Berberis vulgaris and its constituent berberine as antidotes and protective agents against natural or chemical toxicities


1 School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Pharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran


Berberis vulgaris L (B. vulgaris) and its main constituent berberine have been used in traditional medicine for a long time. This medicinal plant and berberine have many properties that have attracted the attention of researchers over the time. According to several studies, B. vulgaris and berberine exhibited anti-inflammatory, antioxidant, anticonvulsant, antidepressant, anti-Alzheimer, anti-cancer, anti-arrhythmic, antiviral, antibacterial and anti-diabetic effects in both in vitro and in vivo experiments. In regard to many reports on protective effects of B. vulgaris and berberine on natural and chemical toxins, in the current review article, the inhibitory effects of these compounds against natural, industrial, environmental and chemical toxicities with focus on cellular mechanism have been categorized. It has been mentioned that berberine could ameliorate toxicity of chemical toxins in brain, heart, kidney, liver and lung in part through antioxidant, anti-inflammatory, anti-apoptotic, modulation of mitogen-activated protein kinase (MAPK) and nuclear factor-ĸB (NF-ĸB) signaling pathways.


1. Mokhber-Dezfuli N, Saeidnia S, Gohari AR, Kurepaz-Mahmoodabadi M. Phytochemistry and pharmacology of berberis species. Pharmacogn  Rev 2014; 8:8-15.

2. Singh IP, Mahajan S. Berberine and its derivatives: a patent review (2009–2012). Expert Opin Ther Pat 2013; 23:215-231.

3. Liu C-S, Zheng Y-R, Zhang Y-F, Long X-Y. Research progress on berberine with a special focus on its oral bioavailability. Fitoterapia 2016; 109:274-282.

4. Imenshahidi M, Hosseinzadeh H. Berberis vulgaris and berberine: an update review. Phytotherapy Research 2016;3:1745-1764.

5. Imanshahidi M, Hosseinzadeh H. Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine. Phytother Res 2008; 22:999-1012.

6. Tang J, Feng Y, Tsao S, Wang N, Curtain R, Wang Y. Berberine and Coptidis rhizoma as novel antineoplastic agents: A review of traditional use and biomedical investigations. Journal of Ethnopharmacol 2009; 126:5-17.

7. Kulkarni SK, Dhir A. Berberine: a plant alkaloid with therapeutic potential for central nervous system disorders. Phytotherapy Research 2010; 24:317-324.

8. Siow YL, Sarna L, O K. Redox regulation in health and disease — Therapeutic potential of berberine. Food Research Inte 2011; 44:2409-2417.

9. Yin J, Zhang H, Ye J. Traditional Chinese medicine in treatment of metabolic syndrome. Endocr Metab Immune Disord Drug Targets 2008; 8:99-111.

10. Tabeshpour J, Imenshahidi M, Hosseinzadeh H. A review of the effects of Berberis vulgaris and its major component, berberine, in metabolic syndrome. Iran J Basic Med Sci 2017. 20: In Press.

11. Zhang H-q, Wang H-d, Lu D-x, Qi R-b, Wang Y-p, Yan Y-x, et al. Berberine inhibits cytosolic phospholipase A2 and protects against LPS-induced lung injury and lethality independent of the α2-adrenergic receptor in mice. Shock 2008; 29:617-622.

12. Moneim AEA. Mercury-induced neurotoxicity and neuroprotective effects of berberine. Neural Regen Res 2015; 10:881-882.

13. Lee T, Heo H, Kim Kwon Y. Effect of berberine on cell survival in the developing rat brain damaged by MK-801. Exp Neurobiol 2010; 19:140-145.

14. Li J, Pan Y, Kan M, Xiao X, Wang Y, Guan F, et al. Hepatoprotective effects of berberine on liver fibrosis via activation of AMP-activated protein kinase. Life Sci 2014; 98:24-30.

15. Domitrović R, Cvijanović O, Pernjak-Pugel E, Škoda M, Mikelić L, Crnčević-Orlić Ž. Berberine exerts nephroprotective effect against cisplatin-induced kidney damage through inhibition of oxidative/nitrosative stress, inflammation, autophagy and apoptosis. Food Chem Toxicol 2013; 62:397-406.

16. Lv X, Yu X, Wang Y, Wang F, Li H, Wang Y, et al. Berberine inhibits doxorubicin-triggered cardiomyocyte apoptosis via attenuating mitochondrial dysfunction and increasing Bcl-2 expression. PLoS One 2012; 7:e47351.

17. Chitra P, Saiprasad G, Manikandan R, Sudhandiran G. Berberine attenuates bleomycin induced pulmonary toxicity and fibrosis via suppressing NF-κB dependant TGF-β activation: A biphasic experimental study. Toxicol Lett 2013; 219:178-193.

18. Tavakkoli A, Ahmadi A, Razavi BM, Hosseinzadeh H. Black seed (Nigella sativa) and its constituent thymoquinone as an antidote or a protective agent against natural or chemical toxicities. Iran J Pharm Res 2017; 16:2-23.

19. Razavi BM, Hosseinzadeh H. Saffron as an antidote or a protective agent against natural or chemical toxicities. Daru 2015; 23:31.

20. Rabbani G, Butler T, Knight J, Sanyal S, Alam K. Randomized controlled trial of berberine sulfate therapy for diarrhea due to enterotoxigenic Escherichia coli and Vibrio cholerae. J Infect Dis 1987; 155:979-984.

21. 17.Lin W-C, Lin J-Y. Berberine down-regulates the Th1/Th2 cytokine gene expression ratio in mouse primary splenocytes in the absence or presence of lipopolysaccharide in a preventive manner. Int Immunopharmacol 2011; 11:1984-1990.

22. Wu Y, Chuang S, Hong W, Lai Y, Chang G, Pang JS. Berberine reduces leukocyte adhesion to LPS-stimulated endothelial cells and VCAM-1 expression both in vivo and in vitro. Int J Immunopathol Pharmacol  2012; 25:741-750.

23. Yu X, Yu S, Chen L, Liu H, Zhang J, Ge H, et al. Tetrahydroberberrubine attenuates lipopolysaccharide-induced acute lung injury by down-regulating MAPK, AKT, and NF-κB signaling pathways. Biomed Pharmacother. 2016; 82:489-497.

24. Fu K, Lv X, Li W, Wang Y, Li H, Tian W, et al. Berberine hydrochloride attenuates lipopolysaccharide-induced endometritis in mice by suppressing activation of NF-κB signal pathway. Int Immunopharmacol 2015; 24:128-132.

25. Zhang Q, Piao X-L, Piao X-S, Lu T, Wang D, Kim SW. Preventive effect of Coptis chinensis and berberine on intestinal injury in rats challenged with lipopolysaccharides. Food Chem Toxicol 2011; 49:61-69.

26. Niu L, Qiao W, Hu Z, Li N, Huang Q, Gong J, et al. Berberine attenuates lipopolysaccharide-induced impairments of intestinal glutamine transport and glutaminase activity in rat. Fitoterapia 2011; 82:323-330.

27. Jiang Q, Liu P, Wu X, Liu W, Shen X, Lan T, et al. Berberine attenuates lipopolysaccharide-induced extracelluar matrix accumulation and inflammation in rat mesangial cells: involvement of NF-κB signaling pathway. Mol Cell Endocrinol 2011; 331:34-40.

28. Zhou X, Zhang C, Wang X, An B, Zhang P, Zhu Za. Berberine inhibits lipopolysaccharide-and polyethylene particle-induced mouse calvarial osteolysis in vivo. J Surg Res 2012; 173:e47-e52.

29. Xiao H-B, Sun Z-L, Zhang H-B, Zhang D-S. Berberine inhibits dyslipidemia in C57BL/6 mice with lipopolysaccharide induced inflammation. Pharmacol Rep 2012; 64:889-895.

30. Lee D, Bae J, Kim YK, Gil M, Lee J-Y, Park C-S, et al. Inhibitory effects of berberine on lipopolysaccharide-induced inducible nitric oxide synthase and the high-mobility group box 1 release in macrophages. Biochem Biophys Res Commun 2013; 431:506-511.

31. Lee D-U, Kang YJ, Park MK, Lee YS, Seo HG, Kim TS, et al. Effects of 13-alkyl-substituted berberine alkaloids on the expression of COX-II, TNF-α, iNOS, and IL-12 production in LPS-stimulated macrophages. Life Sci 2003; 73:1401-1412.

32. Li F, Wang H-d, Lu D-x, Wang Y-p, Qi R-b, Fu Y-m, et al. Neutral sulfate berberine modulates cytokine secretion and increases survival in endotoxemic mice. Acta Pharmacologica sinica 2006; 27:1199-1205.

33. Li H-m, Wang Y-y, Wang H-d, Cao W-j, Yu X-h, Lu D-x, et al. Berberine protects against lipopolysaccharide-induced intestinal injury in mice via alpha 2 adrenoceptor-independent mechanisms. Acta Pharmacol Sin 2011; 32:1364-1372.

34. Gao M-y, Chen L, Yang L, Yu X, Kou J-p, Yu B-y. Berberine inhibits LPS-induced TF procoagulant activity and expression through NF-κB/p65, Akt and MAPK pathway in THP-1 cells. Pharmacol Rep 2014; 66:480-484.

35. Swabb EA, Tai Y-H, Jordan L. Reversal of cholera toxin-induced secretion in rat ileum by luminal berberine. Am J Physiol Gastrointest Liver Physiol 1981; 241:G248-G252.

36. Sack RB, Froehlich JL. Berberine inhibits intestinal secretory response of Vibrio cholerae and Escherichia coli enterotoxins. Infect Immun 1982; 35:471-475.

37. Dutta N, Marker P, Rao N. Berberine in toxin‐induced experimental cholera. Br J Pharmacol 1972; 44:153-159.

38. Majeed W, Aslam B, Javed I, Khaliq T, Muhammad F, Ali A, et al. Histopathological evaluation of gastro protective effect of Berberis vulgaris (Zereshk) seeds against aspirin induced ulcer in albino mice. Pak J Pharm Sci 2015; 1:1953-1958.

39. Minaiyan M, Ghannadi A, Mahzouni P, Jaffari-Shirazi E. Comparative study of Berberis vulgaris fruit extract and berberine chloride effects on acetic acid-induced colitis in rats. Iran J Pharm Res 2011:97-104.

40. Zhou H, Mineshita S. The effect of berberine chloride on experimental colitis in rats in vivo and in vitro. J Pharm Exp Ther  2000; 294:822-829.

41. Sathish R, Sahu A, Natarajan K. Antiulcer and antioxidant activity of ethanolic extract of Passiflora foetida L. Indian J Pharmacol 2011; 43:336.

42. Zhang M, Long Y, Sun Y, Wang Y, Li Q, Wu H, et al. Evidence for the complementary and synergistic effects of the three-alkaloid combination regimen containing berberine, hypaconitine and skimmianine on the ulcerative colitis rats induced by trinitrobenzene-sulfonic acid. Eur  J Pharmacol 2011; 651:187-196.

43. Gross TJ, Hunninghake GW. Idiopathic pulmonary fibrosis. N Engl J Med 2001; 345:517-525.

44. Green FH. Overview of pulmonary fibrosis. Chest  2002; 122:334S-339S.

45. Chitra P, Saiprasad G, Manikandan R, Sudhandiran G. Berberine inhibits Smad and non-Smad signaling cascades and enhances autophagy against pulmonary fibrosis. J Mol Med 2015; 93:1015-1031.

46. Sun B, Chen Y. Advances in the mechanism of paraquat-induced pulmonary injury. Eur Rev Med Pharmacol Sci. 2016; 20:1597-1602.

47. Javad-Mousavi SA, Hemmati AA, Mehrzadi S, Hosseinzadeh A, Houshmand G, Nooshabadi MRR, et al. Protective effect of Berberis vulgaris fruit extract against paraquat-induced pulmonary fibrosis in rats. Biomed  Pharmacother 2016; 81:329-336.

48. Lin K, Liu S, Shen Y, Li Q. Berberine attenuates cigarette smoke-induced acute lung inflammation. Inflammation 2013; 36:1079-1086.

49. Pfefferbaum A, Sullivan EV, Rosenbloom MJ, Mathalon DH, Lim KO. A controlled study of cortical gray matter and ventricular changes in alcoholic men over a 5-year interval. Arch Gen Psychiatry 1998; 55:905-912.

50. Mantle D, Preedy V. Free radicals as mediators of alcohol toxicity. Adverse Drug React Toxicol Rev 1999; 18:235-252.

51. Nordmann R, Ribiere C, Rouach H. Ethanol-induced lipid peroxidation and oxidative stress in extrahepatic tissues. Alcohol Alcohol 1990; 25:231-237.

52. Bhutada P, Mundhada Y, Bansod K, Hiware R, Rathod S, Dixit P, et al. Berberine protects C57BL/6J mice against ethanol withdrawal‐induced hyperexcitability. Phytother Res 2011; 25:302-307.

53. Patil S, Tawari S, Mundhada D, Nadeem S. Protective effect of berberine, an isoquinoline alkaloid ameliorates ethanol-induced oxidative stress and memory dysfunction in rats. Pharmacol Biochem Behav 2015; 136:13-20.

54. Bhutada P, Mundhada Y, Bansod K, Rathod S, Hiware R, Dixit P, et al. Inhibitory effect of berberine on the motivational effects of ethanol in mice. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34:1472-1479.

55. Klinkenberg I, Blokland A. The validity of scopolamine as a pharmacological model for cognitive impairment: a review of animal behavioral studies. Neurosci Biobehav Rev 2010; 34:1307-1350.

56. Elrod K, Buccafusco JJ. An evaluation of the mechanism of scopolamine-induced impairment in two passive avoidance protocols. Pharmacol Biochem Behav 1988; 29:15-21.

57.Peng W-H, Hsieh M-T, Wu C-R. Effect of Long-Term Administration of berberine on scopolamine induced amnesia in rats. Jpn J Pharmacol 1997; 74:261-266.

58. Lee B, Sur B, Shim I, Lee H, Hahm D-H. Phellodendron amurense and its major alkaloid compound, berberine ameliorates scopolamine-induced neuronal impairment and memory dysfunction in rats. Korean J Physiol Pharmacol 2012; 16:79-89.

59.Moneim AEA. The neuroprotective effect of berberine in mercury-induced neurotoxicity in rats. Metab Brain Dis 2015; 30:935-942.

60. Lim JS, Kim H, Choi Y, Kwon H, Shin KS, Joung I, et al. Neuroprotective effects of berberine in neurodegeneration model rats induced by ibotenic acid. Animal Cells Syst 2008; 12:203-209.

61. Kim M, Cho K-H, Shin M-S, Lee J-M, Cho H-S, Kim C-J, et al. Berberine prevents nigrostriatal dopaminergic neuronal loss and suppresses hippocampal apoptosis in mice with Parkinson's disease. Int J Mol Med 2014; 33:870-878.

62. Zhou W, Zhang F, Liu H, Tang S, Lai M, Zhu H, et al. Effects of training and withdrawal periods on heroin seeking induced by conditioned cue in an animal of model of relapse. Psychopharmacology 2009; 203:677-684.

63. Yoo J-H, Yang E-M, Cho J-H, Lee J-H, Jeong S, Nah S-Y, et al. Inhibitory effects of berberine against morphine-induced locomotor sensitization and analgesic tolerance in mice. Neuroscience 2006; 142:953-961.

64. Lee B, Sur B, Yeom M, Shim I, Lee H, Hahm D-H. Effect of berberine on depression-and anxiety-like behaviors and activation of the noradrenergic system induced by development of morphine dependence in rats. Korean J Physiol Pharmacol 2012; 16:379-386.

65. Imenshahidi M, Qaredashi R, Hashemzaei M, Hosseinzadeh H. Inhibitory Effect of Berberis vulgaris aqueous extract on acquisition and reinstatement effects of morphine in conditioned place preferences (CPP) in mice. Jundishapur J Nat Pharm Prod 2014; 9:e16145.

66. Panahi N, Mahmoudian M, Mortazavi P, Hashjin GS. Effects of berberine on β-secretase activity in a rabbit model of Alzheimer’s disease. Arch Med Sci 2013; 9:146-150.

67. Zhang J, Yang J-Q, He B-C, Zhou Q-X, Yu H-R, Tang Y, et al. Berberine and total base from rhizoma coptis chinensis attenuate brain injury in an aluminum-induced rat model of neurodegenerative disease. Saudi Med J 2009; 30:760-766.

68. Lee B, Yang CH, Hahm DH, Lee HJ, Choe ES, Pyun KH, et al. Coptidis Rhizoma attenuates repeated nicotine‐induced behavioural sensitization in the rat. J Pharm Pharmacol 2007; 59:1663-1669.

69. Agostinho P, Pliássova A, Oliveira CR, Cunha RA. Localization and trafficking of amyloid-β protein precursor and secretases: impact on Alzheimer's disease. J Alzheimers Dis 2015; 45:329-347.

70. Jiang H, Wang X, Huang L, Luo Z, Su T, Ding K, et al. Benzenediol-berberine hybrids: multifunctional agents for Alzheimer’s disease. Bioorg Med Chem2011; 19:7228-7235.

71. Zhu F, Qian C. Berberine chloride can ameliorate the spatial memory impairment and increase the expression of interleukin-1beta and inducible nitric oxide synthase in the rat model of Alzheimer's disease. BMC neuroscience 2006; 7:1.

72. Haghani M, Shabani M, Tondar M. The therapeutic potential of berberine against the altered intrinsic properties of the CA1 neurons induced by Aβ neurotoxicity. Eur J Pharmacol 2015; 758:82-88.

73. Handforth A. Harmaline tremor: underlying mechanisms in a potential animal model of essential tremor. Tremor Other Hyperkinet Mov 2012; 2:769

74. Miwa, H.Rodent models of tremor Cerebellum 2007; 6:  66-72.

75. O’Hearn E, Molliver ME. The olivocerebellar projection mediates ibogaine-induced degeneration of Purkinje cells: a model of indirect, trans-synaptic excitotoxicity. J Neurosci 1997; 17:8828-8841.

76. Llinas R, Volkind R. The olivo-cerebellar system: functional properties as revealed by harmaline-induced tremor. Expe Brain Res 1973; 18:69-87.

77. Vaziri Z, Abbassian H, Sheibani V, Haghani M, Nazeri M, Aghaei I, et al. The therapeutic potential of Berberine chloride hydrate against harmaline-induced motor impairments in a rat model of tremor. Neurosci Lett 2015; 590:84-90.

78. Amin B, Malekzadeh M, Heidari MR, Hosseinzadeh H. Effect of Crocus sativus extracts and its active constituent safranal on the harmaline-induced tremor in mice. Iran J Basic Med Sci 2015; 18:449-458.

79. Bhutada P, Mundhada Y, Bansod K, Dixit P, Umathe S, Mundhada D. Anticonvulsant activity of berberine, an isoquinoline alkaloid in mice. Epilepsy  Behav 2010; 18:207-210.

80. Gao F, Gao Y, Liu Y-f, Wang L, Li Y-j. Berberine exerts an anticonvulsant effect and ameliorates memory impairment and oxidative stress in a pilocarpine-induced epilepsy model in the rat. Neuropsychiatr Dis Treat 2014; 10:2139.

81. Curia G, Longo D, Biagini G, Jones RS, Avoli M. The pilocarpine model of temporal lobe epilepsy. J Neurosci Methods 2008; 172:143-157.

82. Graham ML, Janecek JL, Kittredge JA, Hering BJ, Schuurman H-J. The streptozotocin-induced diabetic nude mouse model: differences between animals from different sources. Comp Med 2011; 61:356-360.

83. Bhutada P, Mundhada Y, Bansod K, Tawari S, Patil S, Dixit P, et al. Protection of cholinergic and antioxidant system contributes to the effect of berberine ameliorating memory dysfunction in rat model of streptozotocin-induced diabetes. Behav Brain Res 2011; 220:30-41.

84. Zhou J, Du X, Long M, Zhang Z, Zhou S, Zhou J, et al. Neuroprotective effect of berberine is mediated by MAPK signaling pathway in experimental diabetic neuropathy in rats. Eur J Pharmacol 2016; 774:87-94.

85.Kalalian-Moghaddam H, Baluchnejadmojarad T, Roghani M, Goshadrou F, Ronaghi A. Hippocampal synaptic plasticity restoration and anti-apoptotic effect underlie berberine improvement of learning and memory in streptozotocin-diabetic rats. Eur J Pharmacol 2013; 698:259-266.

86. Kumar A, Mishra J, Chopra K, Dhull DK. Possible role of P-glycoprotein in the neuroprotective mechanism of berberine in intracerebroventricular streptozotocin-induced cognitive dysfunction. Psychopharmacology 2016; 233:137-152.

87. Kim SO, Kim HJ. Berberine ameliorates cold and mechanical allodynia in a rat model of diabetic neuropathy. J Med Food 2013; 16:511-517.

88. Hosseinzadeh H, Sadeghnia H. Protective effect of safranal on pentylenetetrazol-induced seizures in the rat: involvement of GABAergic and opioids systems. Phytomedicine 2007; 14:256-262.

89. Sadeghnia HR, Darbarpanah S, Hosseini SM. Effect of berberine on pentylenetetrazol-induced seizures in rats. Avicenna J Phytomed 2011; 1:78-82.

90. Hosseinzadeh H, Ramezani M, Shafaei H, Taghiabadi E. Anticonvulsant effect of Berberis integerrima L. root extracts in mice. J Acupunct Meridian Stud 2013; 6:12-17.

91. Kulkarni SK, Dhir A. On the mechanism of antidepressant-like action of berberine chloride. Eur J Pharmacol 2008; 589:163-172.

92. Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL. Doxorubicin-induced cardiomyo-pathy: from molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol 2012; 52:1213-1225.

93. Hao G, Yu Y, Gu B, Xing Y, Xue M. Protective effects of berberine against doxorubicin-induced cardiotoxicity in rats by inhibiting metabolism of doxorubicin. Xenobiotica 2015; 45:1024-1029.

94. Zhao X, Zhang J, Tong N, Liao X, Wang E, Li Z, et al. Berberine attenuates doxorubicin-induced cardiotoxicity in mice. J Int Med Res 2011; 39:1720-1727.

95. Ying Y, Zhu H, Liang Z, Ma X, Li S. GLP1 protects cardiomyocytes from palmitate-induced apoptosis via Akt/GSK3b/b-catenin pathway. J Mol Endocrinol 2015; 55:245-262.

96. Chang W, Zhang M, Meng Z, Yu Y, Yao F, Hatch GM, et al. Berberine treatment prevents cardiac dysfunction and remodeling through activation of 5′-adenosine monophosphate-activated protein kinase in type 2 diabetic rats and in palmitate-induced hypertrophic H9c2 cells. Eur J Pharmacol 2015; 769:55-63.

97. Liu W-h, Hei Z-q, Nie H, Tang F-t, Huang H-q, Li X-j, et al. Berberine ameliorates renal injury in streptozotocin-induced diabetic rats by suppression of both oxidative stress and aldose reductase. Chin Med J 2008; 121:706-712.

98. Yang Y, Ni W, Cai M, Tang L, Wei W. The renoprotective effects of berberine via the EP4-Gαs-cAMP signaling pathway in different stages of diabetes in rats. J Recept Signal Transduct Res 2014; 34:445-455.

99. Kennedy CR, Xiong H, Rahal S, Vanderluit J, Slack RS, Zhang Y, et al. Urine concentrating defect in prostaglandin EP1-deficient mice. Am J Physiol Renal Physiol 2007; 292: 868-875.

100. Ni WJ, Tang LQ, Zhou H, Ding HH, Qiu YY. Renoprotective effect of berberine via regulating the PGE2‐EP1‐Gαq‐Ca2+ signalling pathway in glomerular mesangial cells of diabetic rats. J Cell Mol Med 2016; 20: 1491–1502.

101. Tang LQ, Ni WJ, Cai M, Ding HH, Liu S, Zhang ST. Renoprotective effects of berberine and its potential effect on the expression of β‐arrestins and intercellular adhesion molecule‐1 and vascular cell adhesion molecule‐1 in streptozocin‐diabetic nephropathy rats. J Diabetes 2016; 8: 693-700.

102. Wu D, Wen W, Qi C-L, Zhao R-X, Lü J-H, Zhong C-Y, et al. Ameliorative effect of berberine on renal damage in rats with diabetes induced by high-fat diet and streptozotocin. Phytomedicine 2012; 19:712-718.

103. Wang FL, Tang LQ, Yang F, Zhu LN, Cai M, Wei W. Renoprotective effects of berberine and its possible molecular mechanisms in combination of high-fat diet and low-dose streptozotocin-induced diabetic rats. Mol Biol Rep 2013; 40:2405-2418.

104. Su J, Zhang P, Zhang J-J, Qi X-M, Wu Y-G, Shen J-J. Effects of total glucosides of paeony on oxidative stress in the kidney from diabetic rats. Phytomedicine 2010; 17:254-260.

105. Lim AK, Tesch GH. Inflammation in diabetic nephropathy. Mediat Inflamm 2012; 2012. 146-154

106. Sun SF, Zhao TT, Zhang HJ, Huang XR, Zhang WK, Zhang L, et al. Renoprotective effect of berberine on type 2 diabetic nephropathy in rats. Clin Exp Pharmacol Physiol 2015; 42:662-670.

107. Zhang X, He H, Liang D, Jiang Y, Liang W, Chi Z-H,  et al. Protective effects of berberine on renal injury in streptozotocin (STZ)-induced diabetic mice. Int J Mol Sci 2016; 17:1327.

108. Adil M, Kandhare AD, Dalvi G, Ghosh P, Venkata S, Raygude KS, et al. Ameliorative effect of berberine against gentamicin-induced nephrotoxicity in rats via attenuation of oxidative stress, inflammation, apoptosis and mitochondrial dysfunction. Renal Fail  2016; 38:996-1006.

109. Othman MS, Safwat G, Aboulkhair M, Moneim AEA. The potential effect of berberine in mercury-induced hepatorenal toxicity in albino rats. Food Chem Toxicol 2014; 69:175-181.

110. Philips FS, Sternberg SS, Cronin AP, Vidal PM. Cyclophosphamide and urinary bladder toxicity. Cancer Res 1961; 21:1577-1589.

111. Xu X, Malavé A. Protective Effect of Berberine on Cyclophosphamide‐Induced Haemorrhagic Cystitis in Rats. Pharmacol  Toxicol 2001; 88:232-237.

112. Liu W, Zhang X, Liu P, Shen X, Lan T, Li W, et al. Effects of berberine on matrix accumulation and NF-kappa B signal pathway in alloxan-induced diabetic mice with renal injury. Eur J Pharmacol 2010; 638:150-155.

113. Lan T, Shen X, Liu P, Liu W, Xu S, Xie X, et al. Berberine ameliorates renal injury in diabetic C57BL/6 mice: Involvement of suppression of SphK–S1P signaling pathway. Arch Biochem Biophys 2010; 502:112-120.

114. Domitrović R, Jakovac H, Marchesi VV, Blažeković B. Resolution of liver fibrosis by isoquinoline alkaloid berberine in CCl4-intoxicated mice is mediated by suppression of oxidative stress and upregulation of MMP-2 expression. J Med Food 2013; 16:518-528.

115. Zhang BJ, Xu D, Guo Y, Ping J, Chen Lb, Wang H. Protevtion by and anti-oxidant mechanism of berberine against rat liver fibrosis induced by multiple hepatotoxic factors. Clin Exp Pharmacol Physiol 2008; 35:303-309.

116. Domitrović R, Jakovac H, Blagojević G. Hepatoprotective activity of berberine is mediated by inhibition of TNF-α, COX-2, and iNOS expression in CCl 4-intoxicated mice. Toxicology 2011; 280:33-43.

117. Feng Y, Siu K-Y, Ye X, Wang N, Yuen M-F, Leung C-H, et al. Hepatoprotective effects of berberine on carbon tetrachloride-induced acute hepatotoxicity in rats. Chin Med 2010; 5:1.

118. Sarhadynejad Z, Sharififar F, Pardakhty A, Nematollahi M-H, Sattaie-Mokhtari S, Mandegary A. Pharmacological safety evaluation of a traditional herbal medicine “Zereshk-e-Saghir” and assessment of its hepatoprotective effects on carbon tetrachloride induced hepatic damage in rats. J Ethnopharmacol 2016; 22:387-395.

119. Zhang P, Ma D, Wang Y, Zhang M, Qiang X, Liao M, et al. Berberine protects liver from ethanol-induced oxidative stress and steatosis in mice. Food Chem Toxicol 2014; 74:225-232.

120. Hasanein P, Ghafari-Vahed M, Khodadadi I. Effects of isoquinoline alkaloid berberine on lipid peroxidation, antioxidant defense system, and liver damage induced by lead acetate in rats. Redox Report 2016:1-9.

121. Germoush MO, Mahmoud AM. Berberine mitigates cyclophosphamide-induced hepatotoxicity by modula-ting antioxidant status and inflammatory cytokines. J Cancer Res Clin Oncol 2014; 140:1103-1109.

122. Hwang J-M, Wang C-J, Chou F-P, Tseng T-H, Hsieh Y-S, Lin W-L, et al. Inhibitory effect of berberine on tert-butyl hydroperoxide-induced oxidative damage in rat liver. Arch Toxicol 2002; 76:664-670.

123. Zhao X, Zhang J, Tong N, Chen Y, Luo Y. Protective effects of berberine on doxorubicin-induced hepato-toxicity in mice. Biol Pharm Bull 2012; 35:796-800.

124. Janbaz K, Gilani A. Studies on preventive and curative effects of berberine on chemical-induced hepatotoxicity in rodents. Fitoterapia 2000; 71:25-33.

125. Recknagel RO, Glende EA, Dolak JA, Waller RL. Mechanisms of carbon tetrachloride toxicity. Pharmacol Ther 1989; 43:139-154.

126. Sudharsan PT, Mythili Y, Selvakumar E, Varalakshmi P. Lupeol and its ester exhibit protective role against cyclophosphamide-induced cardiac mitochondrial toxicity. J Cardiovasc Pharmacol 2006; 47:205-210.

127. Lindley C, Hamilton G, McCune JS, Faucette S, Shord SS, Hawke RL, et al. The effect of cyclophosphamide with and without dexamethasone on cytochrome P450 3A4 and 2B6 in human hepatocytes. Drug Metab Dispos 2002; 30:814-822.

128. Joyeux M, Rolland A, Fleurentin J, Mortier F, Dorfman P. tert-Butyl hydroperoxide-induced injury in isolated rat hepatocytes: a model for studying anti-hepatotoxic crude drugs. Planta Med 1990; 56:171-174.

129. Högberg J, Orrenius S, O'brien PJ. Further studies on lipid‐peroxide formation in isolated hepatocytes. Eur J Biochem 1975; 59:449-455.

130. Laskin DL, Gardner CR, Price VF, Jollow DJ. Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen. Hepatology 1995; 21:1045-1050.

131. Hinson JA, Roberts DW, James LP. Mechanisms of acetaminophen-induced liver necrosis. Handb Exp Pharmacol 2010; 196:369-405.

132. Wang J, Yang Z, Lin L, Zhao Z, Liu Z, Liu X. Protective effect of naringenin against lead-induced oxidative stress in rats. Biol Trace Elem Res 2012; 146:354-359.