A series of new flavanone derivatives of farrerol was designed and synthesized as a potent inhibitor of vascular smooth muscle cells(VSMCs) vegetation according to a convenient method. The structures of all the synthe...A series of new flavanone derivatives of farrerol was designed and synthesized as a potent inhibitor of vascular smooth muscle cells(VSMCs) vegetation according to a convenient method. The structures of all the synthesized compounds were confirmed by 1H NMR, 13C NMR and EIHR-MS. The biological activities of these compounds against VSMCs in vitro were evaluated. The assay results indicate that two compounds, 5,7-dihydroxy-6,8-dimethyl- 2-(2-nitrophenyl)chroman-4-one(7f) and 2,3-dibromo-4,5-dihydroxydiphenylmethanone(7j) exhibited high activity against VSMCs in vitro with IC50 values of 9.9 and 6.7 μmol/L, respectively, and the preliminary structure-activity relationship(SAR) was described.展开更多
OBJECTIVE To investigate the cerebralvasorelaxant material basis of Xiaoxuming decoction.METHODS According to the Xiaoxuming decoction herb sources,we retrieved the chemical structure from the literatures and the Chin...OBJECTIVE To investigate the cerebralvasorelaxant material basis of Xiaoxuming decoction.METHODS According to the Xiaoxuming decoction herb sources,we retrieved the chemical structure from the literatures and the Chinese Natural Product Database(http://pharmdata.ncmi.cn).By using microvessel tension system,we checked the vasorelaxanteffects of Xiaoxuming decoction anti-cerebral ischemia effective components group(XXMDECG)and the available composition compounds on pre-contracted basilar artery ring.RESULTS963 compoundsin the decoction,including 81Fangfeng,77 Mahuang,130 Shengjiang,31 Guizhi,91 Huangqin,127 Renshen,73 Chuanxiong,44 Shaoyao,39 Xingren,42 Fangji,62 Fuzi and 166 Gancao were collected.The five largest number classes of compounds in the decoction are volatile oil(32%),flavone(32%),alkaloid(13%),saponin(7%),polyphenol and organic acid(5%).XXMDECG at concentration from 1 to 400μg·mL-1can dilate the KCl(60 mmol·L-1)and ET-1(0.01μmol·L-1)pre-contracted rat basilar artery rings in a dose-dependent manner.There are 6 compounds with vasorelaxant ratio more than 50%at the concentration of 10μmol·L-1.CONCLUSION Xiaoxuming decoction contains abundant chemical structure.It has the material basis of multiple ingredients and multiple targets.The XXMDECG are able to dilate the rat basilar artery rings in a dose-dependent manner.The network interactions between varies of chemical compounds in Xiaoxuming decoction and the vasoconstriction associated targets result in the comprehensive regulation mechanisms of vascular function.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 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
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 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 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 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 The plant of Anchusa italicahas been traditionally used in Uighur medicine for the treatment of cardiovascular and cerebrovascular diseases in China.Our previous study showed that total flavonoids from Anchu...OBJECTIVE The plant of Anchusa italicahas been traditionally used in Uighur medicine for the treatment of cardiovascular and cerebrovascular diseases in China.Our previous study showed that total flavonoids from Anchusa italica(TFAI)exhibited potent cardioprotection on acute ischemia/reperfusion injured rats.This study was undertaken to investigate the effects of TFAI on chronic myocardial infarction in mice and the underlying mechanism.METHODS Total flavonoids were extracted from the whole herb of Anchusa italica and were characterized using HPLC-MS analysis.The left anterior descending branch of coronary artery was ligated to induce myocardial infarction in mice.After surgery,the mice were orally fed with TFAI at the doses of 10,30 and 50 mg·kg-1 body mass per day for a total of four weeks.Cardiac function and infarct size were measured,and the levels of inflammatory mediators were detected.Hematoxylin and eosin(HE)stain and Masson Trichrome stain were performed.The apoptotic factors such as Bax,Bcl-2 and cleaved caspase 3 as well as the key proteins in the PI3K/Akt/mTOR signaling pathway were examined by Western blotting.RESULTS The content of total flavonoids in TFAI was 56.2%.Four weeks following the MI surgery,TFAI enhanced the survival rate in post-MI mice.TFAI administration at the doses of 30 and 50 mg·kg-1 significantly reduced the infarct size and improved cardiac function indicated by elevated EF and FS.Assay of inflammation factors showed that the sera levels of TNF-α,IL-1β and IL-6 were significantly decreased by TFAI treatment as compared to the MI group.HE stain and Masson Trichrome stain demonstrated that TFAI suppressed myocyte hypertrophy and cardiac fibrosis indicated by decreased cross-section area and collagen volume.Western blot analysis showed that cleaved caspase 3 and Bax/Bcl-2 were signifi⁃cantly downregulated following TFAI treatment.Additionally,TFAI treatment significantly suppressed the activation of the PI3K/Akt/mTOR signaling pathway.CONCLUSION TFAI exerts a protective effect against chronic myocardial infarction and its beneficial effects on cardiac function and cardiac remodeling might be at least attributable to anti-inflammation and suppression of the PI3K/Akt/mTOR signaling pathway.展开更多
目的:评价3种盐酸吡格列酮(pioglitazone hydrochloride,PGH)共晶在SD大鼠体内的生物吸收过程,改善PGH水溶性差、生物利用度低等问题。方法:采用悬浮液法制备得到盐酸吡格列酮-对氨基苯甲酸、盐酸吡格列酮-对氨基水杨酸和盐酸吡格列酮-...目的:评价3种盐酸吡格列酮(pioglitazone hydrochloride,PGH)共晶在SD大鼠体内的生物吸收过程,改善PGH水溶性差、生物利用度低等问题。方法:采用悬浮液法制备得到盐酸吡格列酮-对氨基苯甲酸、盐酸吡格列酮-对氨基水杨酸和盐酸吡格列酮-没食子酸3种新型共晶物质,通过多种分析检测技术进行表征,并采用HPLC-MS法测定大鼠血浆中PGH浓度,分析大鼠口服PGH共晶后的药动学参数。结果:3种共晶均具有良好的稳定性和溶解度,其中盐酸吡格列酮-对氨基苯甲酸和盐酸吡格列酮-没食子酸2个共晶能够改善大鼠口服PGH的生物利用度、达峰浓度(peak concentration,C_(max))和血药物浓度-时间曲线下面积(area under the cure,AUC)。结论:共晶技术是改变药物PGH溶解度和体内吸收特点的一种重要方法。展开更多
基金Supported by the National High-Tech Research and Development Program of China(No.2006AA09Z446)the Fund of State Key Laboratory of Natural and Biomimetic Drags+7 种基金 Peking UniversityChina(No.20080210)the Shanxi Provincial Foundation for Overseas Returned China(No.2009021005)the Program for the Top Young and Middle-aged Innovative Talents of Higher Learning Institutions of Shanxi Province China(No.20091041-1)the Innovative Program of Shanxi Medical University China (No.38)
文摘A series of new flavanone derivatives of farrerol was designed and synthesized as a potent inhibitor of vascular smooth muscle cells(VSMCs) vegetation according to a convenient method. The structures of all the synthesized compounds were confirmed by 1H NMR, 13C NMR and EIHR-MS. The biological activities of these compounds against VSMCs in vitro were evaluated. The assay results indicate that two compounds, 5,7-dihydroxy-6,8-dimethyl- 2-(2-nitrophenyl)chroman-4-one(7f) and 2,3-dibromo-4,5-dihydroxydiphenylmethanone(7j) exhibited high activity against VSMCs in vitro with IC50 values of 9.9 and 6.7 μmol/L, respectively, and the preliminary structure-activity relationship(SAR) was described.
基金The project supported by Major Scientific and Technological Special Project for "Significant New Drug Creation"(2013ZX09508104,2013ZX09402203)by Central Public Scientific Research Institution Fundamental Project(2014CX05)
文摘OBJECTIVE To investigate the cerebralvasorelaxant material basis of Xiaoxuming decoction.METHODS According to the Xiaoxuming decoction herb sources,we retrieved the chemical structure from the literatures and the Chinese Natural Product Database(http://pharmdata.ncmi.cn).By using microvessel tension system,we checked the vasorelaxanteffects of Xiaoxuming decoction anti-cerebral ischemia effective components group(XXMDECG)and the available composition compounds on pre-contracted basilar artery ring.RESULTS963 compoundsin the decoction,including 81Fangfeng,77 Mahuang,130 Shengjiang,31 Guizhi,91 Huangqin,127 Renshen,73 Chuanxiong,44 Shaoyao,39 Xingren,42 Fangji,62 Fuzi and 166 Gancao were collected.The five largest number classes of compounds in the decoction are volatile oil(32%),flavone(32%),alkaloid(13%),saponin(7%),polyphenol and organic acid(5%).XXMDECG at concentration from 1 to 400μg·mL-1can dilate the KCl(60 mmol·L-1)and ET-1(0.01μmol·L-1)pre-contracted rat basilar artery rings in a dose-dependent manner.There are 6 compounds with vasorelaxant ratio more than 50%at the concentration of 10μmol·L-1.CONCLUSION Xiaoxuming decoction contains abundant chemical structure.It has the material basis of multiple ingredients and multiple targets.The XXMDECG are able to dilate the rat basilar artery rings in a dose-dependent manner.The network interactions between varies of chemical compounds in Xiaoxuming decoction and the vasoconstriction associated targets result in the comprehensive regulation mechanisms of vascular function.
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(81573645,81673422)
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 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CAMS Innovation Fund for Medical Sciences(CIFMS)318(2016-I2M-3-007)National Natural Science Foundation of China(81673422and 81202538)
文摘OBJECTIVE The plant of Anchusa italicahas been traditionally used in Uighur medicine for the treatment of cardiovascular and cerebrovascular diseases in China.Our previous study showed that total flavonoids from Anchusa italica(TFAI)exhibited potent cardioprotection on acute ischemia/reperfusion injured rats.This study was undertaken to investigate the effects of TFAI on chronic myocardial infarction in mice and the underlying mechanism.METHODS Total flavonoids were extracted from the whole herb of Anchusa italica and were characterized using HPLC-MS analysis.The left anterior descending branch of coronary artery was ligated to induce myocardial infarction in mice.After surgery,the mice were orally fed with TFAI at the doses of 10,30 and 50 mg·kg-1 body mass per day for a total of four weeks.Cardiac function and infarct size were measured,and the levels of inflammatory mediators were detected.Hematoxylin and eosin(HE)stain and Masson Trichrome stain were performed.The apoptotic factors such as Bax,Bcl-2 and cleaved caspase 3 as well as the key proteins in the PI3K/Akt/mTOR signaling pathway were examined by Western blotting.RESULTS The content of total flavonoids in TFAI was 56.2%.Four weeks following the MI surgery,TFAI enhanced the survival rate in post-MI mice.TFAI administration at the doses of 30 and 50 mg·kg-1 significantly reduced the infarct size and improved cardiac function indicated by elevated EF and FS.Assay of inflammation factors showed that the sera levels of TNF-α,IL-1β and IL-6 were significantly decreased by TFAI treatment as compared to the MI group.HE stain and Masson Trichrome stain demonstrated that TFAI suppressed myocyte hypertrophy and cardiac fibrosis indicated by decreased cross-section area and collagen volume.Western blot analysis showed that cleaved caspase 3 and Bax/Bcl-2 were signifi⁃cantly downregulated following TFAI treatment.Additionally,TFAI treatment significantly suppressed the activation of the PI3K/Akt/mTOR signaling pathway.CONCLUSION TFAI exerts a protective effect against chronic myocardial infarction and its beneficial effects on cardiac function and cardiac remodeling might be at least attributable to anti-inflammation and suppression of the PI3K/Akt/mTOR signaling pathway.
文摘目的:评价3种盐酸吡格列酮(pioglitazone hydrochloride,PGH)共晶在SD大鼠体内的生物吸收过程,改善PGH水溶性差、生物利用度低等问题。方法:采用悬浮液法制备得到盐酸吡格列酮-对氨基苯甲酸、盐酸吡格列酮-对氨基水杨酸和盐酸吡格列酮-没食子酸3种新型共晶物质,通过多种分析检测技术进行表征,并采用HPLC-MS法测定大鼠血浆中PGH浓度,分析大鼠口服PGH共晶后的药动学参数。结果:3种共晶均具有良好的稳定性和溶解度,其中盐酸吡格列酮-对氨基苯甲酸和盐酸吡格列酮-没食子酸2个共晶能够改善大鼠口服PGH的生物利用度、达峰浓度(peak concentration,C_(max))和血药物浓度-时间曲线下面积(area under the cure,AUC)。结论:共晶技术是改变药物PGH溶解度和体内吸收特点的一种重要方法。
