Mitochondrial dysfunction and oxidative stress are widely regarded as primary drivers of aging and are associated with several neurodegenerative diseases.The degeneration of motor neurons during aging is a critical pa...Mitochondrial dysfunction and oxidative stress are widely regarded as primary drivers of aging and are associated with several neurodegenerative diseases.The degeneration of motor neurons during aging is a critical pathological factor contributing to the progression of sarcopenia.However,the morphological and functional changes in mitochondria and their interplay in the degeneration of the neuromuscular junction during aging remain poorly understood.A defined systematic search of the Pub Med,Web of Science and Embase databases(last accessed on October 30,2024)was conducted with search terms including'mitochondria','aging'and'NMJ'.Clinical and preclinical studies of mitochondrial dysfunction and neuromuscular junction degeneration during aging.Twentyseven studies were included in this systematic review.This systematic review provides a summary of morphological,functional and biological changes in neuromuscular junction,mitochondrial morphology,biosynthesis,respiratory chain function,and mitophagy during aging.We focus on the interactions and mechanisms underlying the relationship between mitochondria and neuromuscular junctions during aging.Aging is characterized by significant reductions in mitochondrial fusion/fission cycles,biosynthesis,and mitochondrial quality control,which may lead to neuromuscular junction dysfunction,denervation and poor physical performance.Motor nerve terminals that exhibit redox sensitivity are among the first to exhibit abnormalities,ultimately leading to an early decline in muscle strength through impaired neuromuscular junction transmission function.Parg coactivator 1 alpha is a crucial molecule that regulates mitochondrial biogenesis and modulates various pathways,including the mitochondrial respiratory chain,energy deficiency,oxidative stress,and inflammation.Mitochondrial dysfunction is correlated with neuromuscular junction denervation and acetylcholine receptor fragmentation,resulting in muscle atrophy and a decrease in strength during aging.Physical therapy,pharmacotherapy,and gene therapy can alleviate the structural degeneration and functional deterioration of neuromuscular junction by restoring mitochondrial function.Therefore,mitochondria are considered potential targets for preserving neuromuscular junction morphology and function during aging to treat sarcopenia.展开更多
Resistance exercise has been confirmed to be important for maintaining muscle mass and function.However,despite considerable experimental studies,the underlying mechanisms still requires further investigation to be el...Resistance exercise has been confirmed to be important for maintaining muscle mass and function.However,despite considerable experimental studies,the underlying mechanisms still requires further investigation to be elucidated.Sestrin1 is a stress-inducible protein strongly associated with the occurrence and development of skeletal muscle dysfunction.Besides,oxidative stress is believed to be a major pathogenic mechanism in the development of skeletal muscle atrophy,whereas regular exercise training induces the endogenous antioxidative system and protects the body against adverse effects of oxidative stress.Nevertheless,whether Sestrin1 is involved in the amelioration of resistance exercise on muscle atrophy and the role of its antioxidant function in this process remains unknown.Here we show that six-week resistance exercise training significantly improved muscle function,muscle mass,and oxidative damage and maintained the level of Sestrin1 in dexamethasone-treated C57BL/6J mice.Mechanistically,Sestrin1 overexpression rescued protein degradation and oxidative stress in atrophied myotubes.Furthermore,an emerging regulator of cellular defense against toxic and oxidative insults,nuclear factor erythroid2–related factor 2(Nrf2)controls the basal and induced expression of an array of antioxidant response element–dependent genes to regulate the pathophysiological outcomes of oxidant exposure.In this study,we found that Nrf2 is a target of Sestrin1,and Nrf2 nuclear translocation is facilitated by Sestrin1.ML385(an Nrf2 inhibitor)treatment mitigated the regulatory effects of overexpression-Sestrin1.Therefore,Sestrin1 was involved in the process of resistance exercise against skeletal muscle atrophy,which may be closely related to its antioxidant capacity,revealing a potential therapeutic strategy for reducing the loss of skeletal muscle.展开更多
Oxidative stress significantly contributes to secondary damage after spinal cord injury.Despite its importance,research on oxidative stress in spinal cord injury remains limited.Investigating the expression and regula...Oxidative stress significantly contributes to secondary damage after spinal cord injury.Despite its importance,research on oxidative stress in spinal cord injury remains limited.Investigating the expression and regulation of oxidative stress-related genes could enhance the diagnosis and treatment of spinal cord injury.In this study,we analyzed the sequencing data of human blood samples and injured mouse spinal cord tissue that were sourced from GEO databases and identified diagnostic biomarkers associated with the severity of spinal cord injury.We also explored the expression patterns of oxidative stress-related genes,potential regulatory mechanisms,and therapeutic drugs.To validate our findings,we performed immunofluorescence and quantitative polymerase chain reaction to assess gene expression in the injured spinal cord.Our results revealed biomarkers associated with oxidative stress and immune responses across different levels of spinal cord injury in humans.We identified differentially expressed oxidative stress-related genes and key hub genes in injured mouse spinal cord tissue and revealed their temporal expression patterns at both the tissue and single-cell levels.We also clarified the signaling pathways associated with oxidative stress and identified ligand-receptor pairs among various cell types at different time points after injury.Furthermore,we discovered microRNAs,long non-coding RNAs,and transcription factors that regulate these hub genes and revealed their roles in modulating gene expression at various stages after spinal cord injury.We also identified drugs targeting these hub genes.The findings from this study not only aid in identifying diagnostic biomarkers that reflect the severity of spinal cord injury,but also provide insights into the expression dynamics of oxidative stress-related genes.In addition,the study reveals potential regulatory mechanisms and identifies potential drugs to treat patients with spinal cord injury.展开更多
Background:Myocardial infarction(MI)remains a major global public health challenge.Although advances in reperfusion therapy have reduced acute mortality,post-infarction cardiac remodeling continues to pose a substanti...Background:Myocardial infarction(MI)remains a major global public health challenge.Although advances in reperfusion therapy have reduced acute mortality,post-infarction cardiac remodeling continues to pose a substantial threat to long-term cardiovascular health.Oxidative stress and the ensuing inflammatory response are key drivers of this pathological process,leading to cardiomyocyte death,myocardial fibrosis,and functional impairment.Among the regulatory pathways involved,the kelch-like ECH-associated protein 1(Keap1)/nuclear factor erythroid 2-related factor 2(Nrf2)axis has emerged as a critical therapeutic target for mitigating post-MI cardiac injury.Methods:A murine MI model was established by permanent ligation of the left anterior descending coronary artery.Mice received oral Tongxinbi formula(TXB)at low,medium,or high doses(9/18/36 g/kg)once daily for 28 days.Cardiac function was assessed by echocardiography;myocardial fibrosis by Masson’s trichrome;and endothelial integrity by CD31 immunofluorescence.Plasma markers of endothelial function and inflammation were quantified.In vitro,oxidative stress was induced by H2O2 in vascular endothelial cells and cardiomyocytes,followed by treatment with TXB drug-containing serum.Western blot and RT-qPCR were used to measure components of the Keap1/Nrf2 pathway;ELISA quantified oxidative stress and inflammatory indices.Conditioned-medium experiments evaluated endothelial cell–mediated paracrine protection of cardiomyocytes.Results:TXB significantly improved cardiac function and reduced myocardial fibrosis after MI,in association with preservation of microvascular structure and systemic attenuation of oxidative stress and inflammation.In vitro,TXB activated the endothelial Keap1/Nrf2 pathway,enhanced cellular antioxidant defenses,increased VEGF secretion,and,via endothelial cell-mediated paracrine signaling,alleviated cardiomyocyte injury under oxidative stress.Conclusion:TXB exerts anti-fibrotic and cardioprotective effects by activating Nrf2 signaling and engaging endothelial-mediated paracrine mechanisms,collectively mitigating oxidative stress and inflammation in the post-MI setting.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
The aim of this study is to investigate the mechanism of magnesium isoglycyrrhizinate(MgIG)in the treatment of myocardial remodeling induced by isoproterenol(ISO)in mice.We assessed the impact of MgIG on ISO-induced m...The aim of this study is to investigate the mechanism of magnesium isoglycyrrhizinate(MgIG)in the treatment of myocardial remodeling induced by isoproterenol(ISO)in mice.We assessed the impact of MgIG on ISO-induced myocardial remodeling by activating the PI3K/AKT1 pathway.The cardiac function of mice was evaluated by echocardiography,revealing that MgIG could improve left ventricular function.Pathological staining analysis showed that MgIG could reduce the degree of myocardial injury caused by ISO.Serum data detected by ELISA demonstrated that MgIG could decrease the levels of CK-MB,MDA,and LDH while increasing the activity of GSH-Px.Western blotting analysis revealed that protein expression levels of Collagen I,BNP,Bax,cleaved caspase-3,p-PI3K,and p-AKT1 were decreased,whereas the protein expressions of Bcl-2,COX2,and SOD1 were increased upon MgIG treatment.However,the activation of the PI3K pathway reversed the cardioprotective effects of MgIG,as evidenced by the addition of PI3K activators.Taken together,our comprehensive results suggested that MgIG could improve ISO-induced myocardial remodeling,potentially through its mechanism of inhibiting the PI3K/AKT1 pathway to regulate apoptosis and oxidative stress.展开更多
Objective:To investigate the protective effects of naringin on doxorubicin(DOX)-induced liver injury.Methods:A total of 50 male rats were allocated into five groups:the control group,the DOX group,the DOX groups treat...Objective:To investigate the protective effects of naringin on doxorubicin(DOX)-induced liver injury.Methods:A total of 50 male rats were allocated into five groups:the control group,the DOX group,the DOX groups treated with 50 mg/kg and 100 mg/kg of naringin by gastric lavage for 10 days,as well as the group treated with 100 mg/kg of naringin alone.Liver and serum samples were collected for biochemical,histopathological,and molecular analyses,including liver enzyme activity,oxidative stress markers,inflammation,apoptosis-related proteins,and DNA damage indicators.Results:Naringin attenuated DOX-induced elevation in liver enzyme activity and inflammation markers while enhancing antioxidant activities.Naringin also activated the Nrf2-HO-1 signaling pathway,with the most pronounced effect in the high-dose naringin group.In addition,naringin modulated apoptotic signaling by downregulating the expression of PI3K-AKT and BAX,and upregulating Bcl-2,as well as reduced the level of 8-OHdG.Histopathological evaluation showed that DOX-induced structural liver alterations,such as cellular degeneration and necrosis,were notably attenuated by naringin treatment.Conclusions:Naringin treatment exerts protective effects against DOX-induced liver injury through its antioxidative,anti-inflammatory,and anti-apoptotic effects.展开更多
OBJECTIVES:To investigate the effect of Bushen Tongluo recipe(BSTLR, 补肾通络方) on rats with diabetic kidney disease(DKD) and to explore the underlying mechanism of action. METHODS:The rat model of DKD was establishe...OBJECTIVES:To investigate the effect of Bushen Tongluo recipe(BSTLR, 补肾通络方) on rats with diabetic kidney disease(DKD) and to explore the underlying mechanism of action. METHODS:The rat model of DKD was established, and rats were treated with different doses of BSTLR. Body weight and the levels of urinary protein, α1-microglobulin, glucose, blood urea nitrogen, creatinine, Cystatin C, superoxide dismutase, malondialdehyde, and catalase were analyzed biochemically or by enzyme-linked immunosorbent assay. The pathological damage to renal tissues was assessed by hematoxylin-eosin staining. Immunohistochemical staining was carried out to detect the expression levels of fibronectin, E-cadherin, α-smooth muscle actin, laminin, vimentin, collagen type Ⅳ in kidney tissues. Western blot analysis was conducted to analyze the expression levels of Nephrin, Desmin, Podocin, transforming growth factor-β1, mothers against decapentaplegic homolog 3(Smad3), Notch1, jagged, hairy and enhancer of split 1(Hes1) in kidney tissues, and the expression levels of maternally expressed gene 3(MEG3) and mi R-145 were measured by quantitative reverse transcription-polymerase chain reaction. Moreover, dual-luciferase reporter assay was employed to verify the binding of mi R-145 to MEG3. RESULTS:BSTLR increased the body weight of DKD rats, effectively ameliorated the renal function and pathological injury in DKD, regulated the balance of renal oxidative stress, inhibited the TGF/Notch signaling pathway, and affected the variations in the lnc RNA MEG3/mi R-145 axis. CONCLUSION:BSTLR improved oxidative stress homeostasis, inhibited the TGF/Notch signaling pathway, and regulated the lnc RNA MEG3/mi R-145 axis, effectively delaying the progression of DKD.展开更多
Varicocele,the most common and treatable cause of male infertility,significantly impacts fertility.The pathophysiological mechanisms of varicocele have not been fully understood yet.Recent studies have focused on the ...Varicocele,the most common and treatable cause of male infertility,significantly impacts fertility.The pathophysiological mechanisms of varicocele have not been fully understood yet.Recent studies have focused on the pathophysiology of varicocele-induced infertility,highlighting inflammation and oxidative stress as key contributing factors.We reviewed recent research on the roles of inflammation and oxidative stress in the pathophysiology of varicocele and found that they negatively impact semen parameters,spermatogenesis,and testicular and epididymal function.In addition,this article summarizes the related factors of inflammation and oxidative stress caused by varicocele.Finally,a brief consideration on the treatments to address inflammation and oxidative stress is proposed.This review may provide treatment options and targets for varicocele-induced infertility.However,the relationship between inflammation and oxidative stress in varicocele still needs further study.展开更多
T-2 toxin,an omnipresent environmental contaminant,poses a serious risk to the health of humans and animals due to its pronounced cardiotoxicity.This study aimed to elucidate the molecular mechanism of cardiac tissue ...T-2 toxin,an omnipresent environmental contaminant,poses a serious risk to the health of humans and animals due to its pronounced cardiotoxicity.This study aimed to elucidate the molecular mechanism of cardiac tissue damage by T-2 toxin.Twenty-four male Sprague-Dawley rats were orally administered T-2 toxin through gavage for 12 weeks at the dose of 0,10,and 100 nanograms per gram body weight per day(ng/(g·day)),respectively.Morphological,pathological,and ultrastructural alterations in cardiac tissue were meticulously examined.Non-targeted metabolomics analysis was employed to analyze alterations in cardiac metabolites.The expression of the Sirt3/FoxO3α/MnSOD signaling pathway and the level of oxidative stress markers were detected.The results showed that exposure to T-2 toxin elicited myocardial tissue disorders,interstitial hemorrhage,capillary dilation,and fibrotic damage.Mitochondria were markedly impaired,including swelling,fusion,matrix degradation,and membrane damage.Metabonomics analysis unveiled that T-2 toxin could cause alterations in cardiacmetabolic profiles as well as in the Sirt3/FoxO3α/MnSOD signaling pathway.T-2 toxin could inhibit the expressions of the signaling pathway and elevate the level of oxidative stress.In conclusion,the T-2 toxin probably induces cardiac fibrotic impairment by affecting amino acid and choline metabolism as well as up-regulating oxidative stress mediated by the Sirt3/FoxO3α/MnSOD signaling pathway.This study is expected to provide targets for preventing and treating T-2 toxin-induced cardiac fibrotic injury.展开更多
Background:Dry eye disease(DED)predominantly results from elevated tear film os-molarity,which can not only cause ocular inconvenience but may lead to visual impair-ments,severely compromising patient well-being and e...Background:Dry eye disease(DED)predominantly results from elevated tear film os-molarity,which can not only cause ocular inconvenience but may lead to visual impair-ments,severely compromising patient well-being and exerting substantial economic burdens as well.Astaxanthin(AST),a member of the xanthophylls and recognized for its robust abilities to combat inflammation and oxidation,is a common dietary sup-plement.Nonetheless,the precise molecular pathways through which AST influences DED are still poorly understood.Methods:Therapeutic targets for AST were identified using data from the GeneCards,PharmMapper,and Swiss Target Prediction databases,and STITCH datasets.Similarly,targets for dry eye disease(DED)were delineated leveraging resources such as the Therapeutic Target Database(TTD),DisGeNET,GeneCards,and OMIM databases,and DrugBank datasets.Interactions among shared targets were charted and dis-played using CytoScape 3.9.0.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were conducted to elucidate the functions of pivotal tar-gets within the protein-protein interaction network.Molecular interactions between AST and key targets were confirmed through molecular docking using AutoDock and PyMOL.Molecular dynamics simulations were performed using GROMACS 2022.3.Viability of human corneal epithelial cells(hCEC)was assessed across varying concen-trations of AST.A mouse model of experimental DED was developed using 0.1%ben-zalkonium chloride(BAC),and the animals were administered 100 mg/kg/day of AST orally for 7 days.The efficacy of the treatments was assessed through a series of di-agnostic tests to evaluate the condition of the ocular surface after the interventions.The levels of inflammation and oxidative stress were quantitatively assessed using methods such as reverse transcription-polymerase chain reaction(RT-PCR),Western blot,and immunofluorescence staining.Results:Network pharmacology suggests that AST may alleviate DED by influenc-ing oxidation-reduction signaling pathways and reducing oxidative stress provoked by BAC.In vivo experiments demonstrated an improved overall condition in AST-administered mice in contrast to the control group.Immunofluorescence staining analyses indicated a decrease in Keap1 protein in the corneal tissues of AST-treated mice and a significant increase in Nrf2 and HO-1 protein.In vitro studies demon-strated that AST significantly enhanced cell viability and suppressed reactive oxy-gen species expression under hyperosmotic(HS)conditions,thereby protecting the human corneal epithelium.Conclusion:AST is capable of shielding mice from BAC-induced DED,decelerating the progression of DED,and mitigating oxidative stress damage under HS conditions in hCEC cells.The protective impact of AST on DED may operate through stimulating the Keap1-Nrf2/HO-1 signaling pathway.Our research findings indicate that AST may be a promising treatment for DED,offering new insights into DED treatment.展开更多
Hearing loss is the third leading cause of human disability.Age-related hearing loss,one type of acquired sensorineural hearing loss,is largely responsible for this escalating global health burden.Noise-induced,ototox...Hearing loss is the third leading cause of human disability.Age-related hearing loss,one type of acquired sensorineural hearing loss,is largely responsible for this escalating global health burden.Noise-induced,ototoxic,and idiopathic sudden sensorineural are other less common types of acquired hearing loss.The etiology of these conditions is complex and multi-fa ctorial involving an interplay of genetic and environmental factors.Oxidative stress has recently been proposed as a likely linking cause in most types of acquired sensorineural hearing loss.Short non-coding RNA sequences known as microRNAs(miRNAs)have increasingly been shown to play a role in cellular hypoxia and oxidative stress responses including promoting an apoptotic response.Sensory hair cell death is a central histopathological finding in sensorineural hearing loss.As these cells do not regenerate in humans,it underlies the irreversibility of human age-related hearing loss.Ovid EMBASE,Ovid MEDLINE,Web of Science Core Collection,and ClinicalTrials.gov databases over the period August 1,2018 to July 31,2023 were searched with"hearing loss,""hypoxamiRs,""hypoxia,""microRNAs,""ischemia,"and"oxidative stress"text words for English language primary study publications or registered clinical trials.Registe red clinical trials known to the senior author we re also assessed.A total of 222studies were thus identified.After excluding duplicates,editorials,retra ctions,secondary research studies,and non-English language articles,39 primary studies and clinical trials underwent full-text screening.This resulted in 11 animal,in vitro,and/or human subject journal articles and 8 registered clinical trial database entries which form the basis of this narrative review.MiRNAs miR-34a and miR-29b levels increase with age in mice.These miRNAs were demonstrated in human neuroblastoma and murine cochlear cell lines to target Sirtuin 1/peroxisome proliferato r-activated receptor gamma coactivator-1-alpha(SIRT1/P GC-1α),SIRT1p53,and SIRT1/hypoxia-inducible factor 1-alpha signaling pathways resulting in increased apoptosis.Furthermore,hypoxia and oxidative stress had a similar adve rse apoptotic effect,which was inhibited by resve ratrol and a myocardial inhibitorassociated transcript,a miR-29b competing endogenous mRNA.Gentamicin reduced miR-182-5p levels and increased cochlear oxidative stress and cell death in mice-an effect that was corrected by inner ear stem cell-derived exosomes.There is ongoing work seeking to determine if these findings can be effectively translated to humans.展开更多
Diabetes mellitus(DM)is a debilitating disorder that impacts all systems of the body and has been increasing in prevalence throughout the globe.DM represents a significant clinical challenge to care for individuals an...Diabetes mellitus(DM)is a debilitating disorder that impacts all systems of the body and has been increasing in prevalence throughout the globe.DM represents a significant clinical challenge to care for individuals and prevent the onset of chronic disability and ultimately death.Underlying cellular mechanisms for the onset and development of DM are multi-factorial in origin and involve pathways associated with the production of reactive oxygen species and the generation of oxidative stress as well as the dysfunction of mitochondrial cellular organelles,programmed cell death,and circadian rhythm impairments.These pathways can ultimately involve failure in the glymphatic pathway of the brain that is linked to circadian rhythms disorders during the loss of metabolic homeostasis.New studies incorporate a number of promising techniques to examine patients with metabolic disorders that can include machine learning and artificial intelligence pathways to potentially predict the onset of metabolic dysfunction.展开更多
BACKGROUND Cyclophosphamide(CP)is a potent chemotherapeutic and immunosuppressant agent,but its hepatotoxicity remains a significant concern.Ambroxol(ABX)is a mucolytic agent with emerging beneficial effects against o...BACKGROUND Cyclophosphamide(CP)is a potent chemotherapeutic and immunosuppressant agent,but its hepatotoxicity remains a significant concern.Ambroxol(ABX)is a mucolytic agent with emerging beneficial effects against oxidative stress and inflammation.AIM To investigate the hepatoprotective effects of ABX against CP-induced liver injury,focusing on oxidative stress,inflammation,and the possible role of cytoglobin,thioredoxin reductase 1(TXNRD1)and high-mobility group box 1(HMGB1).METHODS ABX(20 mg/kg)was orally administered for 7 days,and the rats received a single injection of CP(100 mg/kg)on day 5.Blood and liver samples were collected for analyses,and the affinity of ABX towards cytoglobin,TXNRD1,and HMGB1 was evaluated using molecular docking.RESULTS CP administration significantly elevated alanine aminotransferase,aspartate aminotransferase,and alkaline phosphatase,reduced albumin,and caused multiple histopathological alterations in the liver.ABX effectively restored liver function biomarkers and attenuated histopathological alterations.CP-induced oxidative stress was evidenced by increased malondialdehyde and decreased glutathione and antioxidant enzyme activities,all of which were ameliorated by ABX.CP upregulated toll-like receptor 4(TLR-4),nuclear factor-kappaB(NF-κB)p65 and pro-inflammatory cytokines,while downregulating cytoglobin,TXNRD1 and HMGB1.ABX suppressed TLR-4/NF-κB signaling and pro-inflammatory cytokines,and upregulated cytoglobin,TXNRD1 and HMGB1.In silico molecular docking revealed the affinity of ABX to bind with cytoglobin,TXNRD1,and HMGB1.CONCLUSION ABX protects against CP hepatotoxicity by mitigating oxidative stress,suppressing TLR-4/NF-κB signaling,and upregulating cytoglobin,TXNRD1 and HMGB1.ABX showed binding affinity towards cytoglobin,TXNRD1 and HMGB1.These findings suggest that ABX has therapeutic potential in alleviating hepatotoxicity associated with CP treatment.展开更多
Objective:To investigate the effect of cerebrolysin(CBL)on motor impairment,neuroinflammation,oxidative stress,and neurotransmitter profile in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced Parkinson’s di...Objective:To investigate the effect of cerebrolysin(CBL)on motor impairment,neuroinflammation,oxidative stress,and neurotransmitter profile in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced Parkinson’s disease(PD)in zebrafish.Methods:In the current study,zebrafish were treated with CBL at doses of 1.25,2.5,and 5 mL/kg body weight for 7 consecutive days.MPTP(20 mg/kg body weight)was administered on alternative days-1st,3rd,5th,and 7th.On day 7,zebrafish were sacrificed,and their brains were isolated for biochemical,neurochemical,histopathological,IHC,and neurotransmitter analysis.Results:The treatment with CBL significantly increased total distance traveled and the number of entries in the top zone,which was impaired by MPTP.CBL treatment significantly restored the level of glutathione,superoxide dismutase,and catalase while reducing malondialdehyde level.It also reduced the level of pro-inflammatory mediators interleukin-1β,interleukin-6,and tumor necrosis factor-αin the MPTP-induced PD in the zebrafish model.In histopathological evaluation,pyknotic cells and signs of inflammation were significantly reduced in CBL-treated groups.A significant dose-dependent reduction in glutamate,along with elevations in dopamine,gamma-aminobutyric acid,serotonin,and noradrenaline,was observed in zebrafish treated with CBL.An immunohistochemistry analysis demonstrated that Akt was phosphorylated promptly by CBL,which was downregulated in MPTP-induced PD in zebrafish.Conclusions:These findings suggest that CBL exerts a neuroprotective effect through activation of Akt and may hold therapeutic potential for the treatment of this devastating neurological condition.展开更多
Objective Electronic cigarettes(ECs)differ from traditional tobacco smoke but may contribute to cardiopulmonary remodeling.Pulmonary hypertension(PH),characterized by pulmonary artery and right ventricle remodeling,po...Objective Electronic cigarettes(ECs)differ from traditional tobacco smoke but may contribute to cardiopulmonary remodeling.Pulmonary hypertension(PH),characterized by pulmonary artery and right ventricle remodeling,poses a significant risk of mortality in infants,children,and adolescents.However,the impact of maternal EC exposure on PH development in offspring remains unclear.To address this,we established a PH rat model with maternal EC exposure.Methods Maternal EC exposure was initiated on gestation day 12 via electronic nicotine delivery systems.Offspring were administered monocrotaline(MCT)at 6 weeks of age(6-wo)to induce PH.Mechanistic experiments were conducted at 10-week-old(10-wo).Protein expression of NADPH oxidases,DNA methyltransferases,and autophagy-related markers was analyzed by Western blot.Morphological changes and the severity of PH were evaluated via hematoxylin and eosin(HE)staining and echocardiography,respectively.Furthermore,the involvement of the oxidative stress/DNA methylation/autophagy axis in response to maternal EC exposure was confirmed through a combination of ELISA,Western blot,HE staining,and echocardiography.Additionally,ATG5 mRNA expression was measured by qRT-PCR.Results Compared with control conditions,maternal EC exposure significantly worsened MCT-induced PH in male offspring.This was associated with increased oxidative stress,DNA hypomethylation,and anomalous autophagy in the offspring.In vivo treatment with chloroquine inhibited autophagy and ameliorated PH development in offspring exposed to maternal EC.Furthermore,N-acetylcysteine(NAC),an antioxidant,attenuated maternal EC exposure-induced oxidative stress,DNA hypomethylation,and excessive autophagy,thereby improving PH.DNA hypermethylation also reversed PH development,accompanied by reduced oxidative stress and suppressed autophagy.ATG5,a key regulator of autophagy,was identified as a potential therapeutic target,as its repression mitigated PH in maternal EC-exposed offspring.Conclusion Maternal EC exposure induces oxidative stress and DNA hypomethylation in offspring,leading to anomalous autophagy and exacerbation of PH development.Targeting ATG5-mediated autophagy may represent a novel therapeutic approach for improving PH outcomes in offspring exposed to maternal EC.Graphical Abstract Pregnant rats were exposed to either EC vapor or standard air from gestation day 12 until 2 days before delivery,with all offspring undergoing PH induction at 6-wo.Offspring exposed to maternal EC presented increased oxidative stress,which in turn affected DNA methylation patterns.The decreased DNA methylation in male offspring led to the activation of autophagy,exacerbating the development of PH.Treatment with ATG5 siRNA inhibited autophagy and alleviated heightened PH in male offspring with maternal EC exposure.展开更多
Objective:Limb ischemia-reperfusion injury(LIRI)may lead to tissue necrosis and loss of function,even life-threatening.Our previous study found that Tao-Hong-Si-Wu decoction(THSWD)had some efficacy in treating of LIRI...Objective:Limb ischemia-reperfusion injury(LIRI)may lead to tissue necrosis and loss of function,even life-threatening.Our previous study found that Tao-Hong-Si-Wu decoction(THSWD)had some efficacy in treating of LIRI.Quercetin,the major component of THSWD,was selected further to uncover the molecular mechanism underlying its treatment of LIRI.Methods:In this study,myoblasts were isolated fromrat gastrocnemiusmuscle tissue,and an in vitro LIRI model was established.The cell counting kit-8(CCK-8)and colony formation assay were used to evaluate the impact of quercetin on LIRI-induced myoblast viability and proliferation.Lactate dehydrogenase(LDH)activity wasmeasured to detectmyoblast injury in the LIRI model.Theapoptosis ofmyoblasts was evaluated byHoechst staining and flow cytometry.In addition,molecular docking analysis was performed to predict the interaction between quercetin and NADPH oxidase 2(NOX-2).Subsequently,we investigated the molecular mechanism of quercetin in LIRI-induced myoblasts by overexpressing NOX-2.Results:The myogenic marker Desmin was highly expressed in isolatedmyoblasts.In the LIRImodel,myoblast viability and proliferation were decreased,and cell injury and apoptosis levels were increased.In addition,NOX-2 was highly expressed in the LIRI model.At the same time,LIRI induction promoted the up-regulation of oxidative stress and inflammatory response.Quercetin significantly reversed the effects of LIRI treatment on myoblasts in a concentration-dependent manner.Molecular docking suggested an interaction between quercetin and NOX-2.Further overexpression of NOX-2 inhibited the effect of quercetin on LIRI-induced myoblasts.Conclusion:Quercetin could reduce inflammatory response and oxidative stress by inhibiting NOX-2,thus playing a therapeutic role in treating LIRI.展开更多
Identification of natural substances with antioxidant properties is ongoing research for addressing issues related to oxidative stress especially attributed to environmental effects.Our previous study demonstrated tha...Identification of natural substances with antioxidant properties is ongoing research for addressing issues related to oxidative stress especially attributed to environmental effects.Our previous study demonstrated that Lateolabrax japonicus peptides(LPH),rich in Glu,Gly,and hydrophobic amino acids,exhibited remarkable antioxidant activity in vitro,with though its action mechanism yet to be revealed.Therefore,to assess the in vivo antioxidative properties of LPH,we employed H_(2)O_(2) to generate oxidative stress in Drosophila melanogaster model.Results indicated that LPH significantly prolonged the lifespan of Drosophila subjected to oxidative stress mostly mediated via LPH’s enhancement of the antioxidant defense system and intestinal functions.Antioxidant effects were manifested by a decrease in malondialdehyde(MDA)levels,elevated superoxide dismutase(SOD),catalase(CAT),and glutathione peroxidase(GSH-Px)activities,decreased levels of reactive oxygen species(ROS)in intestinal epithelial cells,and the preservation of intestinal length.LPH effectively controlled the excessive proliferation and differentiation of oxidative stress-induced Drosophila intestinal stem cells.At the gene level,LPH upregulated the expression of antioxidant-related Nrf2 genes while concurrently downregulated mTOR expression level.Furthermore,high-throughput 16S rDNA sequencing revealed that the addition of LPH significantly influenced the diversity and abundance of the intestinal microbiota in H_(2)O_(2)-induced Drosophila.These findings provide a deeper understanding of the antioxidative mechanism of LPH,suggesting its potential applications in food industry and to be assessed using other in vivo oxidative stress models.展开更多
Background:Cisplatin(CDDP)is a cornerstone chemotherapeutic agent for many solid tumors,but its clinical use is severely limited by dose-dependent nephrotoxicity,which results in acute kidney injury(AKI)in a significa...Background:Cisplatin(CDDP)is a cornerstone chemotherapeutic agent for many solid tumors,but its clinical use is severely limited by dose-dependent nephrotoxicity,which results in acute kidney injury(AKI)in a significant proportion of patients.CDDP-induced AKI involves interconnected mechanisms,including inflammation,oxidative stress,and tubular cell death.In this study,we aimed to investigate the renoprotective effects of esculetin(ES),a natural antioxidant coumarin,in a murine model of CDDP-induced AKI.Methods:Male C57BL/6 mice(8–10 weeks)received a single intraperitoneal injection of CDDP(20 mg/kg)with or without ES(40 mg/kg/day,oral gavage).Renal function,histopathology,and molecular markers of inflammation,oxidative stress,mitogen-activated protein kinase(MAPK)activation,endoplasmic reticulum(ER)stress,apoptosis,and ferroptosis were assessed by standard biochemical,histological,and immunoblotting techniques.Results:ES significantly reduced CDDP-induced elevations in serum creatinine and blood urea nitrogen,preserved renal structure,and decreased histological injury scores.Molecular analyses showed that ES suppressed the production of systemic and renal proinflammatory cytokines and inhibited the expression of chemokines and adhesion molecules.ES also suppressed the phosphorylation of extracellular signal-regulated kinase 1/2 and p38 MAPKs,mitigating stress-induced inflammatory and apoptotic signaling.Additionally,ES treatment reduced the expression of unfolded protein response markers,such as C/EBP homologous protein,which is indicative of alleviated ER stress.Oxidative injury was reduced,as evidenced by lower malondialdehyde and 4-hydroxynonenal levels and restored glutathione content.Importantly,ES mitigated ferroptosis,as demonstrated by decreased expression of pro-ferroptotic markers and preservation of anti-ferroptotic mediators,including glutathione peroxidase 4 and solute carrier family 7member 1.Conclusion:Collectively,our findings provide the first in vivo evidence that ES robustly protects against CDDP-induced AKI by simultaneously targeting oxidative stress,inflammation,MAPK,and ER stress pathways,apoptosis,and ferroptosis.These results highlight ES as a potential candidate for preventing CDDP-induced nephrotoxicity.展开更多
Nanoplastic(NP)contaminants are receiving increasing attention due to the harm they can cause to aquatic organisms and their accumulation in the human body through the food web.The goal of this study was to evaluate t...Nanoplastic(NP)contaminants are receiving increasing attention due to the harm they can cause to aquatic organisms and their accumulation in the human body through the food web.The goal of this study was to evaluate the oxidative stress caused by NPs on the clams Meretrix meretrix and Sinonovacula constricta.Specimens were exposed to three concentrations of fluorescently labeled polystyrene NPs(PS-NPs;0,0.1,and 1 mg L^(-1))for 7 d followed by a 3 d recovery period.The activities of antioxidant enzymes,such as catalase(CAT),superoxide dismutase(SOD),glutathione peroxidase(GPx)and the content of malonaldehyde(MDA)were measured in the digestive gland,gills,and mantle tissues.Results showed that the SOD activity in the gills of M.meretrix was significantly higher than that of the control at day 1,and PS-NPs exposure inhibited the CAT activity in the gills and SOD and GPx activities in the mantle.Exposure to low or high concentrations of PS-NPs increased the activities of both CAT and GPx in the gills of S.constricta at day 3.The oxidative damage was more severe in the digestive gland of M.meretrix and in the mantle of S.constricta based on MDA level,and it returned to normal after recovery.Integrated biomarker response,index version 2(IBRv2)values showed that the gills were more sensitive to PS-NPs than mantle and digestive gland.Therefore,the oxidative stress by PS-NPs depended on exposure time,dose,organ,and species.展开更多
基金supported by grants from Collaborative Research Fund(Ref:C4032-21GF)General Research Grant(Ref:14114822)+1 种基金Group Research Scheme(Ref:3110146)Area of Excellence(Ref:Ao E/M-402/20)。
文摘Mitochondrial dysfunction and oxidative stress are widely regarded as primary drivers of aging and are associated with several neurodegenerative diseases.The degeneration of motor neurons during aging is a critical pathological factor contributing to the progression of sarcopenia.However,the morphological and functional changes in mitochondria and their interplay in the degeneration of the neuromuscular junction during aging remain poorly understood.A defined systematic search of the Pub Med,Web of Science and Embase databases(last accessed on October 30,2024)was conducted with search terms including'mitochondria','aging'and'NMJ'.Clinical and preclinical studies of mitochondrial dysfunction and neuromuscular junction degeneration during aging.Twentyseven studies were included in this systematic review.This systematic review provides a summary of morphological,functional and biological changes in neuromuscular junction,mitochondrial morphology,biosynthesis,respiratory chain function,and mitophagy during aging.We focus on the interactions and mechanisms underlying the relationship between mitochondria and neuromuscular junctions during aging.Aging is characterized by significant reductions in mitochondrial fusion/fission cycles,biosynthesis,and mitochondrial quality control,which may lead to neuromuscular junction dysfunction,denervation and poor physical performance.Motor nerve terminals that exhibit redox sensitivity are among the first to exhibit abnormalities,ultimately leading to an early decline in muscle strength through impaired neuromuscular junction transmission function.Parg coactivator 1 alpha is a crucial molecule that regulates mitochondrial biogenesis and modulates various pathways,including the mitochondrial respiratory chain,energy deficiency,oxidative stress,and inflammation.Mitochondrial dysfunction is correlated with neuromuscular junction denervation and acetylcholine receptor fragmentation,resulting in muscle atrophy and a decrease in strength during aging.Physical therapy,pharmacotherapy,and gene therapy can alleviate the structural degeneration and functional deterioration of neuromuscular junction by restoring mitochondrial function.Therefore,mitochondria are considered potential targets for preserving neuromuscular junction morphology and function during aging to treat sarcopenia.
基金funded by research grant from National Natural Science Foundation of China(32171135).
文摘Resistance exercise has been confirmed to be important for maintaining muscle mass and function.However,despite considerable experimental studies,the underlying mechanisms still requires further investigation to be elucidated.Sestrin1 is a stress-inducible protein strongly associated with the occurrence and development of skeletal muscle dysfunction.Besides,oxidative stress is believed to be a major pathogenic mechanism in the development of skeletal muscle atrophy,whereas regular exercise training induces the endogenous antioxidative system and protects the body against adverse effects of oxidative stress.Nevertheless,whether Sestrin1 is involved in the amelioration of resistance exercise on muscle atrophy and the role of its antioxidant function in this process remains unknown.Here we show that six-week resistance exercise training significantly improved muscle function,muscle mass,and oxidative damage and maintained the level of Sestrin1 in dexamethasone-treated C57BL/6J mice.Mechanistically,Sestrin1 overexpression rescued protein degradation and oxidative stress in atrophied myotubes.Furthermore,an emerging regulator of cellular defense against toxic and oxidative insults,nuclear factor erythroid2–related factor 2(Nrf2)controls the basal and induced expression of an array of antioxidant response element–dependent genes to regulate the pathophysiological outcomes of oxidant exposure.In this study,we found that Nrf2 is a target of Sestrin1,and Nrf2 nuclear translocation is facilitated by Sestrin1.ML385(an Nrf2 inhibitor)treatment mitigated the regulatory effects of overexpression-Sestrin1.Therefore,Sestrin1 was involved in the process of resistance exercise against skeletal muscle atrophy,which may be closely related to its antioxidant capacity,revealing a potential therapeutic strategy for reducing the loss of skeletal muscle.
基金supported by Shenzhen Science and Technology Program, No. JCYJ20230807110259002 (to JL)The Seventh Affiliated Hospital of Sun Yat-sen University, No. ZSQYRSFPD0050 (to JL)The Postdoctoral Fellowship Program of CPSF, No. GZC20242074 (to KT)
文摘Oxidative stress significantly contributes to secondary damage after spinal cord injury.Despite its importance,research on oxidative stress in spinal cord injury remains limited.Investigating the expression and regulation of oxidative stress-related genes could enhance the diagnosis and treatment of spinal cord injury.In this study,we analyzed the sequencing data of human blood samples and injured mouse spinal cord tissue that were sourced from GEO databases and identified diagnostic biomarkers associated with the severity of spinal cord injury.We also explored the expression patterns of oxidative stress-related genes,potential regulatory mechanisms,and therapeutic drugs.To validate our findings,we performed immunofluorescence and quantitative polymerase chain reaction to assess gene expression in the injured spinal cord.Our results revealed biomarkers associated with oxidative stress and immune responses across different levels of spinal cord injury in humans.We identified differentially expressed oxidative stress-related genes and key hub genes in injured mouse spinal cord tissue and revealed their temporal expression patterns at both the tissue and single-cell levels.We also clarified the signaling pathways associated with oxidative stress and identified ligand-receptor pairs among various cell types at different time points after injury.Furthermore,we discovered microRNAs,long non-coding RNAs,and transcription factors that regulate these hub genes and revealed their roles in modulating gene expression at various stages after spinal cord injury.We also identified drugs targeting these hub genes.The findings from this study not only aid in identifying diagnostic biomarkers that reflect the severity of spinal cord injury,but also provide insights into the expression dynamics of oxidative stress-related genes.In addition,the study reveals potential regulatory mechanisms and identifies potential drugs to treat patients with spinal cord injury.
基金the Major Special Project of Jiangsu Administration of Traditional Chinese Medicine(Project No.ZT202116)the Key R&D Project of Jiangsu Province(Project No.BE2020727)+2 种基金the Yangzhou Science and Technology Program(Project No.YZ2021062,YZ2024143 and YZ2024194)the Third Batch of Academic Mentorship Program for Senior TCM Experts in Jiangsu Province(Project No.2019028)the 2023 Jiangsu Pharmaceutical Association–Aosaikang Hospital Pharmacy Research Project(Project No.A202333).
文摘Background:Myocardial infarction(MI)remains a major global public health challenge.Although advances in reperfusion therapy have reduced acute mortality,post-infarction cardiac remodeling continues to pose a substantial threat to long-term cardiovascular health.Oxidative stress and the ensuing inflammatory response are key drivers of this pathological process,leading to cardiomyocyte death,myocardial fibrosis,and functional impairment.Among the regulatory pathways involved,the kelch-like ECH-associated protein 1(Keap1)/nuclear factor erythroid 2-related factor 2(Nrf2)axis has emerged as a critical therapeutic target for mitigating post-MI cardiac injury.Methods:A murine MI model was established by permanent ligation of the left anterior descending coronary artery.Mice received oral Tongxinbi formula(TXB)at low,medium,or high doses(9/18/36 g/kg)once daily for 28 days.Cardiac function was assessed by echocardiography;myocardial fibrosis by Masson’s trichrome;and endothelial integrity by CD31 immunofluorescence.Plasma markers of endothelial function and inflammation were quantified.In vitro,oxidative stress was induced by H2O2 in vascular endothelial cells and cardiomyocytes,followed by treatment with TXB drug-containing serum.Western blot and RT-qPCR were used to measure components of the Keap1/Nrf2 pathway;ELISA quantified oxidative stress and inflammatory indices.Conditioned-medium experiments evaluated endothelial cell–mediated paracrine protection of cardiomyocytes.Results:TXB significantly improved cardiac function and reduced myocardial fibrosis after MI,in association with preservation of microvascular structure and systemic attenuation of oxidative stress and inflammation.In vitro,TXB activated the endothelial Keap1/Nrf2 pathway,enhanced cellular antioxidant defenses,increased VEGF secretion,and,via endothelial cell-mediated paracrine signaling,alleviated cardiomyocyte injury under oxidative stress.Conclusion:TXB exerts anti-fibrotic and cardioprotective effects by activating Nrf2 signaling and engaging endothelial-mediated paracrine mechanisms,collectively mitigating oxidative stress and inflammation in the post-MI setting.
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Jiangxi Provincial Department of Education Science and Technology Project(Grant No.GJJ2401615)Jiangxi Provincial Department of Education Teaching Reform Project(Grant No.JXJG-24-15-15).
文摘The aim of this study is to investigate the mechanism of magnesium isoglycyrrhizinate(MgIG)in the treatment of myocardial remodeling induced by isoproterenol(ISO)in mice.We assessed the impact of MgIG on ISO-induced myocardial remodeling by activating the PI3K/AKT1 pathway.The cardiac function of mice was evaluated by echocardiography,revealing that MgIG could improve left ventricular function.Pathological staining analysis showed that MgIG could reduce the degree of myocardial injury caused by ISO.Serum data detected by ELISA demonstrated that MgIG could decrease the levels of CK-MB,MDA,and LDH while increasing the activity of GSH-Px.Western blotting analysis revealed that protein expression levels of Collagen I,BNP,Bax,cleaved caspase-3,p-PI3K,and p-AKT1 were decreased,whereas the protein expressions of Bcl-2,COX2,and SOD1 were increased upon MgIG treatment.However,the activation of the PI3K pathway reversed the cardioprotective effects of MgIG,as evidenced by the addition of PI3K activators.Taken together,our comprehensive results suggested that MgIG could improve ISO-induced myocardial remodeling,potentially through its mechanism of inhibiting the PI3K/AKT1 pathway to regulate apoptosis and oxidative stress.
基金supported by the Atatürk University Scientific Research Projects Coordinator(Project No:2020/8737)。
文摘Objective:To investigate the protective effects of naringin on doxorubicin(DOX)-induced liver injury.Methods:A total of 50 male rats were allocated into five groups:the control group,the DOX group,the DOX groups treated with 50 mg/kg and 100 mg/kg of naringin by gastric lavage for 10 days,as well as the group treated with 100 mg/kg of naringin alone.Liver and serum samples were collected for biochemical,histopathological,and molecular analyses,including liver enzyme activity,oxidative stress markers,inflammation,apoptosis-related proteins,and DNA damage indicators.Results:Naringin attenuated DOX-induced elevation in liver enzyme activity and inflammation markers while enhancing antioxidant activities.Naringin also activated the Nrf2-HO-1 signaling pathway,with the most pronounced effect in the high-dose naringin group.In addition,naringin modulated apoptotic signaling by downregulating the expression of PI3K-AKT and BAX,and upregulating Bcl-2,as well as reduced the level of 8-OHdG.Histopathological evaluation showed that DOX-induced structural liver alterations,such as cellular degeneration and necrosis,were notably attenuated by naringin treatment.Conclusions:Naringin treatment exerts protective effects against DOX-induced liver injury through its antioxidative,anti-inflammatory,and anti-apoptotic effects.
文摘OBJECTIVES:To investigate the effect of Bushen Tongluo recipe(BSTLR, 补肾通络方) on rats with diabetic kidney disease(DKD) and to explore the underlying mechanism of action. METHODS:The rat model of DKD was established, and rats were treated with different doses of BSTLR. Body weight and the levels of urinary protein, α1-microglobulin, glucose, blood urea nitrogen, creatinine, Cystatin C, superoxide dismutase, malondialdehyde, and catalase were analyzed biochemically or by enzyme-linked immunosorbent assay. The pathological damage to renal tissues was assessed by hematoxylin-eosin staining. Immunohistochemical staining was carried out to detect the expression levels of fibronectin, E-cadherin, α-smooth muscle actin, laminin, vimentin, collagen type Ⅳ in kidney tissues. Western blot analysis was conducted to analyze the expression levels of Nephrin, Desmin, Podocin, transforming growth factor-β1, mothers against decapentaplegic homolog 3(Smad3), Notch1, jagged, hairy and enhancer of split 1(Hes1) in kidney tissues, and the expression levels of maternally expressed gene 3(MEG3) and mi R-145 were measured by quantitative reverse transcription-polymerase chain reaction. Moreover, dual-luciferase reporter assay was employed to verify the binding of mi R-145 to MEG3. RESULTS:BSTLR increased the body weight of DKD rats, effectively ameliorated the renal function and pathological injury in DKD, regulated the balance of renal oxidative stress, inhibited the TGF/Notch signaling pathway, and affected the variations in the lnc RNA MEG3/mi R-145 axis. CONCLUSION:BSTLR improved oxidative stress homeostasis, inhibited the TGF/Notch signaling pathway, and regulated the lnc RNA MEG3/mi R-145 axis, effectively delaying the progression of DKD.
文摘Varicocele,the most common and treatable cause of male infertility,significantly impacts fertility.The pathophysiological mechanisms of varicocele have not been fully understood yet.Recent studies have focused on the pathophysiology of varicocele-induced infertility,highlighting inflammation and oxidative stress as key contributing factors.We reviewed recent research on the roles of inflammation and oxidative stress in the pathophysiology of varicocele and found that they negatively impact semen parameters,spermatogenesis,and testicular and epididymal function.In addition,this article summarizes the related factors of inflammation and oxidative stress caused by varicocele.Finally,a brief consideration on the treatments to address inflammation and oxidative stress is proposed.This review may provide treatment options and targets for varicocele-induced infertility.However,the relationship between inflammation and oxidative stress in varicocele still needs further study.
基金supported by the National Natural Science Foundation of China(No.81872567).
文摘T-2 toxin,an omnipresent environmental contaminant,poses a serious risk to the health of humans and animals due to its pronounced cardiotoxicity.This study aimed to elucidate the molecular mechanism of cardiac tissue damage by T-2 toxin.Twenty-four male Sprague-Dawley rats were orally administered T-2 toxin through gavage for 12 weeks at the dose of 0,10,and 100 nanograms per gram body weight per day(ng/(g·day)),respectively.Morphological,pathological,and ultrastructural alterations in cardiac tissue were meticulously examined.Non-targeted metabolomics analysis was employed to analyze alterations in cardiac metabolites.The expression of the Sirt3/FoxO3α/MnSOD signaling pathway and the level of oxidative stress markers were detected.The results showed that exposure to T-2 toxin elicited myocardial tissue disorders,interstitial hemorrhage,capillary dilation,and fibrotic damage.Mitochondria were markedly impaired,including swelling,fusion,matrix degradation,and membrane damage.Metabonomics analysis unveiled that T-2 toxin could cause alterations in cardiacmetabolic profiles as well as in the Sirt3/FoxO3α/MnSOD signaling pathway.T-2 toxin could inhibit the expressions of the signaling pathway and elevate the level of oxidative stress.In conclusion,the T-2 toxin probably induces cardiac fibrotic impairment by affecting amino acid and choline metabolism as well as up-regulating oxidative stress mediated by the Sirt3/FoxO3α/MnSOD signaling pathway.This study is expected to provide targets for preventing and treating T-2 toxin-induced cardiac fibrotic injury.
基金supported by grants from the Beijing Municipal Public Welfare Development and Reform Pilot Project for Medical Research Institutes(PWD&RPP-MRI,JYY2023-6)the R&D Program of Beijing Municipal Education Commission(KZ20231002543).
文摘Background:Dry eye disease(DED)predominantly results from elevated tear film os-molarity,which can not only cause ocular inconvenience but may lead to visual impair-ments,severely compromising patient well-being and exerting substantial economic burdens as well.Astaxanthin(AST),a member of the xanthophylls and recognized for its robust abilities to combat inflammation and oxidation,is a common dietary sup-plement.Nonetheless,the precise molecular pathways through which AST influences DED are still poorly understood.Methods:Therapeutic targets for AST were identified using data from the GeneCards,PharmMapper,and Swiss Target Prediction databases,and STITCH datasets.Similarly,targets for dry eye disease(DED)were delineated leveraging resources such as the Therapeutic Target Database(TTD),DisGeNET,GeneCards,and OMIM databases,and DrugBank datasets.Interactions among shared targets were charted and dis-played using CytoScape 3.9.0.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were conducted to elucidate the functions of pivotal tar-gets within the protein-protein interaction network.Molecular interactions between AST and key targets were confirmed through molecular docking using AutoDock and PyMOL.Molecular dynamics simulations were performed using GROMACS 2022.3.Viability of human corneal epithelial cells(hCEC)was assessed across varying concen-trations of AST.A mouse model of experimental DED was developed using 0.1%ben-zalkonium chloride(BAC),and the animals were administered 100 mg/kg/day of AST orally for 7 days.The efficacy of the treatments was assessed through a series of di-agnostic tests to evaluate the condition of the ocular surface after the interventions.The levels of inflammation and oxidative stress were quantitatively assessed using methods such as reverse transcription-polymerase chain reaction(RT-PCR),Western blot,and immunofluorescence staining.Results:Network pharmacology suggests that AST may alleviate DED by influenc-ing oxidation-reduction signaling pathways and reducing oxidative stress provoked by BAC.In vivo experiments demonstrated an improved overall condition in AST-administered mice in contrast to the control group.Immunofluorescence staining analyses indicated a decrease in Keap1 protein in the corneal tissues of AST-treated mice and a significant increase in Nrf2 and HO-1 protein.In vitro studies demon-strated that AST significantly enhanced cell viability and suppressed reactive oxy-gen species expression under hyperosmotic(HS)conditions,thereby protecting the human corneal epithelium.Conclusion:AST is capable of shielding mice from BAC-induced DED,decelerating the progression of DED,and mitigating oxidative stress damage under HS conditions in hCEC cells.The protective impact of AST on DED may operate through stimulating the Keap1-Nrf2/HO-1 signaling pathway.Our research findings indicate that AST may be a promising treatment for DED,offering new insights into DED treatment.
文摘Hearing loss is the third leading cause of human disability.Age-related hearing loss,one type of acquired sensorineural hearing loss,is largely responsible for this escalating global health burden.Noise-induced,ototoxic,and idiopathic sudden sensorineural are other less common types of acquired hearing loss.The etiology of these conditions is complex and multi-fa ctorial involving an interplay of genetic and environmental factors.Oxidative stress has recently been proposed as a likely linking cause in most types of acquired sensorineural hearing loss.Short non-coding RNA sequences known as microRNAs(miRNAs)have increasingly been shown to play a role in cellular hypoxia and oxidative stress responses including promoting an apoptotic response.Sensory hair cell death is a central histopathological finding in sensorineural hearing loss.As these cells do not regenerate in humans,it underlies the irreversibility of human age-related hearing loss.Ovid EMBASE,Ovid MEDLINE,Web of Science Core Collection,and ClinicalTrials.gov databases over the period August 1,2018 to July 31,2023 were searched with"hearing loss,""hypoxamiRs,""hypoxia,""microRNAs,""ischemia,"and"oxidative stress"text words for English language primary study publications or registered clinical trials.Registe red clinical trials known to the senior author we re also assessed.A total of 222studies were thus identified.After excluding duplicates,editorials,retra ctions,secondary research studies,and non-English language articles,39 primary studies and clinical trials underwent full-text screening.This resulted in 11 animal,in vitro,and/or human subject journal articles and 8 registered clinical trial database entries which form the basis of this narrative review.MiRNAs miR-34a and miR-29b levels increase with age in mice.These miRNAs were demonstrated in human neuroblastoma and murine cochlear cell lines to target Sirtuin 1/peroxisome proliferato r-activated receptor gamma coactivator-1-alpha(SIRT1/P GC-1α),SIRT1p53,and SIRT1/hypoxia-inducible factor 1-alpha signaling pathways resulting in increased apoptosis.Furthermore,hypoxia and oxidative stress had a similar adve rse apoptotic effect,which was inhibited by resve ratrol and a myocardial inhibitorassociated transcript,a miR-29b competing endogenous mRNA.Gentamicin reduced miR-182-5p levels and increased cochlear oxidative stress and cell death in mice-an effect that was corrected by inner ear stem cell-derived exosomes.There is ongoing work seeking to determine if these findings can be effectively translated to humans.
基金Supported by American Diabetes AssociationAmerican Heart Association+3 种基金NIH NIEHSNIH NIANIH NINDSand NIH ARRA.
文摘Diabetes mellitus(DM)is a debilitating disorder that impacts all systems of the body and has been increasing in prevalence throughout the globe.DM represents a significant clinical challenge to care for individuals and prevent the onset of chronic disability and ultimately death.Underlying cellular mechanisms for the onset and development of DM are multi-factorial in origin and involve pathways associated with the production of reactive oxygen species and the generation of oxidative stress as well as the dysfunction of mitochondrial cellular organelles,programmed cell death,and circadian rhythm impairments.These pathways can ultimately involve failure in the glymphatic pathway of the brain that is linked to circadian rhythms disorders during the loss of metabolic homeostasis.New studies incorporate a number of promising techniques to examine patients with metabolic disorders that can include machine learning and artificial intelligence pathways to potentially predict the onset of metabolic dysfunction.
基金Supported by Princess Nourah bint Abdulrahman University Researchers Supporting Project Number(PNURSP2025R381),Princess Nourah bint Abdulrahman University,Riyadh,Saudi Arabia.
文摘BACKGROUND Cyclophosphamide(CP)is a potent chemotherapeutic and immunosuppressant agent,but its hepatotoxicity remains a significant concern.Ambroxol(ABX)is a mucolytic agent with emerging beneficial effects against oxidative stress and inflammation.AIM To investigate the hepatoprotective effects of ABX against CP-induced liver injury,focusing on oxidative stress,inflammation,and the possible role of cytoglobin,thioredoxin reductase 1(TXNRD1)and high-mobility group box 1(HMGB1).METHODS ABX(20 mg/kg)was orally administered for 7 days,and the rats received a single injection of CP(100 mg/kg)on day 5.Blood and liver samples were collected for analyses,and the affinity of ABX towards cytoglobin,TXNRD1,and HMGB1 was evaluated using molecular docking.RESULTS CP administration significantly elevated alanine aminotransferase,aspartate aminotransferase,and alkaline phosphatase,reduced albumin,and caused multiple histopathological alterations in the liver.ABX effectively restored liver function biomarkers and attenuated histopathological alterations.CP-induced oxidative stress was evidenced by increased malondialdehyde and decreased glutathione and antioxidant enzyme activities,all of which were ameliorated by ABX.CP upregulated toll-like receptor 4(TLR-4),nuclear factor-kappaB(NF-κB)p65 and pro-inflammatory cytokines,while downregulating cytoglobin,TXNRD1 and HMGB1.ABX suppressed TLR-4/NF-κB signaling and pro-inflammatory cytokines,and upregulated cytoglobin,TXNRD1 and HMGB1.In silico molecular docking revealed the affinity of ABX to bind with cytoglobin,TXNRD1,and HMGB1.CONCLUSION ABX protects against CP hepatotoxicity by mitigating oxidative stress,suppressing TLR-4/NF-κB signaling,and upregulating cytoglobin,TXNRD1 and HMGB1.ABX showed binding affinity towards cytoglobin,TXNRD1 and HMGB1.These findings suggest that ABX has therapeutic potential in alleviating hepatotoxicity associated with CP treatment.
基金funded by ICMR,New Delhi(Grant No.45/29/2022-PHA/BMS).
文摘Objective:To investigate the effect of cerebrolysin(CBL)on motor impairment,neuroinflammation,oxidative stress,and neurotransmitter profile in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced Parkinson’s disease(PD)in zebrafish.Methods:In the current study,zebrafish were treated with CBL at doses of 1.25,2.5,and 5 mL/kg body weight for 7 consecutive days.MPTP(20 mg/kg body weight)was administered on alternative days-1st,3rd,5th,and 7th.On day 7,zebrafish were sacrificed,and their brains were isolated for biochemical,neurochemical,histopathological,IHC,and neurotransmitter analysis.Results:The treatment with CBL significantly increased total distance traveled and the number of entries in the top zone,which was impaired by MPTP.CBL treatment significantly restored the level of glutathione,superoxide dismutase,and catalase while reducing malondialdehyde level.It also reduced the level of pro-inflammatory mediators interleukin-1β,interleukin-6,and tumor necrosis factor-αin the MPTP-induced PD in the zebrafish model.In histopathological evaluation,pyknotic cells and signs of inflammation were significantly reduced in CBL-treated groups.A significant dose-dependent reduction in glutamate,along with elevations in dopamine,gamma-aminobutyric acid,serotonin,and noradrenaline,was observed in zebrafish treated with CBL.An immunohistochemistry analysis demonstrated that Akt was phosphorylated promptly by CBL,which was downregulated in MPTP-induced PD in zebrafish.Conclusions:These findings suggest that CBL exerts a neuroprotective effect through activation of Akt and may hold therapeutic potential for the treatment of this devastating neurological condition.
基金supported by National Natural Science Foundation of China(No.82300268)Guangzhou Municipal Science and Technology Project(No.2023B03J1255).
文摘Objective Electronic cigarettes(ECs)differ from traditional tobacco smoke but may contribute to cardiopulmonary remodeling.Pulmonary hypertension(PH),characterized by pulmonary artery and right ventricle remodeling,poses a significant risk of mortality in infants,children,and adolescents.However,the impact of maternal EC exposure on PH development in offspring remains unclear.To address this,we established a PH rat model with maternal EC exposure.Methods Maternal EC exposure was initiated on gestation day 12 via electronic nicotine delivery systems.Offspring were administered monocrotaline(MCT)at 6 weeks of age(6-wo)to induce PH.Mechanistic experiments were conducted at 10-week-old(10-wo).Protein expression of NADPH oxidases,DNA methyltransferases,and autophagy-related markers was analyzed by Western blot.Morphological changes and the severity of PH were evaluated via hematoxylin and eosin(HE)staining and echocardiography,respectively.Furthermore,the involvement of the oxidative stress/DNA methylation/autophagy axis in response to maternal EC exposure was confirmed through a combination of ELISA,Western blot,HE staining,and echocardiography.Additionally,ATG5 mRNA expression was measured by qRT-PCR.Results Compared with control conditions,maternal EC exposure significantly worsened MCT-induced PH in male offspring.This was associated with increased oxidative stress,DNA hypomethylation,and anomalous autophagy in the offspring.In vivo treatment with chloroquine inhibited autophagy and ameliorated PH development in offspring exposed to maternal EC.Furthermore,N-acetylcysteine(NAC),an antioxidant,attenuated maternal EC exposure-induced oxidative stress,DNA hypomethylation,and excessive autophagy,thereby improving PH.DNA hypermethylation also reversed PH development,accompanied by reduced oxidative stress and suppressed autophagy.ATG5,a key regulator of autophagy,was identified as a potential therapeutic target,as its repression mitigated PH in maternal EC-exposed offspring.Conclusion Maternal EC exposure induces oxidative stress and DNA hypomethylation in offspring,leading to anomalous autophagy and exacerbation of PH development.Targeting ATG5-mediated autophagy may represent a novel therapeutic approach for improving PH outcomes in offspring exposed to maternal EC.Graphical Abstract Pregnant rats were exposed to either EC vapor or standard air from gestation day 12 until 2 days before delivery,with all offspring undergoing PH induction at 6-wo.Offspring exposed to maternal EC presented increased oxidative stress,which in turn affected DNA methylation patterns.The decreased DNA methylation in male offspring led to the activation of autophagy,exacerbating the development of PH.Treatment with ATG5 siRNA inhibited autophagy and alleviated heightened PH in male offspring with maternal EC exposure.
基金supported by National Natural Science Foundation of China(Grant 82274541&81674008)Key Project of Hunan Provincial Health Commission(Grant 202204072465)Natural Science Foundation of Hunan Province(Grant 2020JJ4070).
文摘Objective:Limb ischemia-reperfusion injury(LIRI)may lead to tissue necrosis and loss of function,even life-threatening.Our previous study found that Tao-Hong-Si-Wu decoction(THSWD)had some efficacy in treating of LIRI.Quercetin,the major component of THSWD,was selected further to uncover the molecular mechanism underlying its treatment of LIRI.Methods:In this study,myoblasts were isolated fromrat gastrocnemiusmuscle tissue,and an in vitro LIRI model was established.The cell counting kit-8(CCK-8)and colony formation assay were used to evaluate the impact of quercetin on LIRI-induced myoblast viability and proliferation.Lactate dehydrogenase(LDH)activity wasmeasured to detectmyoblast injury in the LIRI model.Theapoptosis ofmyoblasts was evaluated byHoechst staining and flow cytometry.In addition,molecular docking analysis was performed to predict the interaction between quercetin and NADPH oxidase 2(NOX-2).Subsequently,we investigated the molecular mechanism of quercetin in LIRI-induced myoblasts by overexpressing NOX-2.Results:The myogenic marker Desmin was highly expressed in isolatedmyoblasts.In the LIRImodel,myoblast viability and proliferation were decreased,and cell injury and apoptosis levels were increased.In addition,NOX-2 was highly expressed in the LIRI model.At the same time,LIRI induction promoted the up-regulation of oxidative stress and inflammatory response.Quercetin significantly reversed the effects of LIRI treatment on myoblasts in a concentration-dependent manner.Molecular docking suggested an interaction between quercetin and NOX-2.Further overexpression of NOX-2 inhibited the effect of quercetin on LIRI-induced myoblasts.Conclusion:Quercetin could reduce inflammatory response and oxidative stress by inhibiting NOX-2,thus playing a therapeutic role in treating LIRI.
基金supported by National Key R&D Program of China(2023YFD2100205)Fuzhou Science&Technology Project,China(2022-Y-0022022-P-023).
文摘Identification of natural substances with antioxidant properties is ongoing research for addressing issues related to oxidative stress especially attributed to environmental effects.Our previous study demonstrated that Lateolabrax japonicus peptides(LPH),rich in Glu,Gly,and hydrophobic amino acids,exhibited remarkable antioxidant activity in vitro,with though its action mechanism yet to be revealed.Therefore,to assess the in vivo antioxidative properties of LPH,we employed H_(2)O_(2) to generate oxidative stress in Drosophila melanogaster model.Results indicated that LPH significantly prolonged the lifespan of Drosophila subjected to oxidative stress mostly mediated via LPH’s enhancement of the antioxidant defense system and intestinal functions.Antioxidant effects were manifested by a decrease in malondialdehyde(MDA)levels,elevated superoxide dismutase(SOD),catalase(CAT),and glutathione peroxidase(GSH-Px)activities,decreased levels of reactive oxygen species(ROS)in intestinal epithelial cells,and the preservation of intestinal length.LPH effectively controlled the excessive proliferation and differentiation of oxidative stress-induced Drosophila intestinal stem cells.At the gene level,LPH upregulated the expression of antioxidant-related Nrf2 genes while concurrently downregulated mTOR expression level.Furthermore,high-throughput 16S rDNA sequencing revealed that the addition of LPH significantly influenced the diversity and abundance of the intestinal microbiota in H_(2)O_(2)-induced Drosophila.These findings provide a deeper understanding of the antioxidative mechanism of LPH,suggesting its potential applications in food industry and to be assessed using other in vivo oxidative stress models.
基金supported by research grants from Daegu Catholic University in 2024(No.20245001).
文摘Background:Cisplatin(CDDP)is a cornerstone chemotherapeutic agent for many solid tumors,but its clinical use is severely limited by dose-dependent nephrotoxicity,which results in acute kidney injury(AKI)in a significant proportion of patients.CDDP-induced AKI involves interconnected mechanisms,including inflammation,oxidative stress,and tubular cell death.In this study,we aimed to investigate the renoprotective effects of esculetin(ES),a natural antioxidant coumarin,in a murine model of CDDP-induced AKI.Methods:Male C57BL/6 mice(8–10 weeks)received a single intraperitoneal injection of CDDP(20 mg/kg)with or without ES(40 mg/kg/day,oral gavage).Renal function,histopathology,and molecular markers of inflammation,oxidative stress,mitogen-activated protein kinase(MAPK)activation,endoplasmic reticulum(ER)stress,apoptosis,and ferroptosis were assessed by standard biochemical,histological,and immunoblotting techniques.Results:ES significantly reduced CDDP-induced elevations in serum creatinine and blood urea nitrogen,preserved renal structure,and decreased histological injury scores.Molecular analyses showed that ES suppressed the production of systemic and renal proinflammatory cytokines and inhibited the expression of chemokines and adhesion molecules.ES also suppressed the phosphorylation of extracellular signal-regulated kinase 1/2 and p38 MAPKs,mitigating stress-induced inflammatory and apoptotic signaling.Additionally,ES treatment reduced the expression of unfolded protein response markers,such as C/EBP homologous protein,which is indicative of alleviated ER stress.Oxidative injury was reduced,as evidenced by lower malondialdehyde and 4-hydroxynonenal levels and restored glutathione content.Importantly,ES mitigated ferroptosis,as demonstrated by decreased expression of pro-ferroptotic markers and preservation of anti-ferroptotic mediators,including glutathione peroxidase 4 and solute carrier family 7member 1.Conclusion:Collectively,our findings provide the first in vivo evidence that ES robustly protects against CDDP-induced AKI by simultaneously targeting oxidative stress,inflammation,MAPK,and ER stress pathways,apoptosis,and ferroptosis.These results highlight ES as a potential candidate for preventing CDDP-induced nephrotoxicity.
基金supported by the Natural Natural Science Foundation of China(No.41706142)the Earmarked Fund for CARS-49(No.CARS-49).
文摘Nanoplastic(NP)contaminants are receiving increasing attention due to the harm they can cause to aquatic organisms and their accumulation in the human body through the food web.The goal of this study was to evaluate the oxidative stress caused by NPs on the clams Meretrix meretrix and Sinonovacula constricta.Specimens were exposed to three concentrations of fluorescently labeled polystyrene NPs(PS-NPs;0,0.1,and 1 mg L^(-1))for 7 d followed by a 3 d recovery period.The activities of antioxidant enzymes,such as catalase(CAT),superoxide dismutase(SOD),glutathione peroxidase(GPx)and the content of malonaldehyde(MDA)were measured in the digestive gland,gills,and mantle tissues.Results showed that the SOD activity in the gills of M.meretrix was significantly higher than that of the control at day 1,and PS-NPs exposure inhibited the CAT activity in the gills and SOD and GPx activities in the mantle.Exposure to low or high concentrations of PS-NPs increased the activities of both CAT and GPx in the gills of S.constricta at day 3.The oxidative damage was more severe in the digestive gland of M.meretrix and in the mantle of S.constricta based on MDA level,and it returned to normal after recovery.Integrated biomarker response,index version 2(IBRv2)values showed that the gills were more sensitive to PS-NPs than mantle and digestive gland.Therefore,the oxidative stress by PS-NPs depended on exposure time,dose,organ,and species.
