| In recent years,cardiovascular diseases account for more than 40%of residents' deaths by diseases,and prevalence and mortality of cardiovascular diseases are still on the rise.The increasing burden of cardiovascular disease has become a major public health problem.Finding effective treatments from traditional medicine resources including Mongolian medicine is an important way of cardiovascular disease medicine research.Syringa pinnatifolia Hemsl.(SP),an endemic Chinese species belonging to the Oleaceae family,is mainly distributed in the Helan Mountain region between Ningxia and Inner Mongolia provinces of China.The peeled roots,stems,and twigs,called 'Shanchenxiang' in Chinese,is one of the most traditional Mongolian folk medicines for the treatment of cardiovascular symptoms,asthma,pain,and fever,and this remedy has been used for hundreds of years.Our group conducted a preliminary study on the anti-ischemic effect of ethanol total extract(T)of SP,and it was clear that its preventive administration had cardioprotective effect.Then T of SP was separated by macroporous resin chromatography to obtain the a major fraction M and a secondary fraction N.The comparison of the anti-myocardial ischemic effect of M and T showed that M and T had the same protective effect on ischemic heart injury.Based on the previous study,this study looks forward to further clarify the anti-myocardial ischemic pharmacological effect ingredients of SP by evaluating its sub-fractions and main components,and provide some scientific explanations for the clinical application of effect of SP suppressing "HeYi".The study is mainly divided into two aspects.First,separating of M to obtain I and M3 fractions by silica gel column chromatography,and pharmacological evaluation of sub-fractions using a mouse model of left anterior descending myocardial ischemia and completing the further tracking of the effective part of SP.Second,the anti-myocardial ischemic efficacy evaluation of the zerumbone,a characteristic component of the SP,and its mechanism of action from the perspective of anti-fibrosis,to further clarify the material basis of the SP medicine.The following results were obtained:Review about the efficacy and mechanism of zerumboneZerumbone is mainly found in the ginger family.The syringa plant in the genus Oleaceae is the only plant outside the ginger family that contains zerumbone.The volatile oil of Syringa pinnatifolia Hemsl is considered to be one of the anti-myocardial ischemic substances of Mongolian medicine 'Shan-chen-xiang'.The content of zerumbone in volatile oil is as high as 64.7%,suggesting that zerumbone has cardiovascular potential.Zerumbone is a lepidene-type monocyclic sesquiterpene.It is reported that it has a wide range of anti-tumor,anti-inflammatory,antioxidant,analgesic and other pharmacological activities.Among them,anti-tumor activity is the most concentrated,and its mechanism of action involves inhibiting tumor cell growth and proliferation,inducing tumor cell apoptosis,inhibiting tumor cell migration and invasion,inhibiting angiogenesis,regulating the body's immune function,reversing tumor cell multi-drug resistance,etc.There are few studies on its other related mechanisms,which need to be further explored.So far,there have been no reports of zerumbone against myocardial ischemia.Although the research on the effect and mechanism of zerumbone has attracted much attention,there are still a series of problems to be solved.For example,due to the structural characteristics of 11-membered macrocyclic and molecular flexibility in zerumbone molecule,its poor water solubility affects its biological utilization.This article mainly summarizes the efficacy and mechanism of zerumbone,in order to provide a reference for the further research and application of zerumbone.Pharmacological evaluation of fraction I and fraction M3M was separated to obtain subfractions I and M3,and the pharmacological evaluation of M,I,and M3 against myocardial ischemia in mice.The result showed that I and M reduced the values of LVEDd and LVEDs,significantly increased EF and FS values,increased serum CK-MB,LDH and cTnI levels,and reduced in in-flammatory cells infiltration and collagen deposition in the infarcted myocardial tissue,suggesting that M(65mg/kg)and I(47mg/kg)possess the anti-myocardial is chemia equally whereas M3 has no this effect.Related mechanism studies suggested that I(12,24,47mg/kg)can reduce the expression of COX-1,COX-2 and p53 protein in myocardial tissue in a dose-dependent manner.This study lays the foundation for further chemical segmentation and clarification of pharmacological substance groups,paving the way for the full use and benefits to be use of systematic biological methods to analyze the pharmacological basis of SP against myocardial ischemia.Pharmacological evaluation of zerumbone against myocardial ischemiaIn vivo efficacy evaluation:acute myocardial ischemia models were prepared by ligation of LAD coronary artery in mice,and then the mice were given a gavage of zerumbone(5,10,20 mg/kg)of for 21 days consecutively after surgery.The result showed that zerumbone can reduce the values of LVEDd and LVEDs,increase EF and FS values,and effectively improve heart function.It also decreases CK-MB,LDH in serum,and Galectin-3 in plasma,inhibiting the infiltration of inflammatory cells in the marginal area of myocardial infarction and improving myocardial fibrosis in mice.In vitro efficacy evaluation:hypoglycemia and hypoxia model of H9c2 cells was prepared by Tri Gas incubator,and the anti-ischemic efficacy of zerumbone was evaluated under low glucose,hypoxia and serum-free conditions.The CCK8 assay showed that zerumbone can significantly increase cell viability at concentration of 2.5,5,and 10 ?M.The above results suggest that zerumbone has an anti-myocardial ischemic effect.Study on anti-myocardial ischemic mechanism of zerumboneAfter 21 days of intragastric administration,the related indexes in the myocardial tissue of mice were detected to explore the mechanism.The qRT-PCR results showed that zerumbone could significantly reduce the mRNA levels of the Collagen ?,Collagen ?,TGF-?1,and a-SMA genes in the cardiac muscle.The results of immunofluorescence showed that in the myocardial tissue of the zerumbone administration group,the fluorescence intensity of Collagen ?,Collagen ?,and TGF-?1 proteins decreased.Western blot results showed that zerumbone can reduce the protein content of Collagen ?,Collagen ?,TGF-?1,MMP-2,and MMP-9 in myocardial tissue,inhibit the phosphorylation of Smad2,Smad3,and up-regulate the content of Smad7 and TIMP1 proteins.It all suggestes that zerumbone can improve ischemic myocardial fibrosis in mice by regulating TGF-?/Smad pathway.And the results of molecular docking suggest that zerumbone has affinity with TGF-?1 protein through hydrogen bonding,which provides further evidence for the above mechanism.In conclusion,we considered that the mechanisms of myocardial protective effects of I and M in anti-myocardial ischemia effect in mice were related to inhibition of inflammation and apoptosis.And this study reveals zerumbone that the characteristic terpenoid component of Syringa pinnatifolia Hemsl has anti-myocardial ischemia,and the mechanism of action is related to the regulation of TGF-?/Smad pathway to inhibit myocardial fibrosis.This study is one of the important links to further refine the pharmacological effect ingredients and determine the anti-myocardial ischemia of SP,provide scientific basis for SP's clinical use in ischemic heart disease,and provide a certain reference for the drug research of ischemic heart disease. |
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