Dihydrotanshinone-I and Disease-Models--Animal

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

Chemotherapy-induced intestinal mucositis (CIM) is a principal reason for reduced living quality of patients undergoing chemotherapy. Growing evidence showed gut microbiota played an important role in the development of intestinal mucositis. Dihydrotanshinone I (DHTS) is a liposoluble extract of Salvia miltiorrhiza Bunge with many bioactivities. Here we investigated the effect of DHTS on intestinal mucositis induced by 5-fluorouracil and irinotecan in mice. We detected the degree of intestinal mucosal damage and inflammatory response in CIM mice with or without DHTS administration. The body weight and disease activity index (DAI) of mice were monitored each day. H&E staining was used to evaluate pathological damage. The contents of interleukin 6 (IL-6), tumor necrosis factor (TNFα), diacylglycerol (DAO) and triglyceride (TG) in serum were determined by commercial kits. We also investigated the changes of fecal microbiota by 16S rRNA high-throughput sequencing. Spearman correlation analysis was used to evaluate the correlation between fecal microbiota and inflammatory factors. Tax4Funwas performed to infer the potential function of the microbial community. Results showed DHTS significantly reduced DAI, intestinal mucosal damage and inflammatory response in CIM mice by decreasing serum IL-6 and TNFα. In addition, there is an intense correlation between fecal microbiota and inflammatory factors. DHTS efficiently reversed disordered fecal microflora close to normal and increased the abundance of g__Akkermansia. DHTS also enriched bacterial species which promote butyric acid metabolism or negatively correlated with inflammatory factors. Besides, species enriched by DHTS in fecal microbiota were probably involved in glutamine production and ammonia oxidation. In conclusion, our study provides evidence that DHTS effectively attenuates CIM induced by 5-fluorouracil and irinotecan in mice. Regulation of the composition and function of fecal microbiota probably plays a critical role in the therapeutic effect of DHTS in CIM mice.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Bacteria; Colon; Diglycerides; Disease Models, Animal; Feces; Fluorouracil; Furans; Gastrointestinal Microbiome; Interleukin-6; Intestinal Mucosa; Irinotecan; Male; Mice, Inbred C57BL; Mucositis; Phenanthrenes; Quinones; Triglycerides; Tumor Necrosis Factor-alpha

Dihydrotanshinone I (DHTS), extracted from Salvia miltiorrhiza, was found to be the most effective compound of tanshen extracts against cancer cells in our previous studies. However, the therapeutic benefits and underlying mechanisms of DHTS on ovarian cancer remain uncertain. In this study, we demonstrated the cytocidal effects of DHTS on chemosensitive ovarian cancer cells with or without platinum-based chemotherapy. DHTS was able to inhibit proliferation and migration of ovarian cancer cells in vitro and in vivo through modulation of the PI3K/AKT signalling pathways. Combinatorial treatment of DHTS and cisplatin exhibited enhanced DNA damage in ovarian cancer cells. Overall, these findings suggest that DHTS induces ovarian cancer cells death via induction of DNA damage and inhibits ovarian cancer cell proliferation and migration.

Topics: Animals; Carcinoma, Ovarian Epithelial; Cell Death; Cell Line, Tumor; Cell Movement; Cell Proliferation; Class I Phosphatidylinositol 3-Kinases; Disease Models, Animal; Drug Resistance, Neoplasm; Female; Furans; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Ovarian Neoplasms; Phenanthrenes; Phosphatidylinositol 3-Kinases; Platinum; Proto-Oncogene Proteins c-akt; Quinones; Signal Transduction; Transcription, Genetic; Zebrafish

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