Protection of Quercetin against Triptolide-induced apoptosis by suppressing oxidative stress in rat Leydig cells.

Triptolide (TP) is a diterpene triepoxide with variety biological activities, such as anti-inflammatory, anti-cancerogenic, immunomodulatory and pro-apoptotic activities. However, its clinical application was limited by potential toxicity. Quercetin (Que) is a member of flavonoids with anti-oxidant effects. In this study, we aimed to demonstrate the protective effect of Que in TP-induced oxidative stress and decrease of testosterone generation in reproductive damage. Leydig cells were treated with TP (20, 40 and 60 nM), which caused obvious oxidative stress increasing intracellular ROS, decreasing activities and expressions of GPx and SOD. Apoptosis was resulted from depolarization of mitochondrial membrane potential (ΔΨm) and release of cytochrome C (Cyt-C) showing increase of BAX/Bcl-2 ratio, caspase-3 and caspase-9. Treatment of Que (5 μM) prior to triptolide could restore all the TP-induced alteration in a certain dose range indicating that the oxidative stress might be one reason of TP-induced reproductive toxic effect. These results suggest that the compatibility with Que might reduce the TP-induced reproductive toxicity, which provide a probability to extend the usage of TP.

[1]  K. Chopra,et al.  QUERCETIN, AN ANTI‐OXIDANT BIOFLAVONOID, ATTENUATES DIABETIC NEPHROPATHY IN RATS , 2004, Clinical and experimental pharmacology & physiology.

[2]  M. Panemangalore,et al.  Exposure to Low Doses of Endosulfan and Chlorpyrifos Modifies Endogenous Antioxidants in Tissues of Rats , 2003, Journal of environmental science and health. Part. B, Pesticides, food contaminants, and agricultural wastes.

[3]  D. Xue,et al.  Regulation of mitochondrial membrane permeabilization by BCL-2 family proteins and caspases. , 2004, Current opinion in cell biology.

[4]  Lu-yong Zhang,et al.  Triptolide: progress on research in pharmacodynamics and toxicology. , 2014, Journal of ethnopharmacology.

[5]  R. Aitken,et al.  Antioxidant systems and oxidative stress in the testes , 2008, Oxidative medicine and cellular longevity.

[6]  J. Lysiak,et al.  Oxidative stress: a common factor in testicular dysfunction. , 2008, Journal of andrology.

[7]  G. Watanabe,et al.  Quercetin protects embryonic chicken spermatogonial cells from oxidative damage intoxicated with 3-methyl-4-nitrophenol in primary culture. , 2009, Toxicology letters.

[8]  I. Gülçin Antioxidant activity of food constituents: an overview , 2012, Archives of Toxicology.

[9]  A. Steinberger,et al.  Sensitivity of Sertoli and Leydig cells to xenobiotics in in vitro models. , 1993, Reproductive toxicology.

[10]  S. Andric,et al.  Anabolic-androgenic steroids induce apoptosis and NOS2 (nitric-oxide synthase 2) in adult rat Leydig cells following in vivo exposure. , 2012, Reproductive toxicology.

[11]  Yuling Zhang Protective effect of quercetin on aroclor 1254-induced oxidative damage in cultured chicken spermatogonial cells. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[12]  Y. Jo,et al.  Multiple signaling pathways regulating steroidogenesis and steroidogenic acute regulatory protein expression: more complicated than we thought. , 2005, Molecular endocrinology.

[13]  S. Flora,et al.  Oral co-administration of α-lipoic acid, quercetin and captopril prevents gallium arsenide toxicity in rats. , 2009, Environmental toxicology and pharmacology.

[14]  Qiuyan Liu Triptolide and its expanding multiple pharmacological functions. , 2011, International immunopharmacology.

[15]  Luyong Zhang,et al.  Involvement of mitochondrial pathway in triptolide-induced cytotoxicity in human normal liver L-02 cells. , 2008, Biological & pharmaceutical bulletin.

[16]  D. B. Hales,et al.  Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. , 2004, Endocrine reviews.

[17]  G. Genchi,et al.  Proliferative and anti-proliferative effects of retinoic acid at doses similar to endogenous levels in Leydig MLTC-1/R2C/TM-3 cells. , 2010, Biochimica et biophysica acta.

[18]  Tao Wang,et al.  Male Reproductive Toxicity and Toxicokinetics of Triptolide in Rats , 2008, Arzneimittel-Forschung (Drug Research).

[19]  M. Memariani,et al.  Quercetin , 2011, Nutraceuticals.

[20]  H. Tsutsui,et al.  Oxidative stress and mitochondrial DNA damage in heart failure. , 2008, Circulation journal : official journal of the Japanese Circulation Society.

[21]  Yan Chen,et al.  Triptolide induces cell-cycle arrest and apoptosis of human multiple myeloma cells in vitro via altering expression of histone demethylase LSD1 and JMJD2B , 2011, Acta Pharmacologica Sinica.

[22]  B. Wong,et al.  Functional p53 is required for triptolide-induced apoptosis and AP-1 and nuclear factor-κB activation in gastric cancer cells , 2001, Oncogene.

[23]  G. Bartosz,et al.  Antioxidative and prooxidative effects of quercetin on A549 cells , 2007, Cell biology international.

[24]  Paula S. Azevedo,et al.  Rol de la lipoperoxidación en la intensificación de la remodelación ocasionada por el betacaroteno tras infarto , 2009 .

[25]  S. Paiva,et al.  Role of lipoperoxidation in the remodeling intensification induced by beta-carotene after infarction. , 2009, Arquivos brasileiros de cardiologia.

[26]  Liang Liu,et al.  Involvement of oxidative stress in the mechanism of triptolide-induced acute nephrotoxicity in rats. , 2012, Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie.

[27]  D. Durak,et al.  Protective effects of catechin and quercetin on antioxidant status, lipid peroxidation and testis-histoarchitecture induced by chlorpyrifos in male rats. , 2012, Environmental toxicology and pharmacology.

[28]  A. Ore,et al.  Protective Effect of Quercetin on Melphalan-Induced Oxidative Stress and Impaired Renal and Hepatic Functions in Rat , 2014, Chemotherapy research and practice.

[29]  Liang Jinqiang,et al.  Triptolide-induced oxidative stress involved with Nrf2 contribute to cardiomyocyte apoptosis through mitochondrial dependent pathways. , 2014, Toxicology letters.

[30]  Neena Singla,et al.  Reproductive Toxicity of Triptolide in Male House Rat, Rattus rattus , 2014, TheScientificWorldJournal.

[31]  A. Kahraman,et al.  The protective effect of flavonol quercetin against ultraviolet a induced oxidative stress in rats. , 2000, Toxicology.

[32]  S. Kumar,et al.  Apaf-1/cytochrome c apoptosome: an essential initiatorof caspase activation or just a sideshow? , 2003, Cell Death and Differentiation.

[33]  C. B. Pickett,et al.  The pathways and molecular mechanisms regulating Nrf2 activation in response to chemical stress. , 2004, Free radical biology & medicine.

[34]  Y. Kalender,et al.  Protective effect of catechin and quercetin on chlorpyrifos-induced lung toxicity in male rats. , 2010, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.