Effects of Indole-3-Carbinol and Flavonoids Administered Separately and in Combination on Nitric Oxide Production and iNOS Expression in Rats — Oak Academic Publishing
Research ArticleOpen AccessGoogle Scholar indexed
Effects of Indole-3-Carbinol and Flavonoids Administered Separately and in Combination on Nitric Oxide Production and iNOS Expression in Rats
Beneficial effects of natural compounds are often attributed to modulation of NO production; however effects produced by plant extracts do not correlate with effects of purified components. The goal of our work was to study ability of flavonoids and indole-3-carbinol, as well as their combinations to modify NO production, iNOS gene and protein expression in rat tissues. Baicalein and luteolin decreased NO concentration in both intact and LPS-treated animals. Baicalein decreased iNOS gene expression. Luteolin decreased NO production in the liver and heart and number of iNOS-positive cells in the liver of LPS-treated animals. Combination of the two substances did not decrease the NO synthesis triggered by LPS, although it decreased iNOS gene expression. Quercetin decreased NO production in the heart, kidneys and blood of intact rats, but enhanced the LPS effect in testes, spleen and blood on NO production and iNOS protein expression in the liver. Indole-3-carbinol decreased NO concentration in the cerebellum, blood, lungs and skeletal muscles. The drug enhanced the LPS-triggered increase of NO production in all rat organs. It increased iNOS protein expression in intact liver; however it decreased the LPS-triggered outburst of the enzyme biosynthesis. Combination of indole3-carbinol with quercetin decreased NO production in LPS-treated animals however it slightly increased iNOS gene expression. Taken together our results suggest that modifications of NO level in tissues by a natural compound cannot be predicted from data about its effects on NOS expression or activity. Combination of substances can produce an effect differing from that of individual substances. This stresses importance of direct measurements of NO in the tissues.
H. Y. Li, L. Cui and M. Cui, “Hot Topics in Chinese Herbal Drugs Research Documented in PubMed/Medline by Authors inside China and Outside of China in the Past 10 Years: Based on Co-Word Cluster Analysis,” Journal of Alternative and Complementary Medicine, Vol. 15, 2009, pp. 779-785.
H. Zeng, X. Liu, S. Dou, W. Xu, N. Li, X. Liu, W. Zhang, Z. Hu and R. Liu, “Huang-Lian-Jie-Du-Tang Exerts Anti-Inflammatory Effects in Rats through Inhibition of Nitric Oxide Production and Eicosanoid Biosynthesis via the Lipoxygenase Pathway” Journal of Pharmacy and Pharmacology, Vol. 61, 2009, pp. 1699-1707.
V. Bayard, F. Chamorro, J. Motta and N. K. Hollenberg, “Does Flavanol Intake Influence Mortality from Nitric Oxide-Dependent Processes? Ischemic Heart Disease, Stroke, Diabetes Mellitus, and Cancer in Panama,” In-ternational Journal of Medical Microbiology, Vol. 4, 2007, pp. 53-58.
C. A. Schmitt and V. M. Dirsch, “Modulation of Endothe Lial Nitric Oxide by Plant-Derived Products,” Nitric Oxide, Vol. 21, 2009, pp. 77-91.
S. Benito, D. Lopez, M. P. Saiz, S. Buxaderas, J. Sanchez, P. Puig-Parellada and M. T. Mitjavila, “A Flavonoid-Rich Diet Increases Nitric Oxide Production in Rat Aorta,” British Journal of Pharmacology, Vol. 135, 2002, pp. 910-916.
R. Olszanecki, A. Gebska, V. I. Kozlovski and R. J. Gryglewski, “Flavonoids and Nitric Oxide Synthase,” Journal of Physiology and Pharmacology, Vol. 53, 2002, pp. 571-584.
B. H. Kim, S. M. Cho, A. M. Reddy, Y. S. Kim, K. R. Min and Y. Kim, “Down-regulatory Effect of Quercitin Gallate on Nuclear Factor-Kappa B-Dependent Inducible Nitric Oxide Synthase Expression in Lipopolysaccharide- Stimulated Macrophages RAW 264.7,” Biochemical Pharmacology, Vol. 69, 2005, pp. 1577-1183.
T. Wallerath, H. Li, U. Godtel-Ambrust, P. M. Schwarz and U. Forstermann, “A Blend of Polyphenolic Compounds Explains the Stimulatory Effect of Red Wine on Human Endothelial NO Synthase,” Nitric Oxide, Vol. 12, 2005, pp. 97-104.
L. Luo, Q. Sun, Y. Y. Mao, Y. H. Lu and R. X. Tan, “Inhibitory Effects of Flavonoids from Hypericum Perfora-tum on Nitric Oxide Synthase,” Journal of Ethnophar-macology, Vol. 93, 2004, pp. 221-225.
C. K. Chen and C. R. Pace-Asciak, “Vasorelaxing Activity of Resveratrol and Quercetin in Isolated Rat Aorta,” General Pharmacology, Vol. 27, 1996, pp. 363-366.
J. C. Stoclet, A. Kleschyov, E. Andriambeloson, M. Diebolt and R. Andriantsitohaina, “Endothelial NO Release Caused by Red Wine Polyphenols,” Journal of Physiology and Pharmacology, Vol. 50, 1999, pp. 535-540.
N. Sjakste, A. L. Kleschyov, J. L. Boucher, L. Baumane, M. Dzintare, D. Meirena, J. Sjakste, K. Sydow, T. Münzel and I. Kalvinsh, “Endothelium-and Nitric Oxide-Dependent Vasorelaxing Activities of Gamma-Butyrobetaine Esters: Possible Link to the Antiischemic Activities of Mildronate,” European Journal of Pharmacology, Vol. 495, 2004, pp. 67-73.
N. Sjakste, J. Sjakste, J. L. Boucher, L. Baumane, T. Sjakste, M. Dzintare, D. Meirena, J. Sharipova and I. Kalvinsh, “Putative Role of Nitric Oxide Synthase Iso-forms in the Changes of Nitric Oxide Concentration in Rat Brain Cortex and Cerebellum Following Sevoflurane and Isoflurane Anaesthesia,” European Journal of Phar-macology, Vol. 513, 2005, pp. 193-205.
N. Sjakste, V. G. Andrianov, J. L. Boucher, I. Shestakova, L. Baumane, M. Dzintare, D. Meirena and I. Kalvins, “Paradoxical Effects of Two Oximes on Nitric Oxide Production by Purified NO Synthases, in Cell Culture and in Animals,” Nitric Oxide, Vol. 17, pp. 107-114, 2007.
M. E. van Meeteren, J. J. Hendriks, C. D. Dijkstra and E. A. van Tol, “Dietary Compounds Prevent Oxidative Damage and Nitric Oxide Production by Cells Involved in Demyelinating Disease,” Biochemical Pharmacology, Vol. 67, pp. 967-975, 2004.
K. M. Rahman, S. Ali, A. Aboukameel, S. H. Sarkar, Z. Wang, P. A. Philip, W. A. Sakr and A. Raz, “Inactivation of NF-kappaB by 3,3'-diindolylmethane Contributes to Increased Apoptosis Induced by Chemotherapeutic Agent in Breast Cancer Cells,” Molecular Cancer Therapeutics, Vol. 6, 2007, pp. 2757-2765.
S. J. Kim, H. Park and H. P. Kim, “Inhibition of Nitric Oxide Production from Lipopolysaccharide-Treated RAW 264.7 Cells by Synthetic Flavones: Structure-Activity Relationship and Action Mechanism,” Archives of Pharmacal Research, Vol. 27, 2004, pp. 937-943.
J. S. Kim, H. J. Lee, M. H. Lee, J. Kim, C. Jin and J. H. Ryu “Luteolin Inhibits LPS-Stimulated Inducible Nitric Oxide Synthase Expression in BV-2 Microglial Cells,” Planta Medica, Vol. 72, 2006, pp. 65-68.
C. Hu and D. D. Kitts, “Luteolin and Luteolin-7-O-gluco- side from Dandelion Flower Suppress iNOS and COX-2 in RAW264.7 Cells,” Molecular and Cellular Biochemi-stry, Vol. 265, 2004, pp. 107-113.
L. S. Scuro, P. U. Simioni, D. L. Grabriel, E. E. Saviani, L. V. Modolo, W. M. Tamashiro and I. Salgado, “Suppression of Nitric Oxide Production in Mouse Macrophages by Soybean Flavonoids Accumulated in Response to Nitroprusside and Fungal Elicitation,” BMC Medicine, Vol. 5, 2004, pp. 5.
H. Li, N. Xia, I. Brausch, Y. Yao and U. Forstermann, “Flavonoids from Artichoke (Cynara scolymus L.) up-Regulate Endothelial-Type NitricOxide Synthase Gene Expression in Human Endothelial Cells,” Journal of Pharmacology and Experimental Therapeutics, Vol. 310, 2004, pp. 926-932.
C. Gerhäuser, K. Klimo, E. Heiss, I. Neumann, A. Gam-al-Eldeen, J. Knauft, G. Y. Liu, S. Sitthimonchai and N. Frank, “Mechanism-based in Vitro Screening of Potential Cancer Chemopreventive Agents,” Mutation Research, Vol. 523-524, 2003, pp. 163-172.
S. Su, J. Guo, J. Duan, T. Wang, D. Qian, E. Shang and Y. Tang, “Ultra-performance Liquid Chromatography－Tandem Mass Spectrometry Analysis of the Bioactive Components and their Metabolites of Shaofu Zhuyu De-coction Active Extract in Rat Plasma,” Journal of Chro-matography B Analytical Technologies in the Biomedical and Life Sciences, 2009. (in press)
H. J. Chen, X. Li, J. W. Chen, S. Guo and B. C. Cai, “Simultaneous Determination of Eleven Bioactive Compounds in Saururus Chinensis from Different Harvesting Seasons by HPLC-DAD,” Journal of Pharmaceutical and Biomedical Analysis, 2010. (in press)
C. Li, H. Du, L. Wang, Q. Shu, Y. Zheng, Y. Xu, J. Zhang, J. Zhang, R. Yang and Y. Ge, “Flavonoid Composition and Antioxidant Activity of Tree Peony (Paeonia section moutan) Yellow Flowers,” Journal of Agricultural and Food Chemistry, Vol. 57, 2009, pp. 8496-8503.
X. Liang, L. Zhang, X. Zhang, W. Dai, H. Li, L. Hu, H. Liu, J. Su and W. Zhang, “Qualitative and Quantitative Analysis of Traditional Chinese Medicine Niu Huang Jie Du Pill Using Ultra Performance Liquid Chromatography Coupled with Tunable UV Detector and Rapid Resolution Liquid Chromatography Coupled with Time-of-Flight Tandem Mass Spectrometry,” Journal of Pharmaceutical and Biomedical Analysis, Vol. 51, 2010, pp. 565-571.
A. L. Kleschyov, P. Wenzel and T. Münzel, “Electron Paramagnetic Resonance (EPR) Spin Trapping of Bio-logical Nitric Oxide,” Journal of Chromatography B Analytical Technologies in the Biomedical and Life Sciences, Vol. 851, 2007, pp. 12-20.
N. Sjakste, L. Baumane, D. Meirena, L. Lauberte, M. Dzintare and I. Kalvinsh, “Drastic Increase in Nitric Oxide Content in Rat Brain under Halothane Anesthesia, Revealed by EPR Method,” Biochemical Pharmacology, Vol. 58, 1999, pp. 1955-1959.
L. Baumane, M. Dzintare, L. Zvejniece, D. Meirena, L. Lauberte, V. Sile, I. Kalvinsh and N. Sjakste, “Increased Synthesis of Nitric Oxide in Rat Brain Cortex Due to Halogenated Volatile Anesthetics Confirmed by ESR Spectroscopy,” Acta Anaesthesiologica Scandinavica, Vol. 46, 2002, pp. 378-383.
E. Rostoka, L. Baumane, S. Isajevs, A. Line, M. Dzintare, D. Svirina, J. Sharipova, K. Silina, I. Kalvinsh and N. Sjakste, “Effects of Kaempferol and Myricetin on Inducible Nitric Oxide Synthase Expression and NO Production in Rats,” Basic & Clinical Pharmacology & Toxicology, 2010. (in press)
J. Vandesompele, K. De Preter, F. Pattyn, B. Poppe, N. Van Roy, A. De Paepe and F. Speleman, “Accurate Normalization of Real-Time Quantitative RT-PCR Data by Geometric Averaging of Multiple Internal Control Genes,” Genome Biology, 2002, Vol. 18.
A. Radonić, S. Thulke, I. M. Mackay, O. Landt, W. Sie-gert and A. Nitsche, “Guideline to Reference Gene Selection for Quantitative Real-Time PCR,” Biochemical and Biophysical Research Communications, Vol. 313, 2004, pp. 856-862.
K. Ishak, A. Baptista, L. Bianchi, F. Callea, J. De Groote, J. Gudat, F. Gudat, H. Denk, V. Desmet, G. Korb, R. N. MacSween, “Histological Grading and Staging of Chronic Hepatitis,” Journal of Hepatology, Vol. 22, 1995, pp. 696-699.
A. D. Stefano, G. Caramori, T. Oates, A. Capelli, M. Lusuardi, I. Gnemmi, F. Ioli, K. F. Chung, C. F. Donner, P. J. Barnes and I. M. Adcock, “Increased Expression of Nuclear Factor-kB in Bronchial Biopsies from Smokers and Patients with COPD,” European Respiratory Journal, Vol. 20, 2000, pp. 556-563.
J. S. Won, Y. B. Im, M. Khan, A. K. Singh and I. Singh, “Involvement of Phospholipase A2 and Lipoxygenase in Lipopolysaccharide-Induced Inducible Nitric Oxide Syn- Thase Expression in Glial Cells,” Glia, Vol. 51, 2005, pp. 13-21.
C. J. Chen, S. L. Raung, S. L. Liao and S. Y. Chen “Inhibition of Inducible Nitric Oxide Synthase Expression by Baicalein in Endotoxin/Cytokine-Stimulated Microglia,” Biochemical Pharmacology, Vol. 67, 2004, pp. 957-965.
K. Suk, H. Lee, S. S. Kang, G. J. Cho and W. S. Choi, “Flavonoid Baicalein Attenuates Activation-Induced Cell Death of Brain Microglia,” Journal of Pharmacology and Experimental Therapeutics, Vol. 305, 2003, pp. 638-645.
M. Vivancos and J. J. Moreno, “Role of Ca2+-independent Phospholipase A(2) and Cyclooxygenase/Lip-oxygenase Pathways in the Nitric Oxide Production by Murine Macrophages Stimulated by Lipopolysaccharides,” Nitric Oxide, Vol. 6, 2002, pp. 255-262.
I. Wakabayashi, “Inhibitory Effects of Baicalein and Wogonin on Lipopolysaccharide-Induced Nitricoxide Production in Macrophages” Pharmacology & Toxicology, Vol. 84, 1999, pp. 288-291.
Y. Huang, C. M. Wong, C. W. Lau, X. Yao, S. Y. Tsang, Y. L. Su and Z. Y. Chen, “Inhibition of Nitric Oxide/Cyclic GMP-Mediated Relaxation by Purified Flavonoids, Baicalin and Baicalein, in Rat Aortic Rings,” Biochemical Pharmacology, Vol. 67, 2004, pp. 787-794.
T. Hashimoto, M. Kihara, K. Yokoyama, T. Fujita, S. Kobayashi, K. Matsushita, K. Tamura, N. Hirawa, Y. Toya and S. Umemura, “Lipooxygenase Products Regulate Nitric Oxide and Inducible Nitric Oxide Synthase Production in Interleukin-1beta Stimulated Vascular Smooth Muscle Cells,” Hypertension Research, Vol. 26, 2003, pp. 177-184.
H. M. Kim, E. J. Moon, E. Li, K. M. Kim, S. Y. Nam and C. K. Chung, “The Nitric Oxide-Producing Activities of Scutellaria Baicalensis,” Toxicology, Vol. 135, 1999, pp. 109-115.
U. Takahama, T. Oniki and S. Hirota, “Oxidation of Quercetin by Salivary Components. Quercetin-Dependent Reduction of Salivary Nitrite under Acidic Conditions Producing Nitric Oxide,” Journal of Agricultural and Food Chemistry, Vol. 50, 2002, pp. 4317-4322.
R. D. Snyder and P. J. Gillies, “Evaluation of the Clastogenic, DNA Intercalative, and Topoisomerase II-Interactive Properties of Bioflavonoids in Chinese Hamster V79 Cells,” Environmental and Molecular Mutagenesis, Vol. 40, 2002, pp. 266-276.
C. Kellner and S. J Zunino, “Nitric Oxide Is Synthesized in Acute Leukemia Cells after Exposure to Phenolic Anti- Oxidants and Initially Protects against Mitochondrial Membrane Depolarization,” Cancer Letter, Vol. 215, 2004, pp. 43-52.
F. H. Sarkar and Y. Li, “Cell Signaling Pathways Altered by Natural Chemopreventive Agents,” Mutation Research, Vol. 555, 2004, pp. 53-64.
H. Sies, T. Schewe, C. Heiss and M. Kelm, “Cocoa Polyphenols and Inflammatory Mediators,” American Journal of Clinical Nutrition, Vol. 81, 2005, pp. 304S-312S.
F. Orallo, E. Alvarez, M. Camiña, J. M. Leiro, E. Gómez and P. Fernández, “The Possible Implication of Trans-Resveratrol in the Cardioprotective Effects of Long-Term Moderate Wine Consumption,” Molecular Pharmacology, Vol. 61, 2002, pp. 294-302.
K. Fukuzawa, K. Kogure, M. Morita, S. Hama, S. Manabe and A. Tokumura, “Enhancement of Nitric Oxide and Superoxide Generations by Alpha-Tocopheryl Succinate and Its Apoptotic and Anticancer Effects,” Biochemistry, Vol. 69, 2004, pp. 50-57.
K. Kogure, M. Morita, S. Hama, S. Nakashima, A. To- kumura and K. Fukuzawa, “Enhancement by Alpha- to-Copheryl Hemisuccinate of Nitric Oxide Production Induced by Lypopolysaccharide and Interferon-Gamma through the Upregulation of Protein Kinase C in Rat Vascular Smooth Muscle Cells,” European Journal of Biochemistry, Vol. 269, 2002, pp. 2367-2372.
G. M. Raso, R. Meli, G. Di Carlo, M. Pacilio and R. D. Carlo, “Inhibition of Inducible Nitric Oxide Synthase and Cyclooxygenase-2 Expression by Flavonoids in Macro-phage J774A.1,” Life Sciences, Vol. 68, 2001, pp. 921-931.
G. K. Rangan, Y. Wang and D. C. Harris, “Dietary Quercetin Augments Activator Protein-1 and Does Not Reduce Nuclear Factor-Kappa B in the Renal Cortex of Rats with Established Chronic Glomerular Disease,” Nephron, Vol. 90, 2002, pp. 313-319.
T. L. Wadsworth and D. R. Koop, “Effects of the Wine Polyphenolics Quercetin and Resveratrol on Pro-inflammatory Cytokine Expression in RAW 264.7 Macrophages,” Biochemical Pharmacology, Vol. 57, 1999, pp. 941-949.
S. Wang, V. L. DeGroff and S. K. Clinton, “Tomato and soy Polyphenols Reduce Insulin-Like Growth Factor-I- Stimulated Rat Prostate Cancer Cell Proliferation and Apoptotic Resistance in Vitro via Inhibition of Intracellular Signaling Pathways Involving Tyrosine Kinase,” Journal of Nutrition, Vol. 133, 2003, pp. 2367-2376.
J. L. Pang, D. A. Ricupero, S. Huang, N. Fatma, D. P. Sing, J. S. Romero and N. Chattopadhyay, “Differential Activity of Kaempferol and Quercetin in Attenuating Tumor Necrosis Factor Receptor Family Signaling in Bone Cells,” Biochemical Pharmacology, Vol. 71, 2006, pp. 818-886.
V. García-Mediavilla, I. Crespo, P. S. Collado, A. Esteller, S. Sánchez-Campos, M. J. Tuñón and J. González-Gallego, “The Anti-Inflammatory Flavones Quercetin and Kaemp- ferol Cause Inhibition of Inducible Nitric Oxide Synthase, Cyclooxygenase-2 and Reactive C-Protein, and Down- Regulation of the Nuclear Factor Kappab Pathway in Chang Liver Cells,” European Journal of Pharmacology, Vol. 557, 2007, pp. 221-229.
M. Comalada, D. Camuesco, S. Sierra, I. Ballester, J. Xaus, J. Galvez and A. Zarzuelo, “In Vivo Quercitrin Anti-Inflammatory Effect Involves Releases of Quercetin, Which Inhibits Inflammation through Down-Regulation of NF-Kappab Pathway,” European Journal of Immunology, Vol. 35, 2005, pp. 584-592.
M. P. Nair, S. Mahajan, J. L. Reynolds, R. Aalinkeel, H. Nair, S. A. Schwartz and C. Kandaswami, “The Flavonoid Quercetin Inhibits Proinflammatory Cytokine (Tumor Ne-Crosis Factor Alpha) Gene Expression in Normal Peripheral Mononuclear Cells via Modulation of the NF-ΚB System,” Clinical and Vaccine Immunology, Vol. 13, 2006, pp. 319-328.
K. Muraoka, K. Shimizu, X. Sun, T. Tani, R. Izumumi, K. Miwa and K. Yamamoto, “Flavonoids Exert Diverse In-hibitory Effects on the Activation of NF-kB,” Transplantation Proceedings, Vol. 34, 2002, pp. 1335-1340.
C. A. Musonda and J. K. Chipman, “Quercetin Inhibits Hydrogen Peroxide (H2O2)-induced NF-kappaB DNA Binding Activity and DNA Damage in HepG2 Cells,” Carcinogenesis, Vol. 19, 1998, pp. 1583-1589.
S. Martínez-Flórez, M. B. Gutiérrez S. Sánchez-Campos, J. González-Gallego and M. J. Tuñón, “Quercetin Prevents Nitric Oxide Production and Nuclear Factor Kappa B Activation in Interleukin-1Β-Activated Rat Hepatocytes,” Journal of Nutrition, Vol. 135, 2005, pp. 1359- 1365.
J. Chen, F. M. Ho, P. L. Chao, C. P. Chen, K. G. Jeng, H. B. Hsu, S. T. Lee, W. Wen Tung and W. W. Lin, “Inhibi-tion of iNOS Gene Expression by Quercetin Is Mediated By the Inhibition of IΚB Kinase, Nuclear Factor-Kappa B and STAT1, and Depends on Heme Oxygenase-1 Induc-tion in Mouse BV-2 Microglia,” European Journal of Pharmacology, Vol. 52, 2005, pp. 9-20.
T. Banerjee, A. Van der Vliet and V. A. Ziboh, “Down- Regulation of COX-2 and iNOS by Amentoflavone and Quercetin in A549 Human Lung Adenocarcinoma Cell Line,” Prostaglandins Leukot Essent Fatty Acids, Vol. 66, 2002, pp. 485-492.
J. Duarte, R. Jiménez, F. O'Valle, M. Galisteo, R. Pérez-Palencia, F. Vargas, F. Pérez-Vizcaíno, A. Zar-Zuelo and J. Tamargo, “Protective Effects of the Flavonoid Quercetin in Chronic Nitric Oxide Deficient Rats,” Journal of Hypertension, Vol. 20, 2002, pp. 1843-1854.
T. L. Wadsworth and D. R. Koop, “Effects of Ginkgo Biloba Extract (EGb 761) and Quercetin on Lipopoly-saccharide-Induced Release of Nitric Oxide,” Chemico- Biological Interaction, Vol. 137, 2001, pp. 43-58.
T. L. Wadsworth, T. L. McDonald and D. R. Koop, “Effects of Ginkgo Biloba Extract (EGb 761) and Quercetin on Lipopolysaccharide-Induced Signaling Pathways Involved in the Release of Tumor Necrosis Factor-Alpha,” Biochemical Pharmacology, Vol. 62, 2001, pp. 963-974.
H. M. Abd El-Gawad and A. E. Khalifa, “Quercetin, Coenzyme Q10, and L-canavanine as Protective Agents against Lipid Peroxidation and Nitric Oxide Generation in Endotoxin-Induced Shock in Rat Brain,” Pharmacological Research, Vol. 43, 2001, pp. 257-263.
S. C. Shen, W. R. Lee, H. Y. Lin, H. C. Huang, C. H. Ko, L. L. Yang and Y. C. Chen, “In Vivo and In Vitro Inhi-bitory Activities of Rutin, Wogonin and Quercetin on Lipopolysaccharide-Induced Nitric Oxide and Prostaglan- Din E(2) Production,” European Journal of Pharmacol-ogy, Vol. 446, 2002, pp. 187-194.
O. Coskun, M. Kanter, A. Korkmaz and S. Oter, “Quercetin, a Flavonoid Antioxidant, Prevents and Protects Streptozotocin-Induced Oxidative Stress and Beta- Cell Damage in Rat Pancreas,” Pharmacological Research, Vol. 51, 2005, pp. 117-123.
Z. Shutenko, Y. Henry, E. Pinard, J. Seylaz, P. Potier, F. Berthet, P. Girard and R. Sercombe, “Influence of the Antioxidant Quercetin in Vivo on the Level of Nitric Oxide Determined by Electron Paramagnetic Resonance in Rat Brain During Global Ischemia and Reperfusion,” Biochemical Pharmacology, Vol. 57, 1999, pp. 199-208.
J. Da Silva, S. M. Hermann, V. Heuser, W. Peres, N. Marroni, J. González-Gallego and H. Erdtmann, “Evaluation of the Genotoxic Effect of Rutin and Quercetin by Comet Assay and Micronucleus Test,” Food and Chemi-cal Toxicology, Vol. 40, 2002, pp. 941-947.
M. Číž, M. Pavelková, L. Gallová, J. Králová, L. Kubala and A. Lojek, “The Influence of Wine Polyphenols on Reactive Oxygen and Nitrogen Species Production by Murine Macrophages RAW 264.7,” Physiological Re-search, Vol. 57, 2008, pp. 393-402.
S. Bastianetto, W. H. Zheng and R. Quirion, “Neuropro-tective Abilities of Resveratrol and Other Red Wine Con-stituents against Nitric Oxide-Related Toxicity in Cultured Hippocampal Neurons,” British Journal of Pharmacology, Vol. 131, 2000, pp. 711-720.