapy(NPWT)is a potential treatment for diabetic foot ulcers(DFUs),although the mechanisms underlying its effectiveness remain unclear.This study posits that NPWT may improve wound healing by promoting angiogenesis and activating the nuclear factor erythroid 2-related factor 2(Nrf2)/Kelch-like epichlorohydrin-associated protein 1(Keap1)signaling pathway,which is crucial for the body’s defense against oxidative stress.The hypothesis indicates that enhancing antioxidant defenses through NPWT may positively affect the healing process.There are still limited data on the roles of Nrf2,its downstream signaling molecules,and angiogenesis markers in patients undergoing NPWT.AIM To study the mechanism of NPWT in DFUs.METHODS This study included a total of 40 hospitalized patients with DFUs from Xuzhou Central Hospital,who were divided into Control group(n=21)and NPWT group(n=19).The levels of Nrf2 and Keap1 were analyzed in the granulation tissue 7 days after treatment.The wound condition,erythrocyte sedimentation rate(ESR),procalcitonin(PCT),interleukin 6(IL-6),tumor necrosis factor alpha(TNF-α),vascular endothelial growth factor(VEGF),basic fibroblast growth factor(b-FGF),cluster of differentiation 31(CD31),and levels of oxidative stress[malondialdehyde(MDA),superoxide dismutase(SOD),catalase(CAT),and total antioxidant capacity(T-AOC)]were analyzed before and 7 days after treatment by the Mann-Whitney U test.RESULTS The NPWT group demonstrated significant improvements in wound healing compared to the control group after 7 days of treatment.The levels of ESR,PCT,IL-6,and TNF-αwere significantly reduced in the NPWT group compared to the control group(P<0.05),while the levels of CD31,VEGF,and b-FGF showed significant increases(P<0.05).The NPWT group exhibited notable elevations in the levels of Nrf2 and its downstream targets(SOD,CAT,and T-AOC),accompanied by decreases in the levels of Keap1 and MDA(P<0.05).CONCLUSION NPWT may contribute to the healing of DFUs by potentially reducing levels of oxidative stress.Its effects could possibly be enhanced through the action of Nrf2.
文摘Colorectal cancer(CRC)is the third most common malignancy.However,the efficacy of current treatment strategies remains limited.In recent years,monomeric compounds from traditional Chinese medicine have received extensive attention in cancer therapy.Rosmarinic acid(RA),a natural phenolic acid,has multiple biological activities and exhibits anti-oncogenic effects in several cancers.Liu et al previously uncovered that RA could serve as a dual-action therapeutic agent in CRC.By suppressing nuclear factor-kappa B signaling via direct inhibition of inhibitory kappa B kinase beta,RA not only impedes tumor progression but also synergizes with first-line chemotherapeutics(5-fluorouracil/oxaliplatin)to reverse drug resistance.The authors demonstrate RA’s capacity to downregulate nuclear factor-kappa B-driven oncogenes and enhance chemotherapeutic cytotoxicity in vitro through integrative approaches,including molecular docking,luciferase assays,and functional validation.While these findings position RA as a cost-effective adjuvant in precision oncology,critical clinical translational gaps remain,including optimizing RA’s in vivo bioavailability,validating systemic safety in combinatorial regimens,and elucidating its immunomodulatory effects within the tumor microenvironment.This underscores the urgency of bridging phytochemistry and clinical oncology,advocating for biomarker-driven animal studies and phase I trials to translate RA’s potential into actionable CRC therapies.By addressing these hurdles,RA could emerge as a paradigm-shifting agent,harmonizing natural product efficacy with modern therapeutic precision.
基金Supported by the Science and Technology Planning Projects of Guizhou Province,No.QKHJC-MS[2025]384the Science and Technology Planning Projects of Zunyi City,No.ZSKHHZ(2023)470+3 种基金the WBE Liver Fibrosis Foundation,No.CFHPC2025028Chinese Foundation for Hepatitis Prevention and Control Muxin Research Fund of Chronic Hepatitis B,No.MX202404Beijing Liver and Gallbladder Mutual Aid Public Welfare Foundation Artificial Liver Special Fund,No.iGandanF-1082024-RGG018the Student Innovation and Entrepreneurship Training Program of Zunyi Medical University,No.2024106610923.
文摘Metabolic dysfunction-associated steatotic liver disease,characterized by pathological intracellular triglyceride(TG)accumulation,is mechanistically associated with the disrupted spatiotemporal regulation of hepatocyte nuclear factor(HNF)-dependent transcriptional programs.HNFs,including key members such as HNF-1α,HNF-4α,and HNF-6,constitute a liver-enriched family of transcription factors that govern hepatic lipid metabolism through hierarchical transcriptional regulatory networks.These networks critically regulate the dynamic equilibrium of TG metabolism,encompassing TG synthesis,storage,lipolysis,and lipoprotein-mediated export.This review comprehensively deciphers the molecular cascades through which HNF dysfunction exacerbates TG metabolic disorder in metabolic dysfunction-associated steatotic liver disease.Additionally,we evaluate emerging translational strategies targeting key HNF regulatory nodes and discuss current clinical challenges as well as potential solutions.
基金Supported by Joint TCM Science&Technology Projects of National Demonstration Zones for Comprehensive TCM Reform,No.GZYKJS-ZJ-2025-044Ningbo Top Medical and Health Research Program,No.2023020612.
文摘BACKGROUND Metabolic dysfunction-associated steatotic liver disease(MASLD)has emerged as a prominent and pervasive global health challenge.Bicuculline(BIC),which is a key active component of the anti-MASLD prescription"Eight Zhes Decoction",has been preliminarily shown by our research team to have significant potential in treating MASLD.AIM To determine BIC's efficacy in treating MASLD by regulating lipid metabolism and suppressing hepatic inflammation via nuclear factor-kappa B(NF-κB)pathway,identifying it as a therapeutic candidate.METHODS This study explored the potential of BIC in preventing and treating MASLD using zebrafish,cellular(HepG2 and AML12),and mouse models.RESULTS Our results indicate that BIC significantly reduces lipid accumulation and inflammation both in vivo and in vitro.Transcriptomic analysis suggested that the anti-MASLD effects of BIC are linked to the inhibition of the NF-κB pathway,which plays a critical role in mitigating inflammation and lipid deposition.CONCLUSION This study is the first to demonstrate that BIC specifically alleviates lipid accumulation and hepatic steatosis in MASLD models via the NF-κB signaling pathway.Overall,BIC has emerged as a promising candidate for treating MASLD.
基金Supported by the Science and Technology Innovation Project of the Chinese Academy of Traditional Chinese Medicine:Mechanism of An's Anorectal Fumigation Lotion in the Treatment of Inflammatory Mixed hemorrhoids based on Nuclear Factor Kappa-B Pathway(No.CI2021A02104)。
文摘OBJECTIVE:To investigate the mechanism by which An's anorectal fumigation lotion(AAFL)treats inflammatory mixed hemorrhoids.METHODS:Eighty Sprague-Dawley rats,with an equal number of males and females,were randomly assigned to the following four groups:control,model,AAFL,and positive groups.Following hemorrhoid induction,hemorrhoidal tissues were collected from the rats for analysis.Pathological alterations in these tissues were examined via hematoxylin-eosin staining.Immunohistochemistry was used to detect inflammatory markers.The ultrastructural pathological changes in these tissues were observed by transmission electron microscopy.Reverse transcription-polymerase chain reaction and Western blotting were used to analyze the gene and protein expression of nuclear factor kappa-B(NF-κB)p65,inhibitor of kappa-B(IκB),inhibitor of NF-κB kinase(IκK-β),interleukin-1 beta(IL-1β),interleukin-6(IL-6),and tumor necrosis factor-alpha(TNF-α).RESULTS:Compared with the control group,the rats in each treatment group showed general improvements in hemorrhoidal tissue pathology.The AAFL group showed increased IκB expression and decreased IL-1β,IL-6,TNF-α,NF-κB,p65,and IκK-βexpressions.CONCLUSION:AAFL can decrease the production of inflammatory markers by targeting the NF-κB pathway,resulting in improved pathological conditions in mixed hemorrhoids.Our findings will aid in the treatment of mixed hemorrhoids.
基金Supported by the National Natural Science Foundation of China,No.82160192and Guangxi Science and Technology Program,No.2023AB23037.
文摘BACKGROUND In vivo degradation of bone scaffolds is significantly influenced by osteoclast(OC)activity,which is orchestrated by the interplay between receptor activator of nuclear factor-kappa B ligand(RANKL)and osteoprotegerin(OPG).The ratio of RANKL/OPG is a crucial determinant of OC-mediated bone resorption,which plays an integral role in bone remodeling and scaffold degradation.Elevated levels of RANKL relative to OPG enhance osteoclastogenesis,thereby accelerating the degradation process essential for integrating bone scaffolds into the host tissue.AIM To elucidate the effects of OPG gene silencing on osteoclastogenesis within rat bone marrow-derived mesenchymal stem cells(BMSCs).By investigating these effects,the study aimed to provide deeper insights into the regulatory mechanisms that influence bone scaffold degradation,potentially leading to improved bone repair and regeneration strategies.METHODS We employed recombinant lentiviral plasmids to silence the OPG gene in rat BMSCs to achieve the aims.The efficacy of gene silencing was assessed using quantitative reverse transcription polymerase chain reaction and western blot analysis to measure the expression levels of OPG and RANKL.Tartrate-resistant acid phosphatase staining was utilized to evaluate the formation of OCs.Additionally,co-immunoprecipitation assays were conducted to explore the interactions between RANKL and OPG proteins,further assessing the biochemical pathways involved in osteoclastogenesis.RESULTS The silencing of the OPG gene in BMSCs resulted in a significant increase in the RANKL/OPG ratio,evidenced by decreased expression levels of OPG and increased levels of RANKL.Enhanced osteoclastogenesis was observed through tartrate-resistant acid phosphatase staining,which indicated a substantial rise in OC formation in response to the altered RANKL/OPG balance.The co-immunoprecipitation assays provided concrete evidence of the direct interaction between RANKL and OPG proteins,substantiating their pivotal roles in regulating OC activity.CONCLUSION The findings from this study underscore the critical role of the RANKL/OPG axis in osteoclastogenesis.Silencing of the OPG gene in BMSCs effectively increases the RANKL/OPG ratio,promoting OC activity and potentially enhancing bone scaffold degradation.This regulatory mechanism offers a promising avenue for modulating bone remodeling processes,which is essential for effective bone repair and the successful integration of bone scaffolds into damaged sites.Future research might focus on optimizing the control of this axis to better facilitate bone tissue engineering and regenerative therapies.
基金Supported by the National Scientific Foundation:30772878
文摘Objective To investigate the mechanisms of catgut implantation at acupoints on ulcerative colitis. Methods Eighteen SD rats were randomly divided into a normal control group （NC）, a model group （MO） and a catgut implantation group （CI） with 6 rats in each group. Animals in group MO and group CI were treated by trinitro-benzene-sulfonic acid （TNBS） to establish model with colitis. No other treatment was given to the rats in group MO, but catgut was implanted at ＂Shàngjùxū＂ （上 巨虚 ST 37）, ＂Tiānshū＂ （天枢 ST 25） and ＂Dàchángshū＂ （大肠俞 BL 25） in the rats in group CI. The symptoms of diarrhea and bloody stool, and changes in histopathology were detected 15 days after the treatment. Expressions of splenic lymphocyte nuclear factor κB p65（NF-κB p65）and correlated signaling molecules（β2AR）were detected by the western blot method. Results Diarrhea and mucus bloody purulent stool were soon controlled, and mucous injures were obviously improved in group CI. The NF-κB p65 value of splenic lymphocytes was signifi cantly increased （P0.01） and expression of β2AR remarkably reduced in group MO （P0.01）, compared with group NC. But, the NF-κB p65 value was significantly decreased （P0.01） and expression of β2AR remarkably increased in group CI （P 0.01） , compared with group MO. Conclusion Catgut implantation at acupoints is obviously effective in treating experimental colitis. Modulation of NF-κB p65 and the correlated signaling molecules β2AR may be involved in the mechanisms.
