Mediation of mitochondrial translocator protein by tanshinone ⅡA in apoptosis of HepG2 cells / 中国药理学通报

Aim To investigate the role of mitochondrial translocator protein(TSPO)in the apoptosis of HepG2 cells induced by tanshinone IIA(Tan II A)and the involved mechanism. Methods Following the HepG2 cells treated with Tan ⅡA at 2.5, 5 and 10 μmol·L-1, the cell viability was determined by MTT assay, and intracellular ATP content was determined by luciferin-luciferase method. Oxygen utilization was measured polarographically with a Clark oxygen electrode. Cell apoptosis was determined by Hoechst 33342 staining and flow cytometry. The mitochondrial membrane potential was assessed with JC-1 staining. The intracellular distribution of TSPO was examined by TSPO immunostaining, and the expressions of TSPO, Cyto C, caspase-3, caspase-9 were determined by immunoblotting analysis. Results Tan II A inhibited the proliferation of HepG2 cells in a dose-and time-dependent manner. The treatment with Tan II A inhibited ATP production and oxygen utilization of mitochondria. In addition, Tan ⅡA enhanced TSPO expression and accumulation in nuclei and up-regulated the expression of Cyto C, caspase-3 and caspase-9. Conclusions Tan II A induces the apoptosis of HepG2 cells, which may be related to the TSPO-mediated mitochondrial dysfunction.

Tanshinone IIA promotes reverse cholesterol transport to improve atherosclerosis / 中国药理学通报

Aim To explore the effect of tanshinone II A (Tan II A) on reverse cholesterol transport in atherosclerosis model mice and RAW264. 7 cells and the underlying mechanism. Methods Thirty-two male LDLR -/- mice were randomly divided into four groups. These mice were fed with normal diet or high fat diet for 12 weeks. The control group and model group were given normal saline. Tan II A group and atorvastatin group were given Tan II A solution and atorvastatin solution for 12 weeks. RAW264. 7 cells were induced with oxidized low-density lipoprotein (ox-LDL) 100 mg • L-

Preparation and performance of random- and oriented-fiber membranes with core-shell structures via coaxial electrospinning.

The cells and tissue in the human body are orderly and directionally arranged, and constructing an ideal biomimetic extracellular matrix is still a major problem to be solved in tissue engineering. In the field of the bioresorbable vascular grafts, the long-term functional prognosis requires that cells first migrate and grow along the physiological arrangement direction of the vessel itself. Moreover, the graft is required to promote the formation of neointima and the development of the vessel walls while ensuring that the whole repair process does not form a thrombus. In this study, poly (l-lactide-co-ε-caprolactone) (PLCL) shell layers and polyethylene oxide (PEO) core layers with different microstructures and loaded with sodium tanshinone IIA sulfonate (STS) were prepared by coaxial electrospinning. The mechanical properties proved that the fiber membranes had good mechanical support, higher than that of the human aorta, as well as great suture retention strengths. The hydrophilicity of the oriented-fiber membranes was greatly improved compared with that of the random-fiber membranes. Furthermore, we investigated the biocompatibility and hemocompatibility of different functional fiber membranes, and the results showed that the oriented-fiber membranes containing sodium tanshinone IIA sulfonate had an excellent antiplatelet adhesion effect compared to other fiber membranes. Cytological analysis confirmed that the functional fiber membranes were non-cytotoxic and had significant cell proliferation capacities. The oriented-fiber membranes induced cell growth along the orientation direction. Degradation tests showed that the pH variation range had little change, the material mass was gradually reduced, and the fiber morphology was slowly destroyed. Thus, results indicated the degradation rate of the oriented-fiber graft likely is suitable for the process of new tissue regeneration, while the random-fiber graft with a low degradation rate may cause the material to reside in the tissue for too long, which would impede new tissue reconstitution. In summary, the oriented-functional-fiber membranes possessing core-shell structures with sodium tanshinone IIA sulfonate/polyethylene oxide loading could be used as tissue engineering materials for applications such as vascular grafts with good prospects, and their clinical application potential will be further explored in future research.

Tanshinone II A improves the chemosensitivity of breast cancer cells to doxorubicin by inhibiting ß-catenin nuclear translocation.

Numerous evidence link aberrant nuclear ß-catenin accumulation to the development of breast cancer resistance, therefore, targeted inhibition of ß-catenin nuclear translocation may effectively improve the chemosensitivity of breast cancer. Doxorubicin (Dox) is the most commonly used chemotherapeutic drug for breast cancer. Here, we determined that tanshinone II A (Tan II A) could improve the sensitivity of Dox-resistant breast cancer MCF-7/dox cells to Dox, and evaluated whether the sensitization effect of Tan II A on Dox was targeted to inhibit ß-catenin nuclear translocation. The results showed that Tan II A not only significantly inhibited the nuclear translocation of ß-catenin in MCF-7/dox cells treated by Dox but also inhibited the nuclear translocation of ß-catenin in MCF-7 cells treated by Dox to a certain degree. Furthermore, when the above two cells treated by Dox combined with Tan II A were intervened with ß-catenin agonist WAY-262611, with the re-nuclear translocation of ß-catenin in the cells, the sensitization effect of Tan II A on Dox was greatly reduced. These results indicated that Tan II A could improve the chemosensitivity of breast cancer cells to Dox by inhibiting ß-catenin nuclear translocation. Therefore, Tan II A could be used as a potential chemosensitizer in combination with Dox for breast cancer chemotherapy.

Tanshinone IIA inhibits LPS induced inflammation of RAW264.7 cells by regulating TLR4/IκB-α/NF-κB signaling pathway / 中国药理学通报

Aim To establishan inflammatory model of mouse monocyte macrophages ( RAW264. 7) using li-popolysaccharide (LPS), and to investigate the antiinflammatory activity and mechanism of tanshinone II-A (Tan IIA). Methods Cell viability was determined by CCK-8 method. Cell migration was detected by Tr-answell apparatus. TNF-α, IL-6, IL-1 p, MCP-1 content in cell supernatant was analyzed using ELISA method. The protein expression of MMP-2, MMP-9, TLR4, κB-α, p-κB-α, NFκB and p-NFκB in RAW264.7 cells was investigated by Western blot. Results Tan IIA significantly inhibited .the secretion of TNF-α, IL-6, IL-1β and MCP-1 in LPS induced RAW264.7 cell culture medium , and significantly down-regulated the expression of matrix metalloprotein-ase-2 (MMP-2), MMP-9, TLR4, p-κB-α and p-NFκB , inhibited IκB-α phosphorylation and NFκB entry into the nucleus and activation. Conclusion Tan IIA can inhibit the release of inflammatory factors through the regulation of TLR4/IκB-α/NFκB signaling pathway.

Tanshinone II A enhances pyroptosis and represses cell proliferation of HeLa cells by regulating miR-145/GSDMD signaling pathway.

Cervical cancer is the fourth most common cancer in women globally. Lack of effective pharmacotherapies for cervical cancer mainly attributed to an elusive understanding of the mechanism underlying its pathogenesis. Pyroptosis plays a key role in inflammation and cancer. Our study identified microRNA (miR) 145 (miR-145)/gasdermin D (GSDMD) signaling pathway as critical mediators in the effect of tanshinone II A on HeLa cells. In the present study, we found that treatment of tanshinone II A led to an obvious repression of cell proliferation and an increase in apoptosis on HeLa cells, especially in high concentration. Compared with the controlled group, tanshinone II A enhanced the activity of caspase3 and caspase9. Notably, the results demonstrated that tanshinone II A regulated cell proliferation of HeLa cells by regulating miR-145/GSDMD signaling pathway. Treatment of tanshinone II A significantly up-regulated the expression of GSDMD and miR-145. After transfection of si-miR-145 plasmids, the effects of tanshinone II A on HeLa cells were converted, including cell proliferation, apoptosis and pyroptosis. In addition, the results showed that tanshinone II A treatment altered the expression level of PI3K, p-Akt, NF-kB p65 and Lc3-I. Collectively, our findings demonstrate that tanshinone II A exerts anticancer activity on HeLa cells by regulating miR-145/GSDMD signaling. The present study is the first time to identify miR-145 as a candidate target in cervical cancer and show an association between miR-145 and pyroptosis, which provides a novel therapy for the treatment of cervical cancer.

Sodium Tanshinone II A Sulfonate for Coronary Heart Disease: A Systematic Review of Randomized Controlled Trials.

OBJECTIVE: To assess whether an adjunctive therapy of Sodium Tanshinone II A Sulfonate Injection (STS) is effective and safe in improving clinical outcomes in patients with coronary heart disease (CHD). METHODS: A literature search was conducted through PubMed, the Cochrane Library, Knowledge Infrastructure Databases (CNKI), Chinese Biomedical Literature Database (SinoMed), Chinese Science and Technology Periodical Database (VIP) and Wanfang Database up to August 2017. Randomized controlled trials (RCTs) comparing STS with placebo or no additional treatments on the basis of standard conventional medicine therapies were included. The outcomes were all-cause mortality, major acute cardiovascular events (MACEs), cardiac function and inflammatory factors. The risk of bias assessment according to the Cochrane Handbook was used to evaluate the methodological quality of the included trials. Revman 5.3 software was used for data analyses. RESULTS: A total of 22 RCTs involving 1,873 participants were included. All of the trials used STS as adjunctive treatment to standard conventional medicine therapy. Due to the poor quality of methodologies of most trials, only limited evidence showed that a combination of STS with percutaneous coronary intervention (PCI) or thrombolytic therapy (TT) might be more effective on reduction of all cause death rate than TT alone [risk ratio (RR) 0.25, 95% confidence interval (CI) 0.07 to 0.87] or PCI alone (RR 0.42, 95% CI 0.04 to 4.36). The results of 6 trials comparing STS plus TT with TT alone showed that the addition of STS significantly reduced the incidence of cardiac shock (RR 0.35, 95% CI 0.14 to 0.86), heart failure (RR 0.41, 95% CI 0.20 to 0.83) and arrhythmia (RR 0.21, 95% CI 0.12 to 0.46). STS combined with TT also showed a superior effect on cardiac function and inflammatory factor. No severe adverse event was reported related to STS. CONCLUSIONS: As an adjunctive therapy, STS combined with standard conventional medicine seems to be more effective on all-cause mortality or MACEs than conventional medicine treatment alone with less side effects. However, we cannot make a firm conclusion due to low quality of inclusion trials. Well-designed trials with high methodological quality are needed to validate the effect of STS for CHD patients.

Research progress on action and new dosage form oftanshinone IIA inliver diseases / 中国药理学通报

Liver diseases is one of serious public health problems due to their high global prevalence and poor long-term clinical outcomes. As a main active ingredient extracted from the traditional Chinese medicine Salvia miltiorrhiza, Tanshinone II A (Tan IIA) has been widely studied because of its various biological activities. Many experimental and clinical studies have demonstrated that Tan IIA can prevent and slow down the progression of various diseases through anti-inflammation, anti-oxidation, anti-cancer, anti-angiogenesis and other ways. Moreover, it can treat a variety of diseases including cardiovascular and cerebrovascular diseases, liver diseases, cancerand neurodegenerative diseases. However, Tan IIA is a highly hydrophobic compound with the disadvantages of poor oral absorption and bioavailability. To improve the current applications of Tan IIA, it is necessary to prepare new drug delivery systems such as nanoparticles, polymeric micelles, solid dispersions. In this article, an overview of Tan H A will be given with emphasis on the therapeutic activity and newly prepared dosage forms in liver diseases, including inflammation-related liver damage, liver fibrosis, nonalcoholic fatty liver disease(NAFLD)and hepatocellular carcinoma (HCC). This review may provide theoretical clues for clinical therapeutic applications of Tan IIA in liver diseases.

Combination of tanshinone IIA and doxorubicin possesses synergism and attenuation effects on doxorubicin in the treatment of breast cancer.

Doxorubicin (Dox) is a first-line drug for breast cancer chemotherapy. However, with the prolongation of chemotherapy cycle, breast cancer cells are increasingly tempt to resist Dox, and meanwhile, high cumulative dose of Dox brings enhancing toxic side effects, and these effects may lead to chemotherapy failure. Hence, it is necessary to search an agent in combination medication with Dox, which can not only enhance the chemosensitivity of Dox but also reduce the toxic side effects. Tanshinone IIA (Tan IIA) is reported to have antitumor activity in addition to its cardiovascular protective effects. We employed human breast cancer MCF-7 and MCF-7/dox cells in order to assess whether Tan IIA might perform such function. Our in vitro studies showed that Tan IIA could enhance the sensitivity of breast cancer cells to Dox through inhibiting the PTEN/AKT pathway and downregulating the expression of efflux ABC transporters including P-gp, BCRP, and MRP1. In addition, our in vivo studies showed Tan IIA enhanced the chemotherapeutic effect of Dox against breast cancer while reducing its toxic side effects including weight loss, myelosuppression, cardiotoxicity, and nephrotoxicity. Therefore, Tan IIA could be used as a novel agent combined with Dox in breast cancer therapy.

Inhibitory effect of tanshinone II a on proliferation and migration of human liver cancer hepg2 cells and its apoptosis-promoting effect / 吉林大学学报(医学版)

Objective: To observe the inhibitory effect of tanshinone II A (Tan II A) on the proliferation of liver cancer HepG2 cells and its inductive effect on the migration and apoptosis of HepG2 cells, and to explore the possible mechanism Methods: The human liver cancer HepG2 cells were cultured in vitro. The HepG2 cells were divided into blank group and different concentrations of Tan II A groups. The cells in different concentrations of Tan II A groups were added with Tan II A at the final concentrations of 0. 5, 1. 0, 2. 0, 5.0 and 10. 0 mg middot; L-1 Tan II A and cultured for 24 h. The morphology of HepG2 cells in various groups was observed under inverted microscope. The inhibitory rates of proliferation of HepG2 cells in various groups were detected by MTT assay. The migration of HepG2 cells in various groups were evaluated by cell scratch assay. The expression levels of nuclear factor-κB (NF-κB) and matrix metalloproteinase-9 (MMP-9) mRNA were detected by RT-PCR method. Flow cytometry was used to detect the percentages of HepG2 cells at different cell cycles in various groups, and the apoptotic rates of HepG2 cells in various groups were detected by TUNEL method. Results: The morphology of HepG2 cells in different concentrations of Tan II A groups were changed. Compared with blank group, the cells in 1. 0 and 2. 0 Tan II A groups showed shrinkage, scattered connection and poor growth, and the inhibitory rates of proliferation of HepG2 cells in 1. 0, 2. 0, 5.0, and 10. 0 mg middot; L-1 Tan II A groups were significantly increased (P< 0. 05) in a dose-dependent manner. The cell scratch assay results showed that with the increasing of Tan E A concentration, the migration number of the cells in 2. 0 and 5. 0 mg middot; L-1 Tan II A groups were decreased significantly. Compared with 0. 5 mg middot; L-1Tan II A group, the expression levels of MMP-9 and NF-κB mRNA in the HepG2 cells in 1. 0, 2. 0, and 5. 0 mg middot; L-1Tan II A groups were decresed (P<0. 05 or P<0. 01). The flow cytometry results showed that compared with blank group, the percentages of HepG2 cells in S phase in 1. 0, 2. 0, 5. 0, and 10. 0 mg middot; L-1Tan II A groups were decreased (P<0. 05), and the percentages of HepG2 cells in G0/G1 and G2 phases were increased (P<0. 05); the TUNEL results showed that compared with blank group, the apoptotic rates of HepG2 cells in 0. 5, 1. 0, 2. 0, 5. 0, and 10. 0 mg middot; L-1Tan II A groups werer increased (P< 0. 05 or P<0. 01). Conclusion: Different concentrations of Tan II A could significantly inhibit the proliferation and migration of human liver cancer HepG2 cells, and induce the apoptosis in a dose-dependent manner; its mechnasim may be related to the inhibition of the expressions of NF-κB and MMP-9 mRNA.

Influence of tanshinone II a on expressins of cosnic and aopp in kidney tissue of allergic purpura nephritis mice and its mechanism / 吉林大学学报(医学版)

Objective: To explore the influence of tanshinone 11 A on the expressions of molecular chape rone Cosmc. advanced oxidation protein products (AOPP) in the kidney tissue of the allergic purpura nephritis mice and the levels of extracellular signal-regulated kinase/mitogen activated protein kinase (ERK/MAPK) signaling pathway proteins, and to clarify mechanism of tanshinone 11 A in the treatment of allergic purpura nephritis. Methods: A total of 38 mice were divided into control group∗ model group (allergic purpura nephritis model) and tanshinone 11 A group (allergic purpura nephritis model • tanshinone 11 A treatment), with 12 in each group; the other 2 mice were used to verify the success of modeling. The urine red blood cell counts and urine protein levels of the mice in various groups were measured, and the pathomorphology of kidney tissue of the mice in various groups were observed by periodate schiff-reaction (PAS) staining. The AOPP protein levels in the kidney tissue of the mice were determined by enzyme linked immunosorbent assay (ELISA), and the ERK and phosphorylated ERK (p-ERk) protein expression levels were determined by Western blotting method. The expression levels of ERK. p-ERK and Cosmc mRNA in kidney tissue of the mice were determined by RT-PCR. Results: In control group, there was no hyperplasia of glomerular basement membrane and no glomerular sclerosis; in model group, the proliferation of glomerular basement membrane was obvious∗ the inflammatory cells were infiltrated, and glomerular sclerosis appeared; in tanshinone 11 A group, glomerular basement membrane hyperplasia and inflammatory infiltration were not obvious in the mice, there was only small amount of infiltrated inflammatory cells. Compared with control group, the urine red blood cell count, the 24 h urine protein level, the p ERK mRNA and AOPP protein levels of the mice in model group and tanshinone 11 A group were increased ( P<0. 05 or P<0. 01); the Cosmc mRNA expression levels were decreased (P<0. 01). Compared with model group, the urine red blood cell count. 24 h urine protein level, the p-ERK and AOPP protein levels in the kidney tissue of the mice in tanshinone 11 A group were decreased (P<0. 05 or P<0. 01). and the Cosmc mRNA expression level was increased (P

Study of effect of rifampin and tanshinone II A on pravastatin transport via BSEP in sandwich-cultured rat hepatocytes / 中国药理学通报

Aim To elucidate the effect of rifampin and tanshinone II A on BSEP transport capacity using pravastatin as the BSEP substrate in sandwich-cultured rat hepatocytes (SCRH). Methods SCRH model was established. The doses of drugs were determined by MIT. A HPLC-MS/MS method was developed and was conducted method validation to detect the concentration of pravastatin. The effect of rifampin and tanshinone D A on the concentration of pravastatin in the bile duct was investigated. And the biliary excretion index ( BEI) was calculated. Results The SCRH model was successfully developed. The appropriate doses of rifampin, tanshinone DA, glibenclamide and pravastatin were determined. A stable and reliable HPLC-MS/MS method for the determination of pravastatin was established Compared with blank control group, rifampin reduced the concentration of pravastatin in the bile duct and the BEI of pravastatin. The high concentration of rifampin caused the steepest downward trends ( P < 0 . 0 1 ) . Compared with high concentration group of rifampin, the concentration of pravastatin in the bile duct and the BEI of pravastatin gradually increased after the combination of rifampin and tanshinone II A, and the effect of high concentration of tanshinone II A was the most significant ( P < 0. 0 1 ) . Conclusions Rifampin could inhibit the function of BSEP in SCRH. The combination of tanshinone D A and rifampin could reverse the inhibitor)' effect of BSEP transport capacity caused by rifampin.

Sodium tanshinone IIA sulfonate attenuates cardiac dysfunction and improves survival of rats with cecal ligation and puncture-induced sepsis.

Cardiac dysfunction, a common consequence of sepsis, is the major contribution to morbidity and mortality in patients. Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of Tanshinone IIA (TA), a main active component of Salvia miltiorrhiza Bunge, which has been widely used in China for the treatment of cardiovascular and cerebral system diseases. In the present study, the effect of STS on sepsis-induced cardiac dysfunction was investigated and its effect on survival rate of rats with sepsis was also evaluated. STS treatment could significantly decrease the serum levels of C-reactive protein (CRP), procalcitonin (PCT), cardiac troponin I (cTn-I), cardiac troponin T (cTn-T), and brain natriuretic peptide (BNP) in cecal ligation and puncture (CLP)-induced) septic rats and improve left ventricular function, particularly at 48 and 72 h after CLP. As the pathogenesis of septic myocardial dysfunction is attributable to dysregulated systemic inflammatory responses, several key cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-10 (IL-10) and high mobility group protein B1 (HMGB1), were detected to reveal the possible mechanism of attenuation of septic myocardial dysfunction after being treated by STS. Our study showed that STS, especially at a high dose (15 mg·kg-1), could efficiently suppress inflammatory responses in myocardium and reduce myocardial necrosis through markedly reducing production of myocardial TNF-α, IL-6 and HMGB1. STS significantly improved the 18-day survival rate of rats with sepsis from 0% to 30% (P < 0.05). Therefore, STS could suppress inflammatory responses and improve left ventricular function in rats with sepsis, suggesting that it may be developed for the treatment of sepsis.

Sodium Tanshinone II-A Sulfonate (DS-201) Induces Vasorelaxation of Rat Mesenteric Arteries via Inhibition of L-Type Ca2+ Channel.

Background: We previously have proved that sodium tanshinone II-A sulfonate (DS-201), a derivative of traditional Chinese medicinal herb Danshen (Salvia miltiorrhiza), is an opener and vasodilator of BKCa channel in the vascular smooth muscle cells (VSMCs). Vascular tension is closely associated with Ca2+ dynamics and activation of BKCa channel may not be the sole mechanism for the relaxation of the vascular tension by DS-201. Therefore, we hypothesized that the vasorelaxing effect of DS-20 may be also related to Ca2+ channel and cytoplasmic Ca2+ level in the VSMCs. Methods: Arterial tension was measured by Danish Myo Technology (DMT) myograph system in the mesentery vessels of rats, intracellular Ca2+ level by fluorescence imaging system in the VSMCs of rats, and L-type Ca2+ current by patch clamp technique in Ca2+ channels transfected human embryonic kidney 293 (HEK-293) cells. Results: DS-201 relaxed the endothelium-denuded artery rings pre-constricted with PE or high K+ and the vasorelaxation was reversible. Blockade of K+ channel did not totally block the effect of DS-201 on vasorelaxation. DS-201 suppressed [Ca2+]i transient induced by high K+ in a concentration-dependent manner in the VSMCs, including the amplitude of Ca2+ transient, the time for Ca2+ transient reaching to the [Ca2+]i peak and the time to remove Ca2+ from the cytoplasm. DS-201 inhibited L-type Ca2+ channel with an EC50 of 59.5 µM and at about 40% efficacy of inhibition. However, DS-201did not significantly affect the kinetics of Ca2+ channel. The effect of DS-201 on L-type Ca2+ channel was rate-independent. Conclusion: The effect of DS-201 on vasorelaxation was not only via activating BKCa channel, but also blocking Ca2+ channel and inhibiting Ca2+ influx in the VSMCs of rats. The results favor the use of DS-201 and Danshen in the treatment of cardiovascular diseases clinically.

Sodium Tanshinone II A Sulfonate Injection as Adjuvant Treatment for Unstable Angina Pectoris: A Meta-Analysis of 17 Randomized Controlled Trials.

OBJECTIVE: To systematically evaluate the effectiveness and safety of Sodium Tanshinone II A Sulfonate Injection (STS) as one adjuvant therapy for treating unstable angina pectoris (UAP). METHODS: Randomized controlled trials (RCTs) of UAP treated by STS were searched in the China National Knowledge Infrastructure Database (CNKI), VIP Database for Chinese Technical Periodicals (VIP), Wanfang Database, the Chinese Biomedical Literature Database (CBM), Web of Science, the Cochrane Library, Embase, and PubMed, which from inception to January, 2016. The Cochrane Risk Assessment Tool was used to evaluate the methodological quality of the RCTs. The Review Manager 5.3 software was used to conduct the metaanalysis. RESULTS: The results showed that 17 RCTs involving 1,372 patients were included. The meta-analysis indicated that the combined use of STS and Western medicine (WM) in the treatment of UAP can obviously improve the total effective rate [risk ratio (RR)=1.31, 95% confidence interval (CI) (1.24,1.39), P<0.0001], and the total effective rate of electrocardiogram [RR=1.43, 95% CI (1.30,1.56), P<0.0001], decrease the level of CRP [mean difference (MD)=-3.06, 95%CI (-3.85,-2.27), P<0.00001], fibrinogen [MD=-1.03, 95% CI (-1.16,-0.89), P<0.00001], and whole blood high shear viscosity [MD=-0.70, 95% CI (-0.92,-0.49), P<0.00001]. Additionally, the occurrence of adverse drug reaction of the experimental group was significantly higher than that of the control group [RR=3.57, 95% CI (1.28, 9.94), P<0.05]. CONCLUSIONS: Compared with WM, the combined use of STS was more effective.

Sodium Tanshinone II A Sulfonate Injection as Adjuvant Treatment for Unstable Angina Pectoris: A Meta-Analysis of 17 Randomized Controlled Trials / 中国结合医学杂志

<p><b>OBJECTIVE</b>To systematically evaluate the effectiveness and safety of Sodium Tanshinone II A Sulfonate Injection (STS) as one adjuvant therapy for treating unstable angina pectoris (UAP).</p><p><b>METHODS</b>Randomized controlled trials (RCTs) of UAP treated by STS were searched in the China National Knowledge Infrastructure Database (CNKI), VIP Database for Chinese Technical Periodicals (VIP), Wanfang Database, the Chinese Biomedical Literature Database (CBM), Web of Science, the Cochrane Library, Embase, and PubMed, which from inception to January, 2016. The Cochrane Risk Assessment Tool was used to evaluate the methodological quality of the RCTs. The Review Manager 5.3 software was used to conduct the metaanalysis.</p><p><b>RESULTS</b>The results showed that 17 RCTs involving 1,372 patients were included. The meta-analysis indicated that the combined use of STS and Western medicine (WM) in the treatment of UAP can obviously improve the total effective rate [risk ratio (RR)=1.31, 95% confidence interval (CI) (1.24,1.39), P<0.0001], and the total effective rate of electrocardiogram [RR=1.43, 95% CI (1.30,1.56), P<0.0001], decrease the level of CRP [mean difference (MD)=-3.06, 95%CI (-3.85,-2.27), P<0.00001], fibrinogen [MD=-1.03, 95% CI (-1.16,-0.89), P<0.00001], and whole blood high shear viscosity [MD=-0.70, 95% CI (-0.92,-0.49), P<0.00001]. Additionally, the occurrence of adverse drug reaction of the experimental group was significantly higher than that of the control group [RR=3.57, 95% CI (1.28, 9.94), P<0.05].</p><p><b>CONCLUSIONS</b>Compared with WM, the combined use of STS was more effective.</p>

Sodium tanshinone IIA sulfonate attenuates cardiac dysfunction and improves survival of rats with cecal ligation and puncture-induced sepsis / 中国天然药物

Cardiac dysfunction, a common consequence of sepsis, is the major contribution to morbidity and mortality in patients. Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of Tanshinone IIA (TA), a main active component of Salvia miltiorrhiza Bunge, which has been widely used in China for the treatment of cardiovascular and cerebral system diseases. In the present study, the effect of STS on sepsis-induced cardiac dysfunction was investigated and its effect on survival rate of rats with sepsis was also evaluated. STS treatment could significantly decrease the serum levels of C-reactive protein (CRP), procalcitonin (PCT), cardiac troponin I (cTn-I), cardiac troponin T (cTn-T), and brain natriuretic peptide (BNP) in cecal ligation and puncture (CLP)-induced) septic rats and improve left ventricular function, particularly at 48 and 72 h after CLP. As the pathogenesis of septic myocardial dysfunction is attributable to dysregulated systemic inflammatory responses, several key cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10) and high mobility group protein B1 (HMGB1), were detected to reveal the possible mechanism of attenuation of septic myocardial dysfunction after being treated by STS. Our study showed that STS, especially at a high dose (15 mg·kg), could efficiently suppress inflammatory responses in myocardium and reduce myocardial necrosis through markedly reducing production of myocardial TNF-α, IL-6 and HMGB1. STS significantly improved the 18-day survival rate of rats with sepsis from 0% to 30% (P < 0.05). Therefore, STS could suppress inflammatory responses and improve left ventricular function in rats with sepsis, suggesting that it may be developed for the treatment of sepsis.

Sodium tanshinone IIA sulfonate attenuates cardiac dysfunction and improves survival of rats with cecal ligation and puncture-induced sepsis / 中国天然药物

Cardiac dysfunction, a common consequence of sepsis, is the major contribution to morbidity and mortality in patients. Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of Tanshinone IIA (TA), a main active component of Salvia miltiorrhiza Bunge, which has been widely used in China for the treatment of cardiovascular and cerebral system diseases. In the present study, the effect of STS on sepsis-induced cardiac dysfunction was investigated and its effect on survival rate of rats with sepsis was also evaluated. STS treatment could significantly decrease the serum levels of C-reactive protein (CRP), procalcitonin (PCT), cardiac troponin I (cTn-I), cardiac troponin T (cTn-T), and brain natriuretic peptide (BNP) in cecal ligation and puncture (CLP)-induced) septic rats and improve left ventricular function, particularly at 48 and 72 h after CLP. As the pathogenesis of septic myocardial dysfunction is attributable to dysregulated systemic inflammatory responses, several key cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10) and high mobility group protein B1 (HMGB1), were detected to reveal the possible mechanism of attenuation of septic myocardial dysfunction after being treated by STS. Our study showed that STS, especially at a high dose (15 mg·kg), could efficiently suppress inflammatory responses in myocardium and reduce myocardial necrosis through markedly reducing production of myocardial TNF-α, IL-6 and HMGB1. STS significantly improved the 18-day survival rate of rats with sepsis from 0% to 30% (P < 0.05). Therefore, STS could suppress inflammatory responses and improve left ventricular function in rats with sepsis, suggesting that it may be developed for the treatment of sepsis.

Mechanisms of Tanshinone II a inhibits malignant melanoma development through blocking autophagy signal transduction in A375 cell.

BACKGROUND: Malignant melanoma (MM) is one of the high degree of malignancy and early prone to blood and lymph node metastasis. There is not cured for MM. Tan II A has been reported to reduce cancer cell proliferation. But the mechanism by which Tan II A inhibited melanoma growth are not well characterized. We sought to explore the possible mechanism by which Tan II A regulated cell proliferation through autophagy signaling pathway in A375 cells. METHODS: We tested the effects of Tan II A on melanoma A375, MV3, M14, and other human cell lines including Hacat and HUVEC cells in cell culture model. Cell proliferation was assessed by using methyl thiazol tetrazolium (MTT) assay. Cell migration ability melanoma A375 was monitored by using cell scratch assay. Transwell chamber experimental was performed to assess the effect of Tan II A on A375 melanoma cell invasion ability. The autophagy body was examined by using flow cytometry. The expression of autophagy-associated protein beclin-1 and microtubule-associated protein 1 light chain 3(LC3)-II, as well as phosphatidylinositol 3-kinase(PI3K)、protein kinase B (Akt)、mammalian target of rapamycin (mTOR)、p70S6K1 signaling pathways were detected by using Western blotting. The effects of Tan II A on tumor progression was also examined in melanoma A375 induced tumor in mouse model. RESULTS: We found that Tan IIA inhibited melanoma A375, MV3, and M14 cell proliferation in dose and time dependent manner. Tan II A reduced CXCL12-induced A375 cell invasive ability and migration in a dose dependent manner. Tan IIA promoted autophagic body production and increased autophagy-associated protein beclin-1 and LC3-II expression in A375 cells. However, Tan IIA reduced the phosphorylation of PI3K, P-AKT, P-mTOR, and P-p7036k1. We also confirmed that Tan II A reduced melanoma A375 induced tumor volume and weight in mouse model. CONCLUSIONS: We concluded that Tan II A reduced A375 cells proliferation by activation of autophagy production, blocked PI3K- Akt - mTOR - p70S6K1 signaling pathway, increased autophagic related gene beclin-1, LC3-II protein expressions and induced autophagocytosis. Tan II A inhibited melanoma A375 induced tumor development in mouse model.

Tanshinone IIA attenuates epithelial-mesenchymal transition to inhibit the tracheal narrowing.

BACKGROUND: This study examines the effects of tanshinone IIA (TIIA) on epithelial-mesenchymal transition (EMT) in tracheal transplantation and the ability of TIIA to inhibit tracheal narrowing after tracheal transplantation. Mechanisms that may be involved in this process are also explored. METHODS: Human bronchial epithelial cells were treated in vitro with TGF-ß1 for 72 h. The cells were pretreated with TIIA (40 µg/mL) or DMSO for 2 h before TGF-ß1 stimulation. For the in vivo experiments, tracheas (5-6 rings) from Wistar rats were orthotopically transplanted into Sprague-Dawley rats. The experimental group received multiple infusions of sodium TIIA sulfonate (25 mg/kg, qd, intraperitoneally). The control group received infusions of the same volume of saline. Allografts were harvested at 3, 7, 10, 14, 35, and 90 d after transplantation and were examined for tracheal narrowing. Tracheal tissue samples and human bronchial epithelial cell were then subjected to further tests. RESULTS: In the in vitro assay, epithelial cadherin expression was decreased after TGF-ß1 stimulation, whereas α-smooth muscle actin and vimentin expression levels were increased. The expression levels of ZEB1 and Snail1 were also increased. These changes in expression were partially reversed by treatment with TIIA. In the in vivo assay, TIIA alleviated tracheal stenosis after tracheal allograft transplantation in rats and mitigated EMT by inhibiting the Smad signaling pathway and the expression of the transcription factors ZEB1 and Snail1. CONCLUSIONS: Our research suggests that TIIA reduces tracheal narrowing after tracheal transplantation by suppressing TGF-ß1-dependent EMT.