AIM: To investigate the protective effect of paricalcitol and enalapril on renal inflammation and oxidative stress in Apo E-knock out mice. METHODS: Animals treated for 4 mo as group(1) Apo E-knock out plus vehicle, g...AIM: To investigate the protective effect of paricalcitol and enalapril on renal inflammation and oxidative stress in Apo E-knock out mice. METHODS: Animals treated for 4 mo as group(1) Apo E-knock out plus vehicle, group(2) Apo E-knock out plus paricalcitol(200 ng thrice a week),(3) Apo Eknock out plus enalapril(30 mg/L),(4) Apo E-knock out plus paricalcitol plus enalapril and(5) normal. Blood pressure(BP) was recorded using tail cuff method. The kidneys were isolated for biochemical assays using spectrophotometer and Western blot analyses. RESULTS: Apo E-deficient mice developed high BP(127 ± 3 mm Hg) and it was ameliorated by enalapril and enalapril plus paricalcitol treatments but not with paricalcitol alone. Renal malondialdehyde concentrations, p22 phox, manganese-superoxide dismutase, inducible nitric oxide synthase(NOS), monocyte chemoattractant protein-1, tumor necrosis factor-alpha and transforming growth factor-β1 levels significantly elevated but reduced glutathione, Cu Zn-SOD and e NOS levels significantly depleted in Apo E-knock out animals compared to normal. Administration of paricalcitol, enalapril and combined together ameliorated the renal inflammation and oxidative stress in Apo E-knock out animals. CONCLUSION: Paricalcitol and enalapril combo treatment ameliorates renal inflammation as well as oxidative stress in atherosclerotic animals.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
Infection is a public health problem and represents a spectrum of disease that can result in sepsis and septic shock.Sepsis is characterized by a dysregulated immune response to infection.Septic shock is the most seve...Infection is a public health problem and represents a spectrum of disease that can result in sepsis and septic shock.Sepsis is characterized by a dysregulated immune response to infection.Septic shock is the most severe form of sepsis which leads to distributive shock and high mortality rates.There have been significant advances in sepsis management mainly focusing on early identification and therapy.However,complicating matters is the lack of reliable diagnostic tools and the poor specificity and sensitivity of existing scoring tools i.e.,systemic inflammatory response syndrome criteria,sequential organ failure assessment(SOFA),or quick SOFA.These limitations have underscored the modest progress in reducing sepsis-related mortality.This review will focus on novel therapeutics such as oxidative stress targets,cytokine modulation,endothelial cell modulation,etc.,that are being conceptualized for the management of sepsis and septic shock.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
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
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
Objective To evaluate the anti-arthritic efficacy of sarsasapogenin(SG)alone and in combination with the corticosteroid fluticasone(FC)in a rat model of rheumatoid arthritis(RA),which was induced by complete Freund’s...Objective To evaluate the anti-arthritic efficacy of sarsasapogenin(SG)alone and in combination with the corticosteroid fluticasone(FC)in a rat model of rheumatoid arthritis(RA),which was induced by complete Freund’s adjuvant(CFA).Methods Network pharmacology analysis was conducted to identify the potential molecular targets and signaling pathways of SG in RA.Targets were identified with multiple databases,including SwissTargetPrediction,GeneCards,DisGeNET,and Search Tool for the Retrieval of Interacting Genes/Proteins(STRING),and pathway enrichment analysis was performed using Kyoto Encyclopedia of Genes and Genomes(KEGG)and Gene Ontology(GO)databases.Molecular docking was performed to validate the binding affinity of key SG constituents with the predicted hub targets.Male Wistar rats were randomly divided into normal control(NC),CFA,SG,FC,and SG+FC groups(n=6 per group).RA was induced in all groups except NC group by a single intradermal injection of CFA(0.1 mL)into the left hind paw on day 1.After successfully induction of RA(day 12),treatments were administered intradermally from day 12 to 28 as follows:SG(50μg/rat,40μL per paw),FC(50μg/rat,40μL per paw),or a combination of SG and FC(25μg/rat each,total 40μL per paw).Therapeutic outcomes were evaluated via the paw volume,joint diameter,arthritis scores,hematological and biochemical indicators,oxidative stress markers,inflammatory cytokines,and histopathological assessments of rats’ankle joint.The gene expression analysis was performed by quantitative reverse transcription polymerase chain reaction(qRT-PCR).Acute toxicity,body weight,and immune organ indices(spleen and thymus)were also monitored to assess the potential mitigation of SG of corticosteroid-induced adverse effects.Results Network pharmacology analysis revealed 138 potential SG-associated targets,involving 10 key hub genes.KEGG enrichment indicated the participation of pathways involving phosphoinositide-3-kinase regulatory subunit 1(PIK3R1),estrogen receptor 1(ESR1),E1A binding protein P300(EP300),mammalian target of rapamycin(mTOR),C-X-C chemokine receptor type 4(CXCR4),signal transducer and activator of transcription 3(STAT3),and tolllike receptor 4(TLR4).GO enrichment analysis also revealed significant involvement of inflammatory and immune-related biological processes.Molecular docking confirmed strong binding interactions between major SG constituents and the identified hub targets.SG and SG+FC groups preserved body weight,and normalized spleen and thymus indices compared with FC group(P<0.05 or P<0.01),suggesting the mitigation of corticosteroid-induced adverse effects.SG and SG+FC groups significantly reduced paw volume,ankle diameter,and arthritis scores compared with CFA group(P<0.05,P<0.01,or P<0.001).These treatments also significantly normalized hematological indicators[red blood cells(RBC),white blood cells(WBC),hemoglobin(Hb),and platelets(PLT)]and biochemical indicators[aspartate aminotransferase(AST),alanine aminotransferase(ALT),and alkaline phosphatase(ALP)](P<0.05,P<0.01,or P<0.001).Serum proinflammatory cytokine levels[tumor necrosis factor(TNF)-α,interleukin(IL)-6,IL-12,and thromboxane B2(TXB2)]were markedly decreased,accompanied by restored antioxidant defenses[superoxide dismutase(SOD)and glutathione(GSH)]and reduced oxidative stress markers[malondialdehyde(MDA)and myeloperoxidase(MPO)](P<0.05,P<0.01,or P<0.001).The qRT-PCR analysis demonstrated favorable downregulation of STAT3,mTOR,and nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κB)expression levels in joint tissues in all treatment groups compared with CFA group(P<0.05,P<0.01,or P<0.001).Histopathological findings corroborated these effects,indicating reduced inflammatory infiltration and preservation of joint architecture.Conclusion SG exerts protective effects against RA by modulating key inflammatory and immune pathways.The combined application of SG with FC enhances the therapeutic outcomes,while potentially reducing the corticosteroid-related adverse effects.These findings support SG as a promising adjunctive therapy in RA management,offering favorable efficacy and safety alongside conventional corticosteroid treatment.展开更多
Objective:To investigate the protective effect of ursolic acid(UA)on isoproterenol(ISO)-induced kidney injury in mice.Methods:Four groups of mice were used:GroupⅠ(Control)received phosphate-buffered saline i.p.for fo...Objective:To investigate the protective effect of ursolic acid(UA)on isoproterenol(ISO)-induced kidney injury in mice.Methods:Four groups of mice were used:GroupⅠ(Control)received phosphate-buffered saline i.p.for four weeks;GroupⅡ(ISO alone)was administered ISO(10 mg/kg i.p.)daily for four weeks to induce kidney injury;GroupⅢ(ISO+UA)was pretreated with UA(40 mg/kg i.p.)once daily,followed by ISO(10 mg/kg i.p.)once daily for four weeks;GroupⅣ(UA alone)received UA(40 mg/kg i.p.)daily for four weeks.Markers of oxidative stress,inflammation,and apoptosis were analyzed,and the protein expression of p-PI3K and p-Akt was determined.Results:UA treatment significantly alleviated ISO-induced kidney injury,evidenced by lowered levels of malondialdehyde,IL-6,TNF-αand IL-1β,downregulated expression of cleaved caspase-3 and PARP,and upregulated expression of Bcl-2 and Bcl-xL.It also activated the PI3K/Akt pathway.Conclusions:UA demonstrates renoprotective effects against ISO-induced kidney injury by reducing oxidative stress,inflammation,and apoptosis,likely through PI3K/Akt pathway activation.These findings suggest that UA may serve as a potential therapeutic agent for renal diseases linked to inflammation and oxidative stress,meriting further exploration for clinical applications.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:To investigate the protective effects of Lepidium draba L.(L.draba)on cyclophosphamide(CP)-induced hepatotoxicity and nephrotoxicity in rats.Methods:A total of 36 rats were divided into six groups as follows...Objective:To investigate the protective effects of Lepidium draba L.(L.draba)on cyclophosphamide(CP)-induced hepatotoxicity and nephrotoxicity in rats.Methods:A total of 36 rats were divided into six groups as follows:the sham control group,the CP group(CP 100 mg/kg i.p.on days 1,7,14,21,28,and 35),the CP groups treated with L.draba extract(100,200 and 400 mg/kg of L.draba extract for 28 d),and the L.draba extract alone group(400 mg/kg of L.draba extract for 28 d).Serum parameters of renal and hepatic function,as well as pro-inflammatory and anti-inflammatory cytokines associated with liver and kidney damage were measured.Moreover,Bax,Bcl-2,and caspase-3 gene expression and histopathological changes were assessed.Results:L.draba extract alleviated CP-induced hepatotoxicity and nephrotoxicity by decreasing nitric oxide,TBARS,IL-6,TNF-α,and IL-1βlevels,as well as increasing superoxide dismutase,catalase and glutathione peroxidase activities,and FRAP,MIF,and TGF-βlevels.In addition,the extract downregulated the expression of pro-apoptotic genes(Bax and caspase-3)and mitigated the destruction of glomeruli and renal tubules as well as the degeneration of hepatocytes.Conclusions:L.draba extract can protect hepatic and renal structure and function against CP-induced toxicities,and may be used as a therapeutic agent for CP-induced hepatotoxicity and nephrotoxicity.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
Objective To investigate the neuroprotective action of astragaloside Ⅳ(AS-Ⅳ) on spatial learning and memory impairment induced by amyloid-beta 1-42(Aβ1-42) in rats and elucidate its underlying molecular mechanisms....Objective To investigate the neuroprotective action of astragaloside Ⅳ(AS-Ⅳ) on spatial learning and memory impairment induced by amyloid-beta 1-42(Aβ1-42) in rats and elucidate its underlying molecular mechanisms.Methods Adult-male Sprague-Dawley rats(230-250 g) were divided into six groups randomly: control, Aβ1-42, AS-Ⅳ, Aβ1-42 plus 5 mg/kg·d AS-Ⅳ, Aβ1-42 plus 25 mg/kg·d AS-Ⅳ, and Aβ1-42 plus 50 mg/kg·d AS-Ⅳ groups. Aβ1-42 were delivered by intracerebroventricular injection under the guidance of a brain stereotaxic apparatus. The Morris water maze test(hidden platform test, probe trials, visible platform test) was performed one week after Aβ1-42 injection to obtain the ability of rat spatial learning and memory. AS-Ⅳ(5, 25 and 50 mg/kg·d) was administrated intraperitoneally once per day from the 8 th day after Aβ1-42 injection for 5 consecutive days. Average escape latencies, distances for searching for the platform under water and the percentage of total time elapsed and distance swam in the right quadrant after removing platform were determined by behavior softwaresystem. The vision and swim speeds of rats were also determined to exclude the effect of these factors on the parameters of learning and memory. After behavioral tests, the rats were sacrificed immediately by decapitation. Hippocampus were collected. The enzyme activities of superoxide dismutase(SOD), glutathione peroxidase(GSH-px) and catalase(CAT) in the hippocampus obtained from different-treated rat brain were measured by following the manufacturer’s instructions. The levels of interleukin-1 beta(IL-1β) and tumor necrosis factor-alpha(TNF-α) in tissue lysates were assayed with ELISA.Results The water maze test results indicated that chronic treatments with AS-Ⅳ effectively protected the rats from Aβ1-42-induced spatial learning and memory impairment. Furthermore, the activities of SOD, GSH-px and CAT decreased by Aβ1-42 were also restored by AS-Ⅳ treatment in the hippocampus of rats. In addition, AS-Ⅳ significantly decreased the levels of IL-1β and TNF-α in the hippocampus of Aβ1-42-induced amnesia’s rats. Conclusion Our findings suggest that AS-Ⅳ might be a useful chemical in improving the spatial memory and relieving the oxidative stress and neuroinflammation in Alzheimer patients.展开更多
Stroke is a major cause of death and disability worldwide.It is characterized by a highly interconnected and multiphasic neuropathological cascade of events,in which an intense and protracted inflammatory response pla...Stroke is a major cause of death and disability worldwide.It is characterized by a highly interconnected and multiphasic neuropathological cascade of events,in which an intense and protracted inflammatory response plays a crucial role in worsening brain injury.Neuroinflammation,a key player in the pathophysiology of stroke,has a dual role.In the acute phase of stroke,neuroinflammation exacerbates brain injury,contributing to neuronal damage and blood–brain barrier disruption.This aspect of neuroinflammation is associated with poor neurological outcomes.Conversely,in the recovery phase following stroke,neuroinflammation facilitates brain repair processes,including neurogenesis,angiogenesis,and synaptic plasticity.The transition of neuroinflammation from a harmful to a reparative role is not well understood.Therefore,this review seeks to explore the mechanisms underlying this transition,with the goal of informing the development of therapeutic interventions that are both time-and context-specific.This review aims to elucidate the complex and dual role of neuroinflammation in stroke,highlighting the main actors,biomarkers of the disease,and potential therapeutic approaches.展开更多
In this study,a novel polysaccharide GPA-G 2-H was derived from ginseng.Furthermore,the coherent study of its structural characteristics,fermented characteristics in vitro,as well as antioxidant mechanism of fermented...In this study,a novel polysaccharide GPA-G 2-H was derived from ginseng.Furthermore,the coherent study of its structural characteristics,fermented characteristics in vitro,as well as antioxidant mechanism of fermented product FGPA-G 2-H on Aβ25-35-induced PC 12 cells were explored.The structure of GPA-G 2-H was determined by means of zeta potential analysis,FTIR,HPLC,XRD,GC-MS and NMR.The backbone of GPA-G 2-H was mainly composed of→4)-α-D-Glcp-(1→with branches substituted at O-3.Notably,GPA-G 2-H was degraded by intestinal microbiota in vitro with total sugar content and pH value decreasing,and short-chain fatty acids(SCFAs)increasing.Moreover,GPA-G 2-H significantly promoted the proliferation of Lactobacillus,Muribaculaceae and Weissella,thereby making positive alterations in intestinal microbiota composition.Additionally,FGPA-G 2-H activated the Nrf 2/HO-1 signaling pathway,enhanced HO-1,NQO 1,SOD and GSH-Px,while inhabited Keap 1,MDA and LDH,which alleviated Aβ-induced oxidative stress in PC 12 cells.These provide a solid theoretical basis for the further development of ginseng polysaccharides as functional food and antioxidant drugs.展开更多
Dear Editor,Space flight(SF)is substantially increasing at present.The emergence of commercial suborbital SF,such as the Virgin Galactic with VSS Unity and VMS Eve spacecraft,is extending to civilians,being previously...Dear Editor,Space flight(SF)is substantially increasing at present.The emergence of commercial suborbital SF,such as the Virgin Galactic with VSS Unity and VMS Eve spacecraft,is extending to civilians,being previously confined to military and/or professional astronauts only.This new evidence offers additional opportunities for better characterizing the impact that the transition from Earth’s 1G to microgravity in space could have on the astronauts’health while comparing well-trained subjects such as the latt er to space newcomers[1].展开更多
Epilepsy is a complex neurological disorder aggravated by chronic neuroinflammation largely driven by reactive astrocytes.These cells promote epileptogenesis through persistent cytokine secretion and glial scar format...Epilepsy is a complex neurological disorder aggravated by chronic neuroinflammation largely driven by reactive astrocytes.These cells promote epileptogenesis through persistent cytokine secretion and glial scar formation.Current antiepileptic drugs remain ineffective in targeting these mechanisms due to limited blood-brain barrier(BBB)permeability and poor astrocytic specificity.A transferrin-functionalized biomimetic nanotherapeutic loaded with resveratrol(RN@RTA)was developed to regulate astrocyte-mediated inflammation by activating sirtuin 1(SIRT1)and suppressing the mitogen-activated protein kinase/nuclear factor Kappalight-chain-enhancer of activated B cells(MAPK/NF-κB)axis.Using in vitro BBB models,primary astrocytes,and a pilocarpine-induced chronic epilepsy mouse model,we evaluated the capacity of RN@RTA to cross the BBB,inhibit inflammatory signaling,and reduce seizure activity.Mechanistic assays included immunoprecipitation of NF-κB complexes,cytokine quantification,RNA sequencing,and histopathological assessments of glial and synaptic markers.RN@RTA achieved 82%uptake by hippocampal astrocytes and significantly reduced Il6,Tnf-α,and Nlrp3 expression.SIRT1 activation disrupted the NF-κB p65/p300 complex,leading to transcriptional repression of inflammatory genes and enhancement of autophagy.In vivo,seizure frequency decreased by 67%,synaptic structure was preserved,and astrogliosis was markedly alleviated.The findings demonstrate a dual regulatory mechanism in which RN@RTA suppresses neuroinflammatory signaling and restores neural homeostasis,offering a promising molecularly targeted approach for refractory epilepsy.展开更多
Microorganisms constitute an essential component in the indoor environment,which is closely related to hu-man health.However,there is limited evidence regarding the associations between indoor airborne microbiome and ...Microorganisms constitute an essential component in the indoor environment,which is closely related to hu-man health.However,there is limited evidence regarding the associations between indoor airborne microbiome and systemic inflammation,as well as whether this association is modified by indoor particulate matter and the underlying mechanisms.In this prospective repeated-measure study among 66 participants,indoor airborne mi-crobiome was characterized using amplicon sequencing and qPCR.Indoor fine particulate matter(PM_(2.5))and inhalable particulate matter(PM10)were measured.Systemic inflammatory biomarkers were assessed,including white blood cell(WBC),neutrophil(NEUT),monocyte,eosinophil counts,and their proportions.Targeted serum amino acid metabolomics were conducted to explore the underlying mechanisms.Linear mixed-effect models re-vealed that bacterial and fungal Simpson diversity were significantly associated with decreased WBC and NEUT.For example,for each interquartile range increase in the bacterial Simpson diversity,WBC and NEUT changed by-4.53%(95%CI:-8.25%,-0.66%)and-5.95%(95%CI:-11.3%,-0.27%),respectively.Notably,increased inflammatory risks of airborne microbial exposure were observed when indoor PM_(2.5) and PM10 levels were below the WHO air quality guidelines.Mediation analyses indicated that dopamine metabolism partially mediated the anti-inflammatory effects of fungal diversity exposure.Overall,our study indicated protection from a diverse indoor microbial environment on cardiovascular health and proposed an underlying mechanism through amino acid metabolism.Additionally,health risks associated with microbial exposure deserve more attention in con-texts of low indoor particulate matter pollution.Further research is necessary to fully disentangle the complex relationships between indoor microbiome,air pollutants,and human health.展开更多
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
Neuroinflammation is an inflammatory response in the central nervous system associated with various neurological conditions.The inflammatory process is typically treated with non-steroidal and steroidal anti-inflammat...Neuroinflammation is an inflammatory response in the central nervous system associated with various neurological conditions.The inflammatory process is typically treated with non-steroidal and steroidal anti-inflammatory drugs,which have a range of serious adverse effects.As an alternative,naturally derived molecules such as quercetin and its derivatives show promising anti-inflammatory properties and beneficial effects on various physiological functions.Our objective was to synthesize the evidence on the anti-inflammatory effect of quercetin and its derivatives in in vivo models,in the face of neuroinflammatory insults induced by lipopolysaccharide,through a systematic review and meta-analysis.A search of the preclinical literature was conducted across four databases(Pub Med,Web of Science,Scielo,and Google Scholar).Studies were selected based on inclusion and exclusion criteria,assessed for methodological quality using CAMARADES,and risk of bias using the SYRCLE tool,and data were extracted from the studies.The quantitative assessment of quercetin effects on the expression of pro-inflammatory cytokines and microgliosis was performed through a meta-analysis.A total of 384 potentially relevant articles were identified,of which 11 studies were included in the analysis.The methodological quality was assessed,resulting in an average score of 5.8/10,and the overall risk of bias analysis revealed a lack of methodological clarity in most studies.Furthermore,through the meta-analysis,it was observed that treatment with quercetin statistically reduces pro-inflammatory cytokines,such as tumor necrosis factor alpha,interleukin 6,interleukin 1β(n=89;SMD=–2.00;95%CI:–3.29 to–0.71),and microgliosis(n=33;SMD=–2.56;95%CI:–4.07 to–1.10).In terms of underlying mechanisms,quercetin and its derivatives exhibit antioxidant and anti-apoptotic properties,possibly through the nuclear factor erythroid 2-related factor 2(Nrf2)/HO-1 pathways,increasing the expression of antioxidant enzymes and reducing reactive species,and modulating the caspase pathway,increasing levels of anti-apoptotic proteins and decreasing proapoptotic proteins.Quercetin and its derivatives exhibit highly pleiotropic actions that simultaneously contribute to preventing neuroinflammation.However,despite promising results in animal models,future directions should focus on well-designed clinical studies to assess the safety,bioavailability,and efficacy of quercetin and its derivatives in humans.Additionally,standardization of methods and dosages in studies is crucial to ensure consistency of findings and optimize their application in clinical settings.展开更多
Obesity is widely recognized as a global epidemic,primarily driven by an imbalance between energy expenditure and caloric intake associated with a sedentary lifestyle.Diets high in carbohydrates and saturated fats,par...Obesity is widely recognized as a global epidemic,primarily driven by an imbalance between energy expenditure and caloric intake associated with a sedentary lifestyle.Diets high in carbohydrates and saturated fats,particularly palmitic acid,are potent inducers of chronic low-grade inflammation,largely due to disruptions in glucose metabolism and the onset of insulin resistance(Qiu et al.,2022).While many organs are affected,the brain,specifically the hypothalamus,is among the first to exhibit inflammation in response to an unhealthy diet,suggesting that obesity may,in fact,be a brain-centered disease with neuroinflammation as a central factor(Thaler et al., 2012).展开更多
基金Supported by A research grant from Abbott Pharmaceutical,United States
文摘AIM: To investigate the protective effect of paricalcitol and enalapril on renal inflammation and oxidative stress in Apo E-knock out mice. METHODS: Animals treated for 4 mo as group(1) Apo E-knock out plus vehicle, group(2) Apo E-knock out plus paricalcitol(200 ng thrice a week),(3) Apo Eknock out plus enalapril(30 mg/L),(4) Apo E-knock out plus paricalcitol plus enalapril and(5) normal. Blood pressure(BP) was recorded using tail cuff method. The kidneys were isolated for biochemical assays using spectrophotometer and Western blot analyses. RESULTS: Apo E-deficient mice developed high BP(127 ± 3 mm Hg) and it was ameliorated by enalapril and enalapril plus paricalcitol treatments but not with paricalcitol alone. Renal malondialdehyde concentrations, p22 phox, manganese-superoxide dismutase, inducible nitric oxide synthase(NOS), monocyte chemoattractant protein-1, tumor necrosis factor-alpha and transforming growth factor-β1 levels significantly elevated but reduced glutathione, Cu Zn-SOD and e NOS levels significantly depleted in Apo E-knock out animals compared to normal. Administration of paricalcitol, enalapril and combined together ameliorated the renal inflammation and oxidative stress in Apo E-knock out animals. CONCLUSION: Paricalcitol and enalapril combo treatment ameliorates renal inflammation as well as oxidative stress in atherosclerotic animals.
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.
文摘Infection is a public health problem and represents a spectrum of disease that can result in sepsis and septic shock.Sepsis is characterized by a dysregulated immune response to infection.Septic shock is the most severe form of sepsis which leads to distributive shock and high mortality rates.There have been significant advances in sepsis management mainly focusing on early identification and therapy.However,complicating matters is the lack of reliable diagnostic tools and the poor specificity and sensitivity of existing scoring tools i.e.,systemic inflammatory response syndrome criteria,sequential organ failure assessment(SOFA),or quick SOFA.These limitations have underscored the modest progress in reducing sepsis-related mortality.This review will focus on novel therapeutics such as oxidative stress targets,cytokine modulation,endothelial cell modulation,etc.,that are being conceptualized for the management of sepsis and septic shock.
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 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.
文摘Objective To evaluate the anti-arthritic efficacy of sarsasapogenin(SG)alone and in combination with the corticosteroid fluticasone(FC)in a rat model of rheumatoid arthritis(RA),which was induced by complete Freund’s adjuvant(CFA).Methods Network pharmacology analysis was conducted to identify the potential molecular targets and signaling pathways of SG in RA.Targets were identified with multiple databases,including SwissTargetPrediction,GeneCards,DisGeNET,and Search Tool for the Retrieval of Interacting Genes/Proteins(STRING),and pathway enrichment analysis was performed using Kyoto Encyclopedia of Genes and Genomes(KEGG)and Gene Ontology(GO)databases.Molecular docking was performed to validate the binding affinity of key SG constituents with the predicted hub targets.Male Wistar rats were randomly divided into normal control(NC),CFA,SG,FC,and SG+FC groups(n=6 per group).RA was induced in all groups except NC group by a single intradermal injection of CFA(0.1 mL)into the left hind paw on day 1.After successfully induction of RA(day 12),treatments were administered intradermally from day 12 to 28 as follows:SG(50μg/rat,40μL per paw),FC(50μg/rat,40μL per paw),or a combination of SG and FC(25μg/rat each,total 40μL per paw).Therapeutic outcomes were evaluated via the paw volume,joint diameter,arthritis scores,hematological and biochemical indicators,oxidative stress markers,inflammatory cytokines,and histopathological assessments of rats’ankle joint.The gene expression analysis was performed by quantitative reverse transcription polymerase chain reaction(qRT-PCR).Acute toxicity,body weight,and immune organ indices(spleen and thymus)were also monitored to assess the potential mitigation of SG of corticosteroid-induced adverse effects.Results Network pharmacology analysis revealed 138 potential SG-associated targets,involving 10 key hub genes.KEGG enrichment indicated the participation of pathways involving phosphoinositide-3-kinase regulatory subunit 1(PIK3R1),estrogen receptor 1(ESR1),E1A binding protein P300(EP300),mammalian target of rapamycin(mTOR),C-X-C chemokine receptor type 4(CXCR4),signal transducer and activator of transcription 3(STAT3),and tolllike receptor 4(TLR4).GO enrichment analysis also revealed significant involvement of inflammatory and immune-related biological processes.Molecular docking confirmed strong binding interactions between major SG constituents and the identified hub targets.SG and SG+FC groups preserved body weight,and normalized spleen and thymus indices compared with FC group(P<0.05 or P<0.01),suggesting the mitigation of corticosteroid-induced adverse effects.SG and SG+FC groups significantly reduced paw volume,ankle diameter,and arthritis scores compared with CFA group(P<0.05,P<0.01,or P<0.001).These treatments also significantly normalized hematological indicators[red blood cells(RBC),white blood cells(WBC),hemoglobin(Hb),and platelets(PLT)]and biochemical indicators[aspartate aminotransferase(AST),alanine aminotransferase(ALT),and alkaline phosphatase(ALP)](P<0.05,P<0.01,or P<0.001).Serum proinflammatory cytokine levels[tumor necrosis factor(TNF)-α,interleukin(IL)-6,IL-12,and thromboxane B2(TXB2)]were markedly decreased,accompanied by restored antioxidant defenses[superoxide dismutase(SOD)and glutathione(GSH)]and reduced oxidative stress markers[malondialdehyde(MDA)and myeloperoxidase(MPO)](P<0.05,P<0.01,or P<0.001).The qRT-PCR analysis demonstrated favorable downregulation of STAT3,mTOR,and nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κB)expression levels in joint tissues in all treatment groups compared with CFA group(P<0.05,P<0.01,or P<0.001).Histopathological findings corroborated these effects,indicating reduced inflammatory infiltration and preservation of joint architecture.Conclusion SG exerts protective effects against RA by modulating key inflammatory and immune pathways.The combined application of SG with FC enhances the therapeutic outcomes,while potentially reducing the corticosteroid-related adverse effects.These findings support SG as a promising adjunctive therapy in RA management,offering favorable efficacy and safety alongside conventional corticosteroid treatment.
文摘Objective:To investigate the protective effect of ursolic acid(UA)on isoproterenol(ISO)-induced kidney injury in mice.Methods:Four groups of mice were used:GroupⅠ(Control)received phosphate-buffered saline i.p.for four weeks;GroupⅡ(ISO alone)was administered ISO(10 mg/kg i.p.)daily for four weeks to induce kidney injury;GroupⅢ(ISO+UA)was pretreated with UA(40 mg/kg i.p.)once daily,followed by ISO(10 mg/kg i.p.)once daily for four weeks;GroupⅣ(UA alone)received UA(40 mg/kg i.p.)daily for four weeks.Markers of oxidative stress,inflammation,and apoptosis were analyzed,and the protein expression of p-PI3K and p-Akt was determined.Results:UA treatment significantly alleviated ISO-induced kidney injury,evidenced by lowered levels of malondialdehyde,IL-6,TNF-αand IL-1β,downregulated expression of cleaved caspase-3 and PARP,and upregulated expression of Bcl-2 and Bcl-xL.It also activated the PI3K/Akt pathway.Conclusions:UA demonstrates renoprotective effects against ISO-induced kidney injury by reducing oxidative stress,inflammation,and apoptosis,likely through PI3K/Akt pathway activation.These findings suggest that UA may serve as a potential therapeutic agent for renal diseases linked to inflammation and oxidative stress,meriting further exploration for clinical applications.
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 the Basic Research Joint Special General Project of Yunnan Provincial Local Universities(part)(No:202301BA070001-029,202301BA070001-044)Yunnan Province High-level Scientific and Technological Talents and Innovation Team Selection Special Young and Middle-aged Academic and Technical Leaders Reserve Talent Project(No:202405AC350067).
文摘Objective:To investigate the protective effects of Lepidium draba L.(L.draba)on cyclophosphamide(CP)-induced hepatotoxicity and nephrotoxicity in rats.Methods:A total of 36 rats were divided into six groups as follows:the sham control group,the CP group(CP 100 mg/kg i.p.on days 1,7,14,21,28,and 35),the CP groups treated with L.draba extract(100,200 and 400 mg/kg of L.draba extract for 28 d),and the L.draba extract alone group(400 mg/kg of L.draba extract for 28 d).Serum parameters of renal and hepatic function,as well as pro-inflammatory and anti-inflammatory cytokines associated with liver and kidney damage were measured.Moreover,Bax,Bcl-2,and caspase-3 gene expression and histopathological changes were assessed.Results:L.draba extract alleviated CP-induced hepatotoxicity and nephrotoxicity by decreasing nitric oxide,TBARS,IL-6,TNF-α,and IL-1βlevels,as well as increasing superoxide dismutase,catalase and glutathione peroxidase activities,and FRAP,MIF,and TGF-βlevels.In addition,the extract downregulated the expression of pro-apoptotic genes(Bax and caspase-3)and mitigated the destruction of glomeruli and renal tubules as well as the degeneration of hepatocytes.Conclusions:L.draba extract can protect hepatic and renal structure and function against CP-induced toxicities,and may be used as a therapeutic agent for CP-induced hepatotoxicity and nephrotoxicity.
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.
基金Supported by the Natural Science Foundation of Shaanxi Province of China(2015JQ8299)National Science Foundation of China(81703842)Traditional Chinese Medicine Scientific Research Projects of Shaanxi Province of China(JCMS032)
文摘Objective To investigate the neuroprotective action of astragaloside Ⅳ(AS-Ⅳ) on spatial learning and memory impairment induced by amyloid-beta 1-42(Aβ1-42) in rats and elucidate its underlying molecular mechanisms.Methods Adult-male Sprague-Dawley rats(230-250 g) were divided into six groups randomly: control, Aβ1-42, AS-Ⅳ, Aβ1-42 plus 5 mg/kg·d AS-Ⅳ, Aβ1-42 plus 25 mg/kg·d AS-Ⅳ, and Aβ1-42 plus 50 mg/kg·d AS-Ⅳ groups. Aβ1-42 were delivered by intracerebroventricular injection under the guidance of a brain stereotaxic apparatus. The Morris water maze test(hidden platform test, probe trials, visible platform test) was performed one week after Aβ1-42 injection to obtain the ability of rat spatial learning and memory. AS-Ⅳ(5, 25 and 50 mg/kg·d) was administrated intraperitoneally once per day from the 8 th day after Aβ1-42 injection for 5 consecutive days. Average escape latencies, distances for searching for the platform under water and the percentage of total time elapsed and distance swam in the right quadrant after removing platform were determined by behavior softwaresystem. The vision and swim speeds of rats were also determined to exclude the effect of these factors on the parameters of learning and memory. After behavioral tests, the rats were sacrificed immediately by decapitation. Hippocampus were collected. The enzyme activities of superoxide dismutase(SOD), glutathione peroxidase(GSH-px) and catalase(CAT) in the hippocampus obtained from different-treated rat brain were measured by following the manufacturer’s instructions. The levels of interleukin-1 beta(IL-1β) and tumor necrosis factor-alpha(TNF-α) in tissue lysates were assayed with ELISA.Results The water maze test results indicated that chronic treatments with AS-Ⅳ effectively protected the rats from Aβ1-42-induced spatial learning and memory impairment. Furthermore, the activities of SOD, GSH-px and CAT decreased by Aβ1-42 were also restored by AS-Ⅳ treatment in the hippocampus of rats. In addition, AS-Ⅳ significantly decreased the levels of IL-1β and TNF-α in the hippocampus of Aβ1-42-induced amnesia’s rats. Conclusion Our findings suggest that AS-Ⅳ might be a useful chemical in improving the spatial memory and relieving the oxidative stress and neuroinflammation in Alzheimer patients.
基金supported by European Union-NextGeneration EU under the Italian University and Research(MUR)National Innovation Ecosystem grant ECS00000041-VITALITY-CUP E13C22001060006(to MdA)。
文摘Stroke is a major cause of death and disability worldwide.It is characterized by a highly interconnected and multiphasic neuropathological cascade of events,in which an intense and protracted inflammatory response plays a crucial role in worsening brain injury.Neuroinflammation,a key player in the pathophysiology of stroke,has a dual role.In the acute phase of stroke,neuroinflammation exacerbates brain injury,contributing to neuronal damage and blood–brain barrier disruption.This aspect of neuroinflammation is associated with poor neurological outcomes.Conversely,in the recovery phase following stroke,neuroinflammation facilitates brain repair processes,including neurogenesis,angiogenesis,and synaptic plasticity.The transition of neuroinflammation from a harmful to a reparative role is not well understood.Therefore,this review seeks to explore the mechanisms underlying this transition,with the goal of informing the development of therapeutic interventions that are both time-and context-specific.This review aims to elucidate the complex and dual role of neuroinflammation in stroke,highlighting the main actors,biomarkers of the disease,and potential therapeutic approaches.
基金Supported by the National Key Research and Development Program of Traditional Chinese Medicine Modernization Project,China(No.2023YFC3504000)the Science and Technology Development Project of Jilin Province,China(No.20240404043ZP)the Science and Technology Innovation Cooperation Project of Changchun Science and Technology Bureau and Chinese Academy of Sciences,China(No.23SH14)。
文摘In this study,a novel polysaccharide GPA-G 2-H was derived from ginseng.Furthermore,the coherent study of its structural characteristics,fermented characteristics in vitro,as well as antioxidant mechanism of fermented product FGPA-G 2-H on Aβ25-35-induced PC 12 cells were explored.The structure of GPA-G 2-H was determined by means of zeta potential analysis,FTIR,HPLC,XRD,GC-MS and NMR.The backbone of GPA-G 2-H was mainly composed of→4)-α-D-Glcp-(1→with branches substituted at O-3.Notably,GPA-G 2-H was degraded by intestinal microbiota in vitro with total sugar content and pH value decreasing,and short-chain fatty acids(SCFAs)increasing.Moreover,GPA-G 2-H significantly promoted the proliferation of Lactobacillus,Muribaculaceae and Weissella,thereby making positive alterations in intestinal microbiota composition.Additionally,FGPA-G 2-H activated the Nrf 2/HO-1 signaling pathway,enhanced HO-1,NQO 1,SOD and GSH-Px,while inhabited Keap 1,MDA and LDH,which alleviated Aβ-induced oxidative stress in PC 12 cells.These provide a solid theoretical basis for the further development of ginseng polysaccharides as functional food and antioxidant drugs.
基金supported by the Hyperbaric Med School of the Department of Biomedical Sciences at the University of Padova,the Italian Air Force,and the Institute of Clinical Physiology(Milan)-National Research Council(IFC-CNR).
文摘Dear Editor,Space flight(SF)is substantially increasing at present.The emergence of commercial suborbital SF,such as the Virgin Galactic with VSS Unity and VMS Eve spacecraft,is extending to civilians,being previously confined to military and/or professional astronauts only.This new evidence offers additional opportunities for better characterizing the impact that the transition from Earth’s 1G to microgravity in space could have on the astronauts’health while comparing well-trained subjects such as the latt er to space newcomers[1].
基金supported by the Health Commission of Hubei Province scientific research project(No.WJ2021M143)the Fundamental Research Funds for the Central Universities(No.413000714)+2 种基金the Research Fund of Anhui Institute of translational medicine(No.2023zhyx-C61)the Research Fund Project of Anhui Medical University(No.2022xkj148)Hubei Society of Pathology General Project(No.2025HBAP013).
文摘Epilepsy is a complex neurological disorder aggravated by chronic neuroinflammation largely driven by reactive astrocytes.These cells promote epileptogenesis through persistent cytokine secretion and glial scar formation.Current antiepileptic drugs remain ineffective in targeting these mechanisms due to limited blood-brain barrier(BBB)permeability and poor astrocytic specificity.A transferrin-functionalized biomimetic nanotherapeutic loaded with resveratrol(RN@RTA)was developed to regulate astrocyte-mediated inflammation by activating sirtuin 1(SIRT1)and suppressing the mitogen-activated protein kinase/nuclear factor Kappalight-chain-enhancer of activated B cells(MAPK/NF-κB)axis.Using in vitro BBB models,primary astrocytes,and a pilocarpine-induced chronic epilepsy mouse model,we evaluated the capacity of RN@RTA to cross the BBB,inhibit inflammatory signaling,and reduce seizure activity.Mechanistic assays included immunoprecipitation of NF-κB complexes,cytokine quantification,RNA sequencing,and histopathological assessments of glial and synaptic markers.RN@RTA achieved 82%uptake by hippocampal astrocytes and significantly reduced Il6,Tnf-α,and Nlrp3 expression.SIRT1 activation disrupted the NF-κB p65/p300 complex,leading to transcriptional repression of inflammatory genes and enhancement of autophagy.In vivo,seizure frequency decreased by 67%,synaptic structure was preserved,and astrogliosis was markedly alleviated.The findings demonstrate a dual regulatory mechanism in which RN@RTA suppresses neuroinflammatory signaling and restores neural homeostasis,offering a promising molecularly targeted approach for refractory epilepsy.
基金supported by the National Key Research and Development Program of China(No.2022YFC3702704)the National Natural Science Foundation of China(Nos.22376005,22076006 and 82073506).
文摘Microorganisms constitute an essential component in the indoor environment,which is closely related to hu-man health.However,there is limited evidence regarding the associations between indoor airborne microbiome and systemic inflammation,as well as whether this association is modified by indoor particulate matter and the underlying mechanisms.In this prospective repeated-measure study among 66 participants,indoor airborne mi-crobiome was characterized using amplicon sequencing and qPCR.Indoor fine particulate matter(PM_(2.5))and inhalable particulate matter(PM10)were measured.Systemic inflammatory biomarkers were assessed,including white blood cell(WBC),neutrophil(NEUT),monocyte,eosinophil counts,and their proportions.Targeted serum amino acid metabolomics were conducted to explore the underlying mechanisms.Linear mixed-effect models re-vealed that bacterial and fungal Simpson diversity were significantly associated with decreased WBC and NEUT.For example,for each interquartile range increase in the bacterial Simpson diversity,WBC and NEUT changed by-4.53%(95%CI:-8.25%,-0.66%)and-5.95%(95%CI:-11.3%,-0.27%),respectively.Notably,increased inflammatory risks of airborne microbial exposure were observed when indoor PM_(2.5) and PM10 levels were below the WHO air quality guidelines.Mediation analyses indicated that dopamine metabolism partially mediated the anti-inflammatory effects of fungal diversity exposure.Overall,our study indicated protection from a diverse indoor microbial environment on cardiovascular health and proposed an underlying mechanism through amino acid metabolism.Additionally,health risks associated with microbial exposure deserve more attention in con-texts of low indoor particulate matter pollution.Further research is necessary to fully disentangle the complex relationships between indoor microbiome,air pollutants,and human health.
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supported by the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior-Brasil(CAPES)[Finance Code 001](to MGS)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico(CNPq)fellowship[research grants 309840/2022-8]。
文摘Neuroinflammation is an inflammatory response in the central nervous system associated with various neurological conditions.The inflammatory process is typically treated with non-steroidal and steroidal anti-inflammatory drugs,which have a range of serious adverse effects.As an alternative,naturally derived molecules such as quercetin and its derivatives show promising anti-inflammatory properties and beneficial effects on various physiological functions.Our objective was to synthesize the evidence on the anti-inflammatory effect of quercetin and its derivatives in in vivo models,in the face of neuroinflammatory insults induced by lipopolysaccharide,through a systematic review and meta-analysis.A search of the preclinical literature was conducted across four databases(Pub Med,Web of Science,Scielo,and Google Scholar).Studies were selected based on inclusion and exclusion criteria,assessed for methodological quality using CAMARADES,and risk of bias using the SYRCLE tool,and data were extracted from the studies.The quantitative assessment of quercetin effects on the expression of pro-inflammatory cytokines and microgliosis was performed through a meta-analysis.A total of 384 potentially relevant articles were identified,of which 11 studies were included in the analysis.The methodological quality was assessed,resulting in an average score of 5.8/10,and the overall risk of bias analysis revealed a lack of methodological clarity in most studies.Furthermore,through the meta-analysis,it was observed that treatment with quercetin statistically reduces pro-inflammatory cytokines,such as tumor necrosis factor alpha,interleukin 6,interleukin 1β(n=89;SMD=–2.00;95%CI:–3.29 to–0.71),and microgliosis(n=33;SMD=–2.56;95%CI:–4.07 to–1.10).In terms of underlying mechanisms,quercetin and its derivatives exhibit antioxidant and anti-apoptotic properties,possibly through the nuclear factor erythroid 2-related factor 2(Nrf2)/HO-1 pathways,increasing the expression of antioxidant enzymes and reducing reactive species,and modulating the caspase pathway,increasing levels of anti-apoptotic proteins and decreasing proapoptotic proteins.Quercetin and its derivatives exhibit highly pleiotropic actions that simultaneously contribute to preventing neuroinflammation.However,despite promising results in animal models,future directions should focus on well-designed clinical studies to assess the safety,bioavailability,and efficacy of quercetin and its derivatives in humans.Additionally,standardization of methods and dosages in studies is crucial to ensure consistency of findings and optimize their application in clinical settings.
文摘Obesity is widely recognized as a global epidemic,primarily driven by an imbalance between energy expenditure and caloric intake associated with a sedentary lifestyle.Diets high in carbohydrates and saturated fats,particularly palmitic acid,are potent inducers of chronic low-grade inflammation,largely due to disruptions in glucose metabolism and the onset of insulin resistance(Qiu et al.,2022).While many organs are affected,the brain,specifically the hypothalamus,is among the first to exhibit inflammation in response to an unhealthy diet,suggesting that obesity may,in fact,be a brain-centered disease with neuroinflammation as a central factor(Thaler et al., 2012).
