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 activation of the sirtuin1(SIRT1)/nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase 1(HO-1)pathway has been shown to mitigate oxidative stress-induced apoptosis and mitochondrial damage by reducing ...The activation of the sirtuin1(SIRT1)/nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase 1(HO-1)pathway has been shown to mitigate oxidative stress-induced apoptosis and mitochondrial damage by reducing reactive oxygen species(ROS)levels.Clinical trials have demonstrated that Zhongfeng Xingnao Liquid(ZFXN)ameliorates post-stroke cognitive impairment(PSCI).However,the underlying mechanism,particularly whether it involves protecting mitochondria and inhibiting apoptosis through the SIRT1/Nrf2/HO-1 pathway,remains unclear.This study employed an oxygen-glucose deprivation(OGD)cell model using SHSY5Y cells and induced PSCI in rats through modified bilateral carotid artery ligation(2VO).The effects of ZFXN on learning and memory,neuroprotective activity,mitochondrial function,oxidative stress,and the SIRT1/Nrf2/HO-1 pathway were evaluated both in vivo and in vitro.Results indicated that ZFXN significantly increased the B-cell lymphoma 2(Bcl2)/Bcl2-associated X(Bax)ratio,reduced terminal deoxynucleotidyl transferase-mediated d UTP nickend-labeling(TUNEL)+cells,and markedly improved cognition,synaptic plasticity,and neuronal function in the hippocampus and cortex.Furthermore,ZFXN exhibited potent antioxidant activity,evidenced by decreased ROS and malondialdehyde(MDA)content and increased superoxide dismutase(SOD),catalase(CAT),and glutathione(GSH)levels.ZFXN also demonstrated considerable enhancement of mitochondrial membrane potential(MMP),Tom 20 fluorescence intensity,adenosine triphosphate(ATP)and energy charge(EC)levels,and mitochondrial complexⅠandⅢactivity,thereby inhibiting mitochondrial damage.Additionally,ZFXN significantly increased SIRT1 activity and elevated SIRT1,nuclear Nrf2,and HO-1 levels.Notably,these effects were substantially counteracted when SIRT1 was suppressed by the inhibitor EX-527 in vitro.In conclusion,ZFXN alleviates PSCI by activating the SIRT1/Nrf2/HO-1 pathway and preventing mitochondrial damage.展开更多
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 Parkinson's disease(PD)-a progressive neurodegenerative disorder-is characterized by motor and gastrointestinal dysfunction.The exploration of novel therapeutic strategies for PD is vital.AIM To investi...BACKGROUND Parkinson's disease(PD)-a progressive neurodegenerative disorder-is characterized by motor and gastrointestinal dysfunction.The exploration of novel therapeutic strategies for PD is vital.AIM To investigate the potential mechanism of action of rhapontin-a natural compound with known antioxidant and anti-inflammatory properties-in the context of PD.METHODS Network pharmacology was used to predict the targets and mechanisms of action of rhapontin in PD.Behavioral tests and tyrosine hydroxylase immunofluorescence analysis were used to assess the effect of rhapontin on symptoms and pathology in MPTP-induced mice.Interleukin(IL)-6,IL-1β,tumor necrosis factor(TNF)-α,and IL-10 levels in tissues were measured using an enzyme-linked immunosorbent assay(ELISA).Additionally,nuclear factor erythroid 2-related factor 2(NRF2)activation was confirmed using western blotting.RESULTS NRF2 was predicted to be the key transcription factor underlying the therapeutic effects of rhapontin in PD,and its anti-PD action may be associated with its antiinflammatory and antioxidant properties.Rhapontin ameliorated the loss of dopaminergic neurons and gastrointestinal dysfunction in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mice by activating NRF2.Additio-nally,rhapontin treatment significantly decreased pro-inflammatory cytokines(IL-6,TNF-α,IL-1β)in the substantia nigra,striatum,and colon,whereas it increased anti-inflammatory cytokine(IL-10)levels only in the colon,indicating the involvement of gut–brain axis in its neuroprotective potential.Finally,NRF2 was identified as a key transcription factor activated by rhapontin,particularly in the colon.CONCLUSION We elucidated the effects of rhapontin in MPTP-induced PD mouse models using a combination of network pharmacology analysis,behavioral assessments,immunofluorescence,ELISA,and Western blotting.Our findings revealed the multifaceted role of rhapontin in ameliorating PD through its anti-inflammatory and antioxidant properties,particularly by activating NRF2,paving the way for future research into targeted therapies for PD.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
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
OBJECTIVE:To investigate the effect of Neferine(Nef)on diabetic nephropathy(DN)and to explore the mechanism of Nef in DN based on miRNA regulation theory.METHODS:A DN mouse model was constructed and treated with Nef.S...OBJECTIVE:To investigate the effect of Neferine(Nef)on diabetic nephropathy(DN)and to explore the mechanism of Nef in DN based on miRNA regulation theory.METHODS:A DN mouse model was constructed and treated with Nef.Serum creatinine(Crea),blood urea(UREA)and urinary albumin were measured in mice by kits,and renal histopathological changes and fibrosis were observed by hematoxylin-eosin staining and Masson staining.Renal tissue superoxide dismutase(SOD),malondialdehyde(MDA)and glutathione peroxidase(GSH-Px)activities were measured by enzyme-linked immunosorbent assay(ELISA).Western blotting was used to detect the expression of nuclear factor E2-related factor 2(Nrf2)/heme oxygenase 1(HO-1)signaling pathway-related proteins in kidney tissues.Quantitative reverse transcription-polymerase chain reaction(q RT-PCR)was used to detect the expression of miR-17-5p in kidney tissues.Subsequently,a DN in vitro model was constructed by high glucose culture of human mesangial cells(HMCs),cells were transfected with miR-17-5p mimic and/or treated with Nef,and we used q RTPCR to detect cellular miR-17 expression,flow cytometry to detect apoptosis,ELISAs to detect cellular SOD,MDA,and GSH-Px activities,Western blots to detect Nrf2/HO-1 signaling pathway-related protein expression,and dual luciferase reporter gene assays to verify the targeting relationship between Nrf2 and miR-17-5p.RESULTS:Administration of Nef significantly reduced the levels of blood glucose,Crea,and UREA and the expression of miR-17-5p,improved renal histopathology and fibrosis,significantly reduced MDA levels,elevated SOD and GSH-Px activities,and activated Nrf2 expression in kidney tissues from mice with DN.Nrf2 is a post-transcriptional target of miR-17-5p.In HMCs transfected with miR-17-5p mimics,the m RNA and protein levels of Nrf2 were significantly suppressed.Furthermore,miR-17-5p overexpression and Nef intervention resulted in a significant increase in high glucose-induced apoptosis and MDA levels in HMCs and a significant decrease in the protein expression of HO-1 and Nrf2.CONCLUSION:Collectively,these results indicate that Nef has an ameliorative effect on DN,and the mechanism may be through the miR-17-5p/Nrf2 pathway.展开更多
BACKGROUND Diabetic foot ulcers(DFU),as severe complications of diabetes mellitus(DM),significantly compromise patient health and carry risks of amputation and mortality.AIM To offer new insights into the occurrence a...BACKGROUND Diabetic foot ulcers(DFU),as severe complications of diabetes mellitus(DM),significantly compromise patient health and carry risks of amputation and mortality.AIM To offer new insights into the occurrence and development of DFU,focusing on the therapeutic mechanisms of X-Paste(XP)of wound healing in diabetic mice.METHODS Employing traditional Chinese medicine ointment preparation methods,XP combines various medicinal ingredients.High-performance liquid chromatography(HPLC)identified XP’s main components.Using streptozotocin(STZ)-induced diabetic,we aimed to investigate whether XP participated in the process of diabetic wound healing.RNA-sequencing analyzed gene expression differences between XP-treated and control groups.Molecular docking clarified XP’s treatment mechanisms for diabetic wound healing.Human umbilical vein endothelial cells(HUVECs)were used to investigate the effects of Andrographolide(Andro)on cell viability,reactive oxygen species generation,apoptosis,proliferation,and metastasis in vitro following exposure to high glucose(HG),while NF-E2-related factor-2(Nrf2)knockdown elucidated Andro’s molecular mechanisms.RESULTS XP notably enhanced wound healing in mice,expediting the healing process.RNA-sequencing revealed Nrf2 upregulation in DM tissues following XP treatment.HPLC identified 21 primary XP components,with Andro exhibiting strong Nrf2 binding.Andro mitigated HG-induced HUVECs proliferation,metastasis,angiogenic injury,and inflammation inhibition.Andro alleviates HG-induced HUVECs damage through Nrf2/HO-1 pathway activation,with Nrf2 knockdown reducing Andro’s proliferative and endothelial protective effects.CONCLUSION XP significantly promotes wound healing in STZ-induced diabetic models.As XP’s key component,Andro activates the Nrf2/HO-1 signaling pathway,enhancing cell proliferation,tubule formation,and inflammation reduction.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
By critically examining the work,we conducted a comprehensive bibliometric analysis on the role of nuclear factor erythroid 2-related factor 2(NRF2)in nervous system diseases.We also proposed suggestions for future bi...By critically examining the work,we conducted a comprehensive bibliometric analysis on the role of nuclear factor erythroid 2-related factor 2(NRF2)in nervous system diseases.We also proposed suggestions for future bibliometric studies,including the integration of multiple websites,analytical tools,and analytical approaches,The findings presented provide compelling evidence that ferroptosis is closely associated with the therapeutic challenges of nervous system diseases.Targeted modulation of NRF2 to regulate ferroptosis holds substantial potential for effectively treating these diseases.Future NRF2-related research should not only focus on discovering new drugs but also on designing rational drug delivery systems.In particular,nanocarriers offer substantial potential for facilitating the clinical translation of NRF2 research and addressing existing issues related to NRF2-related drugs.展开更多
BACKGROUND The complexity of immunoglobulin G4(IgG4)-related diseases and their potential connection to hematologic malignancies remains unclear.This article provided a review of the diagnosis and treatment of a patie...BACKGROUND The complexity of immunoglobulin G4(IgG4)-related diseases and their potential connection to hematologic malignancies remains unclear.This article provided a review of the diagnosis and treatment of a patient with IgG4-related sclerosing cholangitis(SC)and essential thrombocythemia(ET),along with an analysis of relevant literature to enhance comprehension of this disease.CASE SUMMARY A 56-year-old male was admitted to two hospitals with deteriorating jaundice and pruritus prior to hospitalization.Beyond our expectations,the patient was first diagnosed with IgG4-SC and ET with the Janus kinase 2 V617F mutation.Interestingly,the administration of acetate prednisone significantly resulted in improvements in both IgG4-SC and ET.Clinicians need to pay attention to immune disorders and inflammation as they contribute to the development of various disease phenotypes.CONCLUSION When IgG4-SC is suspected without histopathological evidence,diagnostic therapy and long-term regular follow-up can lead to positive treatment outcomes.Clinicians should be mindful of the potential presence of concurrent hematologic diseases in patients with immune disorders.展开更多
The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular an...The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular and cellular mechanisms by which quinolinic acid contributes to Huntington's disease pathology remain unknown. In this study, we established in vitro and in vivo models of Huntington's disease by administering quinolinic acid to the PC12 neuronal cell line and the striatum of mice, respectively. We observed a decrease in the levels of hydrogen sulfide in both PC12 cells and mouse serum, which was accompanied by down-regulation of cystathionine β-synthase, an enzyme responsible for hydrogen sulfide production. However, treatment with NaHS(a hydrogen sulfide donor) increased hydrogen sulfide levels in the neurons and in mouse serum, as well as cystathionine β-synthase expression in the neurons and the mouse striatum, while also improving oxidative imbalance and mitochondrial dysfunction in PC12 cells and the mouse striatum. These beneficial effects correlated with upregulation of nuclear factor erythroid 2-related factor 2 expression. Finally, treatment with the nuclear factor erythroid 2-related factor 2inhibitor ML385 reversed the beneficial impact of exogenous hydrogen sulfide on quinolinic acid-induced oxidative stress. Taken together, our findings show that hydrogen sulfide reduces oxidative stress in Huntington's disease by activating nuclear factor erythroid 2-related factor 2,suggesting that hydrogen sulfide is a novel neuroprotective drug candidate for treating patients with Huntington's disease.展开更多
Salidroside,the main active ingredient extracted from Rhodiola crenulata,has been shown to be neuroprotective in ischemic cerebral injury,but the underlying mechanism for this neuroprotection is poorly understood.In t...Salidroside,the main active ingredient extracted from Rhodiola crenulata,has been shown to be neuroprotective in ischemic cerebral injury,but the underlying mechanism for this neuroprotection is poorly understood.In the current study,the neuroprotective effect of salidroside on cerebral ischemia-induced oxidative stress and the role of the nuclear factor erythroid 2-related factor 2（Nrf2）pathway was investigated in a rat model of middle cerebral artery occlusion.Salidroside（30 mg/kg）reduced infarct size,improved neurological function and histological changes,increased activity of superoxide dismutase and glutathione-S-transferase,and reduced malon-dialdehyde levels after cerebral ischemia and reperfusion.Furthermore,salidroside apparently increased Nrf2 and heme oxygenase-1 expression.These results suggest that salidroside exerts its neuroprotective effect against cerebral ischemia through anti-oxidant mechanisms and that activation of the Nrf2 pathway is involved.The Nrf2/antioxidant response element pathway may become a new therapeutic target for the treatment of ischemic stroke.展开更多
Coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus 2 is a global pandemic and poses a major threat to human health worldwide.In addition to respiratory symptoms,COVID-19 is usual...Coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus 2 is a global pandemic and poses a major threat to human health worldwide.In addition to respiratory symptoms,COVID-19 is usually accompanied by systemic inflammation and liver damage in moderate and severe cases.Nuclear factor erythroid 2-related factor 2(NRF2)is a transcription factor that regulates the expression of antioxidant proteins,participating in COVID-19-mediated inflammation and liver injury.Here,we show the novel reciprocal regulation between NRF2 and inflammatory mediators associated with COVID-19-related liver injury.Additionally,we describe some mechanisms and treatment strategies.展开更多
Oxidative stress is a key driver in the development and progression of several diseases,including metabolic associated fatty liver disease(MAFLD).This condition includes a wide spectrum of pathological injuries,extend...Oxidative stress is a key driver in the development and progression of several diseases,including metabolic associated fatty liver disease(MAFLD).This condition includes a wide spectrum of pathological injuries,extending from simple steatosis to inflammation,fibrosis,cirrhosis,and hepatocellular carcinoma.Excessive buildup of lipids in the liver is strictly related to oxidative stress in MAFLD,progressing to liver fibrosis and cirrhosis.The nuclear factor erythroid 2-related factor 2(NRF2)is a master regulator of redox homeostasis.NRF2 plays an important role for cellular protection by inducing the expression of genes related to antioxidant,anti-inflammatory,and cytoprotective response.Consistent evidence demonstrates that NRF2 is involved in every step of MAFLD development,from simple steatosis to inflammation,advanced fibrosis,and initiation/progression of hepatocellular carcinoma.NRF2 activators regulate lipid metabolism and oxidative stress alleviating the fatty liver disease by inducing the expression of cytoprotective genes.Thus,modulating NRF2 activation is crucial not only in understanding specific mechanisms underlying MAFLD progression but also to characterize effective therapeutic strategies.This review outlined the current knowledge on the effects of NRF2 pathway,modulators,and mechanisms involved in the therapeutic implications of liver steatosis,inflammation,and fibrosis in MAFLD.展开更多
BACKGROUND： The KEAP1-Nrf2 antioxidant signaling pathway is important in protecting liver from various insults. However,little is known about the expression of Nrf2-related genes in human liver in different diseases....BACKGROUND： The KEAP1-Nrf2 antioxidant signaling pathway is important in protecting liver from various insults. However,little is known about the expression of Nrf2-related genes in human liver in different diseases.METHODS： This study utilized normal donor liver tissues（n=35）, samples from patients with hepatocellular carcinoma（HCC, n=24）, HBV-related cirrhosis（n=27）, alcoholic cirrhosis（n=5） and end-stage liver disease（n=13）. All of the liver tissues were from the Oriental Liver Transplant Center, Beijing,China. The expressions of Nrf2 and Nrf2-related genes, including its negative regulator Kelch-like ECH-associated protein 1（KEAP1）, its targeted gene NAD（P）H-quinone oxidoreductase 1（NQO1）, glutamate-cysteine ligase catalytic subunit（GCLC） and modified subunit（GCLM）, heme oxygenase 1（HO-1） and peroxiredoxin-1（PRDX1） were evaluated. RESULTS： The expression of Nrf2 was decreased in HCC, increased in alcoholic cirrhosis and end-stage liver disease. The expression of KEAP1 was increased in all of the liver samples.The most notable finding was the increased expression of NQO1 in HCC（18-fold）, alcoholic cirrhosis（6-fold）, endstage liver disease（5-fold） and HBV-related cirrhosis（3-fold）.Peri-HCC also had 4-fold higher NQO1 m RNA as compared to the normal livers. GCLC m RNA levels were lower only in HCC, as compared to the normal livers and peri-HCC tissues.GCLM m RNA levels were higher in HBV-related cirrhosis and end-stage liver disease. HO-1 m RNA levels were increased in all liver tissues except for HCC. Peri-HCC had higher PRDX1 m RNA levels compared with HCC and normal livers.CONCLUSION： Nrf2 and Nrf2-related genes are aberrantly expressed in the liver in different diseases and the increase of NQO1 was the most notable finding, especially in HCC.展开更多
BACKGROUND The Nuclear factor erythroid 2-related factor 2(NRF2)transcription factor has attracted much attention in the context of neurological diseases.However,none of the studies have systematically clarified this ...BACKGROUND The Nuclear factor erythroid 2-related factor 2(NRF2)transcription factor has attracted much attention in the context of neurological diseases.However,none of the studies have systematically clarified this field's research hotspots and evolution rules.AIM To investigate the research hotspots,evolution patterns,and future research trends in this field in recent years.METHODS We conducted a comprehensive literature search in the Web of Science Core Collection database using the following methods:(((((TS=(NFE2 L2))OR TS=(Nfe2 L2 protein,mouse))OR TS=(NF-E2-Related Factor 2))OR TS=(NRF2))OR TS=(NFE2L2))OR TS=(Nuclear factor erythroid2-related factor 2)AND(((((((TS=(neurological diseases))OR TS=(neurological disorder))OR TS=(brain disorder))OR TS=(brain injury))OR TS=(central nervous system disease))OR TS=(CNS disease))OR TS=(central nervous system disorder))OR TS=(CNS disorder)AND Language=English from 2010 to 2022.There are just two forms of literature available:Articles and reviews.Data were processed with the software Cite-Space(version 6.1.R6).RESULTS We analyzed 1884 articles from 200 schools in 72 countries/regions.Since 2015,the number of publications in this field has increased rapidly.China has the largest number of publications,but the articles published in the United States have better centrality and H-index.Among the top ten authors with the most published papers,five of them are from China,and the author with the most published papers is Wang Handong.The institution with the most articles was Nanjing University.To their credit,three of the top 10 most cited articles were written by Chinese scholars.The keyword co-occurrence map showed that"oxidative stress","NRF2","activation","expression"and"brain"were the five most frequently used keywords.CONCLUSION Research on the role of NRF2 in neurological diseases continues unabated.Researchers in developed countries published more influential papers,while Chinese scholars provided the largest number of articles.There have been numerous studies on the mechanism of NRF2 transcription factor in neurological diseases.NRF2 is also emerging as a potentially effective target for the treatment of neurological diseases.However,despite decades of research,our knowledge of NRF2 transcription factor in nervous system diseases is still limited.Further studies are needed in the future.展开更多
OBJECTIVE Nuclear factor erythroid 2-related factor 2(Nrf2) is found to be ubiquitiously expressed in many tissues,and works as the key regulator against oxidative stress damage in cells and organs,which makes Nrf2 a ...OBJECTIVE Nuclear factor erythroid 2-related factor 2(Nrf2) is found to be ubiquitiously expressed in many tissues,and works as the key regulator against oxidative stress damage in cells and organs,which makes Nrf2 a widely concerned drug target.Recent research has identified that Nrf2 is involved in the pathology of Alzheimer disease(AD),whereas the mechanism is unknown.The purpose of this study is to figure out the role of Nrf2 in the pathologic process of AD through Nrf2-Keap1-ARE pathway and the effects of Keap1-Nrf2 inhibitor in AD mice models.METHODS Amyloid β^(1-42)(Aβ^(1-42))was injected into the bilateral hippocampus to induce the cognitive dysfunction in eight-week old male mice.The mice were treated with Keap1-Nrf2 inhibitor NXPZ of three doses as well as donepezil as a positive control by intragastric administration one time a day for one week.Several behavior tests were used to analyze the mice learning and memory ability.Additionally,we detected Nrf2 and Aβ in the plasma in mice with ELISA kits,as well as some factors related to oxidative stress in the hippocampus and cortex.The expression levels of Nrf2,Keap1,Tau and p-Tau were measured in the murine brain tissue with Western blotting.SH-SY5 Y cells were studied as an in vitro model to further clarify the mechanism.RESULTS The treatment of NXPZ ameliorated learning and memory dysfunction in AD mice in a dose-dependent manner,and the high dose group recovered better than the positive drug group.The plasma Nrf2 level was increased in a dose-dependent manner in the treatment groups;however,the plasma Aβ was decreased.What′ s more,superoxide dismutase(SOD) and glutathione reductase(GSSH) in the hippocampus and cortex were increased in the treatment group,while the malondialdehyde(MDA) was decreased,meaning that NXPZ treatment promoted expression of the anti-oxidative factors and inhibited the expression of the oxidative factors in the down-stream.Western blotting analysis of hippocampus and cortex showed up-regulated Nrf2,decreased Keap1 and decreased p-Tau in NXPZ treatment mice.In ex vivo experiments,when SH-SY5 Y cells were treated with Aβ,Nrf2 in the cytoplasm was increased,as well as the expression Nrf2 in the nuclear was decreased.The treatment of NXPZ increased nuclear Nrf2,decreased cytoplasm Nrf2,and decreased the expression of p-Tau.CONCLUSION Nrf2 has an important role in neuron function.Nrf2 activation by selective Keap1-Nrf2 inhibitor NXPZ may contribute to improve cognitive function in AD mice.The mechanism may be related to increased generation and release of Nrf2 induced by more disaggregation with Keap1,leading to more expression of anti-oxidative molecules to protect the damage caused by Aβ.These results indicates that Nrf2 may be a novel therapeutic target of AD and Keap1-Nrf2 inhibitor may be a novel medication for protecting the loss of learning and memory ability.展开更多
BACKGROUND A type 2b immunoglobulin G4(IgG4)-related sclerosing cholangitis(SC)without autoimmune pancreatitis is a rare condition with IgG4-SC.While the variety of the imaging modalities have tested its usefulness in...BACKGROUND A type 2b immunoglobulin G4(IgG4)-related sclerosing cholangitis(SC)without autoimmune pancreatitis is a rare condition with IgG4-SC.While the variety of the imaging modalities have tested its usefulness in diagnosing the IgG4-SC,however,the usage of ultrasonography for the assessment of the response to steroidal therapy on the changes of bile duct wall thickness have not been reported in the condition.Therefore,the information of our recent case and reported cases have been summarized.CASE SUMMARY We report the case of an 82-year-old Japanese man diagnosed with isolated IgG4-related SC based on the increase of serum IgG4,narrowing of the bile duct,its wall thickness,no complication of autoimmune pancreatitis,and IgG4 positive inflammatory cell infiltration to the wall with the fibrotic changes.The cholangiogram revealed type 2b according to the classification.Corticosteroid treatment showed a favorable effect,with the smooth decrease in serum IgG4 and the improvement of the bile duct wall thickness.CONCLUSION As isolated type 2b,IgG4-SC is rare,the images,histological findings,and clinical course of our case will be helpful for physicians to diagnose and treat the new cases appropriately.展开更多
Oxidative stress is caused by an imbalance of the antioxidant defense system and excessive production of free radicals,which can damage biological macromolecules such as proteins,lipids and nucleic acids,and can cause...Oxidative stress is caused by an imbalance of the antioxidant defense system and excessive production of free radicals,which can damage biological macromolecules such as proteins,lipids and nucleic acids,and can cause aging,ischemia-reperfusion injury,inflammatory injury,liver and kidney injury and other diseases.The nuclear factor erytheroid-2-related factor 2(Nrf2)is a major regulator of redox balance.The Nrf2 pathway also exerts a central function in cell apoptosis,oxidative stress damage and metabolic diseases.Bioactive peptides are small molecular peptides composed of amino acid residues.They have many biological activities and play important physiological roles in human body.Antioxidant peptide is a kind of peptide which can reduce oxidative stress damage.They are safe,non-toxic and easily absorbed.In this review,we summarized the mechanism of bioactive peptides in regulating oxidative stress,especially antioxidant peptides,through regulating the Nrf2 signaling pathway and the expressions of oxidative stress-related genes,to alleviate oxidative stress-induced damage.The paper will provide valuable reference to investigators in the antioxidant peptide field and also promote the applications of antioxidant peptides in the oxidative stress-associated diseases.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supported by the Science&Technology Department of Sichuan Province(No.2019YFS0040)the Improvement Plan of“Xinglin Scholar”Scientific Research Talent,Chengdu University of Traditional Chinese Medicine(No.XKTD2022002)。
文摘The activation of the sirtuin1(SIRT1)/nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase 1(HO-1)pathway has been shown to mitigate oxidative stress-induced apoptosis and mitochondrial damage by reducing reactive oxygen species(ROS)levels.Clinical trials have demonstrated that Zhongfeng Xingnao Liquid(ZFXN)ameliorates post-stroke cognitive impairment(PSCI).However,the underlying mechanism,particularly whether it involves protecting mitochondria and inhibiting apoptosis through the SIRT1/Nrf2/HO-1 pathway,remains unclear.This study employed an oxygen-glucose deprivation(OGD)cell model using SHSY5Y cells and induced PSCI in rats through modified bilateral carotid artery ligation(2VO).The effects of ZFXN on learning and memory,neuroprotective activity,mitochondrial function,oxidative stress,and the SIRT1/Nrf2/HO-1 pathway were evaluated both in vivo and in vitro.Results indicated that ZFXN significantly increased the B-cell lymphoma 2(Bcl2)/Bcl2-associated X(Bax)ratio,reduced terminal deoxynucleotidyl transferase-mediated d UTP nickend-labeling(TUNEL)+cells,and markedly improved cognition,synaptic plasticity,and neuronal function in the hippocampus and cortex.Furthermore,ZFXN exhibited potent antioxidant activity,evidenced by decreased ROS and malondialdehyde(MDA)content and increased superoxide dismutase(SOD),catalase(CAT),and glutathione(GSH)levels.ZFXN also demonstrated considerable enhancement of mitochondrial membrane potential(MMP),Tom 20 fluorescence intensity,adenosine triphosphate(ATP)and energy charge(EC)levels,and mitochondrial complexⅠandⅢactivity,thereby inhibiting mitochondrial damage.Additionally,ZFXN significantly increased SIRT1 activity and elevated SIRT1,nuclear Nrf2,and HO-1 levels.Notably,these effects were substantially counteracted when SIRT1 was suppressed by the inhibitor EX-527 in vitro.In conclusion,ZFXN alleviates PSCI by activating the SIRT1/Nrf2/HO-1 pathway and preventing mitochondrial damage.
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 Hainan Provincial Natural Science Foundation of China,No.823MS133 and No.821QN0979。
文摘BACKGROUND Parkinson's disease(PD)-a progressive neurodegenerative disorder-is characterized by motor and gastrointestinal dysfunction.The exploration of novel therapeutic strategies for PD is vital.AIM To investigate the potential mechanism of action of rhapontin-a natural compound with known antioxidant and anti-inflammatory properties-in the context of PD.METHODS Network pharmacology was used to predict the targets and mechanisms of action of rhapontin in PD.Behavioral tests and tyrosine hydroxylase immunofluorescence analysis were used to assess the effect of rhapontin on symptoms and pathology in MPTP-induced mice.Interleukin(IL)-6,IL-1β,tumor necrosis factor(TNF)-α,and IL-10 levels in tissues were measured using an enzyme-linked immunosorbent assay(ELISA).Additionally,nuclear factor erythroid 2-related factor 2(NRF2)activation was confirmed using western blotting.RESULTS NRF2 was predicted to be the key transcription factor underlying the therapeutic effects of rhapontin in PD,and its anti-PD action may be associated with its antiinflammatory and antioxidant properties.Rhapontin ameliorated the loss of dopaminergic neurons and gastrointestinal dysfunction in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mice by activating NRF2.Additio-nally,rhapontin treatment significantly decreased pro-inflammatory cytokines(IL-6,TNF-α,IL-1β)in the substantia nigra,striatum,and colon,whereas it increased anti-inflammatory cytokine(IL-10)levels only in the colon,indicating the involvement of gut–brain axis in its neuroprotective potential.Finally,NRF2 was identified as a key transcription factor activated by rhapontin,particularly in the colon.CONCLUSION We elucidated the effects of rhapontin in MPTP-induced PD mouse models using a combination of network pharmacology analysis,behavioral assessments,immunofluorescence,ELISA,and Western blotting.Our findings revealed the multifaceted role of rhapontin in ameliorating PD through its anti-inflammatory and antioxidant properties,particularly by activating NRF2,paving the way for future research into targeted therapies for PD.
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.
基金the Chengdu Health and Wellness Commission:Exploring the Mechanism of Neferine on Diabetic Nephropathy Based on mi R-17/Nrf2 Axis(No.2021127)。
文摘OBJECTIVE:To investigate the effect of Neferine(Nef)on diabetic nephropathy(DN)and to explore the mechanism of Nef in DN based on miRNA regulation theory.METHODS:A DN mouse model was constructed and treated with Nef.Serum creatinine(Crea),blood urea(UREA)and urinary albumin were measured in mice by kits,and renal histopathological changes and fibrosis were observed by hematoxylin-eosin staining and Masson staining.Renal tissue superoxide dismutase(SOD),malondialdehyde(MDA)and glutathione peroxidase(GSH-Px)activities were measured by enzyme-linked immunosorbent assay(ELISA).Western blotting was used to detect the expression of nuclear factor E2-related factor 2(Nrf2)/heme oxygenase 1(HO-1)signaling pathway-related proteins in kidney tissues.Quantitative reverse transcription-polymerase chain reaction(q RT-PCR)was used to detect the expression of miR-17-5p in kidney tissues.Subsequently,a DN in vitro model was constructed by high glucose culture of human mesangial cells(HMCs),cells were transfected with miR-17-5p mimic and/or treated with Nef,and we used q RTPCR to detect cellular miR-17 expression,flow cytometry to detect apoptosis,ELISAs to detect cellular SOD,MDA,and GSH-Px activities,Western blots to detect Nrf2/HO-1 signaling pathway-related protein expression,and dual luciferase reporter gene assays to verify the targeting relationship between Nrf2 and miR-17-5p.RESULTS:Administration of Nef significantly reduced the levels of blood glucose,Crea,and UREA and the expression of miR-17-5p,improved renal histopathology and fibrosis,significantly reduced MDA levels,elevated SOD and GSH-Px activities,and activated Nrf2 expression in kidney tissues from mice with DN.Nrf2 is a post-transcriptional target of miR-17-5p.In HMCs transfected with miR-17-5p mimics,the m RNA and protein levels of Nrf2 were significantly suppressed.Furthermore,miR-17-5p overexpression and Nef intervention resulted in a significant increase in high glucose-induced apoptosis and MDA levels in HMCs and a significant decrease in the protein expression of HO-1 and Nrf2.CONCLUSION:Collectively,these results indicate that Nef has an ameliorative effect on DN,and the mechanism may be through the miR-17-5p/Nrf2 pathway.
基金Supported by the Shanghai Science and Technology Innovation Project,One Belt One Road International Joint Laboratory of Medical Mycology,No.21410750500。
文摘BACKGROUND Diabetic foot ulcers(DFU),as severe complications of diabetes mellitus(DM),significantly compromise patient health and carry risks of amputation and mortality.AIM To offer new insights into the occurrence and development of DFU,focusing on the therapeutic mechanisms of X-Paste(XP)of wound healing in diabetic mice.METHODS Employing traditional Chinese medicine ointment preparation methods,XP combines various medicinal ingredients.High-performance liquid chromatography(HPLC)identified XP’s main components.Using streptozotocin(STZ)-induced diabetic,we aimed to investigate whether XP participated in the process of diabetic wound healing.RNA-sequencing analyzed gene expression differences between XP-treated and control groups.Molecular docking clarified XP’s treatment mechanisms for diabetic wound healing.Human umbilical vein endothelial cells(HUVECs)were used to investigate the effects of Andrographolide(Andro)on cell viability,reactive oxygen species generation,apoptosis,proliferation,and metastasis in vitro following exposure to high glucose(HG),while NF-E2-related factor-2(Nrf2)knockdown elucidated Andro’s molecular mechanisms.RESULTS XP notably enhanced wound healing in mice,expediting the healing process.RNA-sequencing revealed Nrf2 upregulation in DM tissues following XP treatment.HPLC identified 21 primary XP components,with Andro exhibiting strong Nrf2 binding.Andro mitigated HG-induced HUVECs proliferation,metastasis,angiogenic injury,and inflammation inhibition.Andro alleviates HG-induced HUVECs damage through Nrf2/HO-1 pathway activation,with Nrf2 knockdown reducing Andro’s proliferative and endothelial protective effects.CONCLUSION XP significantly promotes wound healing in STZ-induced diabetic models.As XP’s key component,Andro activates the Nrf2/HO-1 signaling pathway,enhancing cell proliferation,tubule formation,and inflammation reduction.
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 The Guangdong Basic and Applied Basic Research Foundation,China,No.2024A1515011236.
文摘By critically examining the work,we conducted a comprehensive bibliometric analysis on the role of nuclear factor erythroid 2-related factor 2(NRF2)in nervous system diseases.We also proposed suggestions for future bibliometric studies,including the integration of multiple websites,analytical tools,and analytical approaches,The findings presented provide compelling evidence that ferroptosis is closely associated with the therapeutic challenges of nervous system diseases.Targeted modulation of NRF2 to regulate ferroptosis holds substantial potential for effectively treating these diseases.Future NRF2-related research should not only focus on discovering new drugs but also on designing rational drug delivery systems.In particular,nanocarriers offer substantial potential for facilitating the clinical translation of NRF2 research and addressing existing issues related to NRF2-related drugs.
基金Natural Science Foundation of Hebei Province,No.H2023206042。
文摘BACKGROUND The complexity of immunoglobulin G4(IgG4)-related diseases and their potential connection to hematologic malignancies remains unclear.This article provided a review of the diagnosis and treatment of a patient with IgG4-related sclerosing cholangitis(SC)and essential thrombocythemia(ET),along with an analysis of relevant literature to enhance comprehension of this disease.CASE SUMMARY A 56-year-old male was admitted to two hospitals with deteriorating jaundice and pruritus prior to hospitalization.Beyond our expectations,the patient was first diagnosed with IgG4-SC and ET with the Janus kinase 2 V617F mutation.Interestingly,the administration of acetate prednisone significantly resulted in improvements in both IgG4-SC and ET.Clinicians need to pay attention to immune disorders and inflammation as they contribute to the development of various disease phenotypes.CONCLUSION When IgG4-SC is suspected without histopathological evidence,diagnostic therapy and long-term regular follow-up can lead to positive treatment outcomes.Clinicians should be mindful of the potential presence of concurrent hematologic diseases in patients with immune disorders.
基金supported by the National Natural Science Foundation of China,Nos.82271327 (to ZW),82072535 (to ZW),81873768 (to ZW),and 82001253 (to TL)。
文摘The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular and cellular mechanisms by which quinolinic acid contributes to Huntington's disease pathology remain unknown. In this study, we established in vitro and in vivo models of Huntington's disease by administering quinolinic acid to the PC12 neuronal cell line and the striatum of mice, respectively. We observed a decrease in the levels of hydrogen sulfide in both PC12 cells and mouse serum, which was accompanied by down-regulation of cystathionine β-synthase, an enzyme responsible for hydrogen sulfide production. However, treatment with NaHS(a hydrogen sulfide donor) increased hydrogen sulfide levels in the neurons and in mouse serum, as well as cystathionine β-synthase expression in the neurons and the mouse striatum, while also improving oxidative imbalance and mitochondrial dysfunction in PC12 cells and the mouse striatum. These beneficial effects correlated with upregulation of nuclear factor erythroid 2-related factor 2 expression. Finally, treatment with the nuclear factor erythroid 2-related factor 2inhibitor ML385 reversed the beneficial impact of exogenous hydrogen sulfide on quinolinic acid-induced oxidative stress. Taken together, our findings show that hydrogen sulfide reduces oxidative stress in Huntington's disease by activating nuclear factor erythroid 2-related factor 2,suggesting that hydrogen sulfide is a novel neuroprotective drug candidate for treating patients with Huntington's disease.
基金supported by the Independent Research Project of Fujian Academy of Traditional Chinese Medicine in China,No.2012fjzyyk-4the Natural Science Foundation of Fujian Province in China,No.2014J01340+1 种基金the Research Project of Fujian Provincial Health and Family Planning Commission,No.2014-ZQN-JC-32a grant from the Platform for Preclinical Studies of Traditional Chinese Medicine and Quality Control Engineering Technology Research Center of Fujian Province in China,No.2009Y2003
文摘Salidroside,the main active ingredient extracted from Rhodiola crenulata,has been shown to be neuroprotective in ischemic cerebral injury,but the underlying mechanism for this neuroprotection is poorly understood.In the current study,the neuroprotective effect of salidroside on cerebral ischemia-induced oxidative stress and the role of the nuclear factor erythroid 2-related factor 2（Nrf2）pathway was investigated in a rat model of middle cerebral artery occlusion.Salidroside（30 mg/kg）reduced infarct size,improved neurological function and histological changes,increased activity of superoxide dismutase and glutathione-S-transferase,and reduced malon-dialdehyde levels after cerebral ischemia and reperfusion.Furthermore,salidroside apparently increased Nrf2 and heme oxygenase-1 expression.These results suggest that salidroside exerts its neuroprotective effect against cerebral ischemia through anti-oxidant mechanisms and that activation of the Nrf2 pathway is involved.The Nrf2/antioxidant response element pathway may become a new therapeutic target for the treatment of ischemic stroke.
基金Supported by National Natural Science Foundation of China,No.82070632.
文摘Coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus 2 is a global pandemic and poses a major threat to human health worldwide.In addition to respiratory symptoms,COVID-19 is usually accompanied by systemic inflammation and liver damage in moderate and severe cases.Nuclear factor erythroid 2-related factor 2(NRF2)is a transcription factor that regulates the expression of antioxidant proteins,participating in COVID-19-mediated inflammation and liver injury.Here,we show the novel reciprocal regulation between NRF2 and inflammatory mediators associated with COVID-19-related liver injury.Additionally,we describe some mechanisms and treatment strategies.
文摘Oxidative stress is a key driver in the development and progression of several diseases,including metabolic associated fatty liver disease(MAFLD).This condition includes a wide spectrum of pathological injuries,extending from simple steatosis to inflammation,fibrosis,cirrhosis,and hepatocellular carcinoma.Excessive buildup of lipids in the liver is strictly related to oxidative stress in MAFLD,progressing to liver fibrosis and cirrhosis.The nuclear factor erythroid 2-related factor 2(NRF2)is a master regulator of redox homeostasis.NRF2 plays an important role for cellular protection by inducing the expression of genes related to antioxidant,anti-inflammatory,and cytoprotective response.Consistent evidence demonstrates that NRF2 is involved in every step of MAFLD development,from simple steatosis to inflammation,advanced fibrosis,and initiation/progression of hepatocellular carcinoma.NRF2 activators regulate lipid metabolism and oxidative stress alleviating the fatty liver disease by inducing the expression of cytoprotective genes.Thus,modulating NRF2 activation is crucial not only in understanding specific mechanisms underlying MAFLD progression but also to characterize effective therapeutic strategies.This review outlined the current knowledge on the effects of NRF2 pathway,modulators,and mechanisms involved in the therapeutic implications of liver steatosis,inflammation,and fibrosis in MAFLD.
基金supported by grants from the Chinese 863 Project(2012AA022409)Guizhou Science and Technology Foundation(2009-70019)
文摘BACKGROUND： The KEAP1-Nrf2 antioxidant signaling pathway is important in protecting liver from various insults. However,little is known about the expression of Nrf2-related genes in human liver in different diseases.METHODS： This study utilized normal donor liver tissues（n=35）, samples from patients with hepatocellular carcinoma（HCC, n=24）, HBV-related cirrhosis（n=27）, alcoholic cirrhosis（n=5） and end-stage liver disease（n=13）. All of the liver tissues were from the Oriental Liver Transplant Center, Beijing,China. The expressions of Nrf2 and Nrf2-related genes, including its negative regulator Kelch-like ECH-associated protein 1（KEAP1）, its targeted gene NAD（P）H-quinone oxidoreductase 1（NQO1）, glutamate-cysteine ligase catalytic subunit（GCLC） and modified subunit（GCLM）, heme oxygenase 1（HO-1） and peroxiredoxin-1（PRDX1） were evaluated. RESULTS： The expression of Nrf2 was decreased in HCC, increased in alcoholic cirrhosis and end-stage liver disease. The expression of KEAP1 was increased in all of the liver samples.The most notable finding was the increased expression of NQO1 in HCC（18-fold）, alcoholic cirrhosis（6-fold）, endstage liver disease（5-fold） and HBV-related cirrhosis（3-fold）.Peri-HCC also had 4-fold higher NQO1 m RNA as compared to the normal livers. GCLC m RNA levels were lower only in HCC, as compared to the normal livers and peri-HCC tissues.GCLM m RNA levels were higher in HBV-related cirrhosis and end-stage liver disease. HO-1 m RNA levels were increased in all liver tissues except for HCC. Peri-HCC had higher PRDX1 m RNA levels compared with HCC and normal livers.CONCLUSION： Nrf2 and Nrf2-related genes are aberrantly expressed in the liver in different diseases and the increase of NQO1 was the most notable finding, especially in HCC.
文摘BACKGROUND The Nuclear factor erythroid 2-related factor 2(NRF2)transcription factor has attracted much attention in the context of neurological diseases.However,none of the studies have systematically clarified this field's research hotspots and evolution rules.AIM To investigate the research hotspots,evolution patterns,and future research trends in this field in recent years.METHODS We conducted a comprehensive literature search in the Web of Science Core Collection database using the following methods:(((((TS=(NFE2 L2))OR TS=(Nfe2 L2 protein,mouse))OR TS=(NF-E2-Related Factor 2))OR TS=(NRF2))OR TS=(NFE2L2))OR TS=(Nuclear factor erythroid2-related factor 2)AND(((((((TS=(neurological diseases))OR TS=(neurological disorder))OR TS=(brain disorder))OR TS=(brain injury))OR TS=(central nervous system disease))OR TS=(CNS disease))OR TS=(central nervous system disorder))OR TS=(CNS disorder)AND Language=English from 2010 to 2022.There are just two forms of literature available:Articles and reviews.Data were processed with the software Cite-Space(version 6.1.R6).RESULTS We analyzed 1884 articles from 200 schools in 72 countries/regions.Since 2015,the number of publications in this field has increased rapidly.China has the largest number of publications,but the articles published in the United States have better centrality and H-index.Among the top ten authors with the most published papers,five of them are from China,and the author with the most published papers is Wang Handong.The institution with the most articles was Nanjing University.To their credit,three of the top 10 most cited articles were written by Chinese scholars.The keyword co-occurrence map showed that"oxidative stress","NRF2","activation","expression"and"brain"were the five most frequently used keywords.CONCLUSION Research on the role of NRF2 in neurological diseases continues unabated.Researchers in developed countries published more influential papers,while Chinese scholars provided the largest number of articles.There have been numerous studies on the mechanism of NRF2 transcription factor in neurological diseases.NRF2 is also emerging as a potentially effective target for the treatment of neurological diseases.However,despite decades of research,our knowledge of NRF2 transcription factor in nervous system diseases is still limited.Further studies are needed in the future.
基金National Natural Science Foundation of China(81703520).
文摘OBJECTIVE Nuclear factor erythroid 2-related factor 2(Nrf2) is found to be ubiquitiously expressed in many tissues,and works as the key regulator against oxidative stress damage in cells and organs,which makes Nrf2 a widely concerned drug target.Recent research has identified that Nrf2 is involved in the pathology of Alzheimer disease(AD),whereas the mechanism is unknown.The purpose of this study is to figure out the role of Nrf2 in the pathologic process of AD through Nrf2-Keap1-ARE pathway and the effects of Keap1-Nrf2 inhibitor in AD mice models.METHODS Amyloid β^(1-42)(Aβ^(1-42))was injected into the bilateral hippocampus to induce the cognitive dysfunction in eight-week old male mice.The mice were treated with Keap1-Nrf2 inhibitor NXPZ of three doses as well as donepezil as a positive control by intragastric administration one time a day for one week.Several behavior tests were used to analyze the mice learning and memory ability.Additionally,we detected Nrf2 and Aβ in the plasma in mice with ELISA kits,as well as some factors related to oxidative stress in the hippocampus and cortex.The expression levels of Nrf2,Keap1,Tau and p-Tau were measured in the murine brain tissue with Western blotting.SH-SY5 Y cells were studied as an in vitro model to further clarify the mechanism.RESULTS The treatment of NXPZ ameliorated learning and memory dysfunction in AD mice in a dose-dependent manner,and the high dose group recovered better than the positive drug group.The plasma Nrf2 level was increased in a dose-dependent manner in the treatment groups;however,the plasma Aβ was decreased.What′ s more,superoxide dismutase(SOD) and glutathione reductase(GSSH) in the hippocampus and cortex were increased in the treatment group,while the malondialdehyde(MDA) was decreased,meaning that NXPZ treatment promoted expression of the anti-oxidative factors and inhibited the expression of the oxidative factors in the down-stream.Western blotting analysis of hippocampus and cortex showed up-regulated Nrf2,decreased Keap1 and decreased p-Tau in NXPZ treatment mice.In ex vivo experiments,when SH-SY5 Y cells were treated with Aβ,Nrf2 in the cytoplasm was increased,as well as the expression Nrf2 in the nuclear was decreased.The treatment of NXPZ increased nuclear Nrf2,decreased cytoplasm Nrf2,and decreased the expression of p-Tau.CONCLUSION Nrf2 has an important role in neuron function.Nrf2 activation by selective Keap1-Nrf2 inhibitor NXPZ may contribute to improve cognitive function in AD mice.The mechanism may be related to increased generation and release of Nrf2 induced by more disaggregation with Keap1,leading to more expression of anti-oxidative molecules to protect the damage caused by Aβ.These results indicates that Nrf2 may be a novel therapeutic target of AD and Keap1-Nrf2 inhibitor may be a novel medication for protecting the loss of learning and memory ability.
文摘BACKGROUND A type 2b immunoglobulin G4(IgG4)-related sclerosing cholangitis(SC)without autoimmune pancreatitis is a rare condition with IgG4-SC.While the variety of the imaging modalities have tested its usefulness in diagnosing the IgG4-SC,however,the usage of ultrasonography for the assessment of the response to steroidal therapy on the changes of bile duct wall thickness have not been reported in the condition.Therefore,the information of our recent case and reported cases have been summarized.CASE SUMMARY We report the case of an 82-year-old Japanese man diagnosed with isolated IgG4-related SC based on the increase of serum IgG4,narrowing of the bile duct,its wall thickness,no complication of autoimmune pancreatitis,and IgG4 positive inflammatory cell infiltration to the wall with the fibrotic changes.The cholangiogram revealed type 2b according to the classification.Corticosteroid treatment showed a favorable effect,with the smooth decrease in serum IgG4 and the improvement of the bile duct wall thickness.CONCLUSION As isolated type 2b,IgG4-SC is rare,the images,histological findings,and clinical course of our case will be helpful for physicians to diagnose and treat the new cases appropriately.
基金the funds from the National Key R&D Program of China(2022YFF1100200).
文摘Oxidative stress is caused by an imbalance of the antioxidant defense system and excessive production of free radicals,which can damage biological macromolecules such as proteins,lipids and nucleic acids,and can cause aging,ischemia-reperfusion injury,inflammatory injury,liver and kidney injury and other diseases.The nuclear factor erytheroid-2-related factor 2(Nrf2)is a major regulator of redox balance.The Nrf2 pathway also exerts a central function in cell apoptosis,oxidative stress damage and metabolic diseases.Bioactive peptides are small molecular peptides composed of amino acid residues.They have many biological activities and play important physiological roles in human body.Antioxidant peptide is a kind of peptide which can reduce oxidative stress damage.They are safe,non-toxic and easily absorbed.In this review,we summarized the mechanism of bioactive peptides in regulating oxidative stress,especially antioxidant peptides,through regulating the Nrf2 signaling pathway and the expressions of oxidative stress-related genes,to alleviate oxidative stress-induced damage.The paper will provide valuable reference to investigators in the antioxidant peptide field and also promote the applications of antioxidant peptides in the oxidative stress-associated diseases.
