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In silico comparative molecular docking analysis and analysis of the anti-inflammatory mechanisms of action of tanshinone from Salvia miltiorrhiza.

ABSTRACT: Tanshinones are a class of abietane diterpene compounds extracted from Salvia miltiorrhiza, and have been used for medical purposes in traditional Chinese medicinal practices. This herb has been used in the treatment of chronic obstructive pulmonary disease (COPD), breast cancer and inflammatory disorders. This study examined the anti-inflammatory properties of tanshinones. In addition, lipid-soluble compounds which were specific to Tanshinone class were also highlighted, out of which two compounds, dihydrotanshinone I and cryptotanshinone were selected with the aim of creating a new research perspective in order to further elucidate the mechanisms of the pathogenesis of inflammatory diseases. Moreover, interaction analyses were carried out successfully to determine the interactions formed between both dihdrotanshinone I and cryptotanshinone, and target proteins. The bioactivity properties and various other pharmacokinetic and pharmacodynamic analyses discerned that crytptotanshinone was more effective dihydrotanshinone and more 'drug-like' than its counterpart. It was found to have a better solubility and permeability, and thus has potential for use as an anti-inflammatory agent.

SUBMITTER: Ruan Z

PROVIDER: S-EPMC6601134 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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In silico comparative molecular docking analysis and analysis of the anti-inflammatory mechanisms of action of tanshinone from Salvia miltiorrhiza.

Ruan Zhengshang Z Niu Lei L Han Li L Ren Rongrong R Xu Zhenyu Z Dong Wenwen W Jiang Lai L

Experimental and therapeutic medicine 20190618 2

Tanshinones are a class of abietane diterpene compounds extracted from Salvia miltiorrhiza, and have been used for medical purposes in traditional Chinese medicinal practices. This herb has been used in the treatment of chronic obstructive pulmonary disease (COPD), breast cancer and inflammatory disorders. This study examined the anti-inflammatory properties of tanshinones. In addition, lipid-soluble compounds which were specific to Tanshinone class were also highlighted, out of which two ...[more]

PMID: 31316608

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Project description:Plant natural products have been co-opted for millennia by humans for various uses such as flavor, fragrances, and medicines. These compounds often are only produced in relatively low amounts and are difficult to chemically synthesize, limiting access. While elucidation of the underlying biosynthetic processes might help alleviate these issues (e.g., via metabolic engineering), investigation of this is hindered by the low levels of relevant gene expression and expansion of the corresponding enzymatic gene families. However, the often-inducible nature of such metabolic processes enables selection of those genes whose expression pattern indicates a role in production of the targeted natural product.Here, we combine metabolomics and transcriptomics to investigate the inducible biosynthesis of the bioactive diterpenoid tanshinones from the Chinese medicinal herb, Salvia miltiorrhiza (Danshen). Untargeted metabolomics investigation of elicited hairy root cultures indicated that tanshinone production was a dominant component of the metabolic response, increasing at later time points. A transcriptomic approach was applied to not only define a comprehensive transcriptome (comprised of 20,972 non-redundant genes), but also its response to induction, revealing 6,358 genes that exhibited differential expression, with significant enrichment for up-regulation of genes involved in stress, stimulus and immune response processes. Consistent with our metabolomics analysis, there appears to be a slower but more sustained increased in transcript levels of known genes from diterpenoid and, more specifically, tanshinone biosynthesis. Among the co-regulated genes were 70 transcription factors and 8 cytochromes P450, providing targets for future investigation.Our results indicate a biphasic response of Danshen terpenoid metabolism to elicitation, with early induction of sesqui- and tri- terpenoid biosynthesis, followed by later and more sustained production of the diterpenoid tanshinones. Our data provides a firm foundation for further elucidation of tanshinone and other inducible natural product metabolism in Danshen.

Project description:Natural products present in low quantity in herb medicines constitute an important source of chemical diversity. However, the isolation of sufficient amounts of these low abundant constituents for structural modification has been a challenge for several decades and subsequently halts research on the utilization of this important source of chemical entities for drug discovery and development. And, pro-angiogenic therapies are being explored as options to treat cardio-cerebral vascular diseases and wound healing recently. The present study investigates the pro-angiogenic potential of tanshinone derivatives produced by one-pot synthesis using zebrafish model.In order to address the difficulty of chemical modification of low abundant constituents in herb medicines, a novel one-pot combinatorial modification was used to diversify a partially purified tanshinone mixture from Salvia miltiorrhiza. This led to the isolation of ten new imidazole-tanshinones (Compounds 1-10) and one oxazole-tanshinone (Compound 11), the structures of which were characterized by spectroscopic methods in combination with single-crystal X-ray crystallographic analysis. The angiogenesis activities of the new tanshinone derivatives were determined in an experimental model of chemical-induced blood vessels damage in zebrafish. Of all the tested new derivatives, compound 10 exhibited the most potent vascular protective and restorative activity with an EC50 value of 0.026 µM. Moreover, the mechanism underlying the pro-angiogenesis effect of 10 probably involved the VEGF/FGF-Src-MAPK and PI3K-P38 signalling pathways by gene expression analysis and a blocking assay with pathways-specific kinase inhibitors.Taken together, our study demonstrated the more distinctive pro-angiogenic properties of 10 than other tanshinones and revealed 10 has potential for development as a pro-angiogenic agent for diseases associated with insufficient angiogenesis. Our results highlighted the great potential of adopting a newly modified one-pot approach to enhance the chemical diversity and biological activities of constituents from natural products regardless of their abundances.

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In silico comparative molecular docking analysis and analysis of the anti-inflammatory mechanisms of action of tanshinone from Salvia miltiorrhiza.

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<i>In silico</i> comparative molecular docking analysis and analysis of the anti-inflammatory mechanisms of action of tanshinone from <i>Salvia miltiorrhiza</i>.

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