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Danshensu, a novel indoleamine 2,3-dioxygenase1 inhibitor, exerts anti-hepatic fibrosis effects via inhibition of JAK2-STAT3 signaling.
Phytomedicine. 2019 Oct; 63:153055.P

Abstract

BACKGROUND

Indoleamine 2,3-dioxygenase 1 (IDO1), an important intracellular rate-limiting enzyme in the development of Hepatic fibrosis (HF), and has been proposed as a hallmark of HF. Danshensu (DSS) is a major bioactive component that isolated from a edible traditional Chinese medicinal herb Salviae Miltiorrhizae Radix et Rhizoma (Danshen), while, the anti-HF mode and mechanism of action of DSS have not been fully elucidated.

METHODS

Carbon tetrachloride (CCl4)-induced rat HF model and TGF-β1-induced hepatic stellate cell (HSC) model were employed to assess the in vivo and in vitro anti-HF effects of DSS. HSC-T6 cells stably expressing IDO1, a constitutively active IDO1 mutant, was used to determine the role of JAK2-STAT3 signaling in the DSS's anti-HF effects.

RESULTS

We found that intragastric administration of DSS potently reduced fibrosis, inhibited IDO1 expression and STAT3 activity both in vitro and in vivo. Using molecular docking and molecular dynamics analysis, DSS was identified as a novel IDO1 inhibitor. Mechanistic studies indicated that DSS inhibited JAK2-STAT3 signaling, it reduced IDO1 expression, STAT3 phosphorylation and STAT3 nuclear localization. More importantly, overexpression of IDO1 diminished DSS's anti-HF effects.

CONCLUSION

Our findings provide a pharmacological justification for the clinical use of DSS in treating HF, and suggest that DSS has the potential to be developed as a modern alternative and/or complimentary agent for HF treatment and prevention.

Authors+Show Affiliations

School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.First Affiliated Hospital of Guiyang College of Traditional Chinese Medicine, Guiyang, China.Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China. Electronic address: sutao@gzucm.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31377585

Citation

Cao, Gang, et al. "Danshensu, a Novel Indoleamine 2,3-dioxygenase1 Inhibitor, Exerts Anti-hepatic Fibrosis Effects Via Inhibition of JAK2-STAT3 Signaling." Phytomedicine : International Journal of Phytotherapy and Phytopharmacology, vol. 63, 2019, p. 153055.
Cao G, Zhu R, Jiang T, et al. Danshensu, a novel indoleamine 2,3-dioxygenase1 inhibitor, exerts anti-hepatic fibrosis effects via inhibition of JAK2-STAT3 signaling. Phytomedicine. 2019;63:153055.
Cao, G., Zhu, R., Jiang, T., Tang, D., Kwan, H. Y., & Su, T. (2019). Danshensu, a novel indoleamine 2,3-dioxygenase1 inhibitor, exerts anti-hepatic fibrosis effects via inhibition of JAK2-STAT3 signaling. Phytomedicine : International Journal of Phytotherapy and Phytopharmacology, 63, 153055. https://doi.org/10.1016/j.phymed.2019.153055
Cao G, et al. Danshensu, a Novel Indoleamine 2,3-dioxygenase1 Inhibitor, Exerts Anti-hepatic Fibrosis Effects Via Inhibition of JAK2-STAT3 Signaling. Phytomedicine. 2019;63:153055. PubMed PMID: 31377585.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Danshensu, a novel indoleamine 2,3-dioxygenase1 inhibitor, exerts anti-hepatic fibrosis effects via inhibition of JAK2-STAT3 signaling. AU - Cao,Gang, AU - Zhu,Ruyi, AU - Jiang,Ting, AU - Tang,Dongxin, AU - Kwan,Hiu Yee, AU - Su,Tao, Y1 - 2019/07/27/ PY - 2019/03/30/received PY - 2019/07/03/revised PY - 2019/07/26/accepted PY - 2019/8/5/pubmed PY - 2020/1/22/medline PY - 2019/8/5/entrez KW - Danshensu KW - Hepatic fibrosis KW - IDO1 KW - JAK2-STAT3 signaling SP - 153055 EP - 153055 JF - Phytomedicine : international journal of phytotherapy and phytopharmacology JO - Phytomedicine VL - 63 N2 - BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1), an important intracellular rate-limiting enzyme in the development of Hepatic fibrosis (HF), and has been proposed as a hallmark of HF. Danshensu (DSS) is a major bioactive component that isolated from a edible traditional Chinese medicinal herb Salviae Miltiorrhizae Radix et Rhizoma (Danshen), while, the anti-HF mode and mechanism of action of DSS have not been fully elucidated. METHODS: Carbon tetrachloride (CCl4)-induced rat HF model and TGF-β1-induced hepatic stellate cell (HSC) model were employed to assess the in vivo and in vitro anti-HF effects of DSS. HSC-T6 cells stably expressing IDO1, a constitutively active IDO1 mutant, was used to determine the role of JAK2-STAT3 signaling in the DSS's anti-HF effects. RESULTS: We found that intragastric administration of DSS potently reduced fibrosis, inhibited IDO1 expression and STAT3 activity both in vitro and in vivo. Using molecular docking and molecular dynamics analysis, DSS was identified as a novel IDO1 inhibitor. Mechanistic studies indicated that DSS inhibited JAK2-STAT3 signaling, it reduced IDO1 expression, STAT3 phosphorylation and STAT3 nuclear localization. More importantly, overexpression of IDO1 diminished DSS's anti-HF effects. CONCLUSION: Our findings provide a pharmacological justification for the clinical use of DSS in treating HF, and suggest that DSS has the potential to be developed as a modern alternative and/or complimentary agent for HF treatment and prevention. SN - 1618-095X UR - https://www.unboundmedicine.com/medline/citation/31377585/Danshensu_a_novel_indoleamine_23_dioxygenase1_inhibitor_exerts_anti_hepatic_fibrosis_effects_via_inhibition_of_JAK2_STAT3_signaling_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0944-7113(19)30221-1 DB - PRIME DP - Unbound Medicine ER -