Dihydrotanshinone-I and tanshinone

Our previous study found that high-dose Tanshinones Capsule (TC) aggravated cholestasis in mice. To explore its underlying mechanism, main tanshinones components (15,16-dihydrotanshinone I (DTI), cryptotanshinone (CTS) and tanshinone IIA (TSA)) form TC were studied separately. Bile acids (BAs) that were primarily metabolized by hydroxylation were identified, and then the inhibitory effect of each tanshinones on their hydroxylation were evaluated. The anti-cholestasis effect of each tanshinones were studied in mice, the hepatic concentrations of BAs and tanshinones were measured and analyzed as well. The effect of tanshinones on Cyp3a11 protein expression was investigated. DTI exhibited inhibitory effect on the hydroxylation of lithocholic acid (LCA), taurolithocholic acid (TLCA) and taurochenodeoxycholic acid (TCDCA), their IC

Topics: Animals; Bile Acids and Salts; Cholestasis; Cytochrome P-450 CYP3A; Ethanol; Hydroxylation; Lithocholic Acid; Membrane Proteins; Mice; Salvia miltiorrhiza

We found that modified Taohong Siwu decoction (MTHSWD) had cardioprotective effects after myocardial ischemia-reperfusion injury. This study was to screen the effective components of MTHSWD that have protective effects on H9c2 cell injury through H

Topics: Animals; Apoptosis; Hydrogen Peroxide; Proto-Oncogene Proteins c-akt; Signal Transduction; Superoxide Dismutase

Tanshinones, the active ingredients derived from the roots of Salvia miltiorrhiza, have been widely used as traditional medicinal herbs for treating human diseases. Although tanshinones showed anti-inflammatory effects in many studies, large knowledge gaps remain regarding their underlying mechanisms. Here, we identified 15 tanshinones that suppressed the activation of NLRP3 inflammasome and studied their structure-activity relationships. Three tanshinones (tanshinone IIA, isocryptotanshinone, and dihydrotanshinone I) reduced mitochondrial reactive-oxygen species production in lipopolysaccharide (LPS)/nigericin-stimulated macrophages and correlated with altered mitochondrial membrane potentials, mitochondria complexes activities, and adenosine triphosphate and protonated-nicotinamide adenine dinucleotide production. The tanshinones may confer mitochondrial protection by promoting autophagy and the AMP-activated protein kinase pathway. Importantly, our findings demonstrate that dihydrotanshinone I improved the survival of mice with LPS shock and ameliorated inflammatory responses in septic and gouty animals. Our results suggest a potential pharmacological mechanism whereby tanshinones can effectively treat inflammatory diseases, such as septic and gouty inflammation.

Topics: Abietanes; AMP-Activated Protein Kinases; Animals; Autophagy; Disease Models, Animal; Female; Furans; Gout; Humans; Inflammasomes; Inflammation; Male; Mice; Mitochondria; NLR Family, Pyrin Domain-Containing 3 Protein; Phenanthrenes; Quinones; Rats; Reactive Oxygen Species; Shock, Septic; Uric Acid

Topics: Abietanes; China; Chromatography, High Pressure Liquid; Cluster Analysis; Furans; Ketones; Limit of Detection; Magnetic Resonance Spectroscopy; Medicine, Chinese Traditional; Phenanthrenes; Plant Extracts; Plant Roots; Protons; Pyridines; Quinones; Reproducibility of Results; Salvia miltiorrhiza

Tanshinones, the major bioactive components in

Topics: Abietanes; Calcium; Calcium Signaling; Furans; Lipopolysaccharides; Phenanthrenes; Plant Proteins; Quinones; Salvia miltiorrhiza; Transcription Factors

The human antigen R (HuR) is an RNA-binding protein known to modulate the expression of target mRNA coding for proteins involved in inflammation, tumorigenesis, and stress responses and is a valuable drug target. We previously found that dihydrotanshinone-I (DHTS, 1) prevents the association of HuR with its RNA substrate, thus imparing its function. Herein, inspired by DHTS structure, we designed and synthesized an array of ortho-quinones (tanshinone mimics) using a function-oriented synthetic approach. Among others, compound 6a and 6n turned out to be more effective than 1, showing a nanomolar K

Topics: Abietanes; Cell Line; Drug Design; ELAV-Like Protein 1; Humans; Molecular Dynamics Simulation; Molecular Mimicry; Protein Binding; Quinones; RNA-Binding Proteins; RNA, Messenger; Structure-Activity Relationship

In this work, a PVP-stabilized graphene was used in MEKC for the separation of tanshinones. Seven structurally similar tanshinones were studied, that is, tanshinone IIB, dihydrotanshinone I, tanshinone I, cryptotanshinone, 1,2-dihydrotanshinone I, miltirone, and tanshinone IIA. To achieve optimal conditions, graphene concentration, sample solvent composition, SDS concentration, 2-propanolconcentration, and buffer pH were investigated. At a separation voltage of 30 kV and a 41.5 cm effective length fused-silica capillary, good resolution within 12 min was performed using 10 mM borate buffer (pH 9.3) containing 30 mM SDS, 10% v/v 2-propanol and 6 μg/mL graphene. The method was validated in terms of linearity (r(2) > 0.9970), intra- and inter-day precision were less than 3.56 and 4.83%, respectively. The proposed method was then successfully applied to Danshentong capsule, an herbal preparation from Salvia miltiorrhiza. Our results indicated the high separation efficiency of PVP-stabilized graphene provided new opportunities for the analysis of complex samples.

Topics: 2-Propanol; Abietanes; Buffers; Chromatography, Micellar Electrokinetic Capillary; Drugs, Chinese Herbal; Furans; Graphite; Hydrogen-Ion Concentration; Phenanthrenes; Povidone; Quinones; Reproducibility of Results; Salvia miltiorrhiza

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.. 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.. 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.. 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.

Topics: Abietanes; Antineoplastic Agents, Phytogenic; ATP Binding Cassette Transporter, Subfamily B; Caco-2 Cells; Camptothecin; Digoxin; Doxorubicin; Drugs, Chinese Herbal; Furans; Gene Expression Regulation, Neoplastic; Humans; Irinotecan; Phenanthrenes; Quinones; Salvia miltiorrhiza

The roots of Salvia miltiorrhiza ("Danshen") are used in traditional Chinese medicine for the treatment of numerous ailments including cardiovascular disease, hypertension, and ischemic stroke. Extracts of S. miltiorrhiza roots in the formulation "Compound Danshen Dripping Pill" are undergoing clinical trials in the United States. To date, the active components of this material have not been conclusively identified. We have determined that S. miltiorrhiza roots contain potent human carboxylesterase (CE) inhibitors, due to the presence of tanshinones. K(i) values in the nM range were determined for inhibition of both the liver and intestinal CEs. As CEs hydrolyze clinically used drugs, the ability of tanshinones and S. miltiorrhiza root extracts to modulate the metabolism of the anticancer prodrug irinotecan (CPT-11) was assessed. Our results indicate that marked inhibition of human CEs occurs following incubation with both pure compounds and crude material and that drug hydrolysis is significantly reduced. Consequently, a reduction in the cytotoxicity of irinotecan is observed following dosing with either purified tanshinones or S. miltiorrhiza root extracts. It is concluded that remedies containing tanshinones should be avoided when individuals are taking esterified agents and that patients should be warned of the potential drug-drug interaction that may occur with this material.

Topics: Abietanes; Algorithms; Camptothecin; Carboxylesterase; Clinical Trials, Phase I as Topic; Drugs, Chinese Herbal; Herb-Drug Interactions; Humans; Irinotecan; Medicine, Chinese Traditional; Molecular Structure; Phenanthrolines; Plant Roots; Salvia miltiorrhiza

In the search for anti-SARS-CoV, tanshinones derived from Salvia miltiorrhiza were found to be specific and selective inhibitors for the SARS-CoV 3CL(pro) and PL(pro), viral cysteine proteases. A literature search for studies involving the seven isolated tanshinone hits showed that at present, none have been identified as coronaviral protease inhibitors. We have identified that all of the isolated tanshinones are good inhibitors of both cysteine proteases. However, their activity was slightly affected by subtle changes in structure and targeting enzymes. All isolated compounds (1-7) act as time dependent inhibitors of PL(pro), but no improved inhibition was observed following preincubation with the 3CL(pro). In a detail kinetic mechanism study, all of the tanshinones except rosmariquinone (7) were identified as noncompetitive enzyme isomerization inhibitors. However, rosmariquinone (7) showed a different kinetic mechanism through mixed-type simple reversible slow-binding inhibition. Furthermore, tanshinone I (5) exhibited the most potent nanomolar level inhibitory activity toward deubiquitinating (IC(50)=0.7 μM). Additionally, the inhibition is selective because these compounds do not exert significant inhibitory effects against other proteases including chymotrysin, papain, and HIV protease. These findings provide potential inhibitors for SARS-CoV viral infection and replication.

Topics: Abietanes; Cysteine Proteinase Inhibitors; Humans; Kinetics; Protein Binding; Salvia miltiorrhiza; Severe Acute Respiratory Syndrome; Severe acute respiratory syndrome-related coronavirus; Ubiquitination

P-Glycoprotein (Pgp) overexpression and alterations in p53 oncogene expression are known to affect chemotherapeutic efficacy in the treatment of human hepatocellular carcinoma (HCC). The present study has demonstrated the anti-HCC potential of cryptotanshinone (1), dihydrotanshinone (2), tanshinone I (3), and tanshinone IIA (4), the active lipophilic constituents of Salvia miltiorrhiza, using MTT and caspase-3 activity assays and poly(ADP-ribose) polymerase cleavage in HepG2, Hep3B, and PLC/PRF/5 cells. THLE-3, a normal human immortalized liver cell line, was used to demonstrate the selective growth inhibitory effect of 3 for a HCC cell line. Compound 1 suppressed doxorubicin efflux, a process mediated by P-glycoprotein, in a Pgp-overexpressed HepG2 subclone (R-HepG2 cells). Despite its moderate cytostatic and pro-apoptotic effects and minimal influence on doxorubicin efflux, 4 provided the best synergism with doxorubicin as determined by the Combination Index, the Loewe additivity model, and the Bliss independence criterion.

Topics: Abietanes; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carcinoma, Hepatocellular; Doxorubicin; Drug Resistance, Neoplasm; Humans; Models, Biological; Molecular Structure; Phenanthrenes; Plants, Medicinal; Salvia miltiorrhiza

The role of reactive oxygen species (ROS) and p38 mitogen-activated protein kinases (MAPK) in tanshinones-induced apoptosis was investigated in HepG2 cells in this study. The major tanshinones (cryptotanshinone, dihydrotanshinone, tanshinone I, tanshinone IIA), isolated from Salvia miltiorrhiza, inhibit cell growth and induce caspase-dependent apoptosis concentration-dependently, with dihydrotanshinone being the most potent. All four tanshinones were found to induce ROS generation, but only dihydrotanshinone can induce activation of p38 MAPK. The p38 MAPK activation by dihydrotanshinone was inhibited by N-acetyl cysteine pretreatment. It is thus concluded that ROS-mediated p38 MAPK activation plays a vital role in dihydrotanshinone-induced apoptosis in HepG2 cells.

Topics: Abietanes; Acetylcysteine; Antineoplastic Agents, Phytogenic; Antioxidants; Apoptosis; bcl-2-Associated X Protein; Carcinoma, Hepatocellular; Caspases; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cytochromes c; Dose-Response Relationship, Drug; Enzyme Activation; Furans; Humans; Imidazoles; Inhibitory Concentration 50; JNK Mitogen-Activated Protein Kinases; L-Lactate Dehydrogenase; Liver Neoplasms; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Phenanthrenes; Phosphorylation; Poly(ADP-ribose) Polymerases; Protein Kinase Inhibitors; Protein Transport; Pyridines; Quinones; Reactive Oxygen Species; Time Factors

This study examined the effects of tanshinone derivatives (tanshinone I, cryptotanshinone, 15,16-dihydrotanshinone I) on prostaglandin (PG) and nitric oxide (NO) metabolism in an attempt to establish their anti-inflammatory mechanisms and to present a scientific rationale for the use of Salvia miltiorrhiza (danshen) in inflammatory conditions. From lipopolysaccharide-treated RAW 264.7 cells, cyclooxygenase-2 (COX-2)-mediated PGE2 production was inhibited by tanshinone I, cryptotanshinone and 15,16-dihydrotanshinone I, while only cryptotanshinone and 15,16-dihydrotanshinone I inhibited inducible NO synthase (iNOS)-mediated NO synthesis at 1-50 microM. Particularly, cryptotanshinone was found to be a down-regulator of proinflammatory molecule expression, including COX-2 and iNOS. The electrophoretic mobility shift assay showed that cryptotanshinone and 15,16-dihydrotanshinone I also inhibited the activation of the transcription factors, such as nuclear transcription factor-kappaB and activator protein-1. Moreover, cryptotanshinone exhibited in vivo anti-inflammatory activity against carrageenan-induced paw edema in rats. Overall, these results provide additional scientific rationale for the anti-inflammatory use of danshen in Chinese medicine. Especially, cryptotanshinone and 15,16-dihydrotanshinone I are important constituents.

Topics: Abietanes; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cell Line; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Edema; Electrophoretic Mobility Shift Assay; Furans; Lipopolysaccharides; Macrophages; Male; Mice; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Phenanthrenes; Plant Roots; Quinones; Rats; Rats, Sprague-Dawley; Salvia miltiorrhiza

A pressurized liquid extraction (PLE) and CEC were developed for the simultaneous determination of four tanshinones (dihydrotanshinone I, cryptotanshinone, tanshinone I, and tanshinone IIA) in Salvia miltiorrhiza. High extraction efficiency (>98.5%) was achieved under the optimum PLE conditions. A good separation was obtained by using a Hypersil C18 capillary (3 microm, 100 microm/25 cm) with a mixture of 30 mM Tris-HCl (pH 8.5)-ACN (1:3, v/v) as BGE solution running at 20 kV and 20 degrees C within 12 min. All the calibration curves showed good linearity (r2 >0.9958) within test ranges. The developed method showed good repeatability for the quantification of four investigated components in S. miltiorrhiza with intra- and interday variations of less than 4.4 and 6.8%, respectively. The validated method was successfully applied to quantify four tanshinones in S. miltiorrhiza, which is helpful to control the quality of S. miltiorrhiza.

Topics: Abietanes; Capillary Electrochromatography; Drugs, Chinese Herbal; Furans; Molecular Structure; Phenanthrenes; Plant Extracts; Quinones; Reproducibility of Results; Salvia miltiorrhiza; Solid Phase Extraction

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.

Topics: Abietanes; Animals; Avoidance Learning; Cognition; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Furans; Male; Memory Disorders; Mice; Mice, Inbred ICR; Phenanthrenes; Quinones; Receptors, GABA-A; Scopolamine

We screened natural products to find compounds with anti-osteoporotic potential using a coculture-based system by which osteoclast differentiation is effectively achieved. We found that methylene chloride soluble fraction of the root of Salvia miltiorrhiza Bunge (Labiatae) suppressed osteoclast differentiation. Five tanshinones, tanshinone IIA (1), tanshinone 1 (2), cryptotanshinone (3), 15,16-dihydrotanshinone I (4), and ferruginol (5) were subsequently isolated from fraction. Among the five compounds, compounds 1-4 reduced the formation of TRAP-positive multinuclear osteoclasts. These results suggest that the identified tanshinones may be useful candidates for development of therapeutic agents to treat osteoporosis and other bone-resorptive diseases.

Topics: Abietanes; Animals; Bone Marrow Cells; Bone Resorption; Cell Differentiation; Cell Survival; Cells, Cultured; Coculture Techniques; Dose-Response Relationship, Drug; Down-Regulation; Drugs, Chinese Herbal; Furans; Mice; Mice, Inbred ICR; Osteoblasts; Osteoclasts; Phenanthrenes; Plant Extracts; Plant Roots; Quinones; Salvia miltiorrhiza