Pinocembrin inhibits angiotensinⅡ-induced vasoconstriction in a Ca^(2+)-dependent and Ca^(2+)-independent manner through blocking AT_1R in the rat aorta

OBJECTIVE To investigate the vasorelaxant effect of pinocembrin(5,7-dihydroxyflavanone),one of the main flavonoids in propolis,on angiotensinⅡ(AngⅡ)induced vasoconstriction and the molecular mechanism of action.METHODS The isometric vascular tone was measured in thoracic aortic rings from SD rat,and the effects of pinocembrin on the single dose and concentration cumulative response curves of AngⅡ were recorded.The binding of pinocembrin to the angiotensin type 1 receptor(AT1R)was studied by using molecule docking analysis.Intracellular[Ca2+]([Ca2+]i)was measured with Fura2/AM in VSMCs.The phosphorylation levels of myosin light chain 2(MLC2)and myosin phosphatase target unit 1(MYPT1),and protein level of Rho kinase 1(ROCK1)in the rat aortic rings were detected by Western blotting.RESULTS Pinocembrin was observed to inhibit AngⅡ-induced vasoconstriction in rat aortic rings with either intact or denuded endothelium.In endothelium-denuded tissues,pinocembrin(pD′2 4.28±0.15)counteracted the contractions evoked by cumulative concentrations of AngⅡ.In a docking model,pinocembrin showed effective binding at the active site of AT1R.Pinocembrin was shown to inhibit both AngⅡ-induced Ca2+ release from internal stores and Ca2+ influx.Moreover,the increase in the phosphorylation of MLC2 and MYPT1,and the increased protein level of ROCK1 induced by AngⅡ was blocked by pinocembrin.CONCLUSION Pinocembrin inhibits AngⅡ-induced rat aortic ring contraction in a Ca2+-dependent and Ca2+-independent manner via blocking AT1R.

Curcumin,from health product to medicine

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.

Salvianolic acid A attenuates vascular remodeling in pulmonary arterial hypertension rats induced by monocrotaline

OBJECTIVE Salvianolic acid A(SAA) is one of the most bioactive compounds from a traditional Chinese medicine called Dan Shen(Salvia Miltiorrhiza Bunge) and exhibits many pharmaco.logical activities.Previous studies have indicated that SAA may inhibit endothelial dysfunction and vascular remodeling in spontaneously hypertensive rats.However,whether SAA improves vascular remodeling induced by pulmonary arterial hypertension(PAH) remains unknown.In this study we examined whether SAA attenuated vascular remodeling in a PAH rat induced by monocrotaline(MCT),and elucidated the underlying mechanisms.METHODS PAH was induced in rats by injecting a single dose of monocrotaline(MCT 60 mg·kg^(-1)).The rats were orally treated with either SAA(0.3,1,3 mg·kg^(-1)·d^(-1)) or a positive con.trol 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 effectively ameliorated MCT-induced pulmonary artery remodeling,pulmonary hemodynamic ab.normalities and the subsequent increases of right ventricular systolic pressure(RVSP).Furthermore,the treatments significantly attenuated MCT-induced hypertrophic damage of myocardium,parenchymal in.jury 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 morphoge.netic protein type Ⅱ receptor(BMPR Ⅱ) 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 pa.tients at high risk of PAH.

Activation of Nrf2 attenuates pulmonary vascular remodeling via inhibiting endothelial-to-mesenchymal transition

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.

Synthesis of quaternary 8-(1-acylethene-1-yl)-13-methylcoptisine chlorides and their selective growth inhibitory activity between human cancer cell lines and normal intestinal epithelial cell-6

In this paper, quaternary 8-（1-acylethene-l-yl）-13-methylcoptisine chlorides targeting thioredoxin reductases （TrxRs） were designed to test the growth inhibitory activity against human cancer cell lines and the effect on viability of the normal intestinal epithelial cell-6 （IEC-6） in vitro and to evaluate structure-activity relationship （SAR）. The introduced α, β-unsaturated ketone groups at C-8 consisting of n-alkanoyls possessing five to ten carbons or aroyls or cyclohexylcarbonyl increased the tested activity against the target cancer cell lines. By and large, this type of improvement was increasingly graced by the elongation of the aliphatic chain of the n-alkanoyls in the range of less than ten carbon atoms. The relatively more polar l-acylethene-l-yls displayed no effect on improving the activity. All the explored aroyls showed significant effect on improving the activity of the target compounds against the tested cancer cell lines with no SAR being observed, The findings of this study suggested that oil]water partition coefficient of the test compounds was one of the key factors impacting the target activity against the tested cancer cell lines. At the concentration of 10 μmol/L, except for the compounds with n-all（anoyls possessing seven or more carbons or with α-naphthoyl, none of the other compounds displayed obvious cytotoxicity on normal IEC-6 cell when co-incubated. The survival rate of IEC-6 cell ranged from 75% to 100% for the noncytotoxic compounds.