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matrine attenuates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via maintaining AMPKα/UCP2 pathway

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Acta Pharmaceutica Sinica B 2019年第4期9卷 690-701页

作者： Can Hu Xin Zhang Wenying Wei Ning Zhang Haiming Wu Zhenguo Ma Lingli Li Wei Deng Qizhu Tang Department of Cardiology Renmin Hospital of Wuhan UniversityWuhan 430060China Cardiovascular Research Institute of Wuhan University Wuhan 430060China Hubei Key Laboratory of Cardiology Wuhan 430060China

Oxidative stress and cardiomyocyte apoptosis are involved in the pathogenesis of doxorubicin(DOX)-induced cardiotoxicity. matrine is well-known for its powerful anti-oxidant and anti-apoptotic capacities. Our present study aimed to investigate the effect of matrine on DOX-induced cardiotoxicity and try to unearth the underlying mechanisms. Mice were exposed with DOX to generate DOX-induced cardiotoxicity or normal saline as control. H9 C2 cells were used to verify the effect of matrine in vitro.DOX injection triggered increased generation of reactive oxygen species(ROS) and excessive cardiomyocyte apoptosis, which were significantly mitigated by matrine. Mechanistically, we found that matrine ameliorated DOX-induced uncoupling protein 2(UCP2) downregulation, and UCP2 inhibition bygenipin could blunt the protective effect of matrine on DOX-induced oxidative stress and cardiomyocyte apoptosis. Besides, 50-AMP-activated protein kinase α2(Ampkα2) deficiency inhibited matrine-mediated UCP2 preservation and abolished the beneficial effect of matrine in mice. Besides, we observed that matrine incubation alleviated DOX-induced H9 C2 cells apoptosis and oxidative stress level via activating AMPKα/UCP2, which were blunted by either AMPKα or UCP2 inhibition with genetic or pharmacological methods. matrine attenuated oxidative stress and cardiomyocyte apoptosis in DOX-induced cardiotoxicity via maintaining AMPKα/UCP2 pathway, and it might be a promising therapeutic agent for the treatment of DOX-induced cardiotoxicity.

关键词： matrine Oxidative stress Apoptosis AMPKα UCP2

matrine suppresses lipopolysaccharide-induced fibrosis in human peritoneal mesothelial cells by inhibiting the epithelial-mesenchymal transition

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Chinese Medical Journal 2019年第6期132卷 664-670页

作者： Yi-Zheng Li Xi Peng Yun-Hua Ma Fu-Ji Li Yun-Hua Liao Scientific Research Department The First Affiliated Hospital of Guangxi Medical University Nanning Guangxi 530021 China Guangxi Medical College Nanning Guangxi 530021 China Department of Nephrology The First People's Hospital of Nanning Nanning Guangxi 530021 China Renal Division Department of Medicine The First Affiliated Hospital of Guangxi Medical University Nanning Guangxi 530021 China

Background: Peritoneal fibrosis is the primary reason that patients with end-stage renal disease (ESRD) have to cease peritoneal dialysis. Peritonitis caused by Gram-negative bacteria such as Escherichia coli (E. coli) were on the rise. We had previously shown that matrine inhibited the formation of biofilm by E. coli. However, the role of matrine on the epithelial-mesenchymal transition (EMT) in peritoneal mesothelial cells under chronic inflammatory conditions is still unknown. Methods: We cultured human peritoneal mesothelial cells (HPMCs) with lipopolysaccharide (LPS) to induce an environment that mimicked peritonitis and investigated whether matrine could inhibit LPS-induced EMT in these cells. In addition, we investigated the change in expression levels of the miR-29b and miR-129-5p. Results: We found that 10 jjig/ml of LPS induced EMT in HPMCs. matrine inhibited LPS-induced EMT in HPMCs in a dose-dependent manner. We observed that treatment with matrine increased the expression of E-cadherin (F= 50.993, Pmatrine promoted the expression levels of miR-29b and miR-129-5P. Conclusions: matrine could inhibit LPS-induced EMT in HPMCs and reverse LPS inhibited expressions of miR-29 b and miR-129- 5P in HPMCs, ultimately reduce peritoneal fibrosis. These findings provide a potential theoretical basis for using matrine in the prevention and treatment of peritoneal fibrosis.

关键词： matrine Human peritoneal mesothelium cells Lipopolysaccharide miR-129-5p miR-29b

matrine promotes neural circuit remodeling to regulate motor function in a mouse model of chronic spinal cord injury

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Neural Regeneration Research 2019年第11期14卷 1961-1967页

作者： Norio Tanabe Tomoharu Kuboyama Chihiro Tohda Division of Neuromedical Science Institute of Natural Medicine University of Toyama

In chronic phase of spinal cord injury, functional recovery is more untreatable compared with early intervention in acute phase of spinal cord injury. In the last decade, several combination therapies successfully improved motor dysfunction in chronic spinal cord injury. However, their effectiveness is not sufficient. We previously found a new effective compound for spinal cord injury, matrine, which induced axonal growth and functional recovery in acute spinal cord injury mice via direct activation of extracellular heat shock protein 90. Although our previous study clarified that matrine was an activator of extracellular heat shock protein 90, the potential of matrine for spinal cord injury in chronic phase has not been sufficiently evaluated. Thus, this study aimed to investigate whether matrine ameliorates chronic spinal cord injury in mice. Once daily intragastric administration of matrine(100 μmol/kg per day) to spinal cord injury mice were starte at 28 days after injury, and continued for 154 days. Continuous mat rine treatment improved hindlimb motor function in chronic spinal cord injury mice. In injured spinal cords of the matrine-treated mice, the density of neurofilament-H-positive axons was increased. Moreover, matrine treatment increased the density of bassoon-positive presynapses in contact with choline acetyltransferase-positive motor neurons in the lumbar spinal cord. These findings suggest that matrine promotes remodeling and reconnection of neural circuits to regulate hindlimb movement. All protocols were approved by the Committee for Animal Care and Use of the Sugitani Campus of the University of Toyama(approval No. A2013 INM-1 and A2016 INM-3) on May 7, 2013 and May 17, 2016, respectively.

关键词： matrine chronic spinal cord injury axonal growth synaptogenesis hindlimb locomotor presynapse immunohistochemistry Basso Mouse Scale Body Support Score Sophora flavescens

matrine inhibits bladder cancer cell growth and invasion in vitro through PI3K/AKT signaling pathway:An experimental study

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Asian Pacific Journal of Tropical Medicine 2017年第5期10卷 489-492页

作者： Yu Yang Jia-Xiang Guo Zhi-Qiang Shao Jiang-Ping Gao Department of Urology First Affiliated Hospital of PLA General HospitalBeijing 100048China

Objective:To study the inhibitory effect of matrine on bladder cancer cell growth and invasion in vitro through PI3K/AKT signaling pathway. Methods:Human T24 bladder cancer cell lines were cultured and treated with different doses of matrine(0.25 mg/mL,0.5 mg/mL and 1.0 mg/mL) as well as 20 μmol/L PI3K inhibitor LY294002 for 24 h,and the cell proliferation activity,the number of invasive cells as well as the expression of p-PI3K,p-AKT,proliferation genes and invasion genes were determined. Results:Different doses of matrine could decrease the cell viability value,the number of invasive cells as well as the expression of p-PI3K,p-AKT,MMP2 and MMP9,and increase the expression of p16,p21 and p27 in dose-dependent manner; p16,p21 and p27 expression in cells of 20 μmol/L LY29002 group were significantly higher than those of 0 μmol/L LY29002 group while MMP2 and MMP9 expression were significantly lower than those of 0 μmol/L LY29002 group(Pmatrine can inhibit bladder cancer cell proliferation and invasion in vitro and regulate the expression of cell cycle-inhibiting molecules and invasion-related genes through PI3K/AKT signaling pathway.

关键词： Bladder cancer matrine PI3K AKT Proliferation Invasion

Anti-tumor and Phenotypic Regulation Effect of matrine on Dendritic Cells through Regulating TLRs Pathway

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Chinese Journal of Integrative Medicine 2021年第7期27卷 520-526页

作者： WANG Jing-kang ZHAO Bao-sheng WANG Min LIU Chen-yue LI Ya-qi MA Quan-tao LI Peng-fei WANG Tie-shan WANG Chun-guo ZHOU Yong-ming School of Chinese Materia Medica Beijing University of Chinese MedicineBeijing100029China Beijing Research Institute of Chinese Medicine Beijing University of Chinese MedicineBeijing100029China School of Traditional Chinese Medicine Beijing University of Chinese MedicineBeijing100029China Department of Oncology Guang'anmen HospitalChina Academy of Chinese Medical SciencesBeijing100053China

Objective To investigate the effects of matrine on antigen presentation of dendritic cells(DCs),and to explore the pharmacological mechanism of matrine on anti-tumor effect.Methods Different concentrations(0,1,2,4,8 and 16µg/mL)of matrine were co-cultured with DCs,the harvested DCs were co-cultured with antigens of Lewis lung cancer(LLC)cells,and then DCs and T cells were co-cultured to produce DCs-activated killer(DAK)cells,which have significant tumor-killing activity.The expression of cytokines,mRNA and protein of toll-like receptors(TLRs)in DCs were detected by enzyme linked immunosobent assay,polymerase chain reaction and Western blot,respectively.And the killing effect of DAK were measured by MTT assay.Results matrine significantly increased the mRNA expression of TLR7,TLR8,myeloid differentiation factor 88(MyD88),tumor necrosis factor receptor-associated factor 6(TRAF-6)and IκB kinase(IKK),as well as the protein expression of TLR7 and TLR8,and up-regulated the levels of interleukin-12(IL-12),IL-6 and tumor necrosis factor-α(TNF-α),meanwhile,it also increased the expressions of MHC-II,CD54,CD80 and CD86 in DCs.DCs-activated effector T cells had significant tumor-killing activity.When the concentration of matrine was more than 4µg/mL,all indices had significant difference(Pmatrine plays an anti-tumor role by regulating TLRs signal transduction pathway,promoting the secretion of inflammatory cytokines and enhancing immune function.

关键词： matrine Chinese medicine dendritic cells tumors toll-like receptors inflammatory cytokines

Antitumor effect of matrine in human hepatoma G2 cells by inducing apoptosis and autophagy

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World Journal of Gastroenterology 2010年第34期16卷 4281-4290页

作者： Zhang, Jun-Qiang Li, Yu-Min Liu, Tao He, Wen-Ting Chen, Ying-Tai Chen, Xiao-Hui Li, Xun Zhou, Wen-Ce Yi, Jian-Feng Ren, Zhi-Jian Lanzhou Univ Hosp 2 Lanzhou 730030 Gansu Province Peoples R China Gansu Prov Key Lab Digest Syst Tumors Lanzhou 730030 Gansu Province Peoples R China Lanzhou Univ Hosp 1 Dept Gen Surg Lanzhou 730000 Gansu Province Peoples R China Lanzhou Univ Clin Med Sch 1 Lanzhou 730000 Gansu Province Peoples R China

AIM: To study the antitumor effect of matrine in human hepatoma G2 (HepG2) cells and its molecular mechanism involved in antineoplastic activities. METHODS: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to detect viability of HepG2 cells. The effect of matrine on cell cycle was detected by flow cytometry. Annexin-V-FITC/PI double staining assay was used to detect cellular apoptosis. Cellular morphological changes were observed under an inverted phase contrast microscope. Transmission electron microscopy was performed to further examine ultrastructural structure of the cells treatedwith matrine. Monodansylcadaverine (MDC) staining was used to detect autophagy. Whether autophagy is blocked by 3-methyladenine (3-MA), an autophagy inhibitor, was evaluated. Expression levels of Bax and Beclin 1 in HepG2 cells were measured by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR).RESULTS: matrine signif icantly inhibited the proliferation of HepG2 cells in a dose- and time-dependent manner, and induced G1-phase cell cycle arrest and apoptosis of HepG2 cells in a dose-dependent manner. The total apoptosis rate was 0.14% for HepG2 cells not treated with matrine. In contrast, the apoptosis rate was 28.91%, 34.36% and 38.80%, respectively, for HepG2 cells treated with matrine at the concentration of 0.5, 1.0 and 2.0 mg/mL. The remarkable morphological changes were observed under an inverted phase contrast microscope. Abundant cytoplasmic vacuoles with varying sizes were observed in HepG2 cells treated with matrine. Furthermore, vacuolization in cytoplasm progressively became larger and denser when the concentration of matrine was increased. Electron microscopy demonstrated formation of abundant autophagic vacuoles in HepG2 cells after matrine treatment. When the specif ic autophagic inhibitor, 3-MA, was applied, the number of autophagic vacuoles greatly decreased. MDC staining showed that the fluorescent density was higher and the number of MDC-labeled particles

关键词： matrine Autophagy Apoptosis Bax Beclin 1 Hepatocellular carcinoma

Synergistic Action between Jasmonic Acid and Nitric Oxide in Inducing matrine Accumulation of Sophora flavescens Suspension Cells

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Journal of Integrative Plant Biology 2008年第1期50卷 92-101页

作者： Mao-Jun Xu Ju-Fang Dong Department of Biotechnology Zhejiang Gongshang University Hangzhou 310035 China

Secondary metabolites not only play important ecological roles in plants but also are important pharmaceutical and source compounds for derivative synthesis. Production of plant secondary metabolites is believed to be controlled by the endogenous signal network of plants. However, the molecular basis is still largely unknown. Here we show that matrine production of Sophora flavescens Ait. cells treated with low levels of jasmonic acid （JA） and nitric oxide （NO） is significantly increased although treatment with low concentrations of JA or NO alone has no effects on matrine production, showing that JA and NO may act synergistically in triggering matrine production. Moreover, treatment with NO triggers lipoxygenase （LOX） activity and enhances JA levels of the cells, showing that NO may activate the endogenous JA biosynthesis of S. flavescens cells. External application of JA induces nitric oxide synthase-like activities and stimulates NO generation of S. flavescens cells, which suggests that JA may trigger NO generation of the cells. Thus, the results reveal a mutually amplifying reaction between JA and NO in S. flavescens cells. Furthermore, JA and NO inhibitors suppress not only the mutually amplifying reaction between JA and NO but also the synergistic effects of NO and JA on matrine production. Therefore, the data demonstrate that the synergistic action of JA and NO in inducing matrine production might be due to the mutually amplifying reaction between JA and NO in the cells.

关键词： jasmonic acid nitric oxide matrine Sophora flavescens cells.

matrine inhibits mycelia growth of Botryosphaeria dothidea by affecting membrane permeability

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Journal of Forestry Research 2019年第3期30卷 1105-1113页

作者： Jialiang Pan Xin Hao Hanwen Yao Kangkang Ge Ling Ma Wei Ma College of Forestry Northeast Forestry University Harbin 150040People’s Republic of China General Station of Forest and Grassland Pest Management National Forestry and Grassland Administration Shenyang 110034People’s Republic of China College of Pharmacy Heilongjiang University of Chinese MedicineHarbin 150040People’s Republic of China

matrine is a promising botanical antifungal;however, the mechanism underlying the antifungal activity is yet limited. We studied the antifungal activity of matrine and the underlying mechanism in Botryosphaeria dothidea as a model strain. matrine strongly inhibited mycelial growth of B. dothidea in a dose-dependent manner. matrine-treated B. dothidea showed morphological and ultrastructural alterations, including shriveled hyphae, plasmolysis, and leakage of cytoplasm related to cell membrane deterioration. In addition, matrine caused significantly high conductivity and absorbance (260 nm) in extracellular matrices and low lipid contents in B. dothidea, indicating increased membrane permeability. Lipid peroxidation showed that matrine resulted in increased malondialdehyde content while enhancing the generation of reactive oxygen species and the activities of superoxide dismutase, catalase, and peroxidase. These results showed that matrine inhibited the mycelial growth of B. dothidea by enhancing cell membrane permeability via membrane lipid peroxidation.

关键词： matrine Antifungal activity Botryosphaeria dothidea Membrane permeability Lipid peroxidation

Relaxant Effects of matrine on Aortic Smooth Muscles of Guinea Pigs

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Biomedical and Environmental Sciences 2009年第4期22卷 327-332页

作者： JIE ZHENG PING ZHENG XU ZHOU LIN YAN RU ZHOU XUE-YAN FU GUI-DONG DAI Department of Pharmacology School of Basic Medical Science Department of Physiology School of Basic Medical Science Ningxia Research Institute of Medicine & Pharmacy Ningxia Medical University Yinchuan 750004 Ningxia China

Objective To determine whether matrine, a kind of traditional Chinese medicinal alkaloid, can relax the aortic smooth muscles isolated from guinea pigs and to investigate the mechanism of its relaxant effects. Methods Phenylephrine or potassium chloride concentration-dependent relaxation response of aortic smooth muscles to matrine was studied in the precontracted guinea pigs. Results matrine （1×10^-4 mol/L -3.3×10^-3 mol/L） relaxed the endothelium-denuded aortic rings pre-contracted sub-maximally with phenylephrine, in a concentration-dependent manner, and its pre-incubation （3.3× 10^- 3 mol/L） produced a significant rightward shift in the phenylephrine dose-response curve, but had no effects on the potassium chloride-induced contraction. The anti-contractile effect of matrine was not reduced by the highly selective ATP-dependent K^＋ channel blocker glibenclamide （10.5 mol/L）, either by the non-selective K^＋channel blocker tetraethylammonium （10^-3 mol/L）, or by the β-antagonist propranolol （10^-5 mol/L）. In either ＂normal＂ or ＂Ca^2＋-free＂ bathing medium, the phenylephrine-induced contraction was attenuated by matrine （3.3×10^-3 mol/L）, indicating that the vasorelaxation was due to inhibition of intracellular and extracellular Ca^2＋ mobilization. Conclusion matrine inhibits phenylephrine-induced contractions by inhibiting activation of α-adrenoceptor and interfering with the release of intracellular Ca^2＋ and the influx of extracellular Ca^2＋.

关键词： matrine Aorta Vascular smooth muscle Relaxation Guinea-pigs Calcium