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
BACKGROUND Ulcerative colitis(UC)is a chronic and treatment-resistant disorder requiring potent therapeutics that are effective and safe.Cedrol(CE)is a bioactive natural product present in many traditional Chinese med...BACKGROUND Ulcerative colitis(UC)is a chronic and treatment-resistant disorder requiring potent therapeutics that are effective and safe.Cedrol(CE)is a bioactive natural product present in many traditional Chinese medicines.It is known for its suppression of inflammation and mitigation of oxidative stress.Its therapeutic efficacy and mechanistic underpinnings in UC remain uncharacterized.AIM To investigate the therapeutic potential and mechanisms of CE in UC.METHODS The anti-inflammatory activity and intestinal barrier-repairing effects of CE were assessed in a dextran sulfate sodium-induced murine colitis model.Network pharmacology was employed to predict potential targets and pathways.Then molecular docking and dynamics simulations were utilized to confirm a stable interaction between CE and the toll-like receptor 4(TLR4)/myeloid differentiation factor 2(MD2)complex.The anti-inflammatory mechanisms were further verified using in vitro assays.Additionally,the gut microbiota composition was analyzed via 16S rRNA gene sequencing.RESULTS CE significantly alleviated colitis symptoms,mitigated histopathological damage,and suppressed inflammation.Moreover,CE restored intestinal barrier integrity by enhancing mucus secretion and upregulating tight junction proteins(zonula occludens 1,occludin,claudin-1).Mechanistically,CE stably bound to MD2,inhibiting lipopolysaccharide-induced TLR4 signaling in RAW264.7 cells.This led to suppression of the downstream mitogen-activated protein kinase and nuclear factor kappa B signaling pathways,downregulating the expression of tumor necrosis factor-alpha,interleukin-1β,and interleukin-6.Gut microbiota analysis revealed that CE reversed dextran sulfate sodium-induced dysbiosis with significant enrichment of butyrogenic Christensenella minuta.CONCLUSION CE acted on MD2 to suppress proinflammatory cascades,promoting mucosal barrier reconstitution and microbiota remodeling and supporting its therapeutic use in UC.展开更多
Background:Cyclin-dependent kinase 4/6(CDK4/6)inhibitors have transformed the management of hormone receptor–positive/HER2–negative(HR+/HER2–)advanced breast cancer,yet evidence for elderly or poor-performance pati...Background:Cyclin-dependent kinase 4/6(CDK4/6)inhibitors have transformed the management of hormone receptor–positive/HER2–negative(HR+/HER2–)advanced breast cancer,yet evidence for elderly or poor-performance patients remains limited.This study examined real-world outcomes of palbociclib plus endocrine therapy in Asian patients,with additional subgroup analyses by age and performance status.Methods:We retrospectively analyzed 46 consecutive Asian patients with recurrent or de novo HR+/HER2−breast cancer treated with first-line palbociclib plus ET between April 2021 and March 2025.The primary endpoint was progression-free survival(PFS).Secondary endpoints included overall response rate(ORR),disease control rate(DCR),and safety.Subgroup analyses were performed by age(<70 vs.≥70 years)and performance status(PS;0–1 vs.2–3).Results:The median PFS was 26.6 months(range,1.4–69.5).Stratified by age,median PFS was 26.9 months in patients<70 years and 26.2 months in those≥70 years(p=0.760).By PS,PFS was 26.9 months for PS 0–1 and 17.8 months for PS 2–3(p=0.099).ORR was 60.9%and DCR 93.5%;notably,all PS 2–3 patients achieved disease control.Hematologic toxicities were common,with neutropenia(80.4%)and leukopenia(86.7%)predominating,but grade≥3 anemia was rare(2.2%).Elderly patients experienced anemia more frequently,while overall toxicity remained manageable.Dose reductions occurred in 47.8%without loss of efficacy.Conclusions:In routine Japanese practice,palbociclib plus ET provided prolonged PFS and high disease control consistent with pivotal trials and international real-world evidence.Importantly,elderly patients tolerated treatment well,and selected PS 2–3 patients also derived clinical benefit.These findings indicate that neither age nor PS alone should preclude the use of palbociclib in carefully monitored real-world patients.展开更多
Acute respiratory distress syndrome(ARDS)is a life-threatening condition that is characterized by high mortality rates and limited therapeutic options.Notably,Zhang et al demonstrated that CD146+mesenchymal stromal ce...Acute respiratory distress syndrome(ARDS)is a life-threatening condition that is characterized by high mortality rates and limited therapeutic options.Notably,Zhang et al demonstrated that CD146+mesenchymal stromal cells(MSCs)exhibited greater therapeutic efficacy than CD146-MSCs.These cells enhance epithelial repair through nuclear factor kappa B/cyclooxygenase-2-associated paracrine signaling and secretion of pro-angiogenic factors.We concur that MSCs hold significant promise for ARDS treatment;however,the heterogeneity of cell products is a translational barrier.Phenotype-aware strategies,such as CD146 enrichment,standardized potency assays,and extracellular vesicle profiling,are essential for improving the consistency of these studies.Further-more,advanced preclinical models,such as lung-on-a-chip systems,may provide more predictive insights into the therapeutic mechanisms.This article underscores the importance of CD146+MSCs in ARDS,emphasizes the need for precision in defining cell products,and discusses how integrating subset selection into translational pipelines could enhance the clinical impact of MSC-based therapies.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
Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0...Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.展开更多
Objective:The aim of the study was to investigate the expression and biological role of nuclear factor erythroid–related factor 2(NRF2)in gastric cancer cells.Methods:Western blotting(WB)and reverse transcription-pol...Objective:The aim of the study was to investigate the expression and biological role of nuclear factor erythroid–related factor 2(NRF2)in gastric cancer cells.Methods:Western blotting(WB)and reverse transcription-polymerase chain reaction(RT-PCR)were used to detect the expression of NRF2 in the tumor tissues of patients with gastric cancer and MKN45 cells.NRF2 was transfected into MKN45 gastric cancer cells,and apoptosis was detected using flow cytometry.The 3-(4,5-dimethylthiazole-2-yl)-2.5-dipheny-tetrazolium bromide(MTT)assay was per-formed to detect cell proliferation.Transwell and scratch experiments were performed to detect cell invasion and migration rates.WB blot-ting was performed to detect Bcl-2,COX-2,PEG2,Bax,and Cyt-C protein expression.RT-PCR was used to detect Bcl-2,COX-2,PEG2,Bax,Cyt-C,miR-340-5p,lncRNA HCG11,and NRF2 mRNA expression.Results:NRF2 expression increased in gastric cancer tissues and in the MKN45 gastric cancer cell model.Compared with the blank group,the shNRF2 knockdown group showed a significant increase in the MKN45 gastric cancer cell apoptosis rate(p<0.05)and a sig-nificant decrease in invasion and migration rates(p<0.05).WB and RT-PCR showed that,in the shNRF2 knockdown group,Bcl-2 protein and mRNA,miR-340-5p,and lncRNA HCG11 expression was significantly increased,whereas COX-2,PEG2,Bax,and Cyt-C protein and mRNA expression was significantly reduced(p<0.05).In the NRF2 overexpression group,Bcl-2 protein and mRNA expression was sig-nificantly reduced,whereas COX-2,PEG2,Bax,and Cyt-C protein and mRNA expression was significantly increased(p<0.05).The op-posite was observed for the NRF2 overexpression group.When miR-340-5p mimics were transfected into MKN45 gastric cancer cells,NRF2 and HCG11 expression significantly reduced(p<0.05).When the miR-340-5p inhibitor was transfected into MKN45 gastric cancer cells,NRF2 and HCG11 expression significantly increased(p<0.05).Conclusions:The invasion,migration,abnormal proliferation,and apoptosis of MKN45 gastric cancer cells are closely related to an im-balance in NRF2 expression,suggesting that MiR-340-5p may target and regulate the lncRNA HCG11,thereby inhibiting NRF2 expression.展开更多
Microglial pyroptosis and neuroinflammation have been implicated in the pathogenesis of sepsis-associated encephalopathy(SAE).OGT-mediated O-GlcNAcylation is involved in neurodevelopment and injury.However,its regulat...Microglial pyroptosis and neuroinflammation have been implicated in the pathogenesis of sepsis-associated encephalopathy(SAE).OGT-mediated O-GlcNAcylation is involved in neurodevelopment and injury.However,its regulatory function in microglial pyroptosis and involvement in SAE remains unclear.In this study,we demonstrated that OGT deficiency augmented microglial pyroptosis and exacerbated secondary neuronal injury.Furthermore,OGT inhibition impaired cognitive function in healthy mice and accelerated the progression in SAE mice.Mechanistically,OGT-mediated O-GlcNAcylation of ATF2 at Ser44 inhibited its phosphorylation and nuclear translocation,thereby amplifying NLRP3 inflammasome activation and promoting inflammatory cytokine production in microglia in response to LPS/Nigericin stimulation.In conclusion,this study uncovers the critical role of OGT-mediated O-GlcNAcylation in modulating microglial activity through the regulation of ATF2 and thus protects against SAE progression.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:To investigate SCL/TAL 1 interrupting locus(STIL)’s role and prognostic significance in lung adenocarcinoma(LUAD)progression,we examined STIL and E2 promoter binding factor 1(E2F1)expression and their impa...Background:To investigate SCL/TAL 1 interrupting locus(STIL)’s role and prognostic significance in lung adenocarcinoma(LUAD)progression,we examined STIL and E2 promoter binding factor 1(E2F1)expression and their impacts on LUAD prognosis using Gene Expression Profiling Interactive Analysis(GEPIA).Methods:Functional assays including CCK-8,wound-healing,5-ethynyl-2-deoxyuridine(EdU),Transwell assays,and flow cytometry,elucidated STIL and E2F1’s effects on cell viability,proliferation,apoptosis,and migration.Gene set enrichment analysis(GSEA)identified potential pathways,while metabolic assays assessed glucose metabolism.Results:Our findings reveal that STIL and E2F1 are overexpressed in LUAD,correlating with adverse outcomes.It enhances cell proliferation,migration,and invasion,and suppresses apoptosis,activating downstream of E2F1.Silencing E2F1 reversed the promotion effect of the STIL overexpression on cell viability and invasiveness.Importantly,STIL modulates glycolysis,influencing glucose consumption,lactate production,and energy balance in LUAD cells.Conclusion:Our model,incorporating STIL,age,and disease stage,robustly predicts patient prognosis,underscored STIL’s pivotal role in LUAD pathogenesis through metabolic reprogramming.This comprehensive approach not only confirms STIL’s prognostic value but also highlights its potential as a therapeutic target in LUAD.展开更多
Objective:Neuropathic pain(NP)is one of the most common forms of chronic pain,yet current treatment options are limited in effectiveness.Peripheral nerve injury activates spinal microglia,altering their inflammatory r...Objective:Neuropathic pain(NP)is one of the most common forms of chronic pain,yet current treatment options are limited in effectiveness.Peripheral nerve injury activates spinal microglia,altering their inflammatory response and phagocytic functions,which contributes to the progression of NP.Most current research on NP focuses on microglial inflammation,with relatively little attention to their phagocytic function.Early growth response factor 2(EGR2)has been shown to regulate microglial phagocytosis,but its specific role in NP remains unclear.This study aims to investigate how EGR2 modulates microglial phagocytosis and its involvement in NP,with the goal of identifying potential therapeutic targets.Methods:Adult male Sprague-Dawley(SD)rats were used to establish a chronic constriction injury(CCI)model of the sciatic nerve.Pain behaviors were assessed on days 1,3,7,10,and 14 post-surgery to confirm successful model induction.The temporal and spatial expression of EGR2 in the spinal cord was examined using real-time quantitative PCR(RT-qPCR),Western blotting,and immunofluorescence staining.Adeno-associated virus(AAV)was used to overexpress EGR2 in the spinal cord,and behavioral assessments were performed to evaluate the effects of EGR2 modulation of NP.CCI and lipopolysaccharide(LPS)models were established in animals and microglial cell lines,respectively,and changes in phagocytic activity were measured using RT-qPCR and fluorescent latex bead uptake assays.After confirming the involvement of microglial phagocytosis in NP,AAV was used to overexpress EGR2 in both in vivo and in vitro models,and phagocytic activity was further evaluated.Finally,eukaryotic transcriptome sequencing was conducted to screen differentially expressed mRNAs,followed by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses to identify potential downstream effectors of EGR2.Results:The CCI model successfully induced NP.Following CCI,EGR2 expression in the spinal cord was upregulated in parallel with NP development.Overexpression of EGR2 via spinal AAV injection enhanced microglial phagocytic activity and increased pain hypersensitivity in rats.Both animal and cellular models showed that CCI or LPS stimulation enhanced microglial phagocytosis,which was further amplified by EGR2 overexpression.Transcriptomic analysis of spinal cord tissues from CCI rats overexpressing EGR2 revealed upregulation of numerous genes associated with microglial phagocytosis and pain regulation.Among them,Lag3 emerged as a potential downstream target of EGR2.Conclusion:EGR2 contributes to the maintenance of NP by enhancing microglial phagocytosis in the spinal dorsal horn.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
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
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
The article by Mansouri et al provides a comprehensive investigation into the effects of L-arginine(L-Arg)on diabetic cardiomyopathy.The authors conclude that while a low dose(0.5 g/kg)of L-Arg improves lipid profiles...The article by Mansouri et al provides a comprehensive investigation into the effects of L-arginine(L-Arg)on diabetic cardiomyopathy.The authors conclude that while a low dose(0.5 g/kg)of L-Arg improves lipid profiles and reduces body weight,higher doses(≥1 g/kg)exacerbate oxidative stress,inflammation,and myocardial damage.In this letter,we aim to expand on the potential role of anti-inflammatory and antioxidant strategies in mitigating these adverse effects.Specifically,we focus on nuclear factor erythroid 2-related factor 2 activation and nitric oxide synthase modulation.These strategies could enhance the clinical utility of L-Arg by preserving its metabolic benefits while reducing its cardiotoxic risks.We believe this perspective will stimulate future research on L-Arg-based therapies in patients with diabetes,with an emphasis on optimizing dosage and exploring synergistic co-therapies.展开更多
AIM:To investigate the protective role of ghrelin against diabetic retinopathy(DR),focusing on its anti-ferroptotic mechanism in high glucose-induced retinal endothelial injury.METHODS:First,small interfering RNA(siRN...AIM:To investigate the protective role of ghrelin against diabetic retinopathy(DR),focusing on its anti-ferroptotic mechanism in high glucose-induced retinal endothelial injury.METHODS:First,small interfering RNA(siRNA)-mediated interference was conducted to knockdown nuclear factor erythroid 2-related factor 2(Nrf2).Using reverse transcription-polymerase chain reaction(RT-PCR),the expression level of Nrf2 was determined from human retinal microvascular endothelial cells(HRMECs)transfected with either si-NC or si-Nrf2.After that,cells were treated with 10 nmol/L ghrelin and then cultured in a high glucose(30 mmol/L)environment.EdU assay was utilized to assess cell proliferation,while transmission electron microscopy was employed to observe mitochondrial morphology.Flow cytometry was used to measure the level of intracellular reactive oxygen species(ROS),and biochemical assays were conducted to detect malondialdehyde(MDA),glutathione(GSH),superoxide dismutase(SOD),and ferrous iron(Fe2+).Western blotting was used to identify the presence of ferroptosis-related proteins such as glutathione peroxidase 4(GPX4),solute carrier family 7 member 11(SLC7A11),Nrf2,and haem oxygenase-1(HO-1).RESULTS:Under a high glucose environment,ghrelin could significantly promote the proliferation of HRMECs and mitochondrial status,remarkably decrease the levels of intracellular ROS and MDA,and up-regulate the level of GSH and SOD.Besides,ghrelin greatly reduced Fe2+level in the cells while increased protein levels of GPX4 and SLC7A11.Subsequently,we found that high glucose induced inactivation of Nrf2/HO-1 axis and the protein expression profile were significantly promoted by ghrelin.Moreover,silencing of Nrf2 by siRNA delivery markedly diminished the changes induced by ghrelin in high glucose-induced HRMECs,shown as reduced cell proliferation and increased mitochondrial malformation,up-regulated ROS,MDA,Fe^(2+),GPX4 and SLC7A11,as well as down-regulated GSH,SOD,Nrf2 and HO-1.CONCLUSION:Ghrelin attenuates high glucose-induced injury of retinal endothelial cells via inhibiting ferroptosis,and activation of Nrf2/HO-1 pathway may be one of the mechanisms involved in this effect of ghrelin.展开更多
Background:Periodontitis is characterized by alveolar bone resorption,aggravated by osteoblast dysfunction,and associated with intracellular oxidative stress linked to the nuclear factor erythroid 2-related factor 2(N...Background:Periodontitis is characterized by alveolar bone resorption,aggravated by osteoblast dysfunction,and associated with intracellular oxidative stress linked to the nuclear factor erythroid 2-related factor 2(NRF2)level.We evaluated the molecular mechanism of periodontitis onset and development and the role of NRF2 in osteogenic differentiation.Methods:Primary murine mandibular osteoblasts were extracted and exposed to Porphyromonas gingivalis lipopolysaccharide(Pg-LPS)or other stimuli.Reactive oxygen species(ROS)and 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide(JC-1)staining were used to detect intracellular oxidative stress.Alkaline phosphatase staining and alizarin red S staining were used to detect the osteogenic differentiation of osteoblasts.Immunofluorescence and western blotting were used to determine the changes in the mitogen-activated protein kinase(MAPK)pathway and related molecule activities.Immunofluorescence colocalization and co-immunoprecipitation were performed to examine the nuclear translocation of NRF2 and its interaction with dual-specific phosphatase 1(DUSP1)in cells.Results:Ligated tissue samples showed higher alveolar bone resorption rate and lower NRF2 level than healthy periodontal tissue samples.Pg-LPS increased intracellular oxidative stress levels and inhibited osteogenic differentiation,whereas changes in NRF2 expression were correlated with changes in the oxidative stress and osteogenesis rate.NRF2 promoted the dephosphorylation of the MAPK pathway by nuclear translocation and the upregulation of DUSP1 expression,thus enhancing the osteogenic differentiation capacity of mandibular osteoblasts.The interaction between NRF2 and DUSP1 was observed.Conclusions:NRF2 and its nuclear translocation can regulate the osteogenic differentiation of mandibular osteoblasts under Pg-LPS conditions by interacting with DUSP1 in a process linked to the MAPK pathway.These findings form the basis of periodontitis treatment.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 Provincial Key Cultivation Laboratory for Digestive Disease Research,No.2021SYS13Shanxi Province’s“Si Ge Yi Pi”Science and Technology Driven Medical Innovation Project,No.2021MX03Shanxi Provincial Basic Research Program,No.202403021222423.
文摘BACKGROUND Ulcerative colitis(UC)is a chronic and treatment-resistant disorder requiring potent therapeutics that are effective and safe.Cedrol(CE)is a bioactive natural product present in many traditional Chinese medicines.It is known for its suppression of inflammation and mitigation of oxidative stress.Its therapeutic efficacy and mechanistic underpinnings in UC remain uncharacterized.AIM To investigate the therapeutic potential and mechanisms of CE in UC.METHODS The anti-inflammatory activity and intestinal barrier-repairing effects of CE were assessed in a dextran sulfate sodium-induced murine colitis model.Network pharmacology was employed to predict potential targets and pathways.Then molecular docking and dynamics simulations were utilized to confirm a stable interaction between CE and the toll-like receptor 4(TLR4)/myeloid differentiation factor 2(MD2)complex.The anti-inflammatory mechanisms were further verified using in vitro assays.Additionally,the gut microbiota composition was analyzed via 16S rRNA gene sequencing.RESULTS CE significantly alleviated colitis symptoms,mitigated histopathological damage,and suppressed inflammation.Moreover,CE restored intestinal barrier integrity by enhancing mucus secretion and upregulating tight junction proteins(zonula occludens 1,occludin,claudin-1).Mechanistically,CE stably bound to MD2,inhibiting lipopolysaccharide-induced TLR4 signaling in RAW264.7 cells.This led to suppression of the downstream mitogen-activated protein kinase and nuclear factor kappa B signaling pathways,downregulating the expression of tumor necrosis factor-alpha,interleukin-1β,and interleukin-6.Gut microbiota analysis revealed that CE reversed dextran sulfate sodium-induced dysbiosis with significant enrichment of butyrogenic Christensenella minuta.CONCLUSION CE acted on MD2 to suppress proinflammatory cascades,promoting mucosal barrier reconstitution and microbiota remodeling and supporting its therapeutic use in UC.
文摘Background:Cyclin-dependent kinase 4/6(CDK4/6)inhibitors have transformed the management of hormone receptor–positive/HER2–negative(HR+/HER2–)advanced breast cancer,yet evidence for elderly or poor-performance patients remains limited.This study examined real-world outcomes of palbociclib plus endocrine therapy in Asian patients,with additional subgroup analyses by age and performance status.Methods:We retrospectively analyzed 46 consecutive Asian patients with recurrent or de novo HR+/HER2−breast cancer treated with first-line palbociclib plus ET between April 2021 and March 2025.The primary endpoint was progression-free survival(PFS).Secondary endpoints included overall response rate(ORR),disease control rate(DCR),and safety.Subgroup analyses were performed by age(<70 vs.≥70 years)and performance status(PS;0–1 vs.2–3).Results:The median PFS was 26.6 months(range,1.4–69.5).Stratified by age,median PFS was 26.9 months in patients<70 years and 26.2 months in those≥70 years(p=0.760).By PS,PFS was 26.9 months for PS 0–1 and 17.8 months for PS 2–3(p=0.099).ORR was 60.9%and DCR 93.5%;notably,all PS 2–3 patients achieved disease control.Hematologic toxicities were common,with neutropenia(80.4%)and leukopenia(86.7%)predominating,but grade≥3 anemia was rare(2.2%).Elderly patients experienced anemia more frequently,while overall toxicity remained manageable.Dose reductions occurred in 47.8%without loss of efficacy.Conclusions:In routine Japanese practice,palbociclib plus ET provided prolonged PFS and high disease control consistent with pivotal trials and international real-world evidence.Importantly,elderly patients tolerated treatment well,and selected PS 2–3 patients also derived clinical benefit.These findings indicate that neither age nor PS alone should preclude the use of palbociclib in carefully monitored real-world patients.
基金the Scientific and Technological Research Council of Türkiye(TÜBİTAK)Under the International Postdoctoral Research Fellowship Program(2219),No.1059B192400980the National Postdoctoral Research Fellowship Program(2218),No.122C158.
文摘Acute respiratory distress syndrome(ARDS)is a life-threatening condition that is characterized by high mortality rates and limited therapeutic options.Notably,Zhang et al demonstrated that CD146+mesenchymal stromal cells(MSCs)exhibited greater therapeutic efficacy than CD146-MSCs.These cells enhance epithelial repair through nuclear factor kappa B/cyclooxygenase-2-associated paracrine signaling and secretion of pro-angiogenic factors.We concur that MSCs hold significant promise for ARDS treatment;however,the heterogeneity of cell products is a translational barrier.Phenotype-aware strategies,such as CD146 enrichment,standardized potency assays,and extracellular vesicle profiling,are essential for improving the consistency of these studies.Further-more,advanced preclinical models,such as lung-on-a-chip systems,may provide more predictive insights into the therapeutic mechanisms.This article underscores the importance of CD146+MSCs in ARDS,emphasizes the need for precision in defining cell products,and discusses how integrating subset selection into translational pipelines could enhance the clinical impact of MSC-based therapies.
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 National Natural Science Foundation of China,Nos.82204360(to HM)and 82270411(to GW)National Science and Technology Innovation 2030 Major Program,No.2021ZD0200900(to YL)。
文摘Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.
基金Funded by the general program of the Nature Fund of InnerMongolia Autonomous Region.
文摘Objective:The aim of the study was to investigate the expression and biological role of nuclear factor erythroid–related factor 2(NRF2)in gastric cancer cells.Methods:Western blotting(WB)and reverse transcription-polymerase chain reaction(RT-PCR)were used to detect the expression of NRF2 in the tumor tissues of patients with gastric cancer and MKN45 cells.NRF2 was transfected into MKN45 gastric cancer cells,and apoptosis was detected using flow cytometry.The 3-(4,5-dimethylthiazole-2-yl)-2.5-dipheny-tetrazolium bromide(MTT)assay was per-formed to detect cell proliferation.Transwell and scratch experiments were performed to detect cell invasion and migration rates.WB blot-ting was performed to detect Bcl-2,COX-2,PEG2,Bax,and Cyt-C protein expression.RT-PCR was used to detect Bcl-2,COX-2,PEG2,Bax,Cyt-C,miR-340-5p,lncRNA HCG11,and NRF2 mRNA expression.Results:NRF2 expression increased in gastric cancer tissues and in the MKN45 gastric cancer cell model.Compared with the blank group,the shNRF2 knockdown group showed a significant increase in the MKN45 gastric cancer cell apoptosis rate(p<0.05)and a sig-nificant decrease in invasion and migration rates(p<0.05).WB and RT-PCR showed that,in the shNRF2 knockdown group,Bcl-2 protein and mRNA,miR-340-5p,and lncRNA HCG11 expression was significantly increased,whereas COX-2,PEG2,Bax,and Cyt-C protein and mRNA expression was significantly reduced(p<0.05).In the NRF2 overexpression group,Bcl-2 protein and mRNA expression was sig-nificantly reduced,whereas COX-2,PEG2,Bax,and Cyt-C protein and mRNA expression was significantly increased(p<0.05).The op-posite was observed for the NRF2 overexpression group.When miR-340-5p mimics were transfected into MKN45 gastric cancer cells,NRF2 and HCG11 expression significantly reduced(p<0.05).When the miR-340-5p inhibitor was transfected into MKN45 gastric cancer cells,NRF2 and HCG11 expression significantly increased(p<0.05).Conclusions:The invasion,migration,abnormal proliferation,and apoptosis of MKN45 gastric cancer cells are closely related to an im-balance in NRF2 expression,suggesting that MiR-340-5p may target and regulate the lncRNA HCG11,thereby inhibiting NRF2 expression.
基金supported by the Jiangsu Provincial Medical Key Discipline(Laboratory)Cultivation Unit(JSDW202249)the Natural Science Foundation of Jiangsu Province(BK20211108)+4 种基金a Scientific Research Project of the Health Commission of Nantong(MS2023035)Nantong Natural Science Foundation(JC2023114)the Scientific Research Innovation Team of Kangda College of Nanjing Medical University(KD2022KYCXTD005)Nantong University Clinical Medicine Special Project(2022JY005)the Postgraduate Research&Practice Innovation Program of Jiangsu province(KYCX23_3416).
文摘Microglial pyroptosis and neuroinflammation have been implicated in the pathogenesis of sepsis-associated encephalopathy(SAE).OGT-mediated O-GlcNAcylation is involved in neurodevelopment and injury.However,its regulatory function in microglial pyroptosis and involvement in SAE remains unclear.In this study,we demonstrated that OGT deficiency augmented microglial pyroptosis and exacerbated secondary neuronal injury.Furthermore,OGT inhibition impaired cognitive function in healthy mice and accelerated the progression in SAE mice.Mechanistically,OGT-mediated O-GlcNAcylation of ATF2 at Ser44 inhibited its phosphorylation and nuclear translocation,thereby amplifying NLRP3 inflammasome activation and promoting inflammatory cytokine production in microglia in response to LPS/Nigericin stimulation.In conclusion,this study uncovers the critical role of OGT-mediated O-GlcNAcylation in modulating microglial activity through the regulation of ATF2 and thus protects against SAE progression.
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:To investigate SCL/TAL 1 interrupting locus(STIL)’s role and prognostic significance in lung adenocarcinoma(LUAD)progression,we examined STIL and E2 promoter binding factor 1(E2F1)expression and their impacts on LUAD prognosis using Gene Expression Profiling Interactive Analysis(GEPIA).Methods:Functional assays including CCK-8,wound-healing,5-ethynyl-2-deoxyuridine(EdU),Transwell assays,and flow cytometry,elucidated STIL and E2F1’s effects on cell viability,proliferation,apoptosis,and migration.Gene set enrichment analysis(GSEA)identified potential pathways,while metabolic assays assessed glucose metabolism.Results:Our findings reveal that STIL and E2F1 are overexpressed in LUAD,correlating with adverse outcomes.It enhances cell proliferation,migration,and invasion,and suppresses apoptosis,activating downstream of E2F1.Silencing E2F1 reversed the promotion effect of the STIL overexpression on cell viability and invasiveness.Importantly,STIL modulates glycolysis,influencing glucose consumption,lactate production,and energy balance in LUAD cells.Conclusion:Our model,incorporating STIL,age,and disease stage,robustly predicts patient prognosis,underscored STIL’s pivotal role in LUAD pathogenesis through metabolic reprogramming.This comprehensive approach not only confirms STIL’s prognostic value but also highlights its potential as a therapeutic target in LUAD.
基金supported by the National Natural Science Foundation of China(82071249 and 81771207).
文摘Objective:Neuropathic pain(NP)is one of the most common forms of chronic pain,yet current treatment options are limited in effectiveness.Peripheral nerve injury activates spinal microglia,altering their inflammatory response and phagocytic functions,which contributes to the progression of NP.Most current research on NP focuses on microglial inflammation,with relatively little attention to their phagocytic function.Early growth response factor 2(EGR2)has been shown to regulate microglial phagocytosis,but its specific role in NP remains unclear.This study aims to investigate how EGR2 modulates microglial phagocytosis and its involvement in NP,with the goal of identifying potential therapeutic targets.Methods:Adult male Sprague-Dawley(SD)rats were used to establish a chronic constriction injury(CCI)model of the sciatic nerve.Pain behaviors were assessed on days 1,3,7,10,and 14 post-surgery to confirm successful model induction.The temporal and spatial expression of EGR2 in the spinal cord was examined using real-time quantitative PCR(RT-qPCR),Western blotting,and immunofluorescence staining.Adeno-associated virus(AAV)was used to overexpress EGR2 in the spinal cord,and behavioral assessments were performed to evaluate the effects of EGR2 modulation of NP.CCI and lipopolysaccharide(LPS)models were established in animals and microglial cell lines,respectively,and changes in phagocytic activity were measured using RT-qPCR and fluorescent latex bead uptake assays.After confirming the involvement of microglial phagocytosis in NP,AAV was used to overexpress EGR2 in both in vivo and in vitro models,and phagocytic activity was further evaluated.Finally,eukaryotic transcriptome sequencing was conducted to screen differentially expressed mRNAs,followed by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses to identify potential downstream effectors of EGR2.Results:The CCI model successfully induced NP.Following CCI,EGR2 expression in the spinal cord was upregulated in parallel with NP development.Overexpression of EGR2 via spinal AAV injection enhanced microglial phagocytic activity and increased pain hypersensitivity in rats.Both animal and cellular models showed that CCI or LPS stimulation enhanced microglial phagocytosis,which was further amplified by EGR2 overexpression.Transcriptomic analysis of spinal cord tissues from CCI rats overexpressing EGR2 revealed upregulation of numerous genes associated with microglial phagocytosis and pain regulation.Among them,Lag3 emerged as a potential downstream target of EGR2.Conclusion:EGR2 contributes to the maintenance of NP by enhancing microglial phagocytosis in the spinal dorsal horn.
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.
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.
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The article by Mansouri et al provides a comprehensive investigation into the effects of L-arginine(L-Arg)on diabetic cardiomyopathy.The authors conclude that while a low dose(0.5 g/kg)of L-Arg improves lipid profiles and reduces body weight,higher doses(≥1 g/kg)exacerbate oxidative stress,inflammation,and myocardial damage.In this letter,we aim to expand on the potential role of anti-inflammatory and antioxidant strategies in mitigating these adverse effects.Specifically,we focus on nuclear factor erythroid 2-related factor 2 activation and nitric oxide synthase modulation.These strategies could enhance the clinical utility of L-Arg by preserving its metabolic benefits while reducing its cardiotoxic risks.We believe this perspective will stimulate future research on L-Arg-based therapies in patients with diabetes,with an emphasis on optimizing dosage and exploring synergistic co-therapies.
基金Supported by the Scientific Research Development Project of North Sichuan Medical College(No.CBY24-QDA01)Science and Technology Program of Shaanxi Province(No.2024SF-YBXM-324,No.2024SFYBXM-341).
文摘AIM:To investigate the protective role of ghrelin against diabetic retinopathy(DR),focusing on its anti-ferroptotic mechanism in high glucose-induced retinal endothelial injury.METHODS:First,small interfering RNA(siRNA)-mediated interference was conducted to knockdown nuclear factor erythroid 2-related factor 2(Nrf2).Using reverse transcription-polymerase chain reaction(RT-PCR),the expression level of Nrf2 was determined from human retinal microvascular endothelial cells(HRMECs)transfected with either si-NC or si-Nrf2.After that,cells were treated with 10 nmol/L ghrelin and then cultured in a high glucose(30 mmol/L)environment.EdU assay was utilized to assess cell proliferation,while transmission electron microscopy was employed to observe mitochondrial morphology.Flow cytometry was used to measure the level of intracellular reactive oxygen species(ROS),and biochemical assays were conducted to detect malondialdehyde(MDA),glutathione(GSH),superoxide dismutase(SOD),and ferrous iron(Fe2+).Western blotting was used to identify the presence of ferroptosis-related proteins such as glutathione peroxidase 4(GPX4),solute carrier family 7 member 11(SLC7A11),Nrf2,and haem oxygenase-1(HO-1).RESULTS:Under a high glucose environment,ghrelin could significantly promote the proliferation of HRMECs and mitochondrial status,remarkably decrease the levels of intracellular ROS and MDA,and up-regulate the level of GSH and SOD.Besides,ghrelin greatly reduced Fe2+level in the cells while increased protein levels of GPX4 and SLC7A11.Subsequently,we found that high glucose induced inactivation of Nrf2/HO-1 axis and the protein expression profile were significantly promoted by ghrelin.Moreover,silencing of Nrf2 by siRNA delivery markedly diminished the changes induced by ghrelin in high glucose-induced HRMECs,shown as reduced cell proliferation and increased mitochondrial malformation,up-regulated ROS,MDA,Fe^(2+),GPX4 and SLC7A11,as well as down-regulated GSH,SOD,Nrf2 and HO-1.CONCLUSION:Ghrelin attenuates high glucose-induced injury of retinal endothelial cells via inhibiting ferroptosis,and activation of Nrf2/HO-1 pathway may be one of the mechanisms involved in this effect of ghrelin.
基金supported by the National Natural Science Foundation of China(Nos.82170954 and 82301066)the Medical Science and Technology Project of Zhejiang Province of China(No.2024KY1064)the Zhejiang Provincial Natural Science Foundation of China(No.LQN25H140005)。
文摘Background:Periodontitis is characterized by alveolar bone resorption,aggravated by osteoblast dysfunction,and associated with intracellular oxidative stress linked to the nuclear factor erythroid 2-related factor 2(NRF2)level.We evaluated the molecular mechanism of periodontitis onset and development and the role of NRF2 in osteogenic differentiation.Methods:Primary murine mandibular osteoblasts were extracted and exposed to Porphyromonas gingivalis lipopolysaccharide(Pg-LPS)or other stimuli.Reactive oxygen species(ROS)and 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide(JC-1)staining were used to detect intracellular oxidative stress.Alkaline phosphatase staining and alizarin red S staining were used to detect the osteogenic differentiation of osteoblasts.Immunofluorescence and western blotting were used to determine the changes in the mitogen-activated protein kinase(MAPK)pathway and related molecule activities.Immunofluorescence colocalization and co-immunoprecipitation were performed to examine the nuclear translocation of NRF2 and its interaction with dual-specific phosphatase 1(DUSP1)in cells.Results:Ligated tissue samples showed higher alveolar bone resorption rate and lower NRF2 level than healthy periodontal tissue samples.Pg-LPS increased intracellular oxidative stress levels and inhibited osteogenic differentiation,whereas changes in NRF2 expression were correlated with changes in the oxidative stress and osteogenesis rate.NRF2 promoted the dephosphorylation of the MAPK pathway by nuclear translocation and the upregulation of DUSP1 expression,thus enhancing the osteogenic differentiation capacity of mandibular osteoblasts.The interaction between NRF2 and DUSP1 was observed.Conclusions:NRF2 and its nuclear translocation can regulate the osteogenic differentiation of mandibular osteoblasts under Pg-LPS conditions by interacting with DUSP1 in a process linked to the MAPK pathway.These findings form the basis of periodontitis treatment.
