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oxymatrine
Oxymatrine (matrine oxide, matrine ''N''-oxide, matrine 1-oxide) is one of many quinolizidine alkaloid compounds extracted from the root of ''Sophora flavescens'', a Chinese herb. It is very similar in structure to matrine, which has one less oxygen atom. Oxymatrine has a variety of effects ''in vitro'' and in animal models, including protection against apoptosis, tumor and fibrotic tissue development, and inflammation.〔Ma L, Wen S, Zhan Y, He Y, Liu X, Jiang J (2008) Anticancer effects of the Chinese medicine matrine on murine hepatocellular carcinoma cells. Planta Med 74:245–251〕〔Jiang H, Hou C, Zhang S, Xie H, Zhou W, Jin Q, Cheng X, Qian R, Zhang X (2007) Matrine upregulates the cell cycle protein E2F-1 and triggers apoptosis via the mitochondrial pathway in K562 cells. Eur J Pharmacol 559:98–108〕〔Yamazaki M (2000) The pharmacological studies on matrine and oxymatrine. Yakugaku Zasshi 120:1025–1033〕 Furthermore, oxymatrine has been shown to decrease cardiac ischemia〔Hong-li, S., Li, L., Shang, L., Zhao, D., Dong, D., Qiao, G., Liu, Y., Chu, W., Yang, B. (2008) Cardioprotective effects and underlying mechanisms of oxymatrine against Ischemic myocardial injuries of rats. Phytotherapy Research 22: 985-989〕 (decreased blood perfusion), myocardial injury,〔Zhang M, Wang X, Wang X, Hou X, Teng P, Jiang Y, Zhang L, Yang X, Tian J, Li G, Cao J, Xu H, Li Y, Wang Y. (2013), Oxymatrine protects against myocardial injury via inhibition of JAK2/STAT3 signaling in rat septic shock. Mol Mod Rep 7(4): 1293-1299.〕 arrhythmias〔Cao Y, Shan, J, Li, L, Gao, J, Shen, Z, Wang, Y, Xu, C, Sun, H. (2010) Antiarrhythmic Effects and Ionic Mechanisms of Oxymatrine from Sophora flavescens. Phytotherapy Research 24: 1844-1849.〕 (irregular heartbeats), and improve heart failure by increasing cardiac function.〔Hu, S, Tang, Y, Shen, Y, Ao, H, Bai, J, Wang, Y, Yang, Y. (2011) Protective effect of oxymatrine on chronic rat heart failure. J Physiol Sci 61: 363-372.〕
==Role in cardiac fibrosis==
Recent research has shown that oxymatrine prevents cardiac fibrosis in rats.〔Shen, X, Yang, Y, Xiao, T, Peng, J, Liu, X. (2011) Protective effect of oxymatrine on myocardial fibrosis induced by acute myocardial infarction in rats involved in TGF-b1-Smads signal pathway. Journal of Asian Natural Products Research 13: 215-224〕 The development of fibrotic tissue in the heart occurs when fibroblasts produce excessive amounts of collagen (particularly types I and III),〔Kacimi, R., Gerdes, A. (2003) Alterations in G protein and MAP kinase signaling pathways during cardiac remodeling in hypertension and heart failure. Hypertension 41: 968–977〕 which accumulate and deposit in the heart. The excessive transformation to fibrotic tissue negatively affects the function and structure of the heart. Additionally, excessive amounts of collagen in the ventricles lead to alterations in gene expression, deposition of extracellular matrix, wall thickening, and ventricular remodeling in a manner that promotes dysfunction.〔Huang, X, Chen, X. (2012) Effect of oxymatrine, the active component from Radix Sophorae flavescentis (Kushen), on ventricular remodeling in spontaneously hypertensive rats. Phytomedicine 20: 202-212.〕
The mechanism by which oxymatrine may inhibit fibrosis is still unidentified. One theory that has been proposed is that oxymatrine inhibits a key signaling pathway involved in collagen production. One of the main signaling receptors involved in this pathway is the TGF-β1 co-receptor (complex of type I and type II receptors), which acts as a trans-membrane protein serine/threonine kinase.〔Levy, L, Hill, CS. (2006). Alterations in components of the TGF-β superfamily signaling pathways in human cancer. Cytokine and Growth Factor Reviews 17(1): 41-58.〕 A receptor assembly factor first activates TGF-β1 type I receptor and then type II. Receptor I is then able to bind proteins Smad2 and Smad3, which form a complex with Smad4. This complex accumulates in the nucleus, and binds to promoter elements of the collagen gene, stimulating the production of collagen.〔S.J. Wicks, T. Grocott, K. Haros, M. Maillard, P. ten Dijke, and A. Chantry (2006) Reversible ubiquitination regulates the Smad/TGF-beta signalling pathway. Biochem. Soc. Trans. 34: 761-763〕
In rats, oxymatrine also inhibits the expression of the Smad3 ligand which binds to TGF-β1 type I and activates the signal transduction pathway.〔 A dose response relationship was observed with increasing intragastric concentrations of oxymatrine resulting in decreased expression of Smad3. By inhibiting this pathway, less collagen was produced and deposited in the heart, preventing the formation of cardiac fibrosis.〔 Huang and Chen (2013) claim that oxymatrine may even be involved in inhibiting the expression of TGF-β1 receptors, which would further support that oxymatrine attenuates the signal transduction pathway involved in collagen production.〔 They also reported that inhibition of the TGF-β1 receptor may also prevent ventricular remodeling.〔
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