Cardio cerebrovascular disease is the general term of cardiovascular disease and cerebrovascular disease. This kind of disease is caused by hypertension, diabetes, dyslipidemia syndrome and other reasons, and manifests as ischemic or hemorrhagic lesions in brain, heart and systemic tissues[1]Pentacyclic triterpenoids are an important class of natural products, most of which exist widely in nature in the form of free or glycosides. Pentacyclic triterpenoids mainly include oleanane type, Ursane type, lupane type, and xylane type4Types. A large number of studies have shown that pentacyclic triterpenoidsCompounds are antiviral[2], antitumor[3]And other important biological activities and a wide range of pharmacological effects. Studies have found that pentacyclic triterpenoids have the effect of treating cardiovascular and cerebrovascular diseases, among which oleanane type and Ursane type compounds have relatively obvious therapeutic effect, while lupane type and corkane type have less relevant reports. In this paper, the research progress of pentacyclic triterpenoids and their derivatives against cardiovascular and cerebrovascular diseases is reviewed, which provides a basis and reference for the research and development of therapeutic drugs for cardiovascular and cerebrovascular diseases.
1 Structural types of pentacyclic triterpenoids
1.1 Oleanane type
Oleanane type, also known asβ-. Most of the structures of this type of compounds containC3-β-OH, which5Among six membered ringsA/B、B/C、C/DThe rings are all in trans,D/EMost of the rings are in CIS. amongoleanolic acid （oleanolic acid，OA）、glycyrrhizic acid（glycyrrhizicacid，GA）、Glycyrrhetinic acid（glycyrrhetinicacid，GTA）、Ivy saponin（hederagenin，Hed）、Hawthorn acid（maslinicacid，MA）, Holly bark acid（rotundicacid，RA）They are oleanane pentacyclic triterpenoids that mainly fight against cardiovascular and cerebrovascular diseases. The structure is shown in Fig1。
1.2 Ursane type
Ursane type, also known asα-. hisA/B、B/C、C/DThe rings are all in trans,D/EThe ring is in CIS. amongUrsolic acid（ursolic acid，UA）、Asiatic Acid（asiatic acid，AA）、Asiaticoside（asiaticoside，AS）、corosolic acid （corosolic acid，CA）Et al. Have anti cardiovascular and cerebrovascular pharmacological effects. The structure is shown in Fig2。
1.3 Lupane type
Lupane pentacyclic triterpenoidsEThe ring is a five membered carbon ring, andEringC-19Bit quiltα-,A/B、B/C、C/D、D/E. The representative compound of lupane pentacyclic triterpene is betulinic acid（betulinic acid，BA）、Betulinic acid（betulinic acid）. The structure is shown in Fig3。
1.4 Cork alkane type
Thromboxane pentacyclic triterpenoids are derived from oleanane methylIt evolved from displacement.A/B、B/C、C/DThe rings are all in trans,D/EThe ring is cis. The representative compounds of pentacyclic triterpenes of the suberane type areCelastrol（celastrol，Cel）. The structure is shown in Fig3。
2 Pharmacological effects of pentacyclic triterpenoids and their derivatives on cardiovascular and cerebrovascular diseases
Pentacyclic triterpenoids and their derivatives have anti myocardial ischemia, anti heart failure, anti arrhythmia, anti atherosclerosis, anti thrombosis, anti myocardial hypertrophy and fibrosis effects on the cardiovascular system; It has a protective effect on cerebral vascular ischemia and hypoxia injury, cerebral ischemia-reperfusion injury, and an inhibitory effect on cerebral nerve apoptosis.
2.1 Heart protection
2.1.1 Anti myocardial ischemia Kimetc.[4]The experiment was performed by perfusing rat atrium ex vivo, which was administered in a dose-dependent mannerOA（atrialnatriuretic peptide，ANP）Levels, and increased atrialANPContent andANP mRNAThe results showed that,OA [10～30 mg/(kg∙d)] Treatment increased the atrial stretch inducedANP. Wang Jun et al[5]To establish a rat model of myocardial ischemia-reperfusion injury and studyGAThe protective effect of preconditioning on myocardial ischemia-reperfusion injury in rats,GAPretreatment low dose group（2 mg/kg）, medium dose group（4 mg/kg）（10 mg/kg）It can obviously alleviate myocardial ischemia-reperfusion injury; Significantly reduced lactate dehydrogenase（lactatedehydrogenase olding，LDH）, troponinT（troponin T，cTnT）, tumor necrosis factor-α（tumornecrosis factor-α，TNF-α）, interleukin-6（interleukin-6，IL-6）, peroxidase（meloperoxidase，MPO）Level; （sphincter of oddi dysfunction，SOD）, glutathione peroxidase（glutathioneperoxidase，GSH-Px）Activity（P＜0.05、0.01）; Significantly reduced myocardial apoptosis index（P＜0.01）; Significantly upregulated cardiac muscleBLymphoblastoma-2Genes（B-cell lymphoma-2，Bcl-2）Expression, downregulationBLymphoblastoma-2Proteins of genes（Bcl-2-associated X，Bax）Expression and upregulationBcl-2/BaxExpression（P＜0.05、0.01）；GAIt can inhibit myocardial apoptosis and has a protective effect on myocardial ischemia-reperfusion injury in rats. Zhaoruifang[6]researchUAProtective effect on myocardial ischemia-reperfusion injury in rats120 mg/kg UAAfter treatment, total antioxidant in serumChemical ability（total antioxidant capacity，T-AOC）（P＜0.05）, in myocardial tissueSODSignificantly increased activity（P＜0.05、0.01），GSH-PxSignificantly increased activity（P＜0.05、0.01），Malondialdehyde（malondialdehyde，MDA）Content significantly decreased（P＜0.01），UAIt can effectively enhance the activity of antioxidant enzymes, inhibit oxidative stress injury, and inhibit myocardial apoptosis. Si Linjie et al[7]observationAA,ig 50、100 mg/(kg∙d)AACan significantly inhibit the contraction of transverse abdominal aorta（transverseaortic constriction，TAC）Induced cardiac hypertrophy, improved cardiac function, and reduced human transforming growth factor-β1（humantransforming growth factor-β1，TGF-β1）Gene and protein expression, and inhibition ofp38Mitogen activated protein kinase（p38 mitogen-activatedprotein kinase，p38MAPK）And extracellular regulated protein kinases（extracellular regulatedprotein kinases，ERK1/2）Phosphorylation.Der Sarkissianetc.[8]findCelCan be achieved by upregulating heme oxygenase-1（hemeoxygenase-1，HO-1）To protect ischemic myocardium,CelCan prolong rat cardiomyocytesH9c2,CelCan trigger myocardial protectionHO-1Expression, inhibiting fibrosis and infarct size; In the peri infarct zone,CelDecreased myofibroblast and macrophage infiltration, inhibitedTGF-βAnd upregulation of collagen genes. [9]withRAAs the lead compound, it was synthesized in alkaline mediumRAderivative3β,19α-Disuccinoyl-Holly bark acid trisodium salt, through researchRAderivative3β,19α-Disuccinoyl-The effect of cortex Ilicis Rotundae trisodium salt on myocardial infarct size in rats with myocardial ischemia. It was found that trisodium salt derivatives can reduce the release of myocardial three enzymes and reduce the degree of myocardial injury under the condition of myocardial ischemia; And under the same dose condition, creatine kinase（creatine kinase，CK）AndLDHThe inhibitory effect of Ginkgo biloba leaf on the release was significantly stronger than that of the positive control drug;RALipid peroxide metabolites in serum of animals in different dose groups of trisodium salt derivativesMDAThe content was significantly lower than that of ischemia model group; andSODHowever, its activity was significantly higher than that of ischemia model group. promptRATrisodium salt derivatives can significantly improve the in vivoSODAnd can effectively reduce lipid peroxidation metabolitesMDA.Tianetc.[10]A series of novel oleanolic acids were synthesized-3-O-β-D-Glucuronide derivatives (see Fig4）, biological evaluation showed that the synthesized derivatives were sensitive toH2O2Induced rat cardiomyocytesH9c2Damage has moderate to good activity, in particular, derivatives28-N-Isobutyl arbutin-3-O-β-D-Galactopyranoside ratio of positive control oleanolic acid-3-O-β-D-Glucuronopyranoside has a stronger protective effect in0.1 μg/mLLower derivative28-N-Isobutyl arbutin-3-O-β-D-Galactopyranoside can better increaseH9c2Cell viability.
2.1.2 Anti heart failure Zheng Lei et al[11]Rat cardiomyocytesH9c2As experimental subjects, exploreGAandGTAFor its reactive oxygen species（reactive oxygen species，ROS）The results showed that the maximum mass concentration0.1 μg/μL GTAWith significant cytotoxicity（P＜0.01）, mass concentrationGAThere was no significant cytotoxicity;0.1～1×10−6 μg/μL GA、0.01～1×10−6μg/μL GTA（P＜0.01）；1×10−5μg/μLAngiotensinIICan significantly elevate intracellularROSLevel（P＜0.01）。1×10−6 μg/μL GAandGTACan significantly reduce angiotensinIIInducedROSLevel（P＜0.01）. promptGAandGTABy reducing intracellularROSLevel to alleviate heart failure.
2.1.3 Antiarrhythmic Zhaoquancheng et al[9]compoundRAderivative3β,19α-Disuccinoyl-Holly bark trisodium salt derivative, research foundRATrisodium salt derivative（100、50、25 mg/kg）Can significantly delayivThe occurrence time of biphasic ventricular arrhythmia induced by barium chloride in rats and the duration of this arrhythmia were shortened, and showed a good dose-response relationship; ,100 mg/kg RA（100 mg/kg）, which can better reflect the superiority of the derivative in the treatment of arrhythmia.
2.1.4 Antiatherosclerotic and antithrombotic Panetc.[12]In order to studyOARole in atherosclerosis, first with100 μg/mLOxidized low density lipoprotein（oxidized low-density lipoproteins，ox-LDL）Treatment of human umbilical vein endothelial cells（humanumbilical vein endothelial cells，HUVECs）24 hThe results showed that compared with the control group, the cell proliferation in the model group was significantly inhibited; However, the application of different concentrations ofOA（0、10、20、40、80、160 μmol/L）Reversibleox-LDL,40μmol/L OAAchieve the best results;ox-LDLInducedHUVECsCell proliferation inhibition was also mediated byOA;OABy adjustingox-LDLInducedHUVECsAngiotensin in the model-(1-7) [angiotensin (1-7)，Ang (1-7)] To exert the anti arteriosclerosis effect.Nielsetc.[13]Studied theOAIn apoEKnockout of anti atherosclerotic effects in mice revealed thatOAIt can exert effective anti atherosclerotic effect, is not affected by plasma lipid levels, and does not affect endothelial nitric oxide synthase（endothelial nitric oxide synthase，eNOS）Mediated acetylcholine relaxation has a major impact.Tzakosetc.[14]findBAHas the potential use of antithrombotic, andBAAntiplatelet effect,BAIt can block the pathological process of tumor like proliferation induced by lipopolysaccharide, and has potential preventive and therapeutic effects[15]。CelIt has pharmacological effects in the treatment of atherosclerosis[16]. Qi Lianwen et al[17]findHedIt has the pharmacological effect of treating coronary atherosclerosis. The experimental results show that compared with the coronary heart disease model group,HedPlasma creatine Myozyme isozyme of rats in the administration group（creatine kinase-MB，CK-MB）And troponin-I（troponin I，Tn I）Compared with the normal control group, the plasma human6-ketone-prostaglandinF1α（human 6-ketone- prostaglandin F1α，6-k-PGFlα）And ThromboxaneB2（thromboalkane B2，TXB2）The expression level of α - Catenin was significantly imbalanced, whileHedCan effectively reverse the plasma of coronary heart disease model rats6-k- PGFlαandTXB2Imbalance, inhibit platelet aggregation;HedIt has a certain protective effect on myocardial damage in coronary heart disease model rats. Sunhongbin et al[18]According to the conventional hydroxyl esterification method, theCAorAAIt reacts with various anhydrides, acyl chlorides, and amino acid methyl esters to obtain a series of hydroxyl protectedCAorAADerivatives (see Fig5）, studies have shown that the derivatives have different degrees of inhibition on glycogen phosphorylase, among which the derivativesN-(2α,3β-Diacetoxy Ursane-12-Alkene- 28-amide)-L-Tyrosine methyl ester had the most significant inhibitory effect（IC50＝11.2 μmol/L），CAorAADerivatives can prevent and treat atherosclerosis and other diseases.
2.1.5 Antifibrotic Wangce[19]researchASThe effect on left ventricular myocardial fibrosis and myocardial tissue in rats with myocardial infarctionTGF-β1、IType I collagen（collagen I，Col I）AndIIIType I collagen（collagen III，Col III）Expression, the results showed that,ASCan reduce the non infarcted area of myocardial infarction ratsTGF-β1, thereby attenuating myocardial tissue in non infarcted areasCol I、Col IIIAbnormal synthesis and deposition can reduce the degree of left ventricular myocardial fibrosis after myocardial infarction and delay the development of left ventricular remodeling. Wangce[20]observationASEffects on left ventricular function and left ventricular collagen remodeling after myocardial infarction in rats. The results showed that,ASIt can improve the left ventricular function of myocardial infarction rats, reduce the abnormal expression of collagen in myocardial tissue of non infarcted area of left ventricle, and alleviate myocardial fibrosis after myocardial infarction in rats.
2.2 Protection of brain tissue
Martínetc.[21]findOAIt can improve experimental autoimmunitySex encephalomyelitis（experimental autoimmune encephalomyelitis，EAE）Tcell1（helper T cell 1，Th1）/auxiliaryTcell2（Th2）. Liuxiujuan et al[22]researchOAFor subarachnoid hemorrhage（subarachnoidhemorrhage，SAH）Early brain injury after（early brain injury，EBI）The results showed that compared with the model group,OAGroup A could significantly increase the body weight and neurological function score of rats, and significantly reduce the brain Evans blue permeability and nuclear transcription factor-κB（nucleartranscription factor-κB，NF-κB）/Intercellular adhesion molecule-1（intercellular adhesion molecule-1，ICAM-1）The expression levels of signaling pathway proteins were statistically significant（P＜0.05、0.01）；OACan significantly alleviate the ratSAHPosteriorEBI. Qi Lianwen et al[23]The model of global cerebral ischemia was established by bilateral ligation of common carotid artery and vagus nerve in miceHedThe results showed that the survival time of mice in the model group was（128.6±31.5）s；HedtoThe survival time of mice in the drug group was200 sAbove, significantly better than the model group（P＜0.05）。HedIt has a good preventive effect on ischemic stroke.Zhangetc.[24]findUAIt can reduce oxidative stress experimentallySAHafterEBIThe results showed that,UAAdministration significantly alleviated theSAHafterEBIIncluding brain edema, blood-brain barrier disruption, neural apoptosis and neurological deficits, and upregulated antioxidant levels in rat cerebral cortex,UAAvailable asSAHafterEBI.Luetc.[25]Research shows that,BA;BAProtectableTNF-αCaused byHUVECsDamage, reductionTNF-αAdhesion between human promyelocytic leukemia cells and human umbilical vein endothelial cells[26]. wangwenjuan et al[27]discussASFor the protective effect and mechanism of ischemia-reperfusion injury, the middle cerebral artery embolization model in rats was established by using the suture method24 hAfter, observeAS（80、40、20mg/kg）The results showed that compared with the model group,ASIt can significantly reduce the neurological function score of ischemia-reperfusion rats, inhibit neural apoptosis, improve histopathological damage, and improve brain tissueSOD、GSH-PxActivity, reducedMDA, protein carbonyl levels, decreased proteaseCaspase-3、BaxmRNAExpression, improveBcl-2 mRNAExpression,ASIt has a significant protective effect on cerebral ischemia-reperfusion rats.
2.3 Protecting the nervous system
Lietc.[28]Isolated from Oleaceae plantsUA, found thatUACan protect the brain from ischemic injury activating transcription factorsE2Correlation factor（nuclear erythroid 2-related factor 2，Nrf 2）Pathways;Nrf 2Activation of the pathway contributes toUANeuroprotective effect on cerebral ischemia. Research findingsMAIt has obvious neuroprotective effect, and its mechanism is related to increasing the expression of glutamate transporter in astrocytes[29], regulated protein kinaseB（protein kinase B，PKB）/glycogen synthetase kinase-3（glycogensynthetase kinase-3，GSK-3）signaling pathway， Promote synaptogenesis and axon regeneration[30]Etc.CelIt has neuroprotective effect on cerebral ischemia-reperfusion injury, and this effect is related to its inhibition of apoptotic cells and microglia activation[31-32]. zhaoweimin et al[33]To study caffeioyl substituted pentacyclic triterpenoid derivatives (see Fig6）It was found that it has a protective effect on nerve injury induced by acute cerebral ischemia. Injection of these derivatives can significantly improve the symptoms of neurobehavioral disorders in animals. After statistical analysis, the behavior scores of animals in the administration group were significantly different from those in the solvent control group（P＜0.01、0.001）; The cerebral ischemic area was significantly smaller than that of the solvent control group. After statistical analysis, the cerebral ischemic injury area of the animals in the administration group was significantly different from that of the solvent control group（P＜0.001）。
2.4 anti-inflammatory effect
Martínetc.[34]proveOAIs treatmentTh1Cell mediated inflammationEffective methods for disease,OAPrevention and treatment of experimental autoimmune myocarditis（experimentalautoimmune myocarditis，EAM）,OATherapeuticEAMCompared with untreated animals, the cardiac index, plasma brain natriuretic peptide level and myosin specific autoantibody production were significantly reduced in animals; Histological cardiac analysis revealedOATreatment reduces cellular infiltration, fibrosis, and dystrophic calcification;OA.Ieongetc.[35]Research shows thatGAIs treatmentSAHPotential candidates for post inflammatory brain injury,GAIt can significantly improve the neurological function score and reduce theHMGB1Positive cells, down regulatedHMGB1OfmRNAAnd protein levels, inhibiting the blood-brain barrier（blood brain barrier，BBB）Permeability, and alleviateSAHNeuronal cell death and apoptosis after;GASuppressableSAHInflammation related molecules in rats（TNF-α、IL-1β）Upregulation of.Wangetc.[36]discussUAIt has cardioprotective effect on diabetic cardiomyopathy rats,UACan make the diabetic groupCK、LDH、MDAIncreased levels,SODThe activity decreased, and the left ventricular dysfunction, cardiomyocyte hypertrophy, inflammatory cell infiltration and myocardial interstitial fibrosis were alleviated; In addition, in myocardial tissueTNF-α, chemotactic proteins-1（monocyte chemotactic protein-1，MCP-1）AndTGF-β1The expression of MMPs was significantly up-regulated（matrixmetalloproteinase- 2，MMP-2）The expression of Bcl-2 was significantly down regulated;UACan improve streptozotocin by reducing oxidative stress, inflammation, and fibrosis（streptozocin，STZ）Induced diabetic cardiomyopathy.Zhangetc.[37]Discussed theGAFor Coxsackie virusB 3Type（coxsackievirus group B type 3，CVB3）The therapeutic effect of induced viral myocarditis and its possible mechanism, the results showed that,GASignificantly improvedCVB3The induced blood glucose level improved the body weight, reduced the serological level of myocardial enzymes, and reduced the survival rate;GACan effectively reduceCVB3. Luo Jian et al[38]In preparation inhibitionTBetulinic acid derivatives were found in drugs for cell differentiation (see Fig6）Can reduceEAEThe release of inflammatory cytokines in mice promotes the production of regulatory cytokines. Betulinic acid derivatives can inhibit the release of inflammatory cytokines fromTh17Cytokines secreted by cellsIL-17AandIL-17FHowever, the expression of regulatoryTCell secretedIL-10andIL-4There is a certain degree of up regulation. .
3 Conclusion and Prospect
Pentacyclic triterpenoids are widely distributed in nature, with abundant resources and less adverse reactions. Studies have found that pentacyclic triterpenoids have anti cardiovascular and cerebrovascular disease effects, especially on myocardial ischemia, coronary heart disease, arteriosclerosis, thrombosis, nerve injury and other diseases induced by cerebral ischemia. However, pentacyclic triterpenoids for the treatment of cardiovascular and cerebrovascular diseases have disadvantages such as poor solubility, low bioavailability, and poor oral effect. Research at this stage shows that the structure modification of pentacyclic triterpenoids can enhance their bioavailability, improve the medicinal value, and make pentacyclic triterpenoids have the effect of treating cardiovascular diseases. It is believed that in the near future, pentacyclic triterpenoids and their derivatives can be widely used in clinical research for the prevention and treatment of cardiovascular and cerebrovascular diseases.
References (omitted)
; Source: white Xue, Wang Xue, Nan minlun, lichuanjing, zhaoyuwei, he Yufang, zhaoquancheng Research progress of natural pentacyclic triterpenoids and their derivatives against cardiovascular and cerebrovascular diseases [j]. Chinese herbal medicine, 2019, 50 (3): 745-752