Platelets are fragments of cytoplasm that are released from the mature megakaryocyte of the bone marrow.The main function of platelets is coagulation and hemostasis.Platelets play a central role in formation of pathol...Platelets are fragments of cytoplasm that are released from the mature megakaryocyte of the bone marrow.The main function of platelets is coagulation and hemostasis.Platelets play a central role in formation of pathological thrombosis.Many ischemic diseases are caused by excessive activa.tion of platelets,which can lead to thrombosis and death.Salvia miltiorrhiza Bunge,the dry roots and rhizomes of the Salvia miltiorrhiza plants,includes some water-soluble compounds,which play positive effects on diverse diseases such as neurodegenerative diseases,diabetic complications or cardiovas.cular diseases.In this paper,the components of the water-soluble in Salvia miltiorrhiza,as well as the applications in thrombotic diseases are summarized.The results show that water-soluble compounds include salvianolic acid A,salvianolic acid B,protocatechuic aldehyde,Danshensu,etc.The water-soluble compounds are applied to ischemic stroke,myocardial infarction and other diseases caused by thrombus.We also discussed the mechanisms of water-soluble compounds on the platelets based on our research results and the data obtained from references.The results indicate that water soluble compounds in Salvia miltiorrhiza play the antiplatelet and antithrombotic effects via different mechanisms,for example,salvianolic acid A inhibits platelet aggregation without promoting bleeding by increasing cAMP,inhibiting phosphoinositide 3-kinase(PI3K) and affecting GPCRs(G protein-coupled receptors) signaling path.ways;salvianolic acid B inhibit platelets as a P2Y12 antagonist and PDE inhibitor;Danshensu inhibits platelet activity may be related to inhibition of calcium influx.In conclusion,thrombotic diseases seriously affect human life and health.The existing antiplatelet drugs have some disadvantages.For example,aspirin may cause intracranial hemorrhage,and clopidogrel may play a slower role.Salvia miltiorrhiza as a traditional Chinese medicine has positive pharmacological activity and exerts antiplatelet aggrega.tion through different mechanisms.In the future,we will develop the new drugs which prevent and treat thrombotic diseases with the further study of the pharmacological effects and mechanisms of Salvia miltiorrhiza.展开更多
Parkinson disease(PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and deposition of cytosolic inclusions in surviving neurons(Lewy bodies),resulting in motor deficits and non-motor sym...Parkinson disease(PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and deposition of cytosolic inclusions in surviving neurons(Lewy bodies),resulting in motor deficits and non-motor symptoms.Although Levodopa remains the gold standard treatment for PD,side effects like dyskinesia followed by long-term use could notbe ignored.Consequently,there is a need for devel.opment new drugs.Baicalein is a flavonoid isolated from traditional Chinese herb,Scutellaria baicalensis Georgi.Our laboratory discovered that baicalein could effectively attenuate neurotoxicity of 6-hydroxydopamine(6-OHDA) and promote the differentiation of PC12 cells through high throughput drug screen.ing at the cellularlevel.In vivo studies have shown that baicalein exerts significant therapeutic effect,particularly in the attenuation of muscle tremor in 6-OHDA-lesioned rats.Based on the result from the so far acquired knowledge and previous findings from our laboratory,we could consider neuroprotec.tive mechanism of baicalein focus on the activities ofanti-oxidation and anti-inflammation.Baicalein could prevent oxidative stress and apoptosis through maintaining the mitochondrial function,inhibition of collapse of mitochondrial membrane potential,increase the activity of antioxidant enzymes and restraint of lipid peroxidation via several pathways such as Keap1/Nrf2/HO-1.Anti-inflammatory activity of baicalein exert by attenuating activation of astrocyte and microglia,as well as the production of cathepsin B and cytokines.Additionally,promoting the degradation of α-synuclein contributes to the neuroprotective effect of baicalein against Lewy bodies toxicity.Furthermore,baicalein also modulates the metabolic balance between glutamate(GLu) and gamma-aminobutyric acid(GABA).Overall,baica.lein could protect nervous systemby inhibiting oxidative damage and neuroinflammation caused by environmental and genetic factors.This article reviewed the developments of studies on pharmacody.namics and mechanism of baicalein in PD therapy and provideda reference for further exploration.展开更多
OBJECTIVE To investigate the effects of kaempferol(KAE)on chronic cerebral ischemia in rats.METHODS Chronic cerebral ischemia was induced in rats by permanent occlusion of bilateral common carotid arteries(2VO).Then,t...OBJECTIVE To investigate the effects of kaempferol(KAE)on chronic cerebral ischemia in rats.METHODS Chronic cerebral ischemia was induced in rats by permanent occlusion of bilateral common carotid arteries(2VO).Then,the rats with chronic cerebral ischemia were randomly divied into three groups:model group,KAE 10 and 30 mg·kg-1group.Another group rats without occlusion of common carotid arteries were used as the sham-operation group.Memory behavior was investigated by Morris water maze test.Prehensile ability was investigated by prehensile traction test.The structure of hippocampus and cortex neurons was observed with Nissel staining.In addition,the SOD activity and MDA content in brain tissue were determined.The DJ-1protein level was determined by Western blotting.RESULTS KAE 10 and 30 mg·kg-1could significantly improve cognitive impairment and prehensile traction ability(P<0.01)induced by chronic cerebral ischemia in rats.The results of the pathological analysis also suggested that KAE could ameliorate the pathological damage induced by chronic cerebral ischemia.In addition,KAE 30 mg·kg-1significantly increased the activity of SOD(P<0.05),but had no effect on the content of MDA in rat brain tissue.Western-blotting confirmed that KAE 10 and30 mg·kg-1could increase the expression of anti-oxidation proteins DJ-1 in hippocampus(P<0.01).CONCLUSION KAE may attenuate the chronic cerebral ischemic injury in rats.展开更多
Flavonoids are a large family of bioactive compounds widely found in foods and plants.Mang studies have proven the preventive and therapeutic effects of flavonoids in cardiovascular disease.Flavonoids has a wide range...Flavonoids are a large family of bioactive compounds widely found in foods and plants.Mang studies have proven the preventive and therapeutic effects of flavonoids in cardiovascular disease.Flavonoids has a wide range of pharmacological effects,including antioxidant,anti-inflammatory,vaso.dilation,avoiding the thrombus formation,improving endothelial function,modifying lipid levels and regulating blood lipids through different mechanisms of action.The cardiovascular protective mechanism of flavo.noids are the enzymes that inhibit the production of oxygen derived free radicals,inhibition of lipid peroxida.tion and inflammatory factor,down-regulation of epoxy synthase activity and the activation of AMPK and nuclear factor kappa B signaling pathway.In this review article we review and summarize the so far acquired knowledge of the most important mechanisms of action of flavonoids,to provide theoretical basis for the research and development of the active monomers in flavonoid and compound preparations.展开更多
OBJECTIVE To investigate the protective effect of salvianolic acid A(Sal A)on isoproterenol-induced myocardial infarction in mice and its possible mechanisms.METHODS The mice were subcutaneously injected with isopropr...OBJECTIVE To investigate the protective effect of salvianolic acid A(Sal A)on isoproterenol-induced myocardial infarction in mice and its possible mechanisms.METHODS The mice were subcutaneously injected with isopropranol(ISO 8mg·kg-1)to induce myocardial infarction and evaluated the myocardial protective effect of Sal A from mortality rate,electrocardiogram(ECG),heart function,myocardial infarction index,serum myocardial enzymes and explored its possible mechanisms from inflammatory,antioxidant and cells apoptosis.RESULTS Sal A can dose-dependently enhanced the heart function of myocardial infarction mice,reduced the heart index,inhibited the myocardial enzyme leakage,showed obvious myocardial protection effects.ELISA results showed that Sal A can reduce the expression of myocardial inflammatory cytokines such as IL-6,TNF-α.Western blotting confirmed that Sal A can increase the expression of anti-apoptotic proteins Bcl-2,reduce the expression of apoptosis protein Bax,and raise the phosphorylation level of PI3K and Akt.CONCLUSION Sal A have displayed significant protective effect against isoproterenol-induced myocardial infarction and its mechanism may be related to increasing of PI3K/Akt signal pathway and inhibition of cell apoptosis and inflammatory reaction.展开更多
OBJECTIVE To evaluate the effect of Guizhi Fuling Capsule active pharmaceutical ingredient(API)and its fractions on human breast cancer cells proliferation by high-throughput screening assay.METHODS The crude fraction...OBJECTIVE To evaluate the effect of Guizhi Fuling Capsule active pharmaceutical ingredient(API)and its fractions on human breast cancer cells proliferation by high-throughput screening assay.METHODS The crude fractions were obtained from the extraction and elution of the API of Guizhi Fuling Capsule,and 929 standard fractions were obtained by the optimal separation conditions.Sulforhodamine B(SRB)method was used to evaluate the effects of the Guizhi Fuling capsule API and929 kinds of fractions on the proliferation of human breast cancer cells MCF-7 and MDA-MB-231.RESULTS The Guizhi Fuling capsule API had a strong ability to inhibit the proliferation of MCF-7 cells at high concentration and the ability to inhibit MDA-MB-231 cells' proliferate at low concentration following 72 h treatment;some samples of 929 fractions(5μg·mL^(-1))was found to have a breast cancer cell growth inhibition rate above 50%,without toxicity on HUVECs proliferation.CONCLUSION The API of Guizhi Fuling capsule had significant cytotoxicity effects on these two human breast cancer cells,with significant concentration-and time-dependent manner.展开更多
OBJECTIVE Salvianolic acid A(SAA),a polyphenols acid,is a bioactive ingredient from a traditional Chinese medicine named Danshen(Salvia Miltiorrhiza Bunge).According to previous studies,it was shown to possess various...OBJECTIVE Salvianolic acid A(SAA),a polyphenols acid,is a bioactive ingredient from a traditional Chinese medicine named Danshen(Salvia Miltiorrhiza Bunge).According to previous studies,it was shown to possess various effects such as anti-oxidative stress,anti-diabetic complications and anti-pulmonary hypertension.This study is aimed to investigate the effect of SAA on pulmonary arterial endothelial-mesenchymal transition(endoMT)induced by hypoxia and the underlying mechanisms.METHODS Primary cultured human pulmonary arterial endothelial cells(HPAECs)were exposed to 1%O2 for 48 h with or without SAA treatment.RESULTS SAA treatment improved the morphology of HPAECs and inhibited the cytoskeleton remodeling and reduced migration distances.It was observed that the produc⁃tion of ROS in cells was significantly reduced by the treatment of SAA.Meanwhile,SAA alleviated the loss of CD31 and slightly inhibited the expression ofα-SMA.The mechanisms study shows that SAA treatment increased the phosphoryla⁃tion levels of Smad1/5,but inhibited that of Smad2/3.Furthermore,SAA attenuated the phosphorylation levels of ERK and Cofilin,which were enhanced by hypoxia.CONCLUSION SAA treatment can protect HPAECs from endoMT induced by hypoxia,which may perform via the downstream effectors of BMPRs or TGFβR including Smads,ERK and ROCK/cofilin pathways.展开更多
OBJECTIVE To explore whether J24924could prevent the development of pristane-induced lupus in a mouse model,and whether it could protect renal and lower the cardiovascular risk.METHODS The effect of J24924 was assesse...OBJECTIVE To explore whether J24924could prevent the development of pristane-induced lupus in a mouse model,and whether it could protect renal and lower the cardiovascular risk.METHODS The effect of J24924 was assessed in female BALB/c mice intraperitoneal injected with 0.5 m L of pristane,and serum autoantibodies were tested every month,blood pressure wasmeasured every 2 months,while serum inflammatory markers,spleen pathologic characteristics,renal injury and vascular function were observed at 6 month.RESULTS J24924 could decrease serum autoantibodies and serum inflammatory markers in the SLE mice and improved the spleen pathologic characteristics,and at the same time improved the renal injury and decreased inflammatory responses in kidneys,reduced blood pressure and improved vascular endothelial function.Western blotting assays revealed that inhibition for the activation of NF-κB and Rho/ROCKs signaling pathways and the downstream signaling molecules might be the potential mechanisms of J24924.CONCLUSION Our findings suggestthat therapy of J24924 may be a strategy to prevent SLE and ameliorate associated kidney and cardiovascular complications.展开更多
OBJECTIVE To evaluate the in vivo anti-inflammatory and allergic rhinitis(AR)alleviating effect as well as in vitro antimicrobial activities of Artemisia ordosica Krasch.(AOK)extracts to verify its ethno-medicinal cla...OBJECTIVE To evaluate the in vivo anti-inflammatory and allergic rhinitis(AR)alleviating effect as well as in vitro antimicrobial activities of Artemisia ordosica Krasch.(AOK)extracts to verify its ethno-medicinal claims.METHODS Crude extracts(methanol/95%-ethanol/ethyl acetate)of AOK root/stem/leaf and fractions(petroleum ether/ethyl acetate/n-butanol/aqueous)of AOK root extractwere prepared.Xylene-induced ear swelling model in mouse and ovalbumin(OVA)-induced AR model in guinea pig were established.Ear swelling degrees of mice were measured.The numbers of rubbing movement and sneezes of guinea pigs were counted to evaluate the symptoms of AR.The serum levels of histamine,INF-γ,IL-2/4/10,and VCAM-1 were measured by ELISA assay.The histological changes of nasal mucosa were investigated by light microscope after H&E staining.Antimicrobial activities of AOK extracts were also tested.LC-MS/MS analysis was performed to characterize the constituents of active extract and molecular docking was conducted to predict the biological mechanism.RESULTS In ear-swelling model,extract(100.00 mg·kg^-1)from the ethyl acetate layer of 95%ethanol(100.00 mg·kg^-1)showed better swelling inhibition in mice than positive control(dexamethasone,191.91 mg·kg^-1).In AR model,extract from the ethyl acetate layer of 95%ethanol significantly alleviated the AR symp⁃toms in guinea pigs,decreased the serum levels of histamine,INF-γ,IL-2/4/10,and VCAM-1,and reduced the infiltration of eosinophil in nasal mucosa.For Staphylococcus aureus,the ethyl acetate extract of AOK stem showed the highest inhibi⁃tion(MIC=1.25 g·L^-1),for Escherichia coli,n-butanol layer of 95%ethanol extract of AOK root showed the highest inhibi⁃tion(MIC=15.00 g·L^-1),for Candida glabrata,95%-ethanol extract of AOK stem showed the best inhibition(MIC=0.064 g·L^-1),while ethyl acetate and n-butanol layers showed similar inhibition on MRSA(MIC=7.50 g·L-1).LC-MS/MS characteriza⁃tion showed that dicaffeoylquinic acids account for more than 30%of ethyl acetate layer of AOK extract.Dicaffeoylquinic acids bind with histamine-1 receptor with high affinities and interesting modes.CONCLUSION Extracts from AOK had interesting anti-inflammatory activity in mice,alleviating effect against OVA-induced AR in guinea pigs,and antimicrobial activities in vitro,which support the ethno-medicinal use of it.The main constituents in ethyl acetate layer of AOK root extract are dicaffeoylquinic acids and could bind with histamine-1 receptor well.These findings highlighted the impor⁃tance of natural product chemistry study of AOK.展开更多
OBJECTIVE Vascular dementia(VD) refers to a progressive decline in memory and cognitive function caused by chronic cerebral ischemia.2-Vessels occlusion(2-VO) has been widely used as a model of VD.Xiao-Xu-Ming decocti...OBJECTIVE Vascular dementia(VD) refers to a progressive decline in memory and cognitive function caused by chronic cerebral ischemia.2-Vessels occlusion(2-VO) has been widely used as a model of VD.Xiao-Xu-Ming decoction,a well-known traditional Chinese medicine prescrip.tion,has been widely used to treat stroke and sequelae of stroke.The present study was to investigate the mechanism of Xiao-Xu-Ming decoction(XXM) against chronic cerebral ischemia injury in rats.METHODS After XXM treatment,rats were performed a memory testing with Morris water maze and motor ability testing using prehensile test and inclined screen test.Neuronal plasticity was observed by immunofluorescent staining with MAP2 antibody.Differentially expressed proteins of rat hippocampus were analyzed by Label-free quantitative proteomics.RESULTS XXM significantly alleviated 2-VOinduced learning and memory deficits,motor ability dysfunction,and neuronal plasticity injury in rats.The mechanism might be involved in up-regulation of 39 proteins and down-regulation of 13 proteins in the hippocampus of rats after XXM treatment vs 2-VO group rats.Gene ontology and pathway analysis showed that the regulated proteins are mainly involved in oxidation reduction process,intracellular signaling cascade process,and protein catabolic process,etc.The signal pathways are mainly involved in ubiquitin mediated proteolysis and phosphatidylinositol signaling system.CONCLUSION Current findings provide new insights into the molecular mechanisms of XXM on chronic cerebral ischemia.展开更多
OBJECTIVE To investigate the pharmacological effect and mechanism of Salvianolic acid A(SAA) on pulmonary vascular remodeling.METHODS In current study,we conducted a series of experiments to clarify the effect of SAA,...OBJECTIVE To investigate the pharmacological effect and mechanism of Salvianolic acid A(SAA) on pulmonary vascular remodeling.METHODS In current study,we conducted a series of experiments to clarify the effect of SAA,a kind of polyphenol compound,in the process of EndMT in human pulmonary arterial endothelial cells and in vivo therapeutic efficacy on vascular remodeling in monocrotaline(MCT)-induced EndMT.EndMT was also induced by TGF-β1 in human pulmonary arterial endothelial cells(HPAECs) in vitro.RESULTS SAA significantly attenuated EndMT,simul.taneously inhibited cell migration and reactive oxygen species(ROS) formation.In MCT-induced pulmonary arterial hypertension(PAH) model,SAA improved vascular function,decreased TGF-β1 level and inhib.ited inflammation.Mechanistically,SAA stimulated Nrf2 translocation and subsequent heme oxygen.ase-1(HO-1) up-regulation.The effect of SAA on EndMT in vitro was abolished by ZnPP,a HO-1 inhibitor.CONCLUSION This study indicates a deleterious impact of oxidative stress on EndMT.Polyphenol antioxidant treatment may provide an adjunctive action to alleviate pulmonary vascular remodeling via inhibiting EndMT.展开更多
OBJECTIVE To investigate the effects of total flavonoids of bugloss(TFB) on left ventricular(LV) remodeling after myocardial infarction(MI),LV size and function was compared in mice subjected to left anterior descendi...OBJECTIVE To investigate the effects of total flavonoids of bugloss(TFB) on left ventricular(LV) remodeling after myocardial infarction(MI),LV size and function was compared in mice subjected to left anterior descending coronary artery ligation.METHODS 28 d after MI,the infarcted fraction of the LV and LV mass,systolic and diastolic function were measured.Capillary density and myocyte width in the nonischemic portion of the LV were also determined.RESULTS 28 d after MI,both groups had dilated LVs with decreased fractional shortening and lower ejection fractions.Although the infarcted size of the LV was similar in both groups,LV end-diastolic internal diameter,end-diastolic volume,and mass were lower,but fractional shortening,ejection fraction,and the maximum rate of developed LV pressure(dp/dtmax) were greater in TFB treated mice than in control mice.Impairment of diastolic func.tion,as measured by the time constant of isovolumic relaxation(t) and the maximum rate of LV pres.sure decay(dp/dtmin),was more marked in control mice than in TFB treated mice.Mortality after MI was greater in control mice than in TFB treated mice.In control mice,capillary density and myocyte width in the nonischemic portion of the LV did not differ before and 28 days after MI,whereas in TFB treated mice,capillary density increased and myocyte width declined after MI.CONCLUSION These results suggest that the presence of TFB limits LV dysfunction and remodeling in a murine model of MI in part by decreasing myocyte hypertrophy in the remote myocardium.展开更多
OBJECTIVE To investigate the effects of ex-tract of Ramulus Cinnamom(RC)against LPS-induced inflammation in microglia.METHODS Activated microglia releases various pro-inflammatory cytokines to induce neuroinflammation...OBJECTIVE To investigate the effects of ex-tract of Ramulus Cinnamom(RC)against LPS-induced inflammation in microglia.METHODS Activated microglia releases various pro-inflammatory cytokines to induce neuroinflammation in stroke.Lipopolysaccaride(LPS)is an endotoxin from the outer membrane of Gram-negative bacteria that activates microglia.MTT assay was used to observe the cell viability.The content of NO in supernatant was measured by Griess reagent.The levels of IL-1β,IL-6 and TNF-αin supernatant were detected by ELISA kits.The intracellular COX-2,TLR4,and My D88expression was assayed by Western blotting.RESULTS RC extract 30 and 100μg·m L-1significantly decreased the production of related inflammatory factors such as NO(P<0.05,P<0.01),IL-1β(P<0.01,P<0.01),IL-6(P<0.05,P<0.01)and TNF-α(P<0.01,P<0.01).Furthermore,RC extract significantly inhibited the COX-2,TLR4,and My D88 expression induced by LPS in BV2cells.CONCLUSION RC extract may have therapeutic potential for the improvement of neuroinflammation,and the mechanism may be involved in down-regulation of TLR4/My D88 inflammation pathway.展开更多
OBJECTIVE Diabetic nephropathy(DN)has been one of the most common complications of diabetes and the leading cause of end-stage renal disease.Glomerular hyperfiltrationis central in earlystage of DN and leads to the pr...OBJECTIVE Diabetic nephropathy(DN)has been one of the most common complications of diabetes and the leading cause of end-stage renal disease.Glomerular hyperfiltrationis central in earlystage of DN and leads to the progression of renal architectonic and functional abnormalities.Salvianolic acid A(SalA)has been proved to protect diabetic complications such as hepatic fibrosis and neuropathy.The present study was designed to investigate the effects of SalA on glomerular endothelial dysfunctionand diabetic nephropathy.METHODS Primary glomerular endothelial cells were subjected to assess permeability under injury of advanced glycation end-products(AGEs).AGEs-induced changes of Rho A/ROCK pathway and cytoskeleton rearrangement were assessed bywestern blotandimmunofluorescence.The beneficial effects of SalA on diabetic nephropathy were investigated in a rat model induced by high-fat and high-glucose diet combined with low dose of streptozocin(35 mg·kg^(-1),ip).Renal function and architectonic changes were evaluated by biochemical assay and PAS staining.RESULTS SalA 3μMameliorated AGEs-induced glomerular endothelial permeability(P<0.05)and suppressed rearrangement of cytoskeleton through inhibiting AGE-RAGE-Rho A/ROCK pathway.SalA1 mg·kg^(-1)markedly reduced endothelium loss(P<0.01)and glomerular hyperfiltration(P<0.05)in diabetic kidney.Subsequently,SalA 1 mg·kg^(-1) suppressed glomerular hypertrophy and mesangial matrix expansion,eventually reduced 24 h-urinary albumin and ameliorated renal function by decreasing blood urine nitrogen(BUN),serum creatinine(Scr)and serum n-acetyl-β-d-glucosaminidase(NAG).AGEs-RAGE-Nox4-induced oxidative stress was suppressed by the treatment of SalA 1 mg·kg^(-1).CONCLUSION SalA ameliorated AGEs-induced glomerular endothelial hyperpermeability,and effectively protected against early-stage diabetic nephropathy by reducing hyperfiltration and alleviating renal structural deterioration through inhibiting AGEs and its downstream pathway.Thus,SalA might be a promising therapeutic agent for the treatment of diabetic nephropathy.展开更多
OBJECTIVE Here we investigated the effects and the underlying mechanism of Ginkgolide K(1,10-dihydroxy-3,14-didehydroginkgolide,GK)on cardiac ER stress.METHODS Cell death,apoptosis,and ER stressrelated signalling path...OBJECTIVE Here we investigated the effects and the underlying mechanism of Ginkgolide K(1,10-dihydroxy-3,14-didehydroginkgolide,GK)on cardiac ER stress.METHODS Cell death,apoptosis,and ER stressrelated signalling pathwayswere measuredin cultured neonatal rat cardiomyocytes(NRCMs),treated with the ER stress inducers tunicamycin,hydrogen peroxide,and thapsigargin.Acute myocardial infarction was established using left coronary artery occlusion in mice,and infarct size was measured by triphenyltetrazolium chloride(TTC)staining.Echocardiography was used to assess heart function and transmission electron microscopy for evaluating ER expansion.RESULTS GK significantly decreased ER stress-induced cell death in both in vitro and in vivomodels.In ischemic injured mice,GK treatment reduced infarct size,rescued heart dysfunction and ameliorated ER dilation.Mechanistic studies revealed that the beneficial effects of GK occur through enhancement of inositol-requiring enzyme 1α(IRE1α)/X box-binding protein-1(XBP1)activity,which in turn leads to increased ER-associated degradation(ERAD)-mediated clearance of misfolded proteins and autophagy.In addition,GK is also able to partially repress the pro-apoptotic action of regulated IRE1-dependent decay(RIDD)and JNK pathway.CONCLUSION GK acts through selective activation of the IRE1α/XBP1 pathway to limit ER stress injury.GK is revealed as a promising therapeutic agent to ameliorate ER stress for treating cardiovascular diseases.展开更多
OBJECTIVE The current therapeutic approaches have a limited effect on the dysregulated pulmonary vascular remodeling,which is characteristic of pulmonary arterial hypertension(PAH).In this study we exam-ined whether s...OBJECTIVE The current therapeutic approaches have a limited effect on the dysregulated pulmonary vascular remodeling,which is characteristic of pulmonary arterial hypertension(PAH).In this study we exam-ined whether salvianolic acid A(SAA)extracted from the traditional Chinese medicine′Dan Shen′attenuated vascular remodeling in a PAH rat model,and elucidated the underlying mechanisms.METHODS PAH was induced in rats by injecting a single dose of monocrotaline(MCT 60 mg·kg-1,sc).The rats were orally treated with either SAA(0.3,1,3 mg·kg-1·d-1)or a positive control bosentan(30 mg·kg-1·d-1)for 4 weeks.Echocardiography and hemodynamic measurements were performed on d 28.Then the hearts and lungs were harvested,the organ indices and pulmonary artery wall thickness were calculated,and biochemical and histochemical analysis were conducted.The levels of apoptotic and signaling proteins in the lungs were measured using immunoblotting.RESULTS Treatment with SAA or bosentan effectively ameliorated MCTinduced pulmonary artery remodeling,pulmonary hemodynamic abnormalities and the subsequent increases of right ventricular systolic pressure(RVSP).Furthermore,the treatments significantly attenuated MCT-induced hypertrophic damage of myocardium,parenchymal injury and collagen deposition in the lungs.Moreover,the treatments attenuated MCT-induced apoptosis and fibrosis in the lungs.The treatments partially restored MCT-induced reductions of bone morphogenetic protein typeⅡreceptor(BMPRⅡ)and phosphorylated Smad1/5 in the lungs.CONCLUSION SAA ameliorates the pulmonary arterial remodeling in MCT-induced PAH rats most likely via activating the BMPRⅡ-Smad pathway and inhibiting apoptosis.Thus,SAA may have therapeutic potential for the patients at high risk of PAH.展开更多
OBJECTIVE To investigate the protective effect of salvianolic acid A(Sal A)on isoproterenol-induced myocardial infarction in mice and its possible mechanisms.METHODS The mice were subcutaneously injected with isopropr...OBJECTIVE To investigate the protective effect of salvianolic acid A(Sal A)on isoproterenol-induced myocardial infarction in mice and its possible mechanisms.METHODS The mice were subcutaneously injected with isopropranol(ISO 8 mg·kg-1)to induce myocardial infarction and evaluated the myocardial protective effect of Sal A from mortality rate,electrocardiogram(ECG),heart function,myocardial infarction index,serum myocardial enzymes and explored its possible mechanisms from inflammatory,antioxidant and cells apoptosis.RESULTS Sal A can dose-dependently enhanced the heart function of myocardial infarction mice,reduced the heart index,inhibited the myocardial enzyme leakage,showed obvious myocardial protection effects.ELISA results showed that Sal A can reduce the expression of myocardial inflammatory cytokines such as IL-6,TNF-α.Western blotting confirmed that Sal A can increase the expression of anti-apoptotic proteins Bcl-2,reduce the expression of apoptosis protein Bax,and raise the phosphorylation level of PI3K and Akt.CONCLUSION Sal A have displayed significant protective effect against isoproterenol-induced myocardial infarction and its mechanism may be related to increasing of PI3K/Akt signal pathway and inhibition of cell apoptosis and inflammatory reaction.展开更多
OBJECTIVE Pulmonary artery hypertension(PAH)is a severe disease characterized by the mean pulmonary artery pressure exceeding 25 mm Hg at rest.PAH could induce right heart failure and has a very high mortality rate.At...OBJECTIVE Pulmonary artery hypertension(PAH)is a severe disease characterized by the mean pulmonary artery pressure exceeding 25 mm Hg at rest.PAH could induce right heart failure and has a very high mortality rate.At present,several kinds of drugs have been used in the treatment of PAH.However,most of these drugs aim to relax pulmonary arteries and do not inhibit the injury of vessels.In other words,the drugs available for PAH treatment do not improve the survival rate of PAH patients and cannot satisfy the needs in clinic.To discover and develop novel candidate compounds effective on the treatment of pulmonary artery injury and remodeling will be very important.Based on these background,the present study aimed to study the protective effect of two novel Rho-kinases(Rho-associated coiledcoil forming protein serine/threonine kinase,ROCK)inhibitors,DL0805 derivatives(DL0805-1and DL0805-2),on pulmonary arterial cells and further evaluate the underlying mechanisms and the possibility of DL0805 derivatives become therapeutic drugs for PAH.METHODS The primary cultured pulmonary arterial cells including human pulmonary artery endothelium cells(HPAECs)and human pulmonary artery smooth muscle cells(HPASMCs)were used in this study.HPAECs were injured under hypoxia environment(1%O2)and treated with or without DL0805 derivatives.After 48 h,the proliferation and oxidative stress were observed.CCK8 was used to detect cell viability.DCFH-DA was used as probe for reactive oxygen species(ROS)under fluorescence imaging system.HPASMCs was stimulated by growth factors including platelet-derived growth factor-BB(PDGF-BB)and Fetal Bovine Serum(FBS).The proliferation was observed in the cells treated with or without DL0805 derivatives.HPASMCs treated with or without DL0805 derivatives were further incubated with endothelin(ET-1),the proliferation and cytoskeleton remodeling of cells were detected by immunofluorescence assay.At last,Western blotting(WB)and immunofluorescence assay were employed to analysis the underlying mechanisms in the above experiments.RESULTS 10μmol·L-1DL0805-2 could inhibit the proliferation of HPAECs induced by hypoxia.Each concentration of DL0805-1 and DL0805-2attenuated the production of ROS in HPAECs.Results from WB indicated that DL0805 derivatives decreased the injury of HPAECs induced by hypoxia through the inhibition of the expression of Rho A and the activity of ROCK.On HPASMCs,DL0805 derivatives reduced the proliferation induced by PDGF-BB and FBS and inhibited cytoskeleton remodeling induced by ET-1.Immunofluorescence assay showed that DL0805 derivatives inhibited ROCK activity and down regulated the phosphorylation levels of ROCK substrates.CONCLUSION DL0805derivatives exhibited protective effect on pulmonary arterial cells including endothelium cells and smooth muscle cells.Among the above experiments,DL0805-2 showed stronger potency than DL0805-1.These two compounds might protect the cells through the inhibition of Rho A/ROCK pathway and they probably have the potential in the treatment of PAH and deserve further evaluation.展开更多
OBJECTIVE To investigate the effects of salvianolic acid A(SAA)in systemic lupus erythematosus(SLE)induced by pristane in BALB/c mice,this study was performed.METHODS Lupus mice were established by confirming elevated...OBJECTIVE To investigate the effects of salvianolic acid A(SAA)in systemic lupus erythematosus(SLE)induced by pristane in BALB/c mice,this study was performed.METHODS Lupus mice were established by confirming elevated levels of autoantibodies and IL-6 after intraperitoneal injection of pristane.Micewere then treated with daily oral doses of SAA for 5months in parallel with mice treated with prednisone and aspirin as positive controls.The levels of autoantibodies were monitored at monthly intervals and nephritic symptoms observed by hematoxylin and eosin(H&E)and periodic acid-Schiff(PAS)staining.Western blot analysis of renal tissue was also employed.RESULTS SAA treatment caused a significant reduction in the levels of anti-Sm autoantibodies and reduced renal histopathological changes and pathological effects.SAA treatment also significantly inhibited the phosphorylation of IKK,IκB and NFκB in renal tissues of lupus mice.CONCLUSION The results suggest that SAA alleviates renal injury in pristane-induced SLE in BALB/c mice through inhibition of phosphorylation of IKK,IκB and NFκB.展开更多
Curcumin is the principal curcuminoid of the rhizomes of Curcuma longa(turmeric,Jiang Huang),which has more than 6000 years of application history in India and other Asian countries.At present,curcumin is sold as an h...Curcumin is the principal curcuminoid of the rhizomes of Curcuma longa(turmeric,Jiang Huang),which has more than 6000 years of application history in India and other Asian countries.At present,curcumin is sold as an herbal supplement,cosmetics ingredient,food flavoring,and food coloring.In China curcumin is mainly used in food,while in western countries it has been regarded as a health care product and is contained in the British Pharmacopoeia(2017),United States Pharmacopeia(40)and European Pharmacopoeia(8.7th ed.).Curcumin has been proved to have multiple pharmacology effects including anti-fibrosis,anti-tumor,anti-inflammation effects and so on.As its broad biological activities,it is applicated in a lot of diseases such as hyperlipidemia,infection and cancer.Among them,the anti-cancer effect of curcumin is the most attractive.In the treatment of cancer and related diseases,curcumin has been tested in phase I and II clinical trials in several research centers across the world and has been approved by the U.S.FDA into the phase III clinical trial.It has been listed as the third generation of cancer chemoprevention agent by the U.S.National Cancer Institute.Curcumin has been proved to inhibit the proliferation of a variety of tumor cells through regulating a variety of tran.scription factors(NF-κB,AP-1,etc),mitogen-activated protein kinase(MAPK),growth factor receptor ki.nase(PDGFR,VEGFR,etc) and cyclooxygenase.It plays an important role in the cell cycle and further to inhibit proliferation.Curcumin can also inhibit the migration of tumor cells by activating caspase and in.ducing tumor cell apoptosis.However,curcumin still needs researches to confirm its effects and mecha.nisms and find its exact indications.There is still a long way to go to make curcumin better applied in clinical practice in the further.展开更多
基金supported by National Key R＆D Plan(2016YFC1000905)
文摘Platelets are fragments of cytoplasm that are released from the mature megakaryocyte of the bone marrow.The main function of platelets is coagulation and hemostasis.Platelets play a central role in formation of pathological thrombosis.Many ischemic diseases are caused by excessive activa.tion of platelets,which can lead to thrombosis and death.Salvia miltiorrhiza Bunge,the dry roots and rhizomes of the Salvia miltiorrhiza plants,includes some water-soluble compounds,which play positive effects on diverse diseases such as neurodegenerative diseases,diabetic complications or cardiovas.cular diseases.In this paper,the components of the water-soluble in Salvia miltiorrhiza,as well as the applications in thrombotic diseases are summarized.The results show that water-soluble compounds include salvianolic acid A,salvianolic acid B,protocatechuic aldehyde,Danshensu,etc.The water-soluble compounds are applied to ischemic stroke,myocardial infarction and other diseases caused by thrombus.We also discussed the mechanisms of water-soluble compounds on the platelets based on our research results and the data obtained from references.The results indicate that water soluble compounds in Salvia miltiorrhiza play the antiplatelet and antithrombotic effects via different mechanisms,for example,salvianolic acid A inhibits platelet aggregation without promoting bleeding by increasing cAMP,inhibiting phosphoinositide 3-kinase(PI3K) and affecting GPCRs(G protein-coupled receptors) signaling path.ways;salvianolic acid B inhibit platelets as a P2Y12 antagonist and PDE inhibitor;Danshensu inhibits platelet activity may be related to inhibition of calcium influx.In conclusion,thrombotic diseases seriously affect human life and health.The existing antiplatelet drugs have some disadvantages.For example,aspirin may cause intracranial hemorrhage,and clopidogrel may play a slower role.Salvia miltiorrhiza as a traditional Chinese medicine has positive pharmacological activity and exerts antiplatelet aggrega.tion through different mechanisms.In the future,we will develop the new drugs which prevent and treat thrombotic diseases with the further study of the pharmacological effects and mechanisms of Salvia miltiorrhiza.
基金supported by National Key R＆D Plan(2016YFC1000905)
文摘Parkinson disease(PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and deposition of cytosolic inclusions in surviving neurons(Lewy bodies),resulting in motor deficits and non-motor symptoms.Although Levodopa remains the gold standard treatment for PD,side effects like dyskinesia followed by long-term use could notbe ignored.Consequently,there is a need for devel.opment new drugs.Baicalein is a flavonoid isolated from traditional Chinese herb,Scutellaria baicalensis Georgi.Our laboratory discovered that baicalein could effectively attenuate neurotoxicity of 6-hydroxydopamine(6-OHDA) and promote the differentiation of PC12 cells through high throughput drug screen.ing at the cellularlevel.In vivo studies have shown that baicalein exerts significant therapeutic effect,particularly in the attenuation of muscle tremor in 6-OHDA-lesioned rats.Based on the result from the so far acquired knowledge and previous findings from our laboratory,we could consider neuroprotec.tive mechanism of baicalein focus on the activities ofanti-oxidation and anti-inflammation.Baicalein could prevent oxidative stress and apoptosis through maintaining the mitochondrial function,inhibition of collapse of mitochondrial membrane potential,increase the activity of antioxidant enzymes and restraint of lipid peroxidation via several pathways such as Keap1/Nrf2/HO-1.Anti-inflammatory activity of baicalein exert by attenuating activation of astrocyte and microglia,as well as the production of cathepsin B and cytokines.Additionally,promoting the degradation of α-synuclein contributes to the neuroprotective effect of baicalein against Lewy bodies toxicity.Furthermore,baicalein also modulates the metabolic balance between glutamate(GLu) and gamma-aminobutyric acid(GABA).Overall,baica.lein could protect nervous systemby inhibiting oxidative damage and neuroinflammation caused by environmental and genetic factors.This article reviewed the developments of studies on pharmacody.namics and mechanism of baicalein in PD therapy and provideda reference for further exploration.
基金The project supported by National Natural Science Foundation of China(81473383,81573645)
文摘OBJECTIVE To investigate the effects of kaempferol(KAE)on chronic cerebral ischemia in rats.METHODS Chronic cerebral ischemia was induced in rats by permanent occlusion of bilateral common carotid arteries(2VO).Then,the rats with chronic cerebral ischemia were randomly divied into three groups:model group,KAE 10 and 30 mg·kg-1group.Another group rats without occlusion of common carotid arteries were used as the sham-operation group.Memory behavior was investigated by Morris water maze test.Prehensile ability was investigated by prehensile traction test.The structure of hippocampus and cortex neurons was observed with Nissel staining.In addition,the SOD activity and MDA content in brain tissue were determined.The DJ-1protein level was determined by Western blotting.RESULTS KAE 10 and 30 mg·kg-1could significantly improve cognitive impairment and prehensile traction ability(P<0.01)induced by chronic cerebral ischemia in rats.The results of the pathological analysis also suggested that KAE could ameliorate the pathological damage induced by chronic cerebral ischemia.In addition,KAE 30 mg·kg-1significantly increased the activity of SOD(P<0.05),but had no effect on the content of MDA in rat brain tissue.Western-blotting confirmed that KAE 10 and30 mg·kg-1could increase the expression of anti-oxidation proteins DJ-1 in hippocampus(P<0.01).CONCLUSION KAE may attenuate the chronic cerebral ischemic injury in rats.
基金supported by National Natural Science Foundation of China(8177393581573645+1 种基金81603101) CAMS Innovation Fund for Medical Sciences(2017-I2M-1-010)
文摘Flavonoids are a large family of bioactive compounds widely found in foods and plants.Mang studies have proven the preventive and therapeutic effects of flavonoids in cardiovascular disease.Flavonoids has a wide range of pharmacological effects,including antioxidant,anti-inflammatory,vaso.dilation,avoiding the thrombus formation,improving endothelial function,modifying lipid levels and regulating blood lipids through different mechanisms of action.The cardiovascular protective mechanism of flavo.noids are the enzymes that inhibit the production of oxygen derived free radicals,inhibition of lipid peroxida.tion and inflammatory factor,down-regulation of epoxy synthase activity and the activation of AMPK and nuclear factor kappa B signaling pathway.In this review article we review and summarize the so far acquired knowledge of the most important mechanisms of action of flavonoids,to provide theoretical basis for the research and development of the active monomers in flavonoid and compound preparations.
基金The project supported by the national scientific&technological major special project″significant creation of new drugs″(2013ZX09103001-008,2012ZX09103101-078,2013ZX09508104)
文摘OBJECTIVE To investigate the protective effect of salvianolic acid A(Sal A)on isoproterenol-induced myocardial infarction in mice and its possible mechanisms.METHODS The mice were subcutaneously injected with isopropranol(ISO 8mg·kg-1)to induce myocardial infarction and evaluated the myocardial protective effect of Sal A from mortality rate,electrocardiogram(ECG),heart function,myocardial infarction index,serum myocardial enzymes and explored its possible mechanisms from inflammatory,antioxidant and cells apoptosis.RESULTS Sal A can dose-dependently enhanced the heart function of myocardial infarction mice,reduced the heart index,inhibited the myocardial enzyme leakage,showed obvious myocardial protection effects.ELISA results showed that Sal A can reduce the expression of myocardial inflammatory cytokines such as IL-6,TNF-α.Western blotting confirmed that Sal A can increase the expression of anti-apoptotic proteins Bcl-2,reduce the expression of apoptosis protein Bax,and raise the phosphorylation level of PI3K and Akt.CONCLUSION Sal A have displayed significant protective effect against isoproterenol-induced myocardial infarction and its mechanism may be related to increasing of PI3K/Akt signal pathway and inhibition of cell apoptosis and inflammatory reaction.
基金supported by National Science and Technology Major Projects of China(2013ZX09402203,2013ZX09508104)Medical and Health Science and Technology Innovation Engineering of Chinese Academy of Medical Sciences(2016-I2M-3-007)National Natural Science Foundation of China(81573454)
文摘OBJECTIVE To evaluate the effect of Guizhi Fuling Capsule active pharmaceutical ingredient(API)and its fractions on human breast cancer cells proliferation by high-throughput screening assay.METHODS The crude fractions were obtained from the extraction and elution of the API of Guizhi Fuling Capsule,and 929 standard fractions were obtained by the optimal separation conditions.Sulforhodamine B(SRB)method was used to evaluate the effects of the Guizhi Fuling capsule API and929 kinds of fractions on the proliferation of human breast cancer cells MCF-7 and MDA-MB-231.RESULTS The Guizhi Fuling capsule API had a strong ability to inhibit the proliferation of MCF-7 cells at high concentration and the ability to inhibit MDA-MB-231 cells' proliferate at low concentration following 72 h treatment;some samples of 929 fractions(5μg·mL^(-1))was found to have a breast cancer cell growth inhibition rate above 50%,without toxicity on HUVECs proliferation.CONCLUSION The API of Guizhi Fuling capsule had significant cytotoxicity effects on these two human breast cancer cells,with significant concentration-and time-dependent manner.
基金CAMS Innovation Fund for Medical Sciences(2017-I2M-1-010)National Natural Science Foundation of China(81773935+1 种基金8157364581603101)
文摘OBJECTIVE Salvianolic acid A(SAA),a polyphenols acid,is a bioactive ingredient from a traditional Chinese medicine named Danshen(Salvia Miltiorrhiza Bunge).According to previous studies,it was shown to possess various effects such as anti-oxidative stress,anti-diabetic complications and anti-pulmonary hypertension.This study is aimed to investigate the effect of SAA on pulmonary arterial endothelial-mesenchymal transition(endoMT)induced by hypoxia and the underlying mechanisms.METHODS Primary cultured human pulmonary arterial endothelial cells(HPAECs)were exposed to 1%O2 for 48 h with or without SAA treatment.RESULTS SAA treatment improved the morphology of HPAECs and inhibited the cytoskeleton remodeling and reduced migration distances.It was observed that the produc⁃tion of ROS in cells was significantly reduced by the treatment of SAA.Meanwhile,SAA alleviated the loss of CD31 and slightly inhibited the expression ofα-SMA.The mechanisms study shows that SAA treatment increased the phosphoryla⁃tion levels of Smad1/5,but inhibited that of Smad2/3.Furthermore,SAA attenuated the phosphorylation levels of ERK and Cofilin,which were enhanced by hypoxia.CONCLUSION SAA treatment can protect HPAECs from endoMT induced by hypoxia,which may perform via the downstream effectors of BMPRs or TGFβR including Smads,ERK and ROCK/cofilin pathways.
基金The project supported by National Science and Technology Major Project(2013ZX09103001-008,2013ZX09402203)the National Natural Science Foundation of China(81573645)
文摘OBJECTIVE To explore whether J24924could prevent the development of pristane-induced lupus in a mouse model,and whether it could protect renal and lower the cardiovascular risk.METHODS The effect of J24924 was assessed in female BALB/c mice intraperitoneal injected with 0.5 m L of pristane,and serum autoantibodies were tested every month,blood pressure wasmeasured every 2 months,while serum inflammatory markers,spleen pathologic characteristics,renal injury and vascular function were observed at 6 month.RESULTS J24924 could decrease serum autoantibodies and serum inflammatory markers in the SLE mice and improved the spleen pathologic characteristics,and at the same time improved the renal injury and decreased inflammatory responses in kidneys,reduced blood pressure and improved vascular endothelial function.Western blotting assays revealed that inhibition for the activation of NF-κB and Rho/ROCKs signaling pathways and the downstream signaling molecules might be the potential mechanisms of J24924.CONCLUSION Our findings suggestthat therapy of J24924 may be a strategy to prevent SLE and ameliorate associated kidney and cardiovascular complications.
基金Science Foundation of Inner Mongolia(2017MS0870)Science and Technology Planning Project of Inner Mongolia(201702139)
文摘OBJECTIVE To evaluate the in vivo anti-inflammatory and allergic rhinitis(AR)alleviating effect as well as in vitro antimicrobial activities of Artemisia ordosica Krasch.(AOK)extracts to verify its ethno-medicinal claims.METHODS Crude extracts(methanol/95%-ethanol/ethyl acetate)of AOK root/stem/leaf and fractions(petroleum ether/ethyl acetate/n-butanol/aqueous)of AOK root extractwere prepared.Xylene-induced ear swelling model in mouse and ovalbumin(OVA)-induced AR model in guinea pig were established.Ear swelling degrees of mice were measured.The numbers of rubbing movement and sneezes of guinea pigs were counted to evaluate the symptoms of AR.The serum levels of histamine,INF-γ,IL-2/4/10,and VCAM-1 were measured by ELISA assay.The histological changes of nasal mucosa were investigated by light microscope after H&E staining.Antimicrobial activities of AOK extracts were also tested.LC-MS/MS analysis was performed to characterize the constituents of active extract and molecular docking was conducted to predict the biological mechanism.RESULTS In ear-swelling model,extract(100.00 mg·kg^-1)from the ethyl acetate layer of 95%ethanol(100.00 mg·kg^-1)showed better swelling inhibition in mice than positive control(dexamethasone,191.91 mg·kg^-1).In AR model,extract from the ethyl acetate layer of 95%ethanol significantly alleviated the AR symp⁃toms in guinea pigs,decreased the serum levels of histamine,INF-γ,IL-2/4/10,and VCAM-1,and reduced the infiltration of eosinophil in nasal mucosa.For Staphylococcus aureus,the ethyl acetate extract of AOK stem showed the highest inhibi⁃tion(MIC=1.25 g·L^-1),for Escherichia coli,n-butanol layer of 95%ethanol extract of AOK root showed the highest inhibi⁃tion(MIC=15.00 g·L^-1),for Candida glabrata,95%-ethanol extract of AOK stem showed the best inhibition(MIC=0.064 g·L^-1),while ethyl acetate and n-butanol layers showed similar inhibition on MRSA(MIC=7.50 g·L-1).LC-MS/MS characteriza⁃tion showed that dicaffeoylquinic acids account for more than 30%of ethyl acetate layer of AOK extract.Dicaffeoylquinic acids bind with histamine-1 receptor with high affinities and interesting modes.CONCLUSION Extracts from AOK had interesting anti-inflammatory activity in mice,alleviating effect against OVA-induced AR in guinea pigs,and antimicrobial activities in vitro,which support the ethno-medicinal use of it.The main constituents in ethyl acetate layer of AOK root extract are dicaffeoylquinic acids and could bind with histamine-1 receptor well.These findings highlighted the impor⁃tance of natural product chemistry study of AOK.
基金supported by National Natural Science Foundation of China(81473383) National Science and Technology Major Project of China(2018ZX09711001-003-019)+1 种基金 CAMS Innovation Fund for Medical Sciences(2016-I2M-3-007) Innovation Fund for Graduate of Beijing Union M
文摘OBJECTIVE Vascular dementia(VD) refers to a progressive decline in memory and cognitive function caused by chronic cerebral ischemia.2-Vessels occlusion(2-VO) has been widely used as a model of VD.Xiao-Xu-Ming decoction,a well-known traditional Chinese medicine prescrip.tion,has been widely used to treat stroke and sequelae of stroke.The present study was to investigate the mechanism of Xiao-Xu-Ming decoction(XXM) against chronic cerebral ischemia injury in rats.METHODS After XXM treatment,rats were performed a memory testing with Morris water maze and motor ability testing using prehensile test and inclined screen test.Neuronal plasticity was observed by immunofluorescent staining with MAP2 antibody.Differentially expressed proteins of rat hippocampus were analyzed by Label-free quantitative proteomics.RESULTS XXM significantly alleviated 2-VOinduced learning and memory deficits,motor ability dysfunction,and neuronal plasticity injury in rats.The mechanism might be involved in up-regulation of 39 proteins and down-regulation of 13 proteins in the hippocampus of rats after XXM treatment vs 2-VO group rats.Gene ontology and pathway analysis showed that the regulated proteins are mainly involved in oxidation reduction process,intracellular signaling cascade process,and protein catabolic process,etc.The signal pathways are mainly involved in ubiquitin mediated proteolysis and phosphatidylinositol signaling system.CONCLUSION Current findings provide new insights into the molecular mechanisms of XXM on chronic cerebral ischemia.
基金supported by National Natural Science Foundation of China(8177393581573645+2 种基金81603101) Natural Science Foundation of Beijing(7174322) CAMS Innovation Fund for Medical Sciences(2017-I2M-1-010)
文摘OBJECTIVE To investigate the pharmacological effect and mechanism of Salvianolic acid A(SAA) on pulmonary vascular remodeling.METHODS In current study,we conducted a series of experiments to clarify the effect of SAA,a kind of polyphenol compound,in the process of EndMT in human pulmonary arterial endothelial cells and in vivo therapeutic efficacy on vascular remodeling in monocrotaline(MCT)-induced EndMT.EndMT was also induced by TGF-β1 in human pulmonary arterial endothelial cells(HPAECs) in vitro.RESULTS SAA significantly attenuated EndMT,simul.taneously inhibited cell migration and reactive oxygen species(ROS) formation.In MCT-induced pulmonary arterial hypertension(PAH) model,SAA improved vascular function,decreased TGF-β1 level and inhib.ited inflammation.Mechanistically,SAA stimulated Nrf2 translocation and subsequent heme oxygen.ase-1(HO-1) up-regulation.The effect of SAA on EndMT in vitro was abolished by ZnPP,a HO-1 inhibitor.CONCLUSION This study indicates a deleterious impact of oxidative stress on EndMT.Polyphenol antioxidant treatment may provide an adjunctive action to alleviate pulmonary vascular remodeling via inhibiting EndMT.
基金supported by National Natural Science Foundation of China (8167342 81573645) and CAMS Innovation Fund for Medical Sciences (2016-12M-3-007)
文摘OBJECTIVE To investigate the effects of total flavonoids of bugloss(TFB) on left ventricular(LV) remodeling after myocardial infarction(MI),LV size and function was compared in mice subjected to left anterior descending coronary artery ligation.METHODS 28 d after MI,the infarcted fraction of the LV and LV mass,systolic and diastolic function were measured.Capillary density and myocyte width in the nonischemic portion of the LV were also determined.RESULTS 28 d after MI,both groups had dilated LVs with decreased fractional shortening and lower ejection fractions.Although the infarcted size of the LV was similar in both groups,LV end-diastolic internal diameter,end-diastolic volume,and mass were lower,but fractional shortening,ejection fraction,and the maximum rate of developed LV pressure(dp/dtmax) were greater in TFB treated mice than in control mice.Impairment of diastolic func.tion,as measured by the time constant of isovolumic relaxation(t) and the maximum rate of LV pres.sure decay(dp/dtmin),was more marked in control mice than in TFB treated mice.Mortality after MI was greater in control mice than in TFB treated mice.In control mice,capillary density and myocyte width in the nonischemic portion of the LV did not differ before and 28 days after MI,whereas in TFB treated mice,capillary density increased and myocyte width declined after MI.CONCLUSION These results suggest that the presence of TFB limits LV dysfunction and remodeling in a murine model of MI in part by decreasing myocyte hypertrophy in the remote myocardium.
基金The project supported by National Natural Science Foundation of China(81473383,81573645)
文摘OBJECTIVE To investigate the effects of ex-tract of Ramulus Cinnamom(RC)against LPS-induced inflammation in microglia.METHODS Activated microglia releases various pro-inflammatory cytokines to induce neuroinflammation in stroke.Lipopolysaccaride(LPS)is an endotoxin from the outer membrane of Gram-negative bacteria that activates microglia.MTT assay was used to observe the cell viability.The content of NO in supernatant was measured by Griess reagent.The levels of IL-1β,IL-6 and TNF-αin supernatant were detected by ELISA kits.The intracellular COX-2,TLR4,and My D88expression was assayed by Western blotting.RESULTS RC extract 30 and 100μg·m L-1significantly decreased the production of related inflammatory factors such as NO(P<0.05,P<0.01),IL-1β(P<0.01,P<0.01),IL-6(P<0.05,P<0.01)and TNF-α(P<0.01,P<0.01).Furthermore,RC extract significantly inhibited the COX-2,TLR4,and My D88 expression induced by LPS in BV2cells.CONCLUSION RC extract may have therapeutic potential for the improvement of neuroinflammation,and the mechanism may be involved in down-regulation of TLR4/My D88 inflammation pathway.
基金supported by National Nature Science Foundation of China(81770847)CAMS Innovation Fund for Medical Sciences(CIFMS)(2016-I2M-3-007,2016-I2M-1-010)National Key Research and Development Plan(2016YFC1000905)
文摘OBJECTIVE Diabetic nephropathy(DN)has been one of the most common complications of diabetes and the leading cause of end-stage renal disease.Glomerular hyperfiltrationis central in earlystage of DN and leads to the progression of renal architectonic and functional abnormalities.Salvianolic acid A(SalA)has been proved to protect diabetic complications such as hepatic fibrosis and neuropathy.The present study was designed to investigate the effects of SalA on glomerular endothelial dysfunctionand diabetic nephropathy.METHODS Primary glomerular endothelial cells were subjected to assess permeability under injury of advanced glycation end-products(AGEs).AGEs-induced changes of Rho A/ROCK pathway and cytoskeleton rearrangement were assessed bywestern blotandimmunofluorescence.The beneficial effects of SalA on diabetic nephropathy were investigated in a rat model induced by high-fat and high-glucose diet combined with low dose of streptozocin(35 mg·kg^(-1),ip).Renal function and architectonic changes were evaluated by biochemical assay and PAS staining.RESULTS SalA 3μMameliorated AGEs-induced glomerular endothelial permeability(P<0.05)and suppressed rearrangement of cytoskeleton through inhibiting AGE-RAGE-Rho A/ROCK pathway.SalA1 mg·kg^(-1)markedly reduced endothelium loss(P<0.01)and glomerular hyperfiltration(P<0.05)in diabetic kidney.Subsequently,SalA 1 mg·kg^(-1) suppressed glomerular hypertrophy and mesangial matrix expansion,eventually reduced 24 h-urinary albumin and ameliorated renal function by decreasing blood urine nitrogen(BUN),serum creatinine(Scr)and serum n-acetyl-β-d-glucosaminidase(NAG).AGEs-RAGE-Nox4-induced oxidative stress was suppressed by the treatment of SalA 1 mg·kg^(-1).CONCLUSION SalA ameliorated AGEs-induced glomerular endothelial hyperpermeability,and effectively protected against early-stage diabetic nephropathy by reducing hyperfiltration and alleviating renal structural deterioration through inhibiting AGEs and its downstream pathway.Thus,SalA might be a promising therapeutic agent for the treatment of diabetic nephropathy.
文摘OBJECTIVE Here we investigated the effects and the underlying mechanism of Ginkgolide K(1,10-dihydroxy-3,14-didehydroginkgolide,GK)on cardiac ER stress.METHODS Cell death,apoptosis,and ER stressrelated signalling pathwayswere measuredin cultured neonatal rat cardiomyocytes(NRCMs),treated with the ER stress inducers tunicamycin,hydrogen peroxide,and thapsigargin.Acute myocardial infarction was established using left coronary artery occlusion in mice,and infarct size was measured by triphenyltetrazolium chloride(TTC)staining.Echocardiography was used to assess heart function and transmission electron microscopy for evaluating ER expansion.RESULTS GK significantly decreased ER stress-induced cell death in both in vitro and in vivomodels.In ischemic injured mice,GK treatment reduced infarct size,rescued heart dysfunction and ameliorated ER dilation.Mechanistic studies revealed that the beneficial effects of GK occur through enhancement of inositol-requiring enzyme 1α(IRE1α)/X box-binding protein-1(XBP1)activity,which in turn leads to increased ER-associated degradation(ERAD)-mediated clearance of misfolded proteins and autophagy.In addition,GK is also able to partially repress the pro-apoptotic action of regulated IRE1-dependent decay(RIDD)and JNK pathway.CONCLUSION GK acts through selective activation of the IRE1α/XBP1 pathway to limit ER stress injury.GK is revealed as a promising therapeutic agent to ameliorate ER stress for treating cardiovascular diseases.
基金Natural Science Foundation of China(81573645,81603101)the National Science and Technology Major Project(2013ZX09103001-008)
文摘OBJECTIVE The current therapeutic approaches have a limited effect on the dysregulated pulmonary vascular remodeling,which is characteristic of pulmonary arterial hypertension(PAH).In this study we exam-ined whether salvianolic acid A(SAA)extracted from the traditional Chinese medicine′Dan Shen′attenuated vascular remodeling in a PAH rat model,and elucidated the underlying mechanisms.METHODS PAH was induced in rats by injecting a single dose of monocrotaline(MCT 60 mg·kg-1,sc).The rats were orally treated with either SAA(0.3,1,3 mg·kg-1·d-1)or a positive control bosentan(30 mg·kg-1·d-1)for 4 weeks.Echocardiography and hemodynamic measurements were performed on d 28.Then the hearts and lungs were harvested,the organ indices and pulmonary artery wall thickness were calculated,and biochemical and histochemical analysis were conducted.The levels of apoptotic and signaling proteins in the lungs were measured using immunoblotting.RESULTS Treatment with SAA or bosentan effectively ameliorated MCTinduced pulmonary artery remodeling,pulmonary hemodynamic abnormalities and the subsequent increases of right ventricular systolic pressure(RVSP).Furthermore,the treatments significantly attenuated MCT-induced hypertrophic damage of myocardium,parenchymal injury and collagen deposition in the lungs.Moreover,the treatments attenuated MCT-induced apoptosis and fibrosis in the lungs.The treatments partially restored MCT-induced reductions of bone morphogenetic protein typeⅡreceptor(BMPRⅡ)and phosphorylated Smad1/5 in the lungs.CONCLUSION SAA ameliorates the pulmonary arterial remodeling in MCT-induced PAH rats most likely via activating the BMPRⅡ-Smad pathway and inhibiting apoptosis.Thus,SAA may have therapeutic potential for the patients at high risk of PAH.
基金The project supported by National Natural Science Foundation of China(81573645,81603101,81473383)
文摘OBJECTIVE To investigate the protective effect of salvianolic acid A(Sal A)on isoproterenol-induced myocardial infarction in mice and its possible mechanisms.METHODS The mice were subcutaneously injected with isopropranol(ISO 8 mg·kg-1)to induce myocardial infarction and evaluated the myocardial protective effect of Sal A from mortality rate,electrocardiogram(ECG),heart function,myocardial infarction index,serum myocardial enzymes and explored its possible mechanisms from inflammatory,antioxidant and cells apoptosis.RESULTS Sal A can dose-dependently enhanced the heart function of myocardial infarction mice,reduced the heart index,inhibited the myocardial enzyme leakage,showed obvious myocardial protection effects.ELISA results showed that Sal A can reduce the expression of myocardial inflammatory cytokines such as IL-6,TNF-α.Western blotting confirmed that Sal A can increase the expression of anti-apoptotic proteins Bcl-2,reduce the expression of apoptosis protein Bax,and raise the phosphorylation level of PI3K and Akt.CONCLUSION Sal A have displayed significant protective effect against isoproterenol-induced myocardial infarction and its mechanism may be related to increasing of PI3K/Akt signal pathway and inhibition of cell apoptosis and inflammatory reaction.
基金The project supported by Central Public Scientific Research Institution Fundamental Project(2016CX09)by National Natural Science Foundation of China(81573645)
文摘OBJECTIVE Pulmonary artery hypertension(PAH)is a severe disease characterized by the mean pulmonary artery pressure exceeding 25 mm Hg at rest.PAH could induce right heart failure and has a very high mortality rate.At present,several kinds of drugs have been used in the treatment of PAH.However,most of these drugs aim to relax pulmonary arteries and do not inhibit the injury of vessels.In other words,the drugs available for PAH treatment do not improve the survival rate of PAH patients and cannot satisfy the needs in clinic.To discover and develop novel candidate compounds effective on the treatment of pulmonary artery injury and remodeling will be very important.Based on these background,the present study aimed to study the protective effect of two novel Rho-kinases(Rho-associated coiledcoil forming protein serine/threonine kinase,ROCK)inhibitors,DL0805 derivatives(DL0805-1and DL0805-2),on pulmonary arterial cells and further evaluate the underlying mechanisms and the possibility of DL0805 derivatives become therapeutic drugs for PAH.METHODS The primary cultured pulmonary arterial cells including human pulmonary artery endothelium cells(HPAECs)and human pulmonary artery smooth muscle cells(HPASMCs)were used in this study.HPAECs were injured under hypoxia environment(1%O2)and treated with or without DL0805 derivatives.After 48 h,the proliferation and oxidative stress were observed.CCK8 was used to detect cell viability.DCFH-DA was used as probe for reactive oxygen species(ROS)under fluorescence imaging system.HPASMCs was stimulated by growth factors including platelet-derived growth factor-BB(PDGF-BB)and Fetal Bovine Serum(FBS).The proliferation was observed in the cells treated with or without DL0805 derivatives.HPASMCs treated with or without DL0805 derivatives were further incubated with endothelin(ET-1),the proliferation and cytoskeleton remodeling of cells were detected by immunofluorescence assay.At last,Western blotting(WB)and immunofluorescence assay were employed to analysis the underlying mechanisms in the above experiments.RESULTS 10μmol·L-1DL0805-2 could inhibit the proliferation of HPAECs induced by hypoxia.Each concentration of DL0805-1 and DL0805-2attenuated the production of ROS in HPAECs.Results from WB indicated that DL0805 derivatives decreased the injury of HPAECs induced by hypoxia through the inhibition of the expression of Rho A and the activity of ROCK.On HPASMCs,DL0805 derivatives reduced the proliferation induced by PDGF-BB and FBS and inhibited cytoskeleton remodeling induced by ET-1.Immunofluorescence assay showed that DL0805 derivatives inhibited ROCK activity and down regulated the phosphorylation levels of ROCK substrates.CONCLUSION DL0805derivatives exhibited protective effect on pulmonary arterial cells including endothelium cells and smooth muscle cells.Among the above experiments,DL0805-2 showed stronger potency than DL0805-1.These two compounds might protect the cells through the inhibition of Rho A/ROCK pathway and they probably have the potential in the treatment of PAH and deserve further evaluation.
基金The project supported by National Natural Science Foundation of China(81573645,81673422)
文摘OBJECTIVE To investigate the effects of salvianolic acid A(SAA)in systemic lupus erythematosus(SLE)induced by pristane in BALB/c mice,this study was performed.METHODS Lupus mice were established by confirming elevated levels of autoantibodies and IL-6 after intraperitoneal injection of pristane.Micewere then treated with daily oral doses of SAA for 5months in parallel with mice treated with prednisone and aspirin as positive controls.The levels of autoantibodies were monitored at monthly intervals and nephritic symptoms observed by hematoxylin and eosin(H&E)and periodic acid-Schiff(PAS)staining.Western blot analysis of renal tissue was also employed.RESULTS SAA treatment caused a significant reduction in the levels of anti-Sm autoantibodies and reduced renal histopathological changes and pathological effects.SAA treatment also significantly inhibited the phosphorylation of IKK,IκB and NFκB in renal tissues of lupus mice.CONCLUSION The results suggest that SAA alleviates renal injury in pristane-induced SLE in BALB/c mice through inhibition of phosphorylation of IKK,IκB and NFκB.
基金supported by National Natural Science Foundation of China(81603101) CAMS Innovation Fund for Medical Sciences(2016-I2M-1-010) Beijing Natural Science Foundation(7174322)
文摘Curcumin is the principal curcuminoid of the rhizomes of Curcuma longa(turmeric,Jiang Huang),which has more than 6000 years of application history in India and other Asian countries.At present,curcumin is sold as an herbal supplement,cosmetics ingredient,food flavoring,and food coloring.In China curcumin is mainly used in food,while in western countries it has been regarded as a health care product and is contained in the British Pharmacopoeia(2017),United States Pharmacopeia(40)and European Pharmacopoeia(8.7th ed.).Curcumin has been proved to have multiple pharmacology effects including anti-fibrosis,anti-tumor,anti-inflammation effects and so on.As its broad biological activities,it is applicated in a lot of diseases such as hyperlipidemia,infection and cancer.Among them,the anti-cancer effect of curcumin is the most attractive.In the treatment of cancer and related diseases,curcumin has been tested in phase I and II clinical trials in several research centers across the world and has been approved by the U.S.FDA into the phase III clinical trial.It has been listed as the third generation of cancer chemoprevention agent by the U.S.National Cancer Institute.Curcumin has been proved to inhibit the proliferation of a variety of tumor cells through regulating a variety of tran.scription factors(NF-κB,AP-1,etc),mitogen-activated protein kinase(MAPK),growth factor receptor ki.nase(PDGFR,VEGFR,etc) and cyclooxygenase.It plays an important role in the cell cycle and further to inhibit proliferation.Curcumin can also inhibit the migration of tumor cells by activating caspase and in.ducing tumor cell apoptosis.However,curcumin still needs researches to confirm its effects and mecha.nisms and find its exact indications.There is still a long way to go to make curcumin better applied in clinical practice in the further.
