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
Let S be a regular semigroup with an inverse transversal S° and C（S） the congruence lattice of S. A relation K° on C（S） is introduced as follows： if p, θ∈ C（S）, then we say that p and 0 are K°-...Let S be a regular semigroup with an inverse transversal S° and C（S） the congruence lattice of S. A relation K° on C（S） is introduced as follows： if p, θ∈ C（S）, then we say that p and 0 are K°-related if Ker pO = Ker θ°, where p°= p｜s°. Expressions for the least and the greatest congruences in the same K°-class as p are provided. A number of equivalent conditions for K° being a congruence are given.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
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 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
This letter to the editor highlights adding the diagnostic utility of immunoglobulin G4(IgG4)measurements and its potential role in IgG4-related spinal pachymeningitis(IgG4-RSP)pathogenesis to the case reported by Cha...This letter to the editor highlights adding the diagnostic utility of immunoglobulin G4(IgG4)measurements and its potential role in IgG4-related spinal pachymeningitis(IgG4-RSP)pathogenesis to the case reported by Chae TS et al,which focused on IgG4-RSP diagnosis based on magnetic resonance imaging findings and increased plasma IgG4 concentrations.A comprehensive understanding of both IgG4 serological and cerebrospinal fluid biomarkers is essential for managing this complex condition.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 Immunoglobulin G4-related disease(IgG4-RD)is a persistent and progressive autoimmune condition marked by inflammation and fibrotic changes in the affected tissues.Cases of IgG4-RD causing pulmonary lesions ...BACKGROUND Immunoglobulin G4-related disease(IgG4-RD)is a persistent and progressive autoimmune condition marked by inflammation and fibrotic changes in the affected tissues.Cases of IgG4-RD causing pulmonary lesions are relatively rare,and some may be misdiagnosed as pulmonary tuberculosis.CASE SUMMARY In this report,we present an uncommon instance of IgG4-related lung disease,which was diagnosed through lung tissue biopsy conducted via puncture.A 67-year-old male was hospitalized with a two-month history of cough and sputum production.Chest computed tomography(CT)revealed infiltrative pulmonary tuberculosis in both upper lungs.However,the initial diagnosis was unclear,and the patient received HZRE quadruple therapy for tuberculosis at a local hospital.After 45 days of anti-tuberculosis treatment,the patient's cough and sputum worsened,and he began coughing up blood,prompting transfer to our hospital.Serum tests revealed elevated IgG4 levels.A biopsy of a right lung showed localized fibrous and extensive plasma cell infiltration,with 30-40 IgG4-positive cells per high-power field,and an IgG4/IgG ratio of 40%.These findings led to a diagnosis of IgG4-related lung disease.Following treatment with prednisone and mycophenolate mofetil,follow-up lung CT scans showed significant lesion improvement.CONCLUSION The chest CT findings of IgG4-RD are diverse and nonspecific,often leading to misdiagnosis as pulmonary tuberculosis,especially in primary care settings with limited diagnostic resources.We confirmed the diagnosis of IgG4-related lung disease through histological examination.展开更多
BACKGROUND Hepatic ischemia reperfusion(HIR)injury is a major complication affecting various major liver surgeries,including liver transplantation.Aprepitant(APRE),a neurokinin-1 receptor antagonist,is commonly used a...BACKGROUND Hepatic ischemia reperfusion(HIR)injury is a major complication affecting various major liver surgeries,including liver transplantation.Aprepitant(APRE),a neurokinin-1 receptor antagonist,is commonly used as an antiemetic to prevent chemotherapy-induced nausea and vomiting.AIM To assess the potential protective effect of APRE against HIR-induced liver injury via targeting the nucleotide-binding oligomerization domain-,leucine-rich repeat-,and pyrin domain-containing receptor 3/interleukin(IL)-1beta signaling pathway.METHODS Six groups of adult male Wistar albino rats were divided as follows:Sham group,Sham/APRE10 group(APRE 10 mg/kg),HIR group,HIR/APRE5 group(APRE 5 mg/kg),HIR/APRE10 group(APRE 10 mg/kg),and HIR/APRE20 group(APRE 20 mg/kg).Serum alanine transaminase,aspartate transaminase,liver malondialdehyde,total antioxidant capacity levels,as well as IL-6,sirtuin 1(Sirt1),caspase-3,cleaved caspase-3,and tumor necrosis factor alpha biomarkers,were evaluated.Hepatic specimens were examined histopathologically and immunohistochemically for nuclear factor erythroid-2-related factor 2(Nrf2)immunoexpression.RESULTS HIR resulted in hepatic damage,as evidenced by histopathological changes and a significant increase in serum alanine transaminase,aspartate transaminase,hepatic malondialdehyde,caspase-3,and tumor necrosis factor alpha levels.Additionally,there were significant increases in hepatic total antioxidant capacity and reductions in IL-6 and cleaved caspase-3 protein levels,as demonstrated by Western blot analysis,along with enhanced immunoexpression of Sirt1 and Nrf2.APRE has significantly reduced various parameters of oxidative stress,inflammation,and apoptosis,and a significant increase in liver Nrf2 immunoexpression,leading to a significant improvement in the histopathological changes.CONCLUSION In conclusion,targeting the Sirt1/Nrf2 signaling pathway,as demonstrated by APRE in our model,could present a promising therapeutic target to protect against HIR-induced liver injury during major liver surgeries.展开更多
BACKGROUND 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
BACKGROUND:The central nervous system is a critical target of severe heatstroke,with oxidative stress and multi-organelle damage being the key pathogenic mechanisms.However,research on endogenous antioxidant defense r...BACKGROUND:The central nervous system is a critical target of severe heatstroke,with oxidative stress and multi-organelle damage being the key pathogenic mechanisms.However,research on endogenous antioxidant defense remains limited.In this study,we aimed to characterize neuronal oxidative damage as a key heatstroke pathological mechanism and assess the neuroprotective effects of nuclear factor E2-related factor 2(NRF2).METHODS:After developing in vivo and in vitro heatstroke models,we employed histological staining,cell viability and apoptosis assays,oxidative stress indicators determination,organelle ultrastructural observation,and molecular expression analysis to investigate the mechanisms of brain injury and changes in the NRF2 pathway following heatstroke.We pretreated mice and SH-SY5Y cells with tert-butylhydroquinone(TBHQ) to activate NRF2 expression.Furthermore,we utilized NRF2 knockout(KO) mice and NRF2 siRNA transfection to suppress NRF2 expression,thereby examining the effects of NRF2 both in vivo and in vitro.RESULTS:We found that heatstroke induced neuronal damage,elevated oxidative stress levels,and caused structural damage to both the mitochondria and the endoplasmic reticulum(ER).Notably,NRF2 activation was insufficient post-heatstroke.Pretreatment with TBHQ effectively activated the NRF2 signaling pathway and mitigated the resulting damage.In contrast,these injuries were exacerbated in NRF2 KO mice and SH-SY5Y cells transfected with NRF2 siRNA.CONCLUSION:This preliminary research shows that the NRF2 antioxidant signaling pathway exerts a protective effect against oxidative stress,mitigating both mitochondrial and ER structural damage in neuronal cells during heatstroke.Therefore,targeting the NRF2 pathway is a promising therapeutic strategy for heatstroke-induced neuronal injury.展开更多
Based on histological and immunohistochemical exami- nation of various organs of patients with autoimmune pancreatitis （AIP）, a novel clinicopathological entity of IgG4-related sclerosing disease has been proposed. ...Based on histological and immunohistochemical exami- nation of various organs of patients with autoimmune pancreatitis （AIP）, a novel clinicopathological entity of IgG4-related sclerosing disease has been proposed. This is a systemic disease that is characterized by extensive IgG4-positive plasma cells and T-lymphocyte infiltration of various organs. Clinical manifestations are apparent in the pancreas, bile duct, gallbladder, salivary gland, retroperitoneum, kidney, lung, and prosrate, in which tissue fibrosis with obliterative phlebitis is pathologically induced. AlP is not simply pancreatitis but, in fact, is a pancreatic disease indicative of IgG4- related sclerosing diseases. This disease includes AlP, sclerosing cholangitis, cholecystitis, sialadenitis, retro-peritoneal fibrosis, tubulointerstitial nephritis, interstitial pneumonia, prostatitis, inflammatory pseudotumor and lymphadenopathy, all IgG4-related. Most IgG4-related sclerosing diseases have been found to be associated with AlP, but also those without pancreatic involvement have been reported. In some cases, only one or two organs are clinically involved, while in others, three or four organs are affected. The disease occurs predominantly in older men and responds well to steroid therapy. Serum IgG4 levels and immunos-taining with anti-IgG4 antibody are useful in making the diagnosis. Since malignant tumors are frequently suspected on initial presentation, IgG4-related sclerosing disease should be considered in the differential diagnosis to avoid unnecessary surgery.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.
文摘Let S be a regular semigroup with an inverse transversal S° and C（S） the congruence lattice of S. A relation K° on C（S） is introduced as follows： if p, θ∈ C（S）, then we say that p and 0 are K°-related if Ker pO = Ker θ°, where p°= p｜s°. Expressions for the least and the greatest congruences in the same K°-class as p are provided. A number of equivalent conditions for K° being a congruence are given.
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.
文摘This letter to the editor highlights adding the diagnostic utility of immunoglobulin G4(IgG4)measurements and its potential role in IgG4-related spinal pachymeningitis(IgG4-RSP)pathogenesis to the case reported by Chae TS et al,which focused on IgG4-RSP diagnosis based on magnetic resonance imaging findings and increased plasma IgG4 concentrations.A comprehensive understanding of both IgG4 serological and cerebrospinal fluid biomarkers is essential for managing this complex condition.
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 Immunoglobulin G4-related disease(IgG4-RD)is a persistent and progressive autoimmune condition marked by inflammation and fibrotic changes in the affected tissues.Cases of IgG4-RD causing pulmonary lesions are relatively rare,and some may be misdiagnosed as pulmonary tuberculosis.CASE SUMMARY In this report,we present an uncommon instance of IgG4-related lung disease,which was diagnosed through lung tissue biopsy conducted via puncture.A 67-year-old male was hospitalized with a two-month history of cough and sputum production.Chest computed tomography(CT)revealed infiltrative pulmonary tuberculosis in both upper lungs.However,the initial diagnosis was unclear,and the patient received HZRE quadruple therapy for tuberculosis at a local hospital.After 45 days of anti-tuberculosis treatment,the patient's cough and sputum worsened,and he began coughing up blood,prompting transfer to our hospital.Serum tests revealed elevated IgG4 levels.A biopsy of a right lung showed localized fibrous and extensive plasma cell infiltration,with 30-40 IgG4-positive cells per high-power field,and an IgG4/IgG ratio of 40%.These findings led to a diagnosis of IgG4-related lung disease.Following treatment with prednisone and mycophenolate mofetil,follow-up lung CT scans showed significant lesion improvement.CONCLUSION The chest CT findings of IgG4-RD are diverse and nonspecific,often leading to misdiagnosis as pulmonary tuberculosis,especially in primary care settings with limited diagnostic resources.We confirmed the diagnosis of IgG4-related lung disease through histological examination.
文摘BACKGROUND Hepatic ischemia reperfusion(HIR)injury is a major complication affecting various major liver surgeries,including liver transplantation.Aprepitant(APRE),a neurokinin-1 receptor antagonist,is commonly used as an antiemetic to prevent chemotherapy-induced nausea and vomiting.AIM To assess the potential protective effect of APRE against HIR-induced liver injury via targeting the nucleotide-binding oligomerization domain-,leucine-rich repeat-,and pyrin domain-containing receptor 3/interleukin(IL)-1beta signaling pathway.METHODS Six groups of adult male Wistar albino rats were divided as follows:Sham group,Sham/APRE10 group(APRE 10 mg/kg),HIR group,HIR/APRE5 group(APRE 5 mg/kg),HIR/APRE10 group(APRE 10 mg/kg),and HIR/APRE20 group(APRE 20 mg/kg).Serum alanine transaminase,aspartate transaminase,liver malondialdehyde,total antioxidant capacity levels,as well as IL-6,sirtuin 1(Sirt1),caspase-3,cleaved caspase-3,and tumor necrosis factor alpha biomarkers,were evaluated.Hepatic specimens were examined histopathologically and immunohistochemically for nuclear factor erythroid-2-related factor 2(Nrf2)immunoexpression.RESULTS HIR resulted in hepatic damage,as evidenced by histopathological changes and a significant increase in serum alanine transaminase,aspartate transaminase,hepatic malondialdehyde,caspase-3,and tumor necrosis factor alpha levels.Additionally,there were significant increases in hepatic total antioxidant capacity and reductions in IL-6 and cleaved caspase-3 protein levels,as demonstrated by Western blot analysis,along with enhanced immunoexpression of Sirt1 and Nrf2.APRE has significantly reduced various parameters of oxidative stress,inflammation,and apoptosis,and a significant increase in liver Nrf2 immunoexpression,leading to a significant improvement in the histopathological changes.CONCLUSION In conclusion,targeting the Sirt1/Nrf2 signaling pathway,as demonstrated by APRE in our model,could present a promising therapeutic target to protect against HIR-induced liver injury during major liver surgeries.
基金Supported by 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.
基金supported by the National Natural Science Foundation of China (No.82202432)the Guangzhou Science and Technology Plan Project (No.2023A04J2059,2024A03J0242)。
文摘BACKGROUND:The central nervous system is a critical target of severe heatstroke,with oxidative stress and multi-organelle damage being the key pathogenic mechanisms.However,research on endogenous antioxidant defense remains limited.In this study,we aimed to characterize neuronal oxidative damage as a key heatstroke pathological mechanism and assess the neuroprotective effects of nuclear factor E2-related factor 2(NRF2).METHODS:After developing in vivo and in vitro heatstroke models,we employed histological staining,cell viability and apoptosis assays,oxidative stress indicators determination,organelle ultrastructural observation,and molecular expression analysis to investigate the mechanisms of brain injury and changes in the NRF2 pathway following heatstroke.We pretreated mice and SH-SY5Y cells with tert-butylhydroquinone(TBHQ) to activate NRF2 expression.Furthermore,we utilized NRF2 knockout(KO) mice and NRF2 siRNA transfection to suppress NRF2 expression,thereby examining the effects of NRF2 both in vivo and in vitro.RESULTS:We found that heatstroke induced neuronal damage,elevated oxidative stress levels,and caused structural damage to both the mitochondria and the endoplasmic reticulum(ER).Notably,NRF2 activation was insufficient post-heatstroke.Pretreatment with TBHQ effectively activated the NRF2 signaling pathway and mitigated the resulting damage.In contrast,these injuries were exacerbated in NRF2 KO mice and SH-SY5Y cells transfected with NRF2 siRNA.CONCLUSION:This preliminary research shows that the NRF2 antioxidant signaling pathway exerts a protective effect against oxidative stress,mitigating both mitochondrial and ER structural damage in neuronal cells during heatstroke.Therefore,targeting the NRF2 pathway is a promising therapeutic strategy for heatstroke-induced neuronal injury.
文摘Based on histological and immunohistochemical exami- nation of various organs of patients with autoimmune pancreatitis （AIP）, a novel clinicopathological entity of IgG4-related sclerosing disease has been proposed. This is a systemic disease that is characterized by extensive IgG4-positive plasma cells and T-lymphocyte infiltration of various organs. Clinical manifestations are apparent in the pancreas, bile duct, gallbladder, salivary gland, retroperitoneum, kidney, lung, and prosrate, in which tissue fibrosis with obliterative phlebitis is pathologically induced. AlP is not simply pancreatitis but, in fact, is a pancreatic disease indicative of IgG4- related sclerosing diseases. This disease includes AlP, sclerosing cholangitis, cholecystitis, sialadenitis, retro-peritoneal fibrosis, tubulointerstitial nephritis, interstitial pneumonia, prostatitis, inflammatory pseudotumor and lymphadenopathy, all IgG4-related. Most IgG4-related sclerosing diseases have been found to be associated with AlP, but also those without pancreatic involvement have been reported. In some cases, only one or two organs are clinically involved, while in others, three or four organs are affected. The disease occurs predominantly in older men and responds well to steroid therapy. Serum IgG4 levels and immunos-taining with anti-IgG4 antibody are useful in making the diagnosis. Since malignant tumors are frequently suspected on initial presentation, IgG4-related sclerosing disease should be considered in the differential diagnosis to avoid unnecessary surgery.
