Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Complementary Medicine and Therapies
Published in: BMC Complementary Medicine and Therapies 1/2019

Open Access 01-12-2019 | Research article

Inhibitory effects of oxymatrine on hepatic stellate cells activation through TGF-β/miR-195/Smad signaling pathway

Authors: Li-Ying Song, Yu-Tao Ma, Wei-Jin Fang, Yang He, Jia-Li Wu, Shan-Ru Zuo, Zhen-Zhen Deng, Sheng-Feng Wang, Shi-Kun Liu

Published in: BMC Complementary Medicine and Therapies | Issue 1/2019

Login to get access

Abstract

Background

Oxymatrine (OM), a quinolizidine alkaloid extracted from a herb Sophorae Flavescentis Radix, has been used to treat liver fibrotic diseases. However, the mechanism of its anti-fibrosis effects is still unclear. TGF-β/Smad signaling and miR-195 have been proved to paly an important role in hepatic stellate cells (HSCs) activation and liver fibrosis. In this study, we investigated whether OM could inhibit HSCs activation through TGF-β1/miR-195/Smads signaling or not.

Methods

First, the effects of OM on HSC-T6 in different concentrations and time points were tested by MTT assay. We choose three appropriate concentrations of OM as treatment concentrations in following experiment. By Quantitative Real-time PCR and Western Blot, then we investigated the effect of OM on miR-195, Smad7 and α-SMA’s expressions to prove the correlation between OM and the TGF-β1/miR-195/Smads signaling. Last, miR-195 mimic and INF-γ were used to investigate the relation between miR-195 and OM in HSC activation.

Results

Our results showed that the proliferation of HSC was significantly inhibited when OM concentration was higher than 200 μg/mL after 24 h, 100 μg/mL after 48 h and 10 μg/mL after 72 h. The IC50 of OM after 24, 48 and 72 h were 539, 454, 387 μg/mL respectively. OM could down-regulate miR-195 and α-SMA (P < 0.01), while up-regulate Smad7 (P < 0.05). In HSC-T6 cells transfected with miR-195 mimic and pretreated with OM, miR-195 and α-SMA were up-regulated (P < 0.05), and Smad7 was down-regulated (P < 0.05) .

Conclusions

Given these results, OM could inhibit TGF-β1 induced activation of HSC-T6 proliferation in a dose-dependent and time-dependent manner to some extent. We proved that OM inhibited HSC activation through down-regulating the expression of miR-195 and up-regulating Smad7.
Literature
1.
Hannivoort RA, Hernandez-Gea V, Friedman SL. Genomics and proteomics in liver fibrosis and cirrhosis. Fibrogenesis Tissue Repair. [Journal Article]. 2012;5(1):1.CrossRef
2.
El BS, El KK, El-Ashmawy MB. Current progress in antifibrotics. Curr Med Chem. [Journal Article; Review]. 2011;18(20):3082–92.
3.
Zhao Q, Qin CY, Zhao ZH, Fan YC, Wang K. Epigenetic modifications in hepatic stellate cells contribute to liver fibrosis. Tohoku J Exp Med. 2013;229(1):35–43 [Journal Article; Research Support, Non-U.S. Gov't; Review].CrossRef
4.
de Gouville AC, Boullay V, Krysa G, Pilot J, Brusq JM, Loriolle F, et al. Inhibition of TGF-beta signaling by an ALK5 inhibitor protects rats from dimethylnitrosamine-induced liver fibrosis. Br J Pharmacol. [Journal Article]. 2005;145(2):166–77.CrossRef
5.
Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol. 2014;14(3):181–94 [Journal Article; Research Support, Non-U.S. Gov't; Review].CrossRef
6.
Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. [Journal Article; Review]. 2017;14(7):397–411.CrossRef
7.
Wang BB, Cheng JY, Gao HH, Zhang Y, Chen ZN, Bian H. Hepatic stellate cells in inflammation-fibrosis-carcinoma axis. Anat Rec (Hoboken). 2010;293(9):1492–6 [Journal Article; Research Support, Non-U.S. Gov't].CrossRef
8.
Heymann F, Tacke F. Immunology in the liver--from homeostasis to disease. Nat Rev Gastroenterol Hepatol. 2016;13(2):88–110 [Journal Article; Research Support, Non-U.S. Gov't; Review].CrossRef
9.
Seki E, Schwabe RF. Hepatic inflammation and fibrosis: functional links and key pathways. Hepatology. 2015;61(3):1066–79 [Journal Article; Research Support, N.I.H., Extramural; Review].CrossRef
10.
Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-beta: the master regulator of fibrosis. Nat Rev Nephrol. 2016;12(6):325–38 Journal Article; Review.CrossRef
11.
Murata M, Yoshida K, Yamaguchi T, Matsuzaki K. Linker phosphorylation of Smad3 promotes fibro-carcinogenesis in chronic viral hepatitis of hepatocellular carcinoma. World J Gastroenterol. 2014;20(41):15018–27 [Journal Article; Review].CrossRef
12.
Wang G, Matsuura I, He D, Liu F. Transforming growth factor-{beta}-inducible phosphorylation of Smad3. J Biol Chem. 2009;284(15):9663–73 [Journal Article; Research Support, N.I.H., Extramural].CrossRef
13.
Yoshida K, Murata M, Yamaguchi T, Matsuzaki K. TGF-beta/Smad signaling during hepatic fibro-carcinogenesis (review). Int J Oncol. 2014;45(4):1363–71 [Journal Article; Review].CrossRef
14.
Zhao HW, Zhang ZF, Chai X, Li GQ, Cui HR, Wang HB, et al. Oxymatrine attenuates CCl4-induced hepatic fibrosis via modulation of TLR4-dependent inflammatory and TGF-beta1 signaling pathways. Int Immunopharmacol. 2016;36:249–55 [Journal Article].CrossRef
15.
Dong XQ, Du Q, Yu WH, Zhang ZY, Zhu Q, Che ZH, et al. Anti-inflammatory Effects of Oxymatrine Through Inhibition of Nuclear Factor-kappa B and Mitogen-activated Protein Kinase Activation in Lipopolysaccharide-induced BV2 Microglia Cells. IRAN J Pharm Res. 2013;12(1):165–74 [Journal Article].PubMedPubMedCentral
16.
Guzman JR, Koo JS, Goldsmith JR, Muhlbauer M, Narula A, Jobin C. Oxymatrine prevents NF-kappaB nuclear translocation and ameliorates acute intestinal inflammation. Sci Rep. 2013;3:1629 [Journal Article; Research Support, N.I.H., Extramural].CrossRef
17.
Ying XJ, Jin B, Chen XW, Xie J, Xu HM, Dong P. Oxymatrine downregulates HPV16E7 expression and inhibits cell proliferation in laryngeal squamous cell carcinoma Hep-2 cells in vitro. Biomed Res Int. 2015;2015:150390 Journal Article; Research Support, Non-U.S. Gov't.PubMedPubMedCentral
18.
Ma ZJ, Li Q, Wang JB, Zhao YL, Zhong YW, Bai YF, et al. Combining Oxymatrine or Matrine with Lamivudine Increased Its Antireplication Effect against the Hepatitis B Virus In Vitro. Evid Based Complement Alternat Med. 2013;2013:186573 [Journal Article].PubMedPubMedCentral
19.
Jian YC, Li W, He Y, Jiang M, Liu YB, Xiong WJ. Effect of oxymatrine on hepatic gene expression profile in experimental liver fibrosis of rats. Chin J Integr Med. 18(6):445–50 [Journal Article; Research Support, Non-U.S. Gov't]. 2012 2012-06-01.CrossRef
20.
Wu XL, Zeng WZ, Jiang MD, Qin JP, Xu H. Effect of Oxymatrine on the TGFbeta-Smad signaling pathway in rats with CCl4-induced hepatic fibrosis. World J Gastroenterol. 2008;14(13):2100–5 [Journal Article; Research Support, Non-U.S. Gov't].CrossRef
21.
Li L, Liu Q, Fan L, Xiao W, Zhao L, Wang Y, et al. Protective effects of oxymatrine against arsenic trioxide-induced liver injury. Oncotarget. 2017;8(8):12792–9 [Journal Article].PubMed
22.
Katsuda T, Ochiya T. microRNAs act as a fine-tuner of liver development, regeneration, and carcinogenesis. Seikagaku. 2012;84(8):666–74 [Journal Article; Review].PubMed
23.
Wang M, Zhang J, Tong L, Ma X, Qiu X. MiR-195 is a key negative regulator of hepatocellular carcinoma metastasis by targeting FGF2 and VEGFA. Int J Clin Exp Pathol. 2015;8(11):14110–20 Journal ArtSSS.PubMedPubMedCentral
24.
Ujifuku K, Mitsutake N, Takakura S, Matsuse M, Saenko V, Suzuki K, et al. miR-195, miR-455-3p and miR-10a( *) are implicated in acquired temozolomide resistance in glioblastoma multiforme cells. Cancer Lett. 2010;296(2):241–8 [Journal Article; Research Support, Non-U.S. Gov't].CrossRef
25.
Soon PS, Tacon LJ, Gill AJ, Bambach CP, Sywak MS, Campbell PR, et al. miR-195 and miR-483-5p Identified as Predictors of Poor Prognosis in Adrenocortical Cancer. Clin Cancer Res. 2009;15(24):7684–92 [Journal Article].CrossRef
26.
Sekiya Y, Ogawa T, Iizuka M, Yoshizato K, Ikeda K, Kawada N. Down-regulation of cyclin E1 expression by microRNA-195 accounts for interferon-beta-induced inhibition of hepatic stellate cell proliferation. J Cell Physiol. 2011;226(10):2535–42 Journal Article; Research Support, Non-U.S. Gov't.CrossRef
27.
Duan Y, Chen Q. TGF-beta1 regulating miR-205/miR-195 expression affects the TGF-beta signal pathway by respectively targeting SMAD2/SMAD7. Oncol Rep. 2016;36(4):1837–44 [Journal Article].CrossRef
28.
Chen G, Cao S, Liu F, Liu Y. miR-195 plays a role in steroid resistance of ulcerative colitis by targeting Smad7. Biochem J. 2015;471(3):357–67 [Journal Article; Research Support, Non-U.S. Gov't].CrossRef
29.
Song LY, Ma YT, Wu CF, Wang CJ, Fang WJ, Liu SK. MicroRNA-195 activates hepatic stellate cells in vitro by targeting Smad7. Biomed Res Int. 2017;2017:1945631 Journal Article.
30.
Lee JI, Wright JH, Johnson MM, Bauer RL, Sorg K, Yuen S, et al. Role of Smad3 in platelet-derived growth factor-C-induced liver fibrosis. Am J Physiol Cell Physiol. 2016;310(6):C436–45 [Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't].CrossRef
31.
Bi WR, Yang CQ, Shi Q. Transforming growth factor-beta1 induced epithelial-mesenchymal transition in hepatic fibrosis. Hepatogastroenterology. 2012;59(118):1960–3 [Journal Article; Review].PubMed
32.
He M, Wu Y, Wang M, Chen W, Yuan W, Jiang J. The Clinical Value of Oxymatrine in Preventing Lamivudine Induced YMDD Mutation: A Meta-Analysis. Evid Based Complement Alternat Med. 2015;2015:971616 [Journal Article; Review].PubMedPubMedCentral
33.
Zhang X, Jiang W, Zhou AL, Zhao M, Jiang DR. Inhibitory effect of oxymatrine on hepatocyte apoptosis via TLR4/PI3K/Akt/GSK-3beta signaling pathway. World J Gastroenterol. 2017;23(21):3839–49 [Journal Article].CrossRef
34.
Shi LJ, Shi L, Song GY, Zhang HF, Hu ZJ, Wang C, et al. Oxymatrine attenuates hepatic steatosis in non-alcoholic fatty liver disease rats fed with high fructose diet through inhibition of sterol regulatory element binding transcription factor 1 (Srebf1) and activation of peroxisome proliferator activated receptor alpha (Pparalpha). Eur J Pharmacol. 2013;714(1–3):89–95 [Journal Article; Research Support, Non-U.S. Gov't].CrossRef
35.
Wu XL, Zeng WZ, Jiang MD, Qin JP, Xu H. Effect of Oxymatrine on the TGFbeta-Smad signaling pathway in rats with CCl4-induced hepatic fibrosis, World J Gastroenterol. 2008;14(13):2100–5 [Journal Article; Research Support, Non-U.S. Gov't].CrossRef
Metadata
Title
Inhibitory effects of oxymatrine on hepatic stellate cells activation through TGF-β/miR-195/Smad signaling pathway
Authors
Li-Ying Song
Yu-Tao Ma
Wei-Jin Fang
Yang He
Jia-Li Wu
Shan-Ru Zuo
Zhen-Zhen Deng
Sheng-Feng Wang
Shi-Kun Liu
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2019
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-019-2560-2

Other articles of this Issue 1/2019

BMC Complementary Medicine and Therapies 1/2019 Go to the issue

Research article

Ocimum gratissimum Linn. Leaves reduce the key enzymes activities relevant to erectile dysfunction in isolated penile and testicular tissues of rats

Research article

Shen Shuai IIRecipe attenuates renal injury and fibrosis in chronic kidney disease by regulating NLRP3 inflammasome and Sirt1/Smad3 deacetylation pathway

Research article

Anti-inflammatory and nephroprotective activity of Juglans mollis against renal ischemia–reperfusion damage in a Wistar rat model

Research article

Coreopsis tinctoria Nutt ameliorates high glucose-induced renal fibrosis and inflammation via the TGF-β1/SMADS/AMPK/NF-κB pathways

Research article

Evaluation of a mouthrinse containing guava leaf extract as part of comprehensive oral care regimen- a randomized placebo-controlled clinical trial

Research article

Calotropis gigantea extract induces apoptosis through extrinsic/intrinsic pathways and reactive oxygen species generation in A549 and NCI-H1299 non-small cell lung cancer cells