This review aims to sum up how Non-coding RNAs(ncRNAs)regulate the development of periodontitis and provides a new perspective for understanding the pathogenesis of periodontitis.We explored the ncRNA's dual role ...This review aims to sum up how Non-coding RNAs(ncRNAs)regulate the development of periodontitis and provides a new perspective for understanding the pathogenesis of periodontitis.We explored the ncRNA's dual role in the development of periodontitis by summarizing evidence from previous in vivo and in vitro studies as well as clinical samples.In our review,the downregulation of 18 miRNAs,22 lncRNAs and 10 circRNAs demonstrates protective roles in periodontitis.In contrast,the expression of other 11 miRNAs,7 lncRNAs and 6 circRNAs are upregulated in periodontitis,which promote the progression of periodontitis.These dysregulated ncRNAs exert their protective or destructive roles by mainly influencing cell proliferation,differentiation and apoptosis via cross-talking with various molecules or signaling pathways.Our findings suggested which and how ncRNAs promote or delay the progression of periodontitis,which may greatly contribute to diagnose and therapy development of periodontitis based on ncRNAs in the future.展开更多
OBJECTIVE To explore the effect of icariside Ⅱ(ICS Ⅱ) on oxygen-glucose deprivation and reoxygenation(OGD/R)-induced injury in cerebral cortical neuronal cels.METHODS Primary cerebral cortical neuronal cells were de...OBJECTIVE To explore the effect of icariside Ⅱ(ICS Ⅱ) on oxygen-glucose deprivation and reoxygenation(OGD/R)-induced injury in cerebral cortical neuronal cels.METHODS Primary cerebral cortical neuronal cells were deprived of oxygen and glucose for 2 h to simulate ischemic stroke injury in vitro.The experiment was divided into 8 groups,which were control,control+ICSⅡ 25 μmol·L^(-1),OGD/R,OGD/R+ICSⅡ(6.25,12.5,25 μmol·L^(-1)),OGD/R+3-methyladenine(3-MA) and OGD/R+Rapamycin(Rap).The protective effect of ICS Ⅱ were detected by MTT assay and lactate dehydrogenase(LDH),respectively.Autophagic flux and autophagy related proteins expressions were detected by using adenovirus harboring tf-LC3 and Western blotting,respectively.RESULTS Compared with OGD/R group,the cell viability treated with ICSⅡwas elevated in a concentration-dependent manner,and the leakage rate of LDH was lowed.Moreover,ICSⅡ not only suppressed OGD/R-induced autophagic flux,but also inhibited the increase of LC3-Ⅱ/LC3-Ⅰ ratio and Beclin 1 after OGD/R insulted.CONCLUSION ICS Ⅱ exerts protective effects on OGD/R-induced cerebral cortical neuronal cells through inhibiting excessive autophagy.展开更多
Accurately assessing and tracking the progression of liver-specific injury remains a major challenge in the field of biomarker research.Here,we took a retrospective validation approach built on the mutuality between s...Accurately assessing and tracking the progression of liver-specific injury remains a major challenge in the field of biomarker research.Here,we took a retrospective validation approach built on the mutuality between serum and tissue biomarkers to characterize the liver-specific damage of bile duct cells caused by a-naphthyl isothiocyanate(ANIT).We found that carboxylesterase 1(CES1),as an intrahepatic marker,and dipeptidyl peptidase 4(DPP-IV),as an extrahepatic marker,can reflect the different pathophysiologies of liver injury.Levels of CES1 and DPP-IV can be used to identify liver damage itself and the inflammatory state,respectively.While the levels of the conventional serological biomarkers alkaline phosphatase(ALP),alanine aminotransferase(ALT),and aspartate aminotransferase(AST)were all concomitantly elevated in serum and tissues after ANIT-induced injury,the levels of bile acids decreased in bile,increased in serum,and ascended in intrahepatic tissue.Although the level of γ-glutamyl transpeptidase(γ-GT)changed in an opposite direction,the duration was much shorter than that of CES1 and was quickly restored to normal levels.Therefore,among the abovementioned biomarkers,only CES1 made it possible to specifically determine whether the liver cells were destroyed or damaged without interference from inflammation.CES1 also enabled accurate assessment of the anti-cholestasis effects of ursodeoxycholic acid(UDCA;single component)and Qing Fei Pai Du Decoction(QFPDD;multicomponent).We found that both QFPDD and UDCA attenuated ANIT-induced liver damage.UDCA was more potent in promoting bile excretion but showed relatively weaker anti-injury and antiinflammatory effects than QFPDD,whereas QFPDD was more effective in blocking liver inflammation and repairing liver damage.Our data highlights the potential of the combined use of CES1(as an intrahepatic marker of liver damage)and DPP-IV(as an extrahepatic marker of inflammation)for the accurate evaluation and tracking of liver-specific injury—an application that allows for the differentiation of liver damage and inflammatory liver injury.展开更多
Background:To explore active components of Lanbuzheng(Gei herba)and its underlying complex mechanism in treating blood deficiency induced by chemotherapy drug based on network pharmacology and mice experimental valida...Background:To explore active components of Lanbuzheng(Gei herba)and its underlying complex mechanism in treating blood deficiency induced by chemotherapy drug based on network pharmacology and mice experimental validation.Methods:Active components of Lanbuzheng(Gei herba)were screened by Lipinski’s rule of five.Targets acted with active components were predicted by PharmMapper database,and targets whose function associated with blood deficiency were screened by Therapeutic Target Database and UniProt.The networks of component-target and target-pathway were constructed by Cytoscape.The levels of peripheral blood and organ indexes were detected in the animal experiments.Results:One hundred and seventy-three components of Lanbuzheng(Gei herba)were collected,and 60 active components were screened according to the rule of five.According to the degree value of compounds,the top 5 compounds were docosyl trans ferulate,C32 decursin,agrimonolide 6-O-β-D-glucoside,degree=11,173-ethoxyphaeophorbide,and eugenol.Finally,59 targets associated with blood deficiency were obtained and the top 5 targets were MAPK14,TTR,CDK2,AKR1B1 and AR.Based on the interaction network of componenttarget and target-pathway,it’s found that 60 active components could act with 59 targets and 44 pathways for treating blood deficiency.And then,the mice experiments showed that Lanbuzheng(Gei herba)could enrich blood by increasing the levels of red blood cell,white blood cell,hemoglobin,red blood cell specific volume and platelet,and the indexes of liver,thymus and spleen,which validated the treating effect of Lanbuzheng(Gei herba).Conclusion:In this study,a network pharmacology approach and animal experiments were established to explore the nourishing blood effect of Lanbuzheng(Gei herba).The results demonstrated that Lanbuzheng(Gei herba)could improve blood deficiency and provide a theoretical basis for the further research on the in-depth mechanism of Lanbuzheng(Gei herba).展开更多
OBJECTIVE Oxidative sress is one of the key factor responsible for occurrence and development of hepatic fibrosis,a common consequence of chronic liver injury of multiple etiology.Nuclear factor erythroid 2-related fa...OBJECTIVE Oxidative sress is one of the key factor responsible for occurrence and development of hepatic fibrosis,a common consequence of chronic liver injury of multiple etiology.Nuclear factor erythroid 2-related factor 2(Nrf2)serves as a major regulator of a celular defense system against oxidative stress.Xiaochaihutang(XCHT),a compound of seven botanical extracts used for liver diseases traditionally in East Asia.However,few studies have investigated its anti-hepatic fibrosis effects and pathophysiological mechanism of action.The present study was designed to confirm the anti-hepatic fibrosis effects and explore its potential mechanism of action by investigating the intervention of Nrf2 pathway.METHODS Liver fibrosis was induced by repeated injection of Carbon tetrachloride(CCl4) over a period of 9 weeks.Starting from the 6 th week,the animals in treatment groups were given the appropriate dose of XCHT granules and silybin.Biochemical parameters,histological changes of the liver and alpha-smooth muscle actin(α-SMA) were determined.The expressions of Nrf2,Keap1,Nqo1,HO-1,Gclc and Gclm were assessed by RT-PCR and Western blot.RESULTS CCl4 caused a significant fibrosis damage in the rat liver and the liver functions and fibrosis degree were significantly improved by XCHT(5 g·kg^(-1) and 10 g·kg^(-1)).XCHT(5 g·kg^(-1) and 10 g·kg^(-1)) treatment significantly decreased the number of cells labeled with α-SMA antibodies.Moreover,XCHT(5 g·kg^(-1) and 10 g·kg^(-1))significantly increase Nqo1,HO-1,Gclc and Gclm expressions in the liver.CONCLUSION T hese studies establish XCHT is a potentially useful therapeutic agent for treatment of hepatic fibrosis and it might be via regulation of Nrf2 pathway in rats against oxidative stress,making further efforts to inhibiting the activated HSCs.Activation or up-regulation of Nrf2 pathway may be an alternative treatment strategy for liver fibrosis.展开更多
OBJECTIVE To investigate the protective effect of icariin(ICA) on lipopolysaccharide(LPS)-induced BV2 microglia injury,and to clarify the role of nuclear factor erythroid 2-related factor 2(Nrf2) signaling pathway in ...OBJECTIVE To investigate the protective effect of icariin(ICA) on lipopolysaccharide(LPS)-induced BV2 microglia injury,and to clarify the role of nuclear factor erythroid 2-related factor 2(Nrf2) signaling pathway in BV2 microglia-mediated neuroinflammation.METHODS BV2 microglia were randomly divided into control,ICA(0.1 μmol·L^(-1)),LPS(1 mg·L^(-1)),LPS + ICA(0.01 μmol·L^(-1)),and LPS + ICA(0.1 μmol·L^(-1))groups.BV2 microglia were treated with ICA for 30 min and then treated with LPS for 24 h.MTT assay was used to determine the cells survival rate,Griess kit and ELISA kits were used to detect the contents of NO,IL-1β and IL-18 in the culture supernatant,Western blotting was used to detect the expression of Nrf2,HO-1 and NQO1.Real time RT-PCR was used to detect the expression of Nrf2,HO-1 and NQO1 after ICA addition for 2,6 and 24 h.And immunofluorescence was used to observe the activation of Nrf2.RESULTS ICA reduced LPS-induced NO,IL-1β and IL-18 production in the culture supernatant,and ICA increase LPS-induced mRNA and protein expression of Nrf2 signaling pathway.CONCLUSION ICA protects LPS induced neuroinflammation by regulating Nrf2 signaling pathway.展开更多
OBJECTIVE To investigate the inhibitory effect and mechanism of sodium ferulate(SF)on myocardial hypertrophy in spontaneously hypertensive(SHR).METHODS Forty 14-week-old SHR male rats were randomly divided into model ...OBJECTIVE To investigate the inhibitory effect and mechanism of sodium ferulate(SF)on myocardial hypertrophy in spontaneously hypertensive(SHR).METHODS Forty 14-week-old SHR male rats were randomly divided into model group(SHR,receive distilled water)and SF treatment groups(SF 20,40 and 80 mg·kg^-1 per day,respectively).Age-matched male Wistar-Kyoto(WKY)rats gavaged with distilled water served as controls.After 12 weeks of treatment,the effects of SF on cardiac hypertrophy were evaluated using echocardiographic measurement,pathological analysis and the expression of atrial natriuretic peptide(ANP),myosin heavy chainβ(β-MHC)-a gene related to myocardial hypertrophy.In order to explore the mechanism of SF on myocardial hypertrophy,the calcium-sensing receptor(CaSR),calcineurin(CaN),nuclear factor of activated T cell 3(NFAT3),phosphorylation NFAT3(p-NFAT3),zinc finger transcription factor(GATA4),phosphorylation GATA4(p-GATA4),protein kinase Cβ(PKC-β),Raf-1,extracellular regulated protein kinase 1/2(ERK 1/2),phosphorylation ERK1/2(p-ERK 1/2)and mitogen-activated protein kinase phosphatase-1(MKP-1)were detected.RESULTS The myocardial hypertrophy parameters,myocardial cell cross section area,left ventricular wall thickness and expression of ANP and β-MHC,CaSR,CaN,NFAT3,p-GATA4,PKC-β,Raf-1,and p-ERK 1/2 were significantly increased,while the left ventricular cavity was significantly smaller,expression of p-NFAT3 and MKP-1 were significantly decreased,meanwhile,the ultra⁃structure of cardiomyocytes was significantly damaged in 26-week-old SHR rats.Notably,SF significantly ameliorated myocardial hyper⁃trophy in 26-week-old SHR rats;suppressed the overexpression of ANP,β-MHC,CaSR,CaN,NFAT3,p-GATA4,PKC-β,Raf-1,and p-ERK 1/2 and increased the expression of p-NFAT3 and MKP-1.CONCLUSION SF can inhibit cardiac hypertrophy in SHR rats,and the mechanism may be related to the inhibition of CaSR mediated signaling pathway.展开更多
Background:Cantharidin is a major active compound from Banmao(Mylabris).Cantharidin has obvious anticancer activity.However,its clinical application is limited due to serious hepatotoxicity.Methods:To evaluate the tox...Background:Cantharidin is a major active compound from Banmao(Mylabris).Cantharidin has obvious anticancer activity.However,its clinical application is limited due to serious hepatotoxicity.Methods:To evaluate the toxicity of human liver LO2 cells exposed to cantharidin by lipidomics.After exposing LO2 cells to different doses of cantharidin,the metabolites in LO2 cells were analyzed by nontargeted lipidomics based on liquid chromatography-mass spectrometry.Partial least-squares discriminant analysis and orthogonal partial least-squares discriminant analysis were used to screen differentially expressed metabolites,and then the main metabolic pathways were analyzed.Results:Pattern recognition analysis showed that the lipid metabolite profiles were changed significantly after cantharidin treatment,and 39 differential lipid metabolites were found.Additional analysis showed that these metabolites could mainly involve the metabolic pathways of triglyceride and acylcarnitine for cantharidin toxicity to LO2 cells.Conclusion:Cantharidin has obvious toxic effects on LO2 cells from the perspective of lipid metabolism.Moreover,the LO2 cytotoxicity induced by cantharidin is mainly related to the disorder of triglyceride and acylcarnitine metabolism.It can provide a scientific basis for cantharidin-induced hepatotoxicity.展开更多
The global spread of severe acute respiratory syndrome coronavirus 2 has resulted in a significant number of individuals developing pulmonary fibrosis(PF),an irreversible lung injury.This condition can manifest within...The global spread of severe acute respiratory syndrome coronavirus 2 has resulted in a significant number of individuals developing pulmonary fibrosis(PF),an irreversible lung injury.This condition can manifest within a short inter-val following the onset of pneumonia symptoms,sometimes even within a few days.While lung transplantation is a potentially lifesaving procedure,its limited availability,high costs,intricate surgeries,and risk of immunological rejection present significant drawbacks.The optimal timing of medication administration for coronavirus disease 2019(COVID-19)-induced PF remains controversial.Despite this,it is crucial to explore pharmacotherapy interventions,involving early and preventative treatment as well as pharmacotherapy options for advanced-stage PF.Additionally,studies have demonstrated disparities in anti-fibrotic treatment based on race and gender factors.Genetic mutations may also impact therapeutic efficacy.Enhancing research efforts on pharmacotherapy interventions,while considering relevant pharmacological factors and optimizing the timing and dosage of medication administration,will lead to enhanced,personalized,and fair treatment for individuals impacted by COVID-19-related PF.These measures are crucial in lessening the burden of the disease on healthcare systems and improving patients'quality of life.展开更多
β-Difluorinated alkyl halides are of significant value in the modular synthesis of gem-difluorinated molecules.An exclusive 1,2-halo migratory gem-difluorination of vinyl halides with in situ-generated PhIF_(2)·...β-Difluorinated alkyl halides are of significant value in the modular synthesis of gem-difluorinated molecules.An exclusive 1,2-halo migratory gem-difluorination of vinyl halides with in situ-generated PhIF_(2)·HF is described.This protocol provides a general and practical approach towards a wide variety ofβ-difluorinated alkyl bromides.Bothα-andβ-bromoalkyl alkenes are suitable substrates,leading to two distinct types of products.The extension of this protocol to vinyl chloride and iodide are also feasible.The synthetic versatility of this method has been highlighted by the late-stage modification of complex small molecules and further transformations of theβ-difluorinated alkyl halides to valuable CF_(2)-containing compounds.展开更多
Icariin,a major prenylated flavonoid found in Epimedium spp.,is a bioactive constituent of Herba Epimedii and has been shown to exert neuroprotective effects in experimental models of Alzheimer’s disease.In this stud...Icariin,a major prenylated flavonoid found in Epimedium spp.,is a bioactive constituent of Herba Epimedii and has been shown to exert neuroprotective effects in experimental models of Alzheimer’s disease.In this study,we investigated the neuroprotective mechanism of icariin in an APP/PS1/Tau triple-transgenic mouse model of Alzheimer’s disease.We performed behavioral tests,pathological examination,and western blot assay,and found that memory deficits of the model mice were obviously improved,neuronal and synaptic damage in the cerebral cortex was substantially mitigated,and amyloid-βaccumulation and tau hyperphosphorylation were considerably reduced after 5 months of intragastric administration of icariin at a dose of 60 mg/kg body weight per day.Furthermore,deficits of proteins in the insulin signaling pathway and their phosphorylation levels were significantly reversed,including the insulin receptor,insulin receptor substrate 1,phosphatidylinositol-3-kinase,protein kinase B,and glycogen synthase kinase 3β,and the levels of glucose transporter 1 and 3 were markedly increased.These findings suggest that icariin can improve learning and memory impairments in the mouse model of Alzheimer’s disease by regulating brain insulin signaling and glucose transporters,which lays the foundation for potential clinical application of icariin in the prevention and treatment of Alzheimer’s disease.展开更多
Adult hippocampal neurogenesis(AHN)facilitates hippocampal circuits plasticity and regulates hippocampus-dependent cognition and emotion.However,AHN malfunction has been widely reported in both human and animal models...Adult hippocampal neurogenesis(AHN)facilitates hippocampal circuits plasticity and regulates hippocampus-dependent cognition and emotion.However,AHN malfunction has been widely reported in both human and animal models of Alzheimer's disease(AD),the most common form of dementia in the elderly.Proneurogenic therapies including rescuing innate AHN,cell engraftment and glianeuron reprogramming hold great potential for compensating the neuronal loss and rewiring the degenerated neuronal network in AD,but there are still great challenges to be overcome.This review covers recent advances in unraveling the involvement of AHN in AD and highlights the prospect of emerging proneurogenic remedies.展开更多
OBJECTIVE To investigate the protective effect of icariin(ICA) on learning and memory function in APP/PS1/Tau triple transgenic Alzheimer disease mice(3×Tg-AD mice),and then to explore whether its mechanism is re...OBJECTIVE To investigate the protective effect of icariin(ICA) on learning and memory function in APP/PS1/Tau triple transgenic Alzheimer disease mice(3×Tg-AD mice),and then to explore whether its mechanism is related to the improvement of brain glucose metabolism disorder.METHODS Three-month-old male 3 ×Tg-AD mice were randomly divided into three groups(n=10):3×Tg group,3×Tg+ICA low-dose group(30 mg·kg-1) and 3×Tg + ICA high-dose group(60 mg·kg-1).Age-matched male wild type(WT) mice were randomly divided into two groups(n=10):WT control group and WT+ICA60 mg·kg-1 group.ICA in vehicle(0.5% Tween-80 in distilled water) was given orally once a day for five months in the 3×Tg+ICA groups.3×Tg and WT control group were given an equal volume vehicle.Morris water maze was used to detect the learning and memory function of mice.Brain glucose metabolism in 3×Tg mice was observed by 18 F-FDG microPET imaging technique.Nissl staining and HE staining were used to evaluate the survival neurons in hippocampus of mice.Glucose oxidase assay was used to detect glucose contents in cortex of mice.The protein expression of APP,Aβ1-40,Aβ1-42 and glucose transporter 1(GLUT1),and the phosphorylation level of tau protein at multiple sites in hippocampus were detected by Western blotting.RESULTS Behavioral examination revealed a profound decrease learning and memory function,accompanied by a decrease in number of neuronal cells in 3×Tg-AD mice.Moreover,the cerebral18 F-FDG uptake rate per gram tissue was reduced and the glucose contents in the cortex were increased in 3×Tg-AD mice.In addition,Western blotting analysis showed that the expression of APP,Aβ1-40,Aβ1-42 proteins and the levels of tau protein phosphorylation at Ser199/202 and PHF-1(Ser396/404) sites were increased significantly,followed by a decrease of GLUT1 expression in hippocampus of 3×Tg-AD mice.All of these changes in behavioral functions,neuronal loss and related protein expression were reversed when mice were treated with ICA.CONCLUSION ICA can improve the learning and memory ability of AD model mice,the mechanism may be related to the improvement of cerebral glucose metabolism dysfunction by increasing the expression of GLUT1.展开更多
OBJECTIVE Alzheimer disease(AD) is a progressive neurodegenerative disorder involving a gradual decline in many cognitive processes and in neurons.The endoplasmic reticulum(ER) is involved in several crucial cellular ...OBJECTIVE Alzheimer disease(AD) is a progressive neurodegenerative disorder involving a gradual decline in many cognitive processes and in neurons.The endoplasmic reticulum(ER) is involved in several crucial cellular functions,eg protein folding and quality control.Massive misfolded or unfolded proteins in ER can disturb the function of ER and induce ER stress,which results in neuronal death in AD.Icariin(ICA) has a wide range of neuro protection and has been researched in AD treatment.However,whether ICA has the effect on ER stress in AD condition,and how ICA affects ER stress remains stil unclear.Therefore,the current study aimed to investigate the mechanism of ICA against cognitive impairments in AD model through ER stress pathway and apoptosis.METHODS Twelve months male APP/PS1 or wild-type(WT)mice were randomly divided into four groups:APP/PS1,and APP/PS1+ICA,WT and WT+ICA groups.The treated mice were given ICA60 mg·kg-1 per day and control mice were received the same volume distilled water for consecutive 3 months.The Morris water maze and novel object recognition were used to detect animals′ behavior.Nissl staining was used to observe the neuronal morphology in hippocampus area.The protein and(or) phosphorylation level of GRP78,p-PERK,PERK,p-IRE1,IRE1,ATF6,p-e IF2α,eIF2α,ATF4,CHOP,the level of cleaved-casepase 3,Bax and Bcl-2 were examined by Western blotting.RESULTS The behavior performance testing by Morris water maze and novel object recognition deteriorated in APP/PS1 mice compared with WT mice,however,ICA significantly improved the behavior performance when compared with APP/PS1.The neuron impairments in APP/PS1 mice also were ameliorated after ICA treatment.The protein expression of GRP78,ATF4,CHOP,and the level of p-PERK and p-eI F2α were higher in APP/PS1 mice than that in WT mice.The Bax/Bcl-2 ratio elevation and caspase 3 activation have been found in APP/PS1 mice.After treated with ICA,those above-mentioned parameters were decreased compared with APP/PS1.However,the levels of IRE1,p-IRE1 and ATF6 were not change among other groups.CONCLUSION ICA may decrease the ER stress and apoptosis in AD model,and may be through inhibiting the PERK/eI F2α pathway,not IRE and ATF6 pathways.展开更多
OBJECTIVE To investigate the effect of icariin Ⅱ(ICS Ⅱ) on lipopolysaccharide(LPS)-induced inflammation and amyloid production in astrocytes.METHODS The cerebral cortex of newborn SD rats was isolated in vitro,and t...OBJECTIVE To investigate the effect of icariin Ⅱ(ICS Ⅱ) on lipopolysaccharide(LPS)-induced inflammation and amyloid production in astrocytes.METHODS The cerebral cortex of newborn SD rats was isolated in vitro,and the primary astrocytes were extracted and cultured.Astrocytes were pre-treated with ICSⅡ(5,10 and20 μmol·L^(-1)) or dexamethasone(1 μmol·L^(-1)) for1 h.Cell inflammation models were established with LPS and treated with ICS Ⅱ or dexamethasone for another 24 h.The anti-neuroinflammation and anti-amyloid effects of ICS Ⅱ in astrocytes were detected by ELISA and Western blotting respectively.RESULTS ICS Ⅱ decreased the levels of beta secretase 1(BACE1),Aβ1-40 and Aβ1-42 in astrocytes in a concentration-dependent manner.Moreover,the levels of tumor necrosis factor-alpha,interleukin-1β,reactive oxygen species,inducible nitric oxide synthase,cyclooxygenase-2 and transforming growth factor-β1 in astrocytes were significantly inhibited by ICS II(5,10 and 20 μmol·L^(-1)).In addition,ICSⅡhas a significant inhibitory effect on LPS-induced IκB-α degradation and NF-κB activation.CONCLUSION ICS Ⅱ exerts neuroprotective effects on LPS-induced inflammation in astrocytes,through regulating IKK/IκB/NF-κB signaling pathway.展开更多
Microglial cells are important resident innate immune components in the central nervous system that are often activated during neuroinflammation.Activated microglia can display one of two phenotypes,M1 or M2,which eac...Microglial cells are important resident innate immune components in the central nervous system that are often activated during neuroinflammation.Activated microglia can display one of two phenotypes,M1 or M2,which each play distinct roles in neuroinflammation.Rutin,a dietary flavonoid,exhibits protective effects against neuroinflammation.However,whether rutin is able to influence the M1/M2 polarization of microglia remains unclear.In this study,in vitro BV-2 cell models of neuroinflammation were established using 100 ng/mL lipopolysaccharide to investigate the effects of 1-hour rutin pretreatment on microglial polarization.The results revealed that rutin pretreatment reduced the expression of the proinflammatory cytokines tumor necrosis factor-α,interleukin-1β,and interleukin-6 and increased the secretion of interleukin-10.Rutin pretreatment also downregulated the expression of the M1 microglial markers CD86 and inducible nitric oxide synthase and upregulated the expression of the M2 microglial markers arginase 1 and CD206.Rutin pretreatment inhibited the expression of Toll-like receptor 4 and myeloid differentiation factor 88 and blocked the phosphorylation of I kappa B kinase and nuclear factor-kappa B.These results showed that rutin pretreatment may promote the phenotypic switch of microglia M1 to M2 by inhibiting the Toll-like receptor 4/nuclear factor-kappa B signaling pathway to alleviate lipopolysaccharide-induced neuroinflammation.展开更多
OBJECTIVE To explore the effects and mechanism of icariside Ⅱ(ICS Ⅱ),a pharmacologically active compound derived from herbal Epimedii with previous study-proved phosphodiesterase 5(PDE5) inhibitors,was investigated ...OBJECTIVE To explore the effects and mechanism of icariside Ⅱ(ICS Ⅱ),a pharmacologically active compound derived from herbal Epimedii with previous study-proved phosphodiesterase 5(PDE5) inhibitors,was investigated in vivo using a middle cerebral artery occlusion/reperfusion(MCAO/R) model in rats and in vitro using an oxygen-glucose deprivation/reperfusion(OGD/R) model in primary hippocampal neurons.METHODS Laser Doppler flowmeter was introduced to examine the cerebral blood flow of MCAO/R rats.The neurological deficits scores,brain water content and infarction volume were assessed after MCAO/R.OGD/R-induced primary hippocampal neuronal injury and apoptosis were examined by MTT,lactate dehydrogenase(LDH) release,TUNEL staining and flow cytometry,respectively.Expressions of PDE5 A and memory-related signaling pathways were measured using Western blotting analysis.The direct interaction between ICS Ⅱand PDE5 was further evaluated by molecular docking.RESULTS ICS Ⅱ significantly decreased the infraction volume in MCAO/R rats.Furthermore,ICS Ⅱ significantly abrogated OGD/R-induced hippocampal neuronal death.Moreover,ICSⅡ not only effectively restored the 3′ 5′-cyclic guanosine monophosphate(cGMP) level and protein kinase G(PKG) activity both in vivo and in vitro,but also increased brain-derived neurotrophic factor(BDNF),tyrosine protein kinase B(TrkB) and cAMP response element-binding protein(CREB) expressions,thereby inhibited hippocampal neuronal apoptosis.Mechanistically,the beneficial effects of ICS Ⅱ was attributed to its activation of the PKG/TrkB/BDNF via increasing BDNF expression,evidenced by that the inhibition effects of ICSⅡ was abrogated by Rp-8-BrcGMPS,a PKG inhibitor,or ANA-12,a TrkB inhibitor.ICSⅡ also decreased both protein level and activity of PDE5.Notably,ICSⅡ might effectively bind and inhibite PDE5 as demonstrated by relatively high binding score.CONCLUSION ICSⅡ significantly protect against cerebral ischemia/reperfusion injury in rats and rescues OGD/Rinduced hippocampal neuronal injury,and the underling mechanisms are,at least partly,due to inhibition of PDE5 and activation of BDNF/TrkB/CREB signaling pathway.Hence ICS Ⅱ may be an effective agent for combating cerebral ischemia/reperfusion injury.展开更多
OBJECTIVE To research the effect of naringenin(NAR) on LPS-induced dopaminergic neurons damage and its potential mechanism.METHODS Rats were randomly divided into the following six groups(n=10):control(0.9% NaCl),NAR ...OBJECTIVE To research the effect of naringenin(NAR) on LPS-induced dopaminergic neurons damage and its potential mechanism.METHODS Rats were randomly divided into the following six groups(n=10):control(0.9% NaCl),NAR alone(100 mg·kg-1),LPS(5 μg),LPS+NAR(50 mg·kg-1) and LPS+NAR(100 mg·kg-1).Rats were received a single LPS unilateral injection into the SN pars compacts,after seven daily intragastric administration of NAR,rats′ behavior was analyzed by rotarod test.Then,the expression of TH,IBA-1 and NLRP3 inflammasome were analyzed by Western blotting and immunofluorescence.In vitro experiments,BV-2 cel s were treated with different doses of NAR,and 1 h later,LPS(1 g·L^(-1)) was added to the medium for 24 h,then collect the culture medium and protein for later experiments.The production of IL-1β and IL-18 in culture medium were tested by ELISA,and the production of NO was detected by Griess reagent.The expression of IBA-1,NLRP3 and p-caspase 1 were detected by Western blotting.MN9 D cells were co-cultured with BV2 cells to mimic the animal experiments.MTT assay was used to analyzed the viability of MN9 D cells,and the expression of TH was detected by Western blotting.RESULTS NAR(100 mg · kg-1) could significantly improve the time of rats on the rotating(116.73 s vs 185.45 s,P<0.05).The result of the pathological analysis also suggested that NAR could decrease the activation of microglia as well as the expression of NLRP3 Inflammasome.In addition,NAR also could suppress the expression of pro-inflammatory factor levels,such as IL-1β(P<0.05),IL-18(P<0.05),and the protection of NAR could be inhibited by siR NA NLRP3.Moreover,an in vitro co-culture system with BV2 and MN9 D cells wasused to find the protection of NAR must via microglia,while there is no effect of NAR were directly added to MN9 D cells.CONCLUSION NAR protection of LPS-induced dopaminergic neurons damage might be through mediating NLRP3 inflammasome.展开更多
Objective:The present study was designed to investigate the effect of resveratrol (Res) on the motor function of Parkinson’s model rats induced by 6-hydroxydopamine (6-OHDA) and to explore its underlying mechanism. M...Objective:The present study was designed to investigate the effect of resveratrol (Res) on the motor function of Parkinson’s model rats induced by 6-hydroxydopamine (6-OHDA) and to explore its underlying mechanism. Methods:After a week of adaptive feeding,50 male Sprague-Dawley (SD) rats were randomly divided into fi ve groups:sham-operated group,normal group (Res,30 mg·kg-1),model group (6-OHDA,8 μg),6-OHDA+Res low-dose group (15 mg·kg-1,6-OHDA+Res high-dose group (30 mg·kg-1). 6-OHDA 8 μg (2 μg·μL-1) were injected into the substantia nigra of the rats to establish the model of dopaminergic neuronal damage,while the rats of sham group were injected with volume-matched saline with 0.2% Vitamin C.Rats were pretreated with Res for 1 day before 6-OHDA treatment. Model and sham groups were administered with volume-matched vehicle for 36 days.Rotarod test was applied to evaluate motor function of rats on 7 th,14 th and 21 th day after surgery,open fi eld experiment and grid-walking test applied on 33 th and 35 th day,respectively.Then the rats were sacrificed.Immunohistochemistry was used to detect the number of TH-positive cells in substantia nigra pars compacta (SNc);the protein expression of TH,Bax,Bcl-2,pro-caspase-3,active-caspase-3,p-PDK1 and p-Akt in midbrain were detected by Western blot. Results:The body weight,motor function,number of dopaminergic neurons in SNc and the protein expression of TH in midbrain of model group were significantly decreased compared with sham group;the protein of Akt phosphorylation levels were decreased while it showed no effect on PDK1,and the expression of apoptosis-related proteins Bax/Bcl-2,active-caspase-3 were significantly increased,pro-caspase-3 decreased. However,compared with model,the body weight,motor function,number of dopaminergic neurons in SNc and the protein expression of TH in midbrain of Res high-dose group were markedly increased;the protein of Akt phosphorylation levels were increased while it showed no effect on PDK1,the protein level of BDNF and TrkB were signifi cantly decreased and the expression of apoptosis-related proteins Bax/Bcl-2,active-caspase-3 were significantly decreased,and pro-caspase-3 were increased.展开更多
基金supported by Guizhou Provincial Science and Technology Foundation(Grant No.[2020]1Y292)Science and technology fund project of Guizhou Provincial Health Commission(NO:gzwkj2023-201)+1 种基金Doctor Startup Foundation of Zunyi Medical University(Grant No.[2017]5733-044)Zunyi Oral Disease Immune Prevention and Medical Biomaterials Research and Development Innovation Talent Team,Zunyi Science Talent[2022]No.1.
文摘This review aims to sum up how Non-coding RNAs(ncRNAs)regulate the development of periodontitis and provides a new perspective for understanding the pathogenesis of periodontitis.We explored the ncRNA's dual role in the development of periodontitis by summarizing evidence from previous in vivo and in vitro studies as well as clinical samples.In our review,the downregulation of 18 miRNAs,22 lncRNAs and 10 circRNAs demonstrates protective roles in periodontitis.In contrast,the expression of other 11 miRNAs,7 lncRNAs and 6 circRNAs are upregulated in periodontitis,which promote the progression of periodontitis.These dysregulated ncRNAs exert their protective or destructive roles by mainly influencing cell proliferation,differentiation and apoptosis via cross-talking with various molecules or signaling pathways.Our findings suggested which and how ncRNAs promote or delay the progression of periodontitis,which may greatly contribute to diagnose and therapy development of periodontitis based on ncRNAs in the future.
基金National Natural Science Foundation of China(81560666)Program for Changjiang Scholarsand Innovative Research Team in University, China(IRT_17R113).
文摘OBJECTIVE To explore the effect of icariside Ⅱ(ICS Ⅱ) on oxygen-glucose deprivation and reoxygenation(OGD/R)-induced injury in cerebral cortical neuronal cels.METHODS Primary cerebral cortical neuronal cells were deprived of oxygen and glucose for 2 h to simulate ischemic stroke injury in vitro.The experiment was divided into 8 groups,which were control,control+ICSⅡ 25 μmol·L^(-1),OGD/R,OGD/R+ICSⅡ(6.25,12.5,25 μmol·L^(-1)),OGD/R+3-methyladenine(3-MA) and OGD/R+Rapamycin(Rap).The protective effect of ICS Ⅱ were detected by MTT assay and lactate dehydrogenase(LDH),respectively.Autophagic flux and autophagy related proteins expressions were detected by using adenovirus harboring tf-LC3 and Western blotting,respectively.RESULTS Compared with OGD/R group,the cell viability treated with ICSⅡwas elevated in a concentration-dependent manner,and the leakage rate of LDH was lowed.Moreover,ICSⅡ not only suppressed OGD/R-induced autophagic flux,but also inhibited the increase of LC3-Ⅱ/LC3-Ⅰ ratio and Beclin 1 after OGD/R insulted.CONCLUSION ICS Ⅱ exerts protective effects on OGD/R-induced cerebral cortical neuronal cells through inhibiting excessive autophagy.
基金This article is supported by the National Key Research and Development Program of China(2017YFC1702000,2020YFC0845400,and 2021YFE0200900)National Natural Science Foundation of China(81773810,81922070,and 81973393).The authors would like to thank Peter for his help in publishing the article,and the support provided by Zhaoyan(Suzhou)New Drug Research Center Co,.Ltd.
文摘Accurately assessing and tracking the progression of liver-specific injury remains a major challenge in the field of biomarker research.Here,we took a retrospective validation approach built on the mutuality between serum and tissue biomarkers to characterize the liver-specific damage of bile duct cells caused by a-naphthyl isothiocyanate(ANIT).We found that carboxylesterase 1(CES1),as an intrahepatic marker,and dipeptidyl peptidase 4(DPP-IV),as an extrahepatic marker,can reflect the different pathophysiologies of liver injury.Levels of CES1 and DPP-IV can be used to identify liver damage itself and the inflammatory state,respectively.While the levels of the conventional serological biomarkers alkaline phosphatase(ALP),alanine aminotransferase(ALT),and aspartate aminotransferase(AST)were all concomitantly elevated in serum and tissues after ANIT-induced injury,the levels of bile acids decreased in bile,increased in serum,and ascended in intrahepatic tissue.Although the level of γ-glutamyl transpeptidase(γ-GT)changed in an opposite direction,the duration was much shorter than that of CES1 and was quickly restored to normal levels.Therefore,among the abovementioned biomarkers,only CES1 made it possible to specifically determine whether the liver cells were destroyed or damaged without interference from inflammation.CES1 also enabled accurate assessment of the anti-cholestasis effects of ursodeoxycholic acid(UDCA;single component)and Qing Fei Pai Du Decoction(QFPDD;multicomponent).We found that both QFPDD and UDCA attenuated ANIT-induced liver damage.UDCA was more potent in promoting bile excretion but showed relatively weaker anti-injury and antiinflammatory effects than QFPDD,whereas QFPDD was more effective in blocking liver inflammation and repairing liver damage.Our data highlights the potential of the combined use of CES1(as an intrahepatic marker of liver damage)and DPP-IV(as an extrahepatic marker of inflammation)for the accurate evaluation and tracking of liver-specific injury—an application that allows for the differentiation of liver damage and inflammatory liver injury.
基金This study was supported by the National Natural Science Foundation of China(No.81760746 and 81803838)Education Department of Guizhou Province of China(GNYL[2017]006)+3 种基金Provincial Department of Education youth talent support program(qiankehe KY[2017]078)Key project at central government level:The ability establishment of sustainable use for valuable Chinese medicine resources(2060302)Science and Technology Department of Zunyi City of Zuniyi City of Guizhou Province of China([2016]35,[2016]33)Innovation talent team of Guizhou science and Technology Department(qiankehe platform talents[2020]5007).
文摘Background:To explore active components of Lanbuzheng(Gei herba)and its underlying complex mechanism in treating blood deficiency induced by chemotherapy drug based on network pharmacology and mice experimental validation.Methods:Active components of Lanbuzheng(Gei herba)were screened by Lipinski’s rule of five.Targets acted with active components were predicted by PharmMapper database,and targets whose function associated with blood deficiency were screened by Therapeutic Target Database and UniProt.The networks of component-target and target-pathway were constructed by Cytoscape.The levels of peripheral blood and organ indexes were detected in the animal experiments.Results:One hundred and seventy-three components of Lanbuzheng(Gei herba)were collected,and 60 active components were screened according to the rule of five.According to the degree value of compounds,the top 5 compounds were docosyl trans ferulate,C32 decursin,agrimonolide 6-O-β-D-glucoside,degree=11,173-ethoxyphaeophorbide,and eugenol.Finally,59 targets associated with blood deficiency were obtained and the top 5 targets were MAPK14,TTR,CDK2,AKR1B1 and AR.Based on the interaction network of componenttarget and target-pathway,it’s found that 60 active components could act with 59 targets and 44 pathways for treating blood deficiency.And then,the mice experiments showed that Lanbuzheng(Gei herba)could enrich blood by increasing the levels of red blood cell,white blood cell,hemoglobin,red blood cell specific volume and platelet,and the indexes of liver,thymus and spleen,which validated the treating effect of Lanbuzheng(Gei herba).Conclusion:In this study,a network pharmacology approach and animal experiments were established to explore the nourishing blood effect of Lanbuzheng(Gei herba).The results demonstrated that Lanbuzheng(Gei herba)could improve blood deficiency and provide a theoretical basis for the further research on the in-depth mechanism of Lanbuzheng(Gei herba).
文摘OBJECTIVE Oxidative sress is one of the key factor responsible for occurrence and development of hepatic fibrosis,a common consequence of chronic liver injury of multiple etiology.Nuclear factor erythroid 2-related factor 2(Nrf2)serves as a major regulator of a celular defense system against oxidative stress.Xiaochaihutang(XCHT),a compound of seven botanical extracts used for liver diseases traditionally in East Asia.However,few studies have investigated its anti-hepatic fibrosis effects and pathophysiological mechanism of action.The present study was designed to confirm the anti-hepatic fibrosis effects and explore its potential mechanism of action by investigating the intervention of Nrf2 pathway.METHODS Liver fibrosis was induced by repeated injection of Carbon tetrachloride(CCl4) over a period of 9 weeks.Starting from the 6 th week,the animals in treatment groups were given the appropriate dose of XCHT granules and silybin.Biochemical parameters,histological changes of the liver and alpha-smooth muscle actin(α-SMA) were determined.The expressions of Nrf2,Keap1,Nqo1,HO-1,Gclc and Gclm were assessed by RT-PCR and Western blot.RESULTS CCl4 caused a significant fibrosis damage in the rat liver and the liver functions and fibrosis degree were significantly improved by XCHT(5 g·kg^(-1) and 10 g·kg^(-1)).XCHT(5 g·kg^(-1) and 10 g·kg^(-1)) treatment significantly decreased the number of cells labeled with α-SMA antibodies.Moreover,XCHT(5 g·kg^(-1) and 10 g·kg^(-1))significantly increase Nqo1,HO-1,Gclc and Gclm expressions in the liver.CONCLUSION T hese studies establish XCHT is a potentially useful therapeutic agent for treatment of hepatic fibrosis and it might be via regulation of Nrf2 pathway in rats against oxidative stress,making further efforts to inhibiting the activated HSCs.Activation or up-regulation of Nrf2 pathway may be an alternative treatment strategy for liver fibrosis.
基金National Natural Science Foundation of China(81760658).
文摘OBJECTIVE To investigate the protective effect of icariin(ICA) on lipopolysaccharide(LPS)-induced BV2 microglia injury,and to clarify the role of nuclear factor erythroid 2-related factor 2(Nrf2) signaling pathway in BV2 microglia-mediated neuroinflammation.METHODS BV2 microglia were randomly divided into control,ICA(0.1 μmol·L^(-1)),LPS(1 mg·L^(-1)),LPS + ICA(0.01 μmol·L^(-1)),and LPS + ICA(0.1 μmol·L^(-1))groups.BV2 microglia were treated with ICA for 30 min and then treated with LPS for 24 h.MTT assay was used to determine the cells survival rate,Griess kit and ELISA kits were used to detect the contents of NO,IL-1β and IL-18 in the culture supernatant,Western blotting was used to detect the expression of Nrf2,HO-1 and NQO1.Real time RT-PCR was used to detect the expression of Nrf2,HO-1 and NQO1 after ICA addition for 2,6 and 24 h.And immunofluorescence was used to observe the activation of Nrf2.RESULTS ICA reduced LPS-induced NO,IL-1β and IL-18 production in the culture supernatant,and ICA increase LPS-induced mRNA and protein expression of Nrf2 signaling pathway.CONCLUSION ICA protects LPS induced neuroinflammation by regulating Nrf2 signaling pathway.
基金National Natural Science Foundation of China(81860732)Scientific and Technological Projects for Social Development in Guizhou Province of China([2011]3036)the State Key Laboratory of Cardiovascular Disease(2017kf-03)
文摘OBJECTIVE To investigate the inhibitory effect and mechanism of sodium ferulate(SF)on myocardial hypertrophy in spontaneously hypertensive(SHR).METHODS Forty 14-week-old SHR male rats were randomly divided into model group(SHR,receive distilled water)and SF treatment groups(SF 20,40 and 80 mg·kg^-1 per day,respectively).Age-matched male Wistar-Kyoto(WKY)rats gavaged with distilled water served as controls.After 12 weeks of treatment,the effects of SF on cardiac hypertrophy were evaluated using echocardiographic measurement,pathological analysis and the expression of atrial natriuretic peptide(ANP),myosin heavy chainβ(β-MHC)-a gene related to myocardial hypertrophy.In order to explore the mechanism of SF on myocardial hypertrophy,the calcium-sensing receptor(CaSR),calcineurin(CaN),nuclear factor of activated T cell 3(NFAT3),phosphorylation NFAT3(p-NFAT3),zinc finger transcription factor(GATA4),phosphorylation GATA4(p-GATA4),protein kinase Cβ(PKC-β),Raf-1,extracellular regulated protein kinase 1/2(ERK 1/2),phosphorylation ERK1/2(p-ERK 1/2)and mitogen-activated protein kinase phosphatase-1(MKP-1)were detected.RESULTS The myocardial hypertrophy parameters,myocardial cell cross section area,left ventricular wall thickness and expression of ANP and β-MHC,CaSR,CaN,NFAT3,p-GATA4,PKC-β,Raf-1,and p-ERK 1/2 were significantly increased,while the left ventricular cavity was significantly smaller,expression of p-NFAT3 and MKP-1 were significantly decreased,meanwhile,the ultra⁃structure of cardiomyocytes was significantly damaged in 26-week-old SHR rats.Notably,SF significantly ameliorated myocardial hyper⁃trophy in 26-week-old SHR rats;suppressed the overexpression of ANP,β-MHC,CaSR,CaN,NFAT3,p-GATA4,PKC-β,Raf-1,and p-ERK 1/2 and increased the expression of p-NFAT3 and MKP-1.CONCLUSION SF can inhibit cardiac hypertrophy in SHR rats,and the mechanism may be related to the inhibition of CaSR mediated signaling pathway.
基金The National Natural Science Foundation of China(Grants no.81760746 and 81803838)Education Department of Guizhou Province of China(GNYL[2017]006)+1 种基金Provincial Department of Education youth talent support program(qiankehe KY[2017]078)Guizhou Provincial Science&Technology“125-Plan”Major Project([2015]039).
文摘Background:Cantharidin is a major active compound from Banmao(Mylabris).Cantharidin has obvious anticancer activity.However,its clinical application is limited due to serious hepatotoxicity.Methods:To evaluate the toxicity of human liver LO2 cells exposed to cantharidin by lipidomics.After exposing LO2 cells to different doses of cantharidin,the metabolites in LO2 cells were analyzed by nontargeted lipidomics based on liquid chromatography-mass spectrometry.Partial least-squares discriminant analysis and orthogonal partial least-squares discriminant analysis were used to screen differentially expressed metabolites,and then the main metabolic pathways were analyzed.Results:Pattern recognition analysis showed that the lipid metabolite profiles were changed significantly after cantharidin treatment,and 39 differential lipid metabolites were found.Additional analysis showed that these metabolites could mainly involve the metabolic pathways of triglyceride and acylcarnitine for cantharidin toxicity to LO2 cells.Conclusion:Cantharidin has obvious toxic effects on LO2 cells from the perspective of lipid metabolism.Moreover,the LO2 cytotoxicity induced by cantharidin is mainly related to the disorder of triglyceride and acylcarnitine metabolism.It can provide a scientific basis for cantharidin-induced hepatotoxicity.
基金Supported by the Project of Special Funds for Science and Technology Cooperation in Guizhou Provinces and Zunyi City,No.Shengshikehe(2015)53.
文摘The global spread of severe acute respiratory syndrome coronavirus 2 has resulted in a significant number of individuals developing pulmonary fibrosis(PF),an irreversible lung injury.This condition can manifest within a short inter-val following the onset of pneumonia symptoms,sometimes even within a few days.While lung transplantation is a potentially lifesaving procedure,its limited availability,high costs,intricate surgeries,and risk of immunological rejection present significant drawbacks.The optimal timing of medication administration for coronavirus disease 2019(COVID-19)-induced PF remains controversial.Despite this,it is crucial to explore pharmacotherapy interventions,involving early and preventative treatment as well as pharmacotherapy options for advanced-stage PF.Additionally,studies have demonstrated disparities in anti-fibrotic treatment based on race and gender factors.Genetic mutations may also impact therapeutic efficacy.Enhancing research efforts on pharmacotherapy interventions,while considering relevant pharmacological factors and optimizing the timing and dosage of medication administration,will lead to enhanced,personalized,and fair treatment for individuals impacted by COVID-19-related PF.These measures are crucial in lessening the burden of the disease on healthcare systems and improving patients'quality of life.
基金This work was supported by the National Natural Science Foundation of China(21961047,21901266,21971261,22022114).
文摘β-Difluorinated alkyl halides are of significant value in the modular synthesis of gem-difluorinated molecules.An exclusive 1,2-halo migratory gem-difluorination of vinyl halides with in situ-generated PhIF_(2)·HF is described.This protocol provides a general and practical approach towards a wide variety ofβ-difluorinated alkyl bromides.Bothα-andβ-bromoalkyl alkenes are suitable substrates,leading to two distinct types of products.The extension of this protocol to vinyl chloride and iodide are also feasible.The synthetic versatility of this method has been highlighted by the late-stage modification of complex small molecules and further transformations of theβ-difluorinated alkyl halides to valuable CF_(2)-containing compounds.
基金supported by the National Natural Science Foundation of China, Nos. 82060727 (to FJ), 81660599 (to FJ)the National Innovation Training Project for College Students, No. 201910661009 (to FJ)the Science and Technology Cooperation Project of Zunyi Science and Technology Bureau and Zunyi Medical University, No. (2019) 47 (to XLF)
文摘Icariin,a major prenylated flavonoid found in Epimedium spp.,is a bioactive constituent of Herba Epimedii and has been shown to exert neuroprotective effects in experimental models of Alzheimer’s disease.In this study,we investigated the neuroprotective mechanism of icariin in an APP/PS1/Tau triple-transgenic mouse model of Alzheimer’s disease.We performed behavioral tests,pathological examination,and western blot assay,and found that memory deficits of the model mice were obviously improved,neuronal and synaptic damage in the cerebral cortex was substantially mitigated,and amyloid-βaccumulation and tau hyperphosphorylation were considerably reduced after 5 months of intragastric administration of icariin at a dose of 60 mg/kg body weight per day.Furthermore,deficits of proteins in the insulin signaling pathway and their phosphorylation levels were significantly reversed,including the insulin receptor,insulin receptor substrate 1,phosphatidylinositol-3-kinase,protein kinase B,and glycogen synthase kinase 3β,and the levels of glucose transporter 1 and 3 were markedly increased.These findings suggest that icariin can improve learning and memory impairments in the mouse model of Alzheimer’s disease by regulating brain insulin signaling and glucose transporters,which lays the foundation for potential clinical application of icariin in the prevention and treatment of Alzheimer’s disease.
基金funded by Natural Science Foundation of China (81901107)The Science and Technology Program of Guizhou Province (Qiankehe zhicheng [2021] yiban 423)
文摘Adult hippocampal neurogenesis(AHN)facilitates hippocampal circuits plasticity and regulates hippocampus-dependent cognition and emotion.However,AHN malfunction has been widely reported in both human and animal models of Alzheimer's disease(AD),the most common form of dementia in the elderly.Proneurogenic therapies including rescuing innate AHN,cell engraftment and glianeuron reprogramming hold great potential for compensating the neuronal loss and rewiring the degenerated neuronal network in AD,but there are still great challenges to be overcome.This review covers recent advances in unraveling the involvement of AHN in AD and highlights the prospect of emerging proneurogenic remedies.
基金National Natural Science Foundation of China(81660599)Foundation of Zunyi Medical University (2013F-686+1 种基金2013F-738)Postgraduate Education Foundation of Guizhou Province(KYJJ2017008).
文摘OBJECTIVE To investigate the protective effect of icariin(ICA) on learning and memory function in APP/PS1/Tau triple transgenic Alzheimer disease mice(3×Tg-AD mice),and then to explore whether its mechanism is related to the improvement of brain glucose metabolism disorder.METHODS Three-month-old male 3 ×Tg-AD mice were randomly divided into three groups(n=10):3×Tg group,3×Tg+ICA low-dose group(30 mg·kg-1) and 3×Tg + ICA high-dose group(60 mg·kg-1).Age-matched male wild type(WT) mice were randomly divided into two groups(n=10):WT control group and WT+ICA60 mg·kg-1 group.ICA in vehicle(0.5% Tween-80 in distilled water) was given orally once a day for five months in the 3×Tg+ICA groups.3×Tg and WT control group were given an equal volume vehicle.Morris water maze was used to detect the learning and memory function of mice.Brain glucose metabolism in 3×Tg mice was observed by 18 F-FDG microPET imaging technique.Nissl staining and HE staining were used to evaluate the survival neurons in hippocampus of mice.Glucose oxidase assay was used to detect glucose contents in cortex of mice.The protein expression of APP,Aβ1-40,Aβ1-42 and glucose transporter 1(GLUT1),and the phosphorylation level of tau protein at multiple sites in hippocampus were detected by Western blotting.RESULTS Behavioral examination revealed a profound decrease learning and memory function,accompanied by a decrease in number of neuronal cells in 3×Tg-AD mice.Moreover,the cerebral18 F-FDG uptake rate per gram tissue was reduced and the glucose contents in the cortex were increased in 3×Tg-AD mice.In addition,Western blotting analysis showed that the expression of APP,Aβ1-40,Aβ1-42 proteins and the levels of tau protein phosphorylation at Ser199/202 and PHF-1(Ser396/404) sites were increased significantly,followed by a decrease of GLUT1 expression in hippocampus of 3×Tg-AD mice.All of these changes in behavioral functions,neuronal loss and related protein expression were reversed when mice were treated with ICA.CONCLUSION ICA can improve the learning and memory ability of AD model mice,the mechanism may be related to the improvement of cerebral glucose metabolism dysfunction by increasing the expression of GLUT1.
基金National Natural Science Foundation of China(81560594).
文摘OBJECTIVE Alzheimer disease(AD) is a progressive neurodegenerative disorder involving a gradual decline in many cognitive processes and in neurons.The endoplasmic reticulum(ER) is involved in several crucial cellular functions,eg protein folding and quality control.Massive misfolded or unfolded proteins in ER can disturb the function of ER and induce ER stress,which results in neuronal death in AD.Icariin(ICA) has a wide range of neuro protection and has been researched in AD treatment.However,whether ICA has the effect on ER stress in AD condition,and how ICA affects ER stress remains stil unclear.Therefore,the current study aimed to investigate the mechanism of ICA against cognitive impairments in AD model through ER stress pathway and apoptosis.METHODS Twelve months male APP/PS1 or wild-type(WT)mice were randomly divided into four groups:APP/PS1,and APP/PS1+ICA,WT and WT+ICA groups.The treated mice were given ICA60 mg·kg-1 per day and control mice were received the same volume distilled water for consecutive 3 months.The Morris water maze and novel object recognition were used to detect animals′ behavior.Nissl staining was used to observe the neuronal morphology in hippocampus area.The protein and(or) phosphorylation level of GRP78,p-PERK,PERK,p-IRE1,IRE1,ATF6,p-e IF2α,eIF2α,ATF4,CHOP,the level of cleaved-casepase 3,Bax and Bcl-2 were examined by Western blotting.RESULTS The behavior performance testing by Morris water maze and novel object recognition deteriorated in APP/PS1 mice compared with WT mice,however,ICA significantly improved the behavior performance when compared with APP/PS1.The neuron impairments in APP/PS1 mice also were ameliorated after ICA treatment.The protein expression of GRP78,ATF4,CHOP,and the level of p-PERK and p-eI F2α were higher in APP/PS1 mice than that in WT mice.The Bax/Bcl-2 ratio elevation and caspase 3 activation have been found in APP/PS1 mice.After treated with ICA,those above-mentioned parameters were decreased compared with APP/PS1.However,the levels of IRE1,p-IRE1 and ATF6 were not change among other groups.CONCLUSION ICA may decrease the ER stress and apoptosis in AD model,and may be through inhibiting the PERK/eI F2α pathway,not IRE and ATF6 pathways.
基金National Natural Science Foundation of China (81560585).
文摘OBJECTIVE To investigate the effect of icariin Ⅱ(ICS Ⅱ) on lipopolysaccharide(LPS)-induced inflammation and amyloid production in astrocytes.METHODS The cerebral cortex of newborn SD rats was isolated in vitro,and the primary astrocytes were extracted and cultured.Astrocytes were pre-treated with ICSⅡ(5,10 and20 μmol·L^(-1)) or dexamethasone(1 μmol·L^(-1)) for1 h.Cell inflammation models were established with LPS and treated with ICS Ⅱ or dexamethasone for another 24 h.The anti-neuroinflammation and anti-amyloid effects of ICS Ⅱ in astrocytes were detected by ELISA and Western blotting respectively.RESULTS ICS Ⅱ decreased the levels of beta secretase 1(BACE1),Aβ1-40 and Aβ1-42 in astrocytes in a concentration-dependent manner.Moreover,the levels of tumor necrosis factor-alpha,interleukin-1β,reactive oxygen species,inducible nitric oxide synthase,cyclooxygenase-2 and transforming growth factor-β1 in astrocytes were significantly inhibited by ICS II(5,10 and 20 μmol·L^(-1)).In addition,ICSⅡhas a significant inhibitory effect on LPS-induced IκB-α degradation and NF-κB activation.CONCLUSION ICS Ⅱ exerts neuroprotective effects on LPS-induced inflammation in astrocytes,through regulating IKK/IκB/NF-κB signaling pathway.
基金Funding： This study was funded by the National Natural Science Foundation of China （81260488 and 81560669）, KeyLab Construction Project of the Educational Department of Guizhou Province （Project No. Guizhou EducationCooperation KY[2014]212） , Science Inovative Talent Team for Medicinal Insect Research and Development in Zunyi（Zunyi shi ke he 2015-40） and Modernization of Traditional Chinese Medicine in Guizhou Province high-tech researchand development projects （Qian ke he ZY 2012-2009）.
基金This study was supported by the Natural Science and Technology Foundation of Zunyi City,China,No.201915(to GPL)Doctor Startup Foundation of Zunyi Medical University,Nos.[2017]5733-045(to GPL),[2017]5733-044(to YYH)Natural Science and Technology Foundation of Guizhou Province,China,No.[2020]1Y292(to YYH).
文摘Microglial cells are important resident innate immune components in the central nervous system that are often activated during neuroinflammation.Activated microglia can display one of two phenotypes,M1 or M2,which each play distinct roles in neuroinflammation.Rutin,a dietary flavonoid,exhibits protective effects against neuroinflammation.However,whether rutin is able to influence the M1/M2 polarization of microglia remains unclear.In this study,in vitro BV-2 cell models of neuroinflammation were established using 100 ng/mL lipopolysaccharide to investigate the effects of 1-hour rutin pretreatment on microglial polarization.The results revealed that rutin pretreatment reduced the expression of the proinflammatory cytokines tumor necrosis factor-α,interleukin-1β,and interleukin-6 and increased the secretion of interleukin-10.Rutin pretreatment also downregulated the expression of the M1 microglial markers CD86 and inducible nitric oxide synthase and upregulated the expression of the M2 microglial markers arginase 1 and CD206.Rutin pretreatment inhibited the expression of Toll-like receptor 4 and myeloid differentiation factor 88 and blocked the phosphorylation of I kappa B kinase and nuclear factor-kappa B.These results showed that rutin pretreatment may promote the phenotypic switch of microglia M1 to M2 by inhibiting the Toll-like receptor 4/nuclear factor-kappa B signaling pathway to alleviate lipopolysaccharide-induced neuroinflammation.
基金National Natural Science Foundation of China(81560585)Program for Excellent Young Talentsof Zunyi Medical University(15zy-002)+2 种基金Scienceand Technology Innovation Talent Team of GuizhouProvince(20154023)the hundred”Level of High—level Innovative Talents in Guizhou Province(QKHRCPT 20165684):Education Department of Guizhou Province of China[GNYL(2017)006,YLXKJS—YS一06]Program for Changjiang Scholars and lnnovative Research Team in University,China(IRT-17R113).
文摘OBJECTIVE To explore the effects and mechanism of icariside Ⅱ(ICS Ⅱ),a pharmacologically active compound derived from herbal Epimedii with previous study-proved phosphodiesterase 5(PDE5) inhibitors,was investigated in vivo using a middle cerebral artery occlusion/reperfusion(MCAO/R) model in rats and in vitro using an oxygen-glucose deprivation/reperfusion(OGD/R) model in primary hippocampal neurons.METHODS Laser Doppler flowmeter was introduced to examine the cerebral blood flow of MCAO/R rats.The neurological deficits scores,brain water content and infarction volume were assessed after MCAO/R.OGD/R-induced primary hippocampal neuronal injury and apoptosis were examined by MTT,lactate dehydrogenase(LDH) release,TUNEL staining and flow cytometry,respectively.Expressions of PDE5 A and memory-related signaling pathways were measured using Western blotting analysis.The direct interaction between ICS Ⅱand PDE5 was further evaluated by molecular docking.RESULTS ICS Ⅱ significantly decreased the infraction volume in MCAO/R rats.Furthermore,ICS Ⅱ significantly abrogated OGD/R-induced hippocampal neuronal death.Moreover,ICSⅡ not only effectively restored the 3′ 5′-cyclic guanosine monophosphate(cGMP) level and protein kinase G(PKG) activity both in vivo and in vitro,but also increased brain-derived neurotrophic factor(BDNF),tyrosine protein kinase B(TrkB) and cAMP response element-binding protein(CREB) expressions,thereby inhibited hippocampal neuronal apoptosis.Mechanistically,the beneficial effects of ICS Ⅱ was attributed to its activation of the PKG/TrkB/BDNF via increasing BDNF expression,evidenced by that the inhibition effects of ICSⅡ was abrogated by Rp-8-BrcGMPS,a PKG inhibitor,or ANA-12,a TrkB inhibitor.ICSⅡ also decreased both protein level and activity of PDE5.Notably,ICSⅡ might effectively bind and inhibite PDE5 as demonstrated by relatively high binding score.CONCLUSION ICSⅡ significantly protect against cerebral ischemia/reperfusion injury in rats and rescues OGD/Rinduced hippocampal neuronal injury,and the underling mechanisms are,at least partly,due to inhibition of PDE5 and activation of BDNF/TrkB/CREB signaling pathway.Hence ICS Ⅱ may be an effective agent for combating cerebral ischemia/reperfusion injury.
基金National Natural Science Foundation of China(8146055681760658).
文摘OBJECTIVE To research the effect of naringenin(NAR) on LPS-induced dopaminergic neurons damage and its potential mechanism.METHODS Rats were randomly divided into the following six groups(n=10):control(0.9% NaCl),NAR alone(100 mg·kg-1),LPS(5 μg),LPS+NAR(50 mg·kg-1) and LPS+NAR(100 mg·kg-1).Rats were received a single LPS unilateral injection into the SN pars compacts,after seven daily intragastric administration of NAR,rats′ behavior was analyzed by rotarod test.Then,the expression of TH,IBA-1 and NLRP3 inflammasome were analyzed by Western blotting and immunofluorescence.In vitro experiments,BV-2 cel s were treated with different doses of NAR,and 1 h later,LPS(1 g·L^(-1)) was added to the medium for 24 h,then collect the culture medium and protein for later experiments.The production of IL-1β and IL-18 in culture medium were tested by ELISA,and the production of NO was detected by Griess reagent.The expression of IBA-1,NLRP3 and p-caspase 1 were detected by Western blotting.MN9 D cells were co-cultured with BV2 cells to mimic the animal experiments.MTT assay was used to analyzed the viability of MN9 D cells,and the expression of TH was detected by Western blotting.RESULTS NAR(100 mg · kg-1) could significantly improve the time of rats on the rotating(116.73 s vs 185.45 s,P<0.05).The result of the pathological analysis also suggested that NAR could decrease the activation of microglia as well as the expression of NLRP3 Inflammasome.In addition,NAR also could suppress the expression of pro-inflammatory factor levels,such as IL-1β(P<0.05),IL-18(P<0.05),and the protection of NAR could be inhibited by siR NA NLRP3.Moreover,an in vitro co-culture system with BV2 and MN9 D cells wasused to find the protection of NAR must via microglia,while there is no effect of NAR were directly added to MN9 D cells.CONCLUSION NAR protection of LPS-induced dopaminergic neurons damage might be through mediating NLRP3 inflammasome.
文摘Objective:The present study was designed to investigate the effect of resveratrol (Res) on the motor function of Parkinson’s model rats induced by 6-hydroxydopamine (6-OHDA) and to explore its underlying mechanism. Methods:After a week of adaptive feeding,50 male Sprague-Dawley (SD) rats were randomly divided into fi ve groups:sham-operated group,normal group (Res,30 mg·kg-1),model group (6-OHDA,8 μg),6-OHDA+Res low-dose group (15 mg·kg-1,6-OHDA+Res high-dose group (30 mg·kg-1). 6-OHDA 8 μg (2 μg·μL-1) were injected into the substantia nigra of the rats to establish the model of dopaminergic neuronal damage,while the rats of sham group were injected with volume-matched saline with 0.2% Vitamin C.Rats were pretreated with Res for 1 day before 6-OHDA treatment. Model and sham groups were administered with volume-matched vehicle for 36 days.Rotarod test was applied to evaluate motor function of rats on 7 th,14 th and 21 th day after surgery,open fi eld experiment and grid-walking test applied on 33 th and 35 th day,respectively.Then the rats were sacrificed.Immunohistochemistry was used to detect the number of TH-positive cells in substantia nigra pars compacta (SNc);the protein expression of TH,Bax,Bcl-2,pro-caspase-3,active-caspase-3,p-PDK1 and p-Akt in midbrain were detected by Western blot. Results:The body weight,motor function,number of dopaminergic neurons in SNc and the protein expression of TH in midbrain of model group were significantly decreased compared with sham group;the protein of Akt phosphorylation levels were decreased while it showed no effect on PDK1,and the expression of apoptosis-related proteins Bax/Bcl-2,active-caspase-3 were significantly increased,pro-caspase-3 decreased. However,compared with model,the body weight,motor function,number of dopaminergic neurons in SNc and the protein expression of TH in midbrain of Res high-dose group were markedly increased;the protein of Akt phosphorylation levels were increased while it showed no effect on PDK1,the protein level of BDNF and TrkB were signifi cantly decreased and the expression of apoptosis-related proteins Bax/Bcl-2,active-caspase-3 were significantly decreased,and pro-caspase-3 were increased.
