Chemical constituents and pharmacological activities of Salvia miltiorrhiza

Salvia miltiorrhiza Bunge(S.miltiorrhiza),a perennial plant of the genus Salvia,is widely used in traditional folklore medicine.Previous chemical research on this plant contains diterpenoid quinones,phenolic acids,polysaccharides and other compounds.The pharmacological investigation of S.miltiorrhiza has shown that it has various pharmacological activities,such as cardiovascular system protection,anti-inflammatory,anti-oxidant,anti-tumor,liver protection,and neuroprotection activities.This research tends to give an overview of the main chemical constituents and pharmacological effects of S.miltiorrhiza,aiming to reveal its potential value and provide reference for its further development.

Traditional Chinese medicine of Salvia miltiorrhiza Bunge: a review of phytochemistry, pharmacology and pharmacokinetics

Salvia miltiorrhiza Bunge,known as red sage or Danshen,is commonly applied in Chinese herbal therapeutics for various biological effects.In 25-220 C.E.,the earliest Chinese Materia Medica referred to as Shengong’s Classic of Materia Medica(Eastern Han Dynasty of China,200 C.E.)initially documented Salvia miltiorrhiza Bunge.Currently,Salvia miltiorrhiza Bunge is one of the most frequently prescribed traditional Chinese medicines in clinics for antidiabetic,antianxiety,antihypertensive,antidepressant,antilipidemic,antiarrhythmic,and anticancer effects.Undoubtedly,it is best known for improving and promoting blood circulation;thus,its recommendation for use in cardiovascular disorders.Regarding this article,important information was sourced both manually and electronically using patent compendium and databases,including Google Scholar,herbal plant monographs,Hindawi,PubMed,Embase,CNKI,pharmacopoeias,Springer,etc.Well-concise details and discussions on the botany,traditional medicinal uses,chemical constituents-phytochemistry,pharmacokinetics,pharmacology,and toxicology information are presented.In perspective,understanding the comprehensive information of the above-stated fields with regards to Salvia miltiorrhiza Bunge would yield an additional positive knowledge on areas that need urgent attention and identify gaps in research and safety for future consideration.

PRIMARY STUDY ON MECHANISM OF COLLAGEN SYNTHESIS INHIBITION IN CULTURED HUMAN FETAL HEPATOCYTES PRETREATED BY SALVIA MILTIORRHIZA BUNGE

Objective The effects of salvia miltiorrhiza bunge (SMB) on collagen synthesis in the human fetal hepatocytes culture were studied. Methods The collagen synthesis of hepatocytes were stimulated by the addition of carbon tetrachloride (CCl 4 ) to the culture medium, the concentration of type procollagen (PC) in the culture medium and the hydroxyproline (Hyp) in hepatocytes were determined, as well as the activity of se dependent glutathione peroxidase (Se GSH Px) and the concentration of malondiadehyde (MDA) in the culture medium. Results A significant decrease in PC, Hyp and MDA production, and the significant increase in Se GSH Px activity were observed in the cultures pretreated with 1 g L -1 SMB for 4 hours compared with the untreated cultures. Analysis of the Se GSH Px/MDA ratio in SMB pretreated group showed more marked increase compared to that of the untreated group ( P <0.01). There was a significant negative correlation between the ratio of Se GSH Px/MDA and the concentration of PC in SMB pretreated group ( r=-0.9017, P <0.01). Conclusion Our results indicate that SMB may suppress the collagen synthesis of cultured human fetal hepatocytes stimulated by CCl 4 , and its mechanism may be related to the increase in Se GSH Px/MDA ratio and the enhancement of hepatocytes antioxidation capability.

EFFECTS OF SALVIA MILTIORRHIZA BUNGE （SMB） ON LIPID PEROXIDATION OF CULTURED HUMAN FATAL HEPATOCYTES

The role of salvia miltiorrhiza bunge (SMB) In protection of lipid peroxidation induced by CCl4 was studied in primary cultured human fetal hepatocytes. The results showed that SMB had significant effect inhibiting lipid peroxidation of the hepatocytes when exposed to CCl4 as compared with the non-protective co4trol. SMB could decrease the production of malondialdehyde (MDA) and the release of ALT, and increase the synthesis of albumin (ALB) and the activity of Se-dependent glutothione peroxidase (Se-GSH-Px). These results suggest that the suppression of lipid peroxidation may be largely due to the increased activity of Se-GSH-Px.

EFFECTS OF SALVIA MILTIORRHIZA BUNGE（SMB）ON LIPID PEROXIDATION AND PLASMA MEMBRANE FLUIDITY OF CULTU

In order to investigate the effect of salvia miltiorrhiza hunge(SMB)on the plasma membrane fluidity and the relationship between the lipid peroxidation and the Plasma membrane fluidityin cultured human fetdal hepatocytes,the plasma membrane fluidity,using 1,6-dipheny-1,3,5-hexatriene(DPH)as a fluorescence probe, malondialdehyde(MDA)production as well as alanine aminotransferase(ALT)release of human fetal hepatocytes cultured in Presence of carbon tetrachloride(CCl4)or SMB puls CCl4 were estimated. In the cultured hepatocytes injured by CCl4,significant increments of the MDA production and the ALT release,and significant decrease in the plasma membrane fluidity were observed.when the culture medium was supplied with SMB prior to the additionof CCl4,the CCl4 induced increments in MDA production and ALT release was suppressed signifi cantly and a concomitant raise of plasma membrane fluidity towards normal occurred.The resultssuggested that SMB could suppress the lipid peroxidation in bepatocytes,thereby normal membranefluidity might be retained.

Cardioprotective effects of Salvia miltiorrhiza Bunge and Lignum dalbergiae odoriferae on rat myocardial ischemia/reperfusion injury

Aim Salvia miltiorrhiza Bunge （SM） and lignum dalbergiae odoriferae （DO） are both traditional Chi- nese medicine that have cardioprotective effects. Here, we further examined the combined effects of SM and DO on rat myocardial ischemia/reperfusion injury. The possible mechanism of SM and DO also were elucidated. Methods DO was divided into aqueous extract of lignum dalbergiae odoriferae （DOW） and lignum dalbergiae odoriferae oil （DOO）. Sprague-Dawley rats were randomized to seven groups： sham group, model group, treatment groups inclu- ding SM （10 g · kg^-1）, DOW （5 g · kg^-1）, DOO （0.5 ml · kg^-1）, SM ＋ DOW （10 g · kg^-1 ＋ 5 g · kg^-1）, SM ＋ DOO （ 10 g · kg^-1 ＋ 0. 5 ml · kg^-1）. Rats were pretreated with homologous drug for 7 days and then subjec- ted to 30 rain of ischemia followed by 180 rain of reperfusion. Electrocardiogram （ECG） and heart rate were moni- tored and recorded continuously. At the end of reperfusion, blood samples were collected to determine the serum levels of creatine kinase-MB （CK-MB） and lactate dehydrogenase （LDH）. Hearts were harvested to assess heart- body rate, infarct size and histopathological changes as well. Maximum and minimum effective points were deter- mined by measuring indicators associate with myocardial injury at different time-points of reperfusion （Smin, 15min, 30min, 45rain, 60min, 120min, 180min）. The potential therapeutic mechanism of SM and SM ＋ DOO were carried out by detecting superoxide dismutase （SOD）, malondialdehyde （MDA）, tumor necrosis factor-alpha （TNF-alpha） and interleukin 6 （IL-6）. Results The results showed SM and DO can ameliorate cardiac function respectively, and this cardioprotective effect was further strengthened by their combinations. Among all the combi- nations, SM ＋ DOO showed predominant potential to improve ECG and heart rate, reduce heart-body rate （28.5% ＋ 1.4% , P 〈 0.01 vs model） and myocardial infarct size （ 20.96% ＋ 1.61% , P 〈 0.01 vs model, P 〈 0.05 vs SM） , attenuate histopathological damage, decrease the levels of CK-MB and LDH （P 〈 0.01 vs model, P 〈 0.05 vs SM）. The maximum effective points of SM and SM ＋ DOO were 15min and 30rain respectively, and the minimum effective points of them were 180rain. In reducing serum level of MDA, TNF-alpha, IL-6 and increasing SOD activ- ity, SM ＋ DOO was similar to SM. Conclusion The results of this study indicated that SM ＋ DOO have combined effects that are highly effective than single pretreatment against myocardial ischemie reperfusion injury in rats. The possible mechanism of SM and DO were likely through its anti-oxidant and anti-inflammatory properties, and thus may be an effective and promising medicine for both prophylaxis and treatment of ischemic heart disease.

Published papers about Salvia miltiorrhiza Bunge as a Chinese medicinal material

Xu Cuihong, Shu Zhiming, Wang Yan, Miao Fang, Zhou ke. The accumulation rule of the main medicinal components in different organs of Salvia miltiorrhiza Bunge. and Salvia miltiorrhiza Bunge. f. alba. Lishizhen Medicine and Materia Medica Research, 2010, 21（09）： 2129-2132. Email： miaofangmf@ 163,com

Published papers about Salvia miltiorrhiza Bunge used in traditional Chinese medicine

Chu Kedan, Ji Guolu, Shi Hong, Xie Weirong, Zhang Yuqin, Zhang Xiaoqin. Study of the alcohol extraction process of Shenhu granules. Strait Pharmaceutical Journal, 2011, 23（03）： 21-24. Email： chukd5917@ 163.com

Molecular mechanism of Salvia miltiorrhiza Bunge and Carthamus tinctorius L. in the treatment of myocardial ischemia based on network pharmacology: a comparative study

Based on network pharmacology and molecular docking technology,the similarities and differences of anti-myocardial ischemia mechanism between Salvia miltiorrhiza Bunge(SM)and Carthamus tinctorius L.(CT)were studied.Firstly,based on the traditional Chinese medicine systems pharmacology(TCMSP),the related compounds of SM and CT were obtained,and the potential targets of these compounds were collected by the target fishing method.Genecards database was used to obtain targets related to myocardial ischemia.The cross targets of CT,SM,and myocardial ischemia were then selected,and the protein-protein interaction(PPI)network was constructed based on the STRING database.The cross targets were imported into the Metascape database for Gene Oncology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis.Cytoscape software was used to build the topological network diagram of the drug-compound-target path.Finally,the binding ability of the active ingredient and the key target was verified by molecular docking.65 active ingredients and 38 potential targets were screened from SM,and 22 active ingredients and 58 potential targets were excavated from CT.Important targets common to SM and CT were TNF,IL6,VEGFA,AKT1,etc.The common enrichment pathways involved are fluid shear stress and atherosclerosis,IL-17 signaling pathway,pathways in cancer,and toxoplasmosis.The findings suggested that the two traditional Chinese medicines exerted the effect of myocardial ischemia through the characteristics of multiple targets,multiple pathways,and multiple compounds.

Informatics-based prediction of molecular networks targeted by active ingredients in Danshen (Salvia miltiorrhiza)

Salvia miltiorrhiza (Chinese, Danshen) is one of the most famous traditional herbs, and has been used to treat cardiovascular disease. Despite the wide application of Danshen in China, the mechanisms of its bioactive components are poorly understood. The present study used bioinformatics to identify possible mechanisms by which Danshen treats cardiovascular disease. Possible human protein targets of Danshen were identified in the PubChem database, possible human gene targets of cardiovascular disease were identified in the NCBI database, and then both sets of targets were analyzed using Ingenuity Pathway Analysis to predict molecular networks affected by Danshen in cardiovascular disease. The results suggest that signaling proteins affected by Danshen in cardiovascular disease, which include FASN, PAFAH1B2, PLA2G7, PAFAH1B3 and IL1B, are involved primarily in LXR/RXR activation, atherosclerosis signaling, hepatic fibrosis/hepatic stellate cell activation, acute phase response signaling. The main networks affected by Danshen are predicted to involve in cellular movement, immune cell trafficking, hematological system development and function;DNA replication, recombination, and repair, cancer, hematological disease;cardiovascular disease, organismal injury and abnormalities, tissue morphology.These results identify several specific proteins and pathways that may be affected by Danshen in cardiovascular disease, and they illustrate the power of integrative bioinformatics and chemical fragment analysis for focusing mechanistic studies.

The anti-pulmonary fibrosis of Salvia miltiorrhiza Bunge: A systematic review

The characteristics of PF are diffuse alveolitis and disruption of alveolar structure leading to pulmonary interstitial fibrosis.At the same time,pulmonary fibrosis reduces lung volume and restricts ventilation,ultimately leading to hypoxemia and respiratory failure.In clinical guidelines,Nintedanib or Pirfenidone is often used for treatment.However,the two drugs,although they may slow the progression of the disease,cannot stop,or reverse fibrosis and generally result in a variety of toxic side effects.In 184-220 A.D.,it was already recorded in Supplementary Records of Famous Physicians that the function of SMB was to invigorate blood circulation and disperse blood stasis.In modern medical research,the active ingredients of SMB have likewise been found to be used in treatments such as anti-fibrosis,anti-inflammatory,antithrombotic,antioxidant,microcirculatory improvement,and antineoplastic.In this review,a comprehensive search of the former literature on SMB and pulmonary fibers was conducted using databases including PubMed,CNKI,the National Science and Technology Library,Hindawi,Chinese Science and Technology Journal Database,and the Scientific Network Database.Meanwhile,this review presents the mechanisms of the active ingredients in SMB which have anti-pulmonary fibrosis effects through the signal pathways,cytokines,inflammation response,oxidative stress,apoptosis,and matrix metalloproteinases.SMB could offer a direction for therapy for pulmonary fibrosis by identifying the possible active components and exploring the potential mechanisms.Those could provide a reference for further research and application of SMB in the treatment of pulmonary fibrosis.

Tyrosine Aminotransferase Gene (SmTAT) Revealed Genetic Diversity and Phylogeny of Cultivated Danshen (Salvia miltiorrhiza) Populations

Chinese traditional medicine Danshen is the radix of the perennial herbs of Salvia miltiorrhiza Bunge, which has a variety of pharmacological effects and is traditionally and extensively applied clinically to treat cardiovascular disorders. In this research, the genomic genes for tyrosine aminotransferase (TAT) of 38 cultivated populations of Danshen in China were cloned and bioinformatic analyses were conducted to reveal its genetic diversity and phylogeny. The full-length SmTAT was 2296 - 2444 bp including 6 exons (encoding 411 amino acids) and 5 introns. Overall, the SmTAT genes in cultivated Danshen populations are highly conserved with a relative low level of genetic diversity. The spliced exons (1236 bp) had 23 SNP variations with a rate of 1.86%, of which 22 occurred in the white flower S. miltiorrhiza Bge.f.alba population (W-SCHY-W-1) and led to 5 amino acid variations. The entire 290 SNP variations with a rate of 24% in the 5 introns occurred exclusively in W-SCHY-W-1. Phylogenetic trees based on the full-length, combined introns, the spliced exons, and the deduced amino acid sequences of SmTAT all showed a two-clade basic structure with W-SCHY-W-1 uniquely standing alone. The SmTAT gene of the white flower population (W-SCHY-W-1) is unique and especially rich in variations. The first time clarified genomic SmTAT gene structure and genetic diversity in cultivated Danshen populations laid an excellent foundation for further studies on the biosynthesis of bioactives and the molecular breeding of Danshen as well as in plant tyrosine metabolism.

Studies on the comparative pharmacokinetic of three phenolic acids of Salvia miltiorrhiza Bunge in normal and hyperlipidemic rats by liquid chromatography-tandem mass spectrometry

The hydrophilic phenolic acid is the main component of Salvia miltiorrhiza Bunge against cardiovascular diseases.A validated and sensitive liquid chromatography-tandem mass spectrometry(LC-MS/MS)method was established to simultaneously determinate three phenolic acids(danshensu,protocatechuic acid and rosmarinic acid)in rats to investigate their pharmacokinetic profiles firstly.The values for limit of quantification were in range of 0.25-1.25μg/L.Meanwhile,the suitable intra-day and inter-day precision as well as extraction recoveries were also obtained.And such an established method was finally successfully applied to compare the pharmacokinetic behaviors of three phenolic acids in normal and hyperlipidemic rats after oral administration of Salvia miltiorrhiza Bunge.The results showed there were significant differences in pharmacokinetic parameters between normal and hyperlipidemic groups.In especial,the plasma level of three phenolic acids in hyperlipidemic groups was significantly higher than normal ones.This comparative pharmacokinetic study provided direct evidence for improving clinical rational use of Salvia miltiorrhiza Bunge.

丹参(Salvia miltiorrhiza)中一对具有新奇结构的立体异构体的结构测定

为了进一步弄清丹参的化学成分，应用化学和色谱分离方法从丹参中分离到一个白色粉末固体，经综合运用先进的波谱分析手段，包括１Ｈ－１ＨＣＯＳＹ、１Ｈ－１３ＣＣＯＳＹ、ＣＯＬＯＣ、ＮＯＥ等二维核磁共振谱确定了它们的化学结构为一对具有螺环缩酮内酯结构的新二萜类立体异构体化合物．

Progress in research into the mechanism of Radix salviae miltiorrhizae in treatment of acute pancreatitis

BACKGROUND: Acute pancreatitis (AP) is a common acute abdomen with high mortality, multiple complications and complicated causes. There is no effective therapy for AP. Radix salviae miltiorrhizae (Danshen), a traditional herbal medicine, has a low price and a wide range of clinical applications. It is effective to promote blood flow, eliminate stagnancy, and relieve pain. It is also found to be effective in treating AP. We reviewed the progress in research into the mechanism of Radix salviae miltiorrhizae in treatment of AP. DATA SOURCES: An english-language literature search was conducted using MEDLINE (1988-2005) on Radix salviae miltiorrhizae (Danshen) and acute pancreatitis. RESULTS: The mechanisms of Danshen in the treatment of AP include improvement of microcirculatory disturbances; elimination of oxygen free radicals; modulation of the metabolism of lipid inflammatory mediator; and blocking of calcium inflow and prevention of calcium overload.CONCLUSION: Danshen can effectively reduce the mortality and complications of AP.

Preliminary study on Salvia miltiorrhiza bung endophytic fungus

Objective To select the strains which can produce tanshinone ⅡA like its host plant Salvia miltiorrhiza bung.Methods A total of 50 strains of endophytic fungi were isolated from healthy,living and symptomless tissues of Salvia miltiorrhiza bung,among which 29 strains were obtained from the root,14 from the stem,3 from the leaf,3 from the flower and 1 from the seed.Their antimicrobial activities against nine different bacteria,including both Gram-negative and Gram-positive bacteria,were measured by Oxford plate agar diffusion bioassay.Results Our data showed that all but four strains had significant antibacterial activities on at least one indicator bacterium to some extent,and five strains(DR1,DR4,DR16,DR18 and DF2)manifested quite prominent antibacterial activities against certain pathogenic bacteria.In some degree,it might indicate that this endophytic fungus isolated from the tissues of Salvia miltiorrhiza bung has a potential value as a natural antibacterial medicine as well.Thin layer chromatography(TLC)and high-performance liquid chromatography(HPLC)were carried out to test selected strains,both inside and outside of the cell to see if any strain can produce tanshinone ⅡA.The result showed that extracts from three strains,labeled as DR12(outside cell),DR21(inside cell)and DF3(inside cell),had a component with the same Rf value in TLC assay as that of authentic tanshinone ⅡA.The extract from DR12(outside cell)and DR21(inside cell)had a peak at retention time identical to that of authentic tanshinone ⅡA in HPLC.Conclusion The fungi appear to produce the bioactive compound tanshinone ⅡA,and they could be used to produce tanshinone ⅡA by fermentation.It provides a new way to synthesize this natural medicine.

Effects of salvia miltiorrhiza bung （SMB） onosteoblast－like cell lin （clonal MC3T3－E1 cells）

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Effects of Salvia Miltiorrhiza Bung on the formation of osteoclastlike cells in mouse bone marrow culture

Objective:To studytheeffectsof SalviaMiltiorrhizaBung(SMB)on theformationof osteoclast-likecellsin vitro.Methods:Mousebonemarrowcellswereculturedwithα-MEMandexposedto SMB(1.0g/L),PGE 2 (1×10 -7 mol/L)or1.25(OH) 2 D 3 (1×10 -8 mol/L)only,andSMB+PGE 2 ,SMB+1.25(OH) 2 D 3 for8d respectively.Tatrate-resistant acidphosphatase(TRACP)-positivecellsweredetectedwithBurstonemethod.Results:Thenumberof TRACPpositive cells(mononuclearcellsonly)ingroupof SMBwas29.8%of thatof thecontrol,thatingroupof combinationof SMB withPGE 2 was35.2%of thatof groupPGE 2 alone,andthatingroupof SMBplus1.25(OH) 2 D 3 was39.3%of thatof group1.25(OH) 2 D 3 alone.SMBinhibitedtheTRACP-positivecellsformationonlyat theconcentrationof1.0g/L,whichwere notonlyinmononuclearcellsbutalsoinmultinuclearcells.In addition,TRACP-positivecellsinthegroupsof1.25(OH) 2 D 3 or PGE 2 were6.68and6.04timesrespectivelyas thatof thecontrols.Conclu sion:SMBhastheinhibitingeffectson osteoclast-likecellsformation,bothosteoclastsandtheirprecursors.

丹参对糖尿病肾病保护作用及机制研究

糖尿病肾病(diabetes nephropathy,DN)是导致终末期肾脏病的首位致病因素,严重威胁患者生命健康。传统中医药在糖尿病肾病的治疗中具有重要潜力作用,丹参作为活血化瘀药代表,具有活血祛瘀、清心除烦之功。经研究发现,丹参含有丹酚酸、丹参酮、挥发油、多糖、含氮类化合物等多种成分,能够通过多途径多靶点改善肾小球超滤过状态和间质纤维化等病理改变,其中丹酚酸类和丹参酮类是丹参发挥糖尿病肾病保护作用的主要生物活性成分,具有降糖、调脂、抗炎、抗氧化应激、改善血流动力学、纠正肠道菌群紊乱、调节自噬水平等多种药理作用。该文参考近年来丹参相关制剂干预糖尿病肾病的临床研究和动物实验,对丹参在糖尿病肾病发生发展过程中起到的作用机制进行归纳总结,以期为临床应用丹参治疗糖尿病肾病提供更好的治疗策略和理论依据。

铬胁迫对丹参种子萌发及幼苗生理特性的影响

为了明确重金属铬胁迫对丹参种子萌发、幼苗生长与生理指标的影响,采用不同浓度(0、50、100、150、200、250 mg/L)K_(2)Cr_(2)O_(7)处理丹参种子,测定种子发芽率和幼苗根长、苗鲜质量、叶绿素含量及抗逆酶活性等指标。结果表明,丹参种子发芽率及幼苗根长、苗鲜质量、叶绿素含量均随着Cr^(6+)浓度增加而下降;随着Cr^(6+)浓度增加,丹参幼苗POD活性显著升高,CAT活性先升高后降低,SOD活性逐渐下降,Pro和MDA含量增加。研究表明,Cr^(6+)对丹参种子萌发及幼苗生长有显著的胁迫和毒害作用,幼苗根的生长受Cr^(6+)胁迫最为严重。