Oxymatrine

Last updated
Oxymatrine
Oxymatrine.svg
Names
IUPAC name
(7aS,13aR,13bR,13cS)dodecahydro-1H,5H,10H-dipyrido[2,1-f:3′,2′,1′-ij][1,6]naphthyridin-10-one 4-oxide
Other names
Matrine oxide, matrine N-oxide, matrine 1-oxide
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.106.342
PubChem CID
UNII
Properties
C15H24N2O2
Molar mass 264.369 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

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. [1] [2] [3] Furthermore, oxymatrine has been shown to decrease cardiac ischemia [4] (decreased blood perfusion), myocardial injury, [5] arrhythmias [6] (irregular heartbeats), and improve heart failure by increasing cardiac function. [7]

Contents

Role in cardiac fibrosis

Recent research has shown that oxymatrine prevents cardiac fibrosis in rats. [8] The development of fibrotic tissue in the heart occurs when fibroblasts produce excessive amounts of collagen (particularly types I and III), [9] 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. [10]

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. [11] 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. [12]

In rats, oxymatrine also inhibits the expression of the Smad3 ligand which binds to TGF-β1 type I and activates the signal transduction pathway. [8] 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. [8] 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. [10] They also reported that inhibition of the TGF-β1 receptor may also prevent ventricular remodeling. [10]

Future studies

Effects of oxymatrine on heart disease in humans has not been studied and the long term side-effects of clinical oxymatrine use have not yet been identified.

Related Research Articles

Paracrine signaling

Paracrine signaling is a form of cell signaling or cell-to-cell communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance, as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.

Myostatin mammalian protein found in Homo sapiens

Myostatin is a myokine, a protein produced and released by myocytes that acts on muscle cells' autocrine function to inhibit myogenesis: muscle cell growth and differentiation. In humans it is encoded by the MSTN gene. Myostatin is a secreted growth differentiation factor that is a member of the TGF beta protein family.

Fibrosis Formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process

Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of permanent scar tissue.

In cardiology, ventricular remodeling refers to changes in the size, shape, structure, and function of the heart. This can happen as a result of exercise or after injury to the heart muscle. The injury is typically due to acute myocardial infarction, but may be from a number of causes that result in increased pressure or volume, causing pressure overload or volume overload on the heart. Chronic hypertension, congenital heart disease with intracardiac shunting, and valvular heart disease may also lead to remodeling. After the insult occurs, a series of histopathological and structural changes occur in the left ventricular myocardium that lead to progressive decline in left ventricular performance. Ultimately, ventricular remodeling may result in diminished contractile (systolic) function and reduced stroke volume.

Transforming growth factor beta

Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms and many other signaling proteins. TGFB proteins are produced by all white blood cell lineages.

Mothers against decapentaplegic homolog 2 protein-coding gene in the species Homo sapiens

Mothers against decapentaplegic homolog 2 also known as SMAD family member 2 or SMAD2 is a protein that in humans is encoded by the SMAD2 gene. MAD homolog 2 belongs to the SMAD, a family of proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways.

Mothers against decapentaplegic homolog 3 protein-coding gene in the species Homo sapiens

Mothers against decapentaplegic homolog 3 also known as SMAD family member 3 or SMAD3 is a protein that in humans is encoded by the SMAD3 gene.

Mothers against decapentaplegic homolog 7 protein-coding gene in the species Homo sapiens

Mothers against decapentaplegic homolog 7 or SMAD7 is a protein that in humans is encoded by the SMAD7 gene.

Smads comprise a family of structurally similar proteins that are the main signal transducers for receptors of the transforming growth factor beta (TGF-B) superfamily, which are critically important for regulating cell development and growth. The abbreviation refers to the homologies to the Caenorhabditis elegans SMA and Drosophila MAD family of genes.

The transforming growth factor beta (TGFB) signaling pathway is involved in many cellular processes in both the adult organism and the developing embryo including cell growth, cell differentiation, apoptosis, cellular homeostasis and other cellular functions. In spite of the wide range of cellular processes that the TGFβ signaling pathway regulates, the process is relatively simple. TGFβ superfamily ligands bind to a type II receptor, which recruits and phosphorylates a type I receptor. The type I receptor then phosphorylates receptor-regulated SMADs (R-SMADs) which can now bind the coSMAD SMAD4. R-SMAD/coSMAD complexes accumulate in the nucleus where they act as transcription factors and participate in the regulation of target gene expression.

TGF beta 1 protein-coding gene in the species Homo sapiens

Transforming growth factor beta 1 or TGF-β1 is a polypeptide member of the transforming growth factor beta superfamily of cytokines. It is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation, and apoptosis. In humans, TGF-β1 is encoded by the TGFB1 gene.

Myofibroblast spindle-shaped cells that contribute to wound healing

A myofibroblast is a cell that is in between a fibroblast and a smooth muscle cell in phenotype.

Alveolar macrophage macrophage found in the pulmonary alveolus

An alveolar macrophage is a type of macrophage, a professional phagocyte, found in the pulmonary alveoli, near the pneumocytes, but separated from the wall.

mir-133 microRNA precursor family

mir-133 is a type of non-coding RNA called a microRNA that was first experimentally characterised in mice. Homologues have since been discovered in several other species including invertebrates such as the fruitfly Drosophila melanogaster. Each species often encodes multiple microRNAs with identical or similar mature sequence. For example, in the human genome there are three known miR-133 genes: miR-133a-1, miR-133a-2 and miR-133b found on chromosomes 18, 20 and 6 respectively. The mature sequence is excised from the 3' arm of the hairpin. miR-133 is expressed in muscle tissue and appears to repress the expression of non-muscle genes.

Pancreatic stellate cells (PaSCs) are classified as myofibroblast-like cells that are located in exocrine regions of the pancreas. PaSCs are mediated by paracrine and autocrine stimuli and share similarities with the hepatic stellate cell. Pancreatic stellate cell activation and expression of matrix molecules constitute the complex process that induces pancreatic fibrosis. Synthesis, deposition, maturation and remodelling of the fibrous connective tissue can be protective, however when persistent it impedes regular pancreatic function.

Myocardial scarring is the accumulation of fibrosis tissue resulting after some form of trauma to the cardiac tissue. Fibrosis is the formation of excess tissue in replacement of necrotic or extensively damaged tissue. Fibrosis in the heart is often hard to detect because fibromas are often formed. Fibromas are scar tissue or small tumors, formed in one cell line. Because they are so small they can be hard to detect by methods such as magnetic resonance imaging. A cell line is a path of fibrosis that follow only a line of cells.

CD-NP, also known as cenderitide, is a novel natriuretic peptide developed by the Mayo Clinic as a potential treatment for heart failure. CD-NP is created by the fusion of the 15 amino acid C-terminus of DNP with the full CNP structure both peptide which are endogenous to humans. This peptide chimera is a dual activator of the natriuretic peptide receptors NPR-A and NPR-B and therefore exhibits the natriuretic and diuretic properties of DNP, as well as the antiproliferative and antifibrotic properties of CNP.

Human HGF plasmid DNA therapy of cardiomyocytes is being examined as a potential treatment for coronary artery disease, as well as treatment for the damage that occurs to the heart after MI. After MI, the myocardium suffers from reperfusion injury which leads to death of cardiomyocytes and detrimental remodelling of the heart, consequently reducing proper cardiac function. Transfection of cardiac myocytes with human HGF reduces ischemic reperfusion injury after MI. The benefits of HGF therapy include preventing improper remodelling of the heart and ameliorating heart dysfunction post-MI.

In molecular biology mir-590 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms.

Fimasartan chemical compound

Fimasartan is a non-peptide angiotensin II receptor antagonist (ARB) used for the treatment of hypertension and heart failure. Through oral administration, fimasartan blocks angiotensin II receptor type 1 (AT1 receptors), reducing pro-hypertensive actions of angiotensin II, such as systemic vasoconstriction and water retention by the kidneys. Concurrent administration of fimasartan with diuretic hydrochlorothiazide has shown to be safe in clinical trials. Fimasartan was approved for use in South Korea in September 9, 2010 and is available under the brand name Kanarb through Boryung Pharmaceuticals, who are presently seeking worldwide partnership. Fimasartan is being marketed in India under the brand name of Fimanta and Fimagen through Ajanta Pharma Ltd.

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ Yamazaki M (2000) The pharmacological studies on matrine and oxymatrine. Yakugaku Zasshi 120:1025–1033
  4. ↑ 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
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. 1 2 3 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
  9. ↑ 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
  10. 1 2 3 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.
  11. ↑ 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.
  12. ↑ 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
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