Tanshinone

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Guoyin Kai - One of the best experts on this subject based on the ideXlab platform.

  • salvia miltiorrhiza in treating cardiovascular diseases a review on its pharmacological and clinical applications
    Frontiers in Pharmacology, 2019
    Co-Authors: Jie Ren, Guoyin Kai, Shivraj Hariram Nile, Jun Zhang
    Abstract:

    Bioactive chemical constitutes from the root of Salvia miltiorrhiza classified in two major groups, viz., liposoluble Tanshinones and water-soluble phenolics. Tanshinone IIA is a major lipid-soluble compound having promising health benefits. The in vivo and in vitro studies showed that the Tanshinone IIA and salvianolate have a wide range of cardiovascular and other pharmacological effects, including antioxidative, anti-inflammatory, endothelial protective, myocardial protective, anticoagulation, vasodilation, and anti-atherosclerosis, as well as significantly help to reduce proliferation and migration of vascular smooth muscle cells. In addition, some of the clinical studies reported that the S. miltiorrhiza preparations in combination with Western medicine were more effective for treatment of various cardiovascular diseases including angina pectoris, myocardial infarction, hypertension, hyperlipidemia, and pulmonary heart diseases. In this review, we demonstrated the potential applications of S. miltiorrhiza, including pharmacological effects of salvianolate, Tanshinone IIA, and its water-soluble derivative, like sodium Tanshinone IIA sulfonate. Moreover, we also provided details about the clinical applications of S. miltiorrhiza preparations in controlling the cardiovascular diseases.

  • enhanced diterpene Tanshinone accumulation and bioactivity of transgenic salvia miltiorrhiza hairy roots by pathway engineering
    Journal of Agricultural and Food Chemistry, 2016
    Co-Authors: Min Shi, Huizhong Wang, Shengxiong Huang, Xiuqin Luo, Tong Zhang, Guoyin Kai
    Abstract:

    Tanshinones are health-promoting diterpenoids found in Salvia miltiorrhiza and have wide applications. Here, SmGGPPS (geranylgeranyl diphosphate synthase) and SmDXSII (1-deoxy-d-xylulose-5-phosphate synthase) were introduced into hairy roots of S. miltiorrhiza. Overexpression of SmGGPPS and SmDXSII in hairy roots produces higher levels of Tanshinone than control and single-gene transformed lines; Tanshinone production in the double-gene transformed line GDII10 reached 12.93 mg/g dry weight, which is the highest Tanshinone content that has been achieved through genetic engineering. Furthermore, transgenic hairy root lines showed higher antioxidant and antitumor activities than control lines. In addition, contents of chlorophylls, carotenoids, indoleacetic acid, and gibberellins were significantly elevated in transgenic Arabidopsis thaliana plants. These results demonstrate a promising method to improve the production of diterpenoids including Tanshinone as well as other natural plastid-derived isoprenoids ...

  • effects of methyl jasmonate and salicylic acid on Tanshinone production and biosynthetic gene expression in transgenic salvia miltiorrhiza hairy roots
    Biotechnology and Applied Biochemistry, 2015
    Co-Authors: Xiaolong Hao, Min Shi, Guoyin Kai, Lijie Cui, Yanjie Zhang
    Abstract:

    Tanshinone is a group of active diterpenes, which are widely used in the treatment of cardiovascular disease. In this study, methyl jasmonate (MJ) and salicylic acid (SA) were used to investigate their effects on Tanshinone accumulation and biosynthetic gene expression in the hairy roots of geranylgeranyl diphosphate synthase (SmGGPPS) overexpression line (G50) in Salvia miltiorrhiza. High-performance liquid chromatography analysis showed that total Tanshinone content in G50 was obviously increased by 3.10-fold (11.33 mg/g) with MJ at 36 H and 1.63 times (5.95 mg/g) after SA treatment for 36 H in comparison with their mimic treatment control. Furthermore, quantitative reverse-transcription PCR analysis showed that the expression of isopentenyl-diphosphate delta-isomerase (SmIPPI), SmGGPPS, copalyl diphosphate synthase (SmCPS), and kaurene synthase-like (SmKSL) increased significantly with MJ treatment. However, the expression of SmIPPI reached the highest level at 144 H, whereas those of SmGGPPS, SmCPS, and SmKSL only increased slightly with SA treatment. The two elicitor treatments suggested that Tanshinone accumulation positively correlated to the expression of key genes such as SmGGPPS, SmCPS, and SmKSL. Meanwhile, the study also indicated that it was a feasible strategy to combine elicitor treatment with transgenic technology for the enhancement of Tanshinone, which paved the way for further metabolic engineering of Tanshinone biosynthesis.

  • increased accumulation of the cardio cerebrovascular disease treatment drug Tanshinone in salvia miltiorrhiza hairy roots by the enzymes 3 hydroxy 3 methylglutaryl coa reductase and 1 deoxy d xylulose 5 phosphate reductoisomerase
    Functional & Integrative Genomics, 2014
    Co-Authors: Min Shi, Xiuqin Luo, Guoyin Kai, Jianbo Xiao, Xiaolong Hao, Qiang Huang, Lijie Cui
    Abstract:

    Tanshinone is widely used for treatment of cardio-cerebrovascular diseases with increasing demand. Herein, key enzyme genes SmHMGR (3-hydroxy-3-methylglutaryl CoA reductase) and SmDXR (1-deoxy-d-xylulose 5-phosphate reductoisomerase) involved in the Tanshinone biosynthetic pathway were introduced into Salvia miltiorrhiza (Sm) hairy roots to enhance Tanshinone production. Over-expression of SmHMGR or SmDXR in hairy root lines can significantly enhance the yield of Tanshinone. Transgenic hairy root lines co-expressing HMGR and DXR (HD lines) produced evidently higher levels of total Tanshinone (TT) compared with the control and single gene transformed lines. The highest Tanshinone production was observed in HD42 with the concentration of 3.25 mg g−1 DW. Furthermore, the transgenic hairy roots showed higher antioxidant activity than control. In addition, transgenic hairy root harboring HMGR and DXR (HD42) exhibited higher Tanshinone content after elicitation by yeast extract and/or Ag+ than before. Tanshinone can be significantly enhanced to 5.858, 6.716, and 4.426 mg g−1 DW by YE, Ag+, and YE-Ag+ treatment compared with non-induced HD42, respectively. The content of cryptoTanshinone and dihydroTanshinone was effectively elevated upon elicitor treatments, whereas there was no obvious promotion effect for the other two compounds Tanshinone I and Tanshinone IIA. Our results provide a useful strategy to improve Tanshinone content as well as other natural active products by combination of genetic engineering with elicitors.

  • molecular mechanism of elicitor induced Tanshinone accumulation in salvia miltiorrhiza hairy root cultures
    Acta Physiologiae Plantarum, 2012
    Co-Authors: Guoyin Kai, Wei Zhou, Pan Liao, Jing Wang, Congcong Zhou, Jianbo Xiao, Yuliang Wang, Lin Zhang
    Abstract:

    To develop an optimal bioprocess for the production of Tanshinone which is mainly used for the treatment of cardiocerebral vascular disease, the Tanshinone biosynthetic pathway regulation must be better understood. In this paper, expression of Tanshinone biosynthetic pathway related genes as well as Tanshinone accumulation in Salvia miltiorrhiza hairy root cultures were investigated, in response to biotic and abiotic elicitors, respectively. Our results showed Tanshinone accumulation in S. miltiorrhiza hairy roots was highly regulated by the coordination of the expression of several genes involved in Tanshinone biosynthesis pathway. Our results showed a positive correlation between gene expression and Tanshinone accumulation, suggesting that Tanshinone accumulation may be the result of the coexpression up-regulation of several genes involved in Tanshinone biosynthesis under the treatment of various elicitors. Meantime, SmHMGR, SmDXS2, SmFPPS, SmGGPPS and SmCPS were identified as the potential key enzymes in the pathway for targeted metabolic engineering to increase accumulation of Tanshinone in S. miltiorrhiza hairy roots. This is the first report integrating comprehensively the transcript and metabolite biosynthesis of Tanshinone in S. miltiorrhiza hairy roots.

Yoichiro Ito - One of the best experts on this subject based on the ideXlab platform.

Duxin Qing - One of the best experts on this subject based on the ideXlab platform.

  • Tanshinone iia elicited vasodilation in rat coronary arteriole roles of nitric oxide and potassium channels
    European Journal of Pharmacology, 2009
    Co-Authors: Guobao Wu, Enxiang Zhou, Duxin Qing
    Abstract:

    Abstract Salvia miltiorrhiza has been widely used in the treatment of various cardiovascular diseases due to its ability to improve coronary microcirculation and increase coronary blood flow. Tanshinone IIA, the major active lipophilic ingredient responsible for the beneficial actions of Salvia miltiorrhiza, was shown to induce vasodilation in coronary arteries. But its effects on coronary arterioles remain unknown. The purpose of this study was to investigate the effects of Tanshinone IIA on isolated rat coronary arteriole and the underlying mechanisms. Coronary arterioles were carefully dissected, cannulated and pressurized. Tanshinone IIA-elicited vascular inner diameter change was recorded by a computerized diameter tracking system. To investigate the mechanisms governing the vasodilative effects of Tanshinone IIA, the roles of endothelium, endothelium-derived vasoactive factors and potassium channels were assessed respectively. Endothelium denudation, inhibition of nitric oxide synthase (NOS), inhibition of the cytochrome P450 epoxygenase, and blockade of the large conductance calcium(Ca2+)-activated potassium channels (BKca) significantly decreased the vasodilation elicited by Tanshinone IIA. The results indicated that Tanshinone IIA induces an endothelium-dependent vasodilation in coronary arterioles; nitric oxide (NO) and cytochrome P450 metabolites contribute to the vasodilation; activation of BKca channels plays an important role in the vasodilation.

  • Tanshinone iia elicited vasodilation in rat coronary arteriole roles of nitric oxide and potassium channels
    European Journal of Pharmacology, 2009
    Co-Authors: Guobao Wu, Enxiang Zhou, Duxin Qing
    Abstract:

    Abstract Salvia miltiorrhiza has been widely used in the treatment of various cardiovascular diseases due to its ability to improve coronary microcirculation and increase coronary blood flow. Tanshinone IIA, the major active lipophilic ingredient responsible for the beneficial actions of Salvia miltiorrhiza, was shown to induce vasodilation in coronary arteries. But its effects on coronary arterioles remain unknown. The purpose of this study was to investigate the effects of Tanshinone IIA on isolated rat coronary arteriole and the underlying mechanisms. Coronary arterioles were carefully dissected, cannulated and pressurized. Tanshinone IIA-elicited vascular inner diameter change was recorded by a computerized diameter tracking system. To investigate the mechanisms governing the vasodilative effects of Tanshinone IIA, the roles of endothelium, endothelium-derived vasoactive factors and potassium channels were assessed respectively. Endothelium denudation, inhibition of nitric oxide synthase (NOS), inhibition of the cytochrome P450 epoxygenase, and blockade of the large conductance calcium(Ca2+)-activated potassium channels (BKca) significantly decreased the vasodilation elicited by Tanshinone IIA. The results indicated that Tanshinone IIA induces an endothelium-dependent vasodilation in coronary arterioles; nitric oxide (NO) and cytochrome P450 metabolites contribute to the vasodilation; activation of BKca channels plays an important role in the vasodilation.

Sam Sik Kang - One of the best experts on this subject based on the ideXlab platform.

  • Tanshinone congeners improve memory impairments induced by scopolamine on passive avoidance tasks in mice
    European Journal of Pharmacology, 2007
    Co-Authors: Donghyun Kim, Su Jin Jeon, Kun Ho Son, Yeong Shik Kim, Ji Wook Jung, Seungjoo Lee, Byung Hoon Yoon, Bum Young Shin, Jae Hoon Cheong, Sam Sik Kang
    Abstract:

    Tanshinones are a group of diterpenoids found in the roots of Salvia miltiorrhiza Bunge which has been used to treat cardiac disease. In the present study, we investigated the effect of the Tanshinone congeners, Tanshinone I, Tanshinone IIA, cryptoTanshinone, and 15, 16-dihydroTanshinone I, on learning and memory impairments induced by scopolamine (1 mg/kg, i.p.), a muscarinic antagonist, using passive avoidance tasks in mice. Tacrine was used as a positive control. Tanshinone I (2 or 4 mg/kg, p.o.), Tanshinone IIA (10 or 20 mg/kg, p.o.), cryptoTanshinone (10 mg/kg, p.o.), and 15, 16-dihydroTanshinone I (2 or 4 mg/kg, p.o.) significantly reversed scopolamine-induced cognitive impairments (P<0.05). Tanshinone I (2 mg/kg, p.o.) and Tanshinone IIA (10 or 20 mg/kg, p.o.) were also reversed diazepam-induced cognitive dysfunctions (P<0.05). In addition, cryptoTanshinone and 15, 16-dihydroTanshinone I were found to have an inhibitory effect on acetylcholinesterase in vitro with IC(50) values 82 and 25 microM, respectively. Furthermore, cryptoTanshinone inhibited acetylcholinesterase activity for 3 h and 15, 16-dihydroTanshinone I for 6 h in an ex-vivo study. These results suggest that Tanshinone congeners may be useful for the treatment of cognitive impairment and that their beneficial effects are mediated, in part, by cholinergic signaling enhancement.

  • Tanshinone congeners improve memory impairments induced by scopolamine on passive avoidance tasks in mice
    European Journal of Pharmacology, 2007
    Co-Authors: Donghyun Kim, Su Jin Jeon, Kun Ho Son, Yeong Shik Kim, Ji Wook Jung, Seungjoo Lee, Byung Hoon Yoon, Bum Young Shin, Jae Hoon Cheong, Sam Sik Kang
    Abstract:

    Abstract Tanshinones are a group of diterpenoids found in the roots of Salvia miltiorrhiza Bunge which has been used to treat cardiac disease. In the present study, we investigated the effect of the Tanshinone congeners, Tanshinone I, Tanshinone IIA, cryptoTanshinone, and 15, 16-dihydroTanshinone I, on learning and memory impairments induced by scopolamine (1 mg/kg, i.p.), a muscarinic antagonist, using passive avoidance tasks in mice. Tacrine was used as a positive control. Tanshinone I (2 or 4 mg/kg, p.o.), Tanshinone IIA (10 or 20 mg/kg, p.o.), cryptoTanshinone (10 mg/kg, p.o.), and 15, 16-dihydroTanshinone I (2 or 4 mg/kg, p.o.) significantly reversed scopolamine-induced cognitive impairments (P

John H K Yeung - One of the best experts on this subject based on the ideXlab platform.

  • reversal of p glycoprotein p gp mediated multidrug resistance in colon cancer cells by cryptoTanshinone and dihydroTanshinone of salvia miltiorrhiza
    Phytomedicine, 2014
    Co-Authors: Lin Wang, John H K Yeung, Lin Zhang, Jing Shen, Ruby L Y Chan, C H Cho
    Abstract:

    Abstract Objective Multidrug resistance (MDR) of cancer cells to a broad spectrum of anticancer drugs is an obstacle to successful chemotherapy. Overexpression of P-glycoprotein (P-gp), an ATP-binding cassette (ABC) membrane transporter, can mediate the efflux of cytotoxic drugs out of cancer cells, leading to MDR and chemotherapy failure. Thus, development of safe and effective P-gp inhibitors plays an important role in circumvention of MDR. This study investigated the reversal of P-gp mediated multidrug resistance in colon cancer cells by five Tanshinones including Tanshinone I, Tanshinone IIA, cryptoTanshinone, dihydroTanshinone and miltirone isolated from Salvia miltiorrhiza (Danshen), known to be safe in traditional Chinese medicine. Methods The inhibitory effects of Tanshinones on P-gp function were compared using digoxin bi-directional transport assay in Caco-2 cells. The potentiation of cytotoxicity of anticancer drugs by effective Tanshinones were evaluated by MTT assay. Doxorubicin efflux assay by flow cytometry, P-gp protein expression by western blot analysis, immunofluorescence for P-gp by confocal microscopy, quantitative real-time PCR and P-gp ATPase activity assay were used to study the possible underlying mechanisms of action of effective Tanshinones. Results Bi-directional transport assay showed that only cryptoTanshinone and dihydroTanshinone decreased digoxin efflux ratio in a concentration-dependent manner, indicating their inhibitory effects on P-gp function; whereas, Tanshinone I, Tanshinone IIA and miltirone had no inhibitory effects. Moreover, both cryptoTanshinone and dihydroTanshinone could potentiate the cytotoxicity of doxorubicin and irinotecan in P-gp overexpressing SW620 Ad300 colon cancer cells. Results from mechanistic studies revealed that these two Tanshinones increased intracellular accumulation of the P-gp substrate anticancer drugs, presumably by down-regulating P-gp mRNA and protein levels, and inhibiting P-gp ATPase activity. Conclusions Taken together, these findings suggest that cryptoTanshinone and dihydroTanshinone could be further developed for sensitizing resistant cancer cells and used as an adjuvant therapy together with anticancer drugs to improve their therapeutic efficacies for colon cancer.

  • major Tanshinones of danshen salvia miltiorrhiza exhibit different modes of inhibition on human cyp1a2 cyp2c9 cyp2e1 and cyp3a4 activities in vitro
    Phytomedicine, 2010
    Co-Authors: Xin Wang, Wayne Y W Lee, Ching Mei Cheung, John H K Yeung
    Abstract:

    Abstract This study investigated the effects of Tanshinones on human CYP1A2 (phenacetin O-deethylase), CYP2C9 (tolbutamide 4-hydroxylase), CYP2E1 (chlorzoxazone 6-hydroxylase) and CYP3A4 (testosterone 6β-hydroxylase) activities in vitro using pooled human liver microsomes and specific human CYP isoforms. Tanshinone I, Tanshinone IIA, and cryptoTanshinone were potent competitive CYP1A2 inhibitors (Ki = 1.5–2.5 μM); medium competitive inhibitors of CYP2C9 (Ki = 22–62 μM); medium competitive inhibitors of CYP2E1 (Ki = 3.67 μM) for Tanshinone I and 10.8 μM for crytoTanshinone; but weak competitive inhibitors of CYP3A4 (Ki = 86–220 μM). DihydroTanshinone was a competitive inhibitor of human CYP1A2 (Ki = 0.53 μM) and CYP2C9 (Ki = 1.92 μM), a noncompetitive inhibitor of CYP3A4 (Ki = 2.11 μM) but an uncompetitive CYP2E1 inhibitor. In conclusion, these results showed that Tanshinones inhibited the metabolism of various CYP probe substrates in human liver microsomes and specific human CYP isoforms in vitro. Given that CYP1A2, 2C9, 2E1 and 3A4 are responsible for the metabolism and disposition of a large number of drugs currently used, the potential herb–drug interactions of Danshen preparations containing the major Tanshinones with drugs which are substrates of these CYPs may be important.

  • major Tanshinones of danshen salvia miltiorrhiza exhibit different modes of inhibition on human cyp1a2 cyp2c9 cyp2e1 and cyp3a4 activities in vitro
    Phytomedicine, 2010
    Co-Authors: Xin Wang, Wayne Y W Lee, Ching Mei Cheung, John H K Yeung
    Abstract:

    This study investigated the effects of Tanshinones on human CYP1A2 (phenacetin O-deethylase), CYP2C9 (tolbutamide 4-hydroxylase), CYP2E1 (chlorzoxazone 6-hydroxylase) and CYP3A4 (testosterone 6beta-hydroxylase) activities in vitro using pooled human liver microsomes and specific human CYP isoforms. Tanshinone I, Tanshinone IIA, and cryptoTanshinone were potent competitive CYP1A2 inhibitors (K(i)=1.5-2.5 microM); medium competitive inhibitors of CYP2C9 (K(i)=22-62 microM); medium competitive inhibitors of CYP2E1 (K(i)=3.67 microM) for Tanshinone I and 10.8 microM for crytoTanshinone; but weak competitive inhibitors of CYP3A4 (K(i)=86-220 microM). DihydroTanshinone was a competitive inhibitor of human CYP1A2 (K(i)=0.53 microM) and CYP2C9 (K(i)=1.92 microM), a noncompetitive inhibitor of CYP3A4 (K(i)=2.11 microM) but an uncompetitive CYP2E1 inhibitor. In conclusion, these results showed that Tanshinones inhibited the metabolism of various CYP probe substrates in human liver microsomes and specific human CYP isoforms in vitro. Given that CYP1A2, 2C9, 2E1 and 3A4 are responsible for the metabolism and disposition of a large number of drugs currently used, the potential herb-drug interactions of Danshen preparations containing the major Tanshinones with drugs which are substrates of these CYPs may be important.

  • pharmacokinetic interaction studies of Tanshinones with tolbutamide a model cyp2c11 probe substrate using liver microsomes primary hepatocytes and in vivo in the rat
    Phytomedicine, 2010
    Co-Authors: Xin Wang, Wayne Y W Lee, John H K Yeung
    Abstract:

    Abstract The effects of Danshen and its active components (Tanshinone I, Tanshinone IIA, dihydroTanshinone and cryptoTanshinone) on tolbutamide 4-hydroxylation was investigated in the rat. Danshen (0.125–2 mg/ml) decreased 4-hydroxy-tolbutamide formation in vitro and in vivo. Enzyme kinetics studies showed that inhibition of tolbutamide 4-hydroxylase activity was competitive and concentration-dependent. The Ki values of the Tanshinones were: dihydroTanshinone (8.92 μM), cryptoTanshinone (24.5 μM), Tanshinone I (80.3 μM) and Tanshinone IIA (242.9 μM). In freshly prepared primary rat hepatocytes, Tanshinones inhibited tolbutamide 4-hydroxylation in a concentration-dependent manner, with EC40 values in the order: cryptoTanshinone (15.8 μM), Tanshinone IIA (16.2 μM), dihydroTanshinone (20.1 μM) and Tanshinone I (48.2 μM). In whole animal studies, single dose Danshen treatment (50 or 200 mg/kg, i.p.) increased tolbutamide clearance (17–26.9%), decreased AUC (14.4–20.9%) and increased the Vd (7.26%). Three-day Danshen treatment (200 mg/kg/day, i.p.) decreased the Cinitial, increased T1/2 and Vd but did not affect tolbutamide clearance and AUC. Tolbutamide-4-hydroxylation in vivo was decreased by Danshen after acute and after 3-day treatment, with decreases in the AUC of 4-hydroxy-tolbutamide (15–28%) over the time period studied. Despite competitive inhibition of rat CYP2C11 in vitro and in vivo, as shown by the decrease in tolbutamide 4-hydroxylation, only minor changes in tolbutamide pharmacokinetics was observed. This study illustrated that the herb-drug interaction potential should be monitored by both in vitro and in vivo biotransformation/ pharmacokinetic parameters.

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