Biological properties and clinical applications of berberine

Abstract

Berberine, an isoquinoline alkaloid isolated from the Chinese herb Coptis chinensis and other Berberis plants, has a wide range of pharmacological properties. Berberine can be used to treat many diseases, such as cancer and digestive, metabolic, cardiovascular, and neurological diseases. Berberine has protective capacities in digestive diseases. It can inhibit toxins and bacteria, including Helicobacter pylori, protect the intestinal epithelial barrier from injury, and ameliorate liver injury. Berberine also inhibits the proliferation of various types of cancer cells and impedes invasion and metastasis. Recent evidence has confirmed that berberine improves the efficacy and safety of chemoradiotherapies. In addition, berberine regulates glycometabolism and lipid metabolism, improves energy expenditure, reduces body weight, and alleviates nonalcoholic fatty liver disease. Berberine also improves cardiovascular hemodynamics, suppresses ischemic arrhythmias, attenuates the development of atherosclerosis, and reduces hypertension. Berberine shows potent neuroprotective effects, including antioxidative, antiapoptotic, and anti-ischemic. Furthermore, berberine exerts protective effects against other diseases. The mechanisms of its functions have been extensively explored, but much remains to be clarified. This article summarizes the main pharmacological actions of berberine and its mechanisms in cancer and digestive, metabolic, cardiovascular, and neurological diseases.

Keywords

berberine / Coptis chinensis / pharmacological properties / mechanism / clinical applications

References

[1] Yarla NS, Bishayee A, Sethi G, Reddanna P, Kalle AM, Dhananjaya BL, Dowluru KS, Chintala R, Duddukuri GR. Targeting arachidonic acid pathway by natural products for cancer prevention and therapy. Semin Cancer Biol 2016; 40-41: 48–81

[2] Hesari A, Ghasemi F, Cicero AFG, Mohajeri M, Rezaei O, Hayat SMG, Sahebkar A. Berberine: a potential adjunct for the treatment of gastrointestinal cancers? J Cell Biochem 2018; 119(12): 9655–9663

[3] Pirillo A, Catapano AL. Berberine, a plant alkaloid with lipid- and glucose-lowering properties: from in vitro evidence to clinical studies. Atherosclerosis 2015; 243(2): 449–461

[4] Subbaiah TV, Amin AH. Effect of berberine sulphate on Entamoeba histolytica. Nature 1967; 215(5100): 527–528

[5] Amin AH, Subbaiah TV, Abbasi KM. Berberine sulfate: antimicrobial activity, bioassay, and mode of action. Can J Microbiol 1969; 15(9): 1067–1076

[6] Dutta NK, Marker PH, Rao NR. Berberine in toxin-induced experimental cholera. Br J Pharmacol 1972; 44(1): 153–159

[7] Wang S, Setlow B, Setlow P, Li YQ. Uptake and levels of the antibiotic berberine in individual dormant and germinating Clostridium difficile and Bacillus cereus spores as measured by laser tweezers Raman spectroscopy. J Antimicrob Chemother 2016; 71(6): 1540–1546

[8] Li Y, Huang J, Li L, Liu L. Synergistic activity of berberine with azithromycin against Pseudomonas aeruginosa isolated from patients with cystic fibrosis of lung in vitro and in vivo. Cell Physiol Biochem 2017; 42(4): 1657–1669

[9] Sack RB, Froehlich JL. Berberine inhibits intestinal secretory response of Vibrio cholerae and Escherichia coli enterotoxins. Infect Immun 1982; 35(2): 471–475

[10] Wen SQ, Jeyakkumar P, Avula SR, Zhang L, Zhou CH. Discovery of novel berberine imidazoles as safe antimicrobial agents by down regulating ROS generation. Bioorg Med Chem Lett 2016; 26(12): 2768–2773

[11] Liu X, Zhang N, Liu Y, Liu L, Zeng Q, Yin M, Wang Y, Song D, Deng H. MPB, a novel berberine derivative, enhances lysosomal and bactericidal properties via TGF-β-activated kinase 1-dependent activating the transcription factor EB. FASEB J 2019; 33(1):1468–1481

[12] Eaker EY, Sninsky CA. Effect of berberine on myoelectric activity and transit of the small intestine in rats. Gastroenterology 1989; 96(6): 1506–1513

[13] Taylor CT, Baird AW. Berberine inhibition of electrogenic ion transport in rat colon. Br J Pharmacol 1995; 116(6): 2667–2672

[14] Rabbani GH, Butler T, Knight J, Sanyal SC, Alam K. Randomized controlled trial of berberine sulfate therapy for diarrhea due to enterotoxigenic Escherichia coli and Vibrio cholerae. J Infect Dis 1987; 155(5): 979–984

[15] Watanabe-Fukuda Y, Yamamoto M, Miura N, Fukutake M, Ishige A, Yamaguchi R, Nagasaki M, Saito A, Imoto S, Miyano S, Takeda J, Watanabe K. Orengedokuto and berberine improve indomethacin-induced small intestinal injury via adenosine. J Gastroenterol 2009; 44(5): 380–389

[16] Liu Y, Liu X, Hua W, Wei Q, Fang X, Zhao Z, Ge C, Liu C, Chen C, Tao Y, Zhu Y. Berberine inhibits macrophage M1 polarization via AKT1/SOCS1/NF-κB signaling pathway to protect against DSS-induced colitis. Int Immunopharmacol 2018; 57: 121–131

[17] Hering NA, Fromm M, Schulzke JD. Determinants of colonic barrier function in inflammatory bowel disease and potential therapeutics. J Physiol 2012; 590(5): 1035–1044

[18] Li GH, Zhang YP, Tang JL, Chen ZT, Hu YD, Wei H, Li DZ, Hao P, Wang DL. Effects of berberine against radiation-induced intestinal injury in mice. Int J Radiat Oncol Biol Phys 2010; 77(5): 1536–1544

[19] Yan F, Wang L, Shi Y, Cao H, Liu L, Washington MK, Chaturvedi R, Israel DA, Cao H, Wang B, Peek RM Jr, Wilson KT, Polk DB. Berberine promotes recovery of colitis and inhibits inflammatory responses in colonic macrophages and epithelial cells in DSS-treated mice. Am J Physiol Gastrointest Liver Physiol 2012; 302(5): G504–G514

[20] Li C, Xi Y, Li S, Zhao Q, Cheng W, Wang Z, Zhong J, Niu X, Chen G. Berberine ameliorates TNBS induced colitis by inhibiting inflammatory responses and Th1/Th17 differentiation. Mol Immunol 2015; 67(2 Pt B): 444–454

[21] Guo BJ, Bian ZX, Qiu HC, Wang YT, Wang Y. Biological and clinical implications of herbal medicine and natural products for the treatment of inflammatory bowel disease. Ann N Y Acad Sci 2017; 1401(1): 37–48

[22] He Y, Yuan X, Zuo H, Sun Y, Feng A. Berberine exerts a protective effect on gut-vascular barrier via the modulation of the Wnt/β-catenin signaling pathway during sepsis. Cell Physiol Biochem 2018; 49(4): 1342–1351

[23] Wu SJ, Don TM, Lin CW, Mi FL. Delivery of berberine using chitosan/fucoidan-taurine conjugate nanoparticles for treatment of defective intestinal epithelial tight junction barrier. Mar Drugs 2014; 12(11): 5677–5697

[24] Shan CY, Yang JH, Kong Y, Wang XY, Zheng MY, Xu YG, Wang Y, Ren HZ, Chang BC, Chen LM. Alteration of the intestinal barrier and GLP2 secretion in berberine-treated type 2 diabetic rats. J Endocrinol 2013; 218(3): 255–262

[25] Gu L, Li N, Gong J, Li Q, Zhu W, Li J. Berberine ameliorates intestinal epithelial tight-junction damage and down-regulates myosin light chain kinase pathways in a mouse model of endotoxinemia. Infect Dis 2011; 203(11): 1602–1612

[26] Vivoli E, Cappon A, Milani S, Piombanti B, Provenzano A, Novo E, Masi A, Navari N, Narducci R, Mannaioni G, Moneti G, Oliveira CP, Parola M, Marra F. NLRP3 inflammasome as a target of berberine in experimental murine liver injury: interference with P2X7 signalling. Clin Sci (Lond) 2016; 130(20): 1793–1806

[27] Guo T, Woo SL, Guo X, Li H, Zheng J, Botchlett R, Liu M, Pei Y, Xu H, Cai Y, Zeng T, Chen L, Li X, Li Q, Xiao X, Huo Y, Wu C. Berberine ameliorates hepatic steatosis and suppresses liver and adipose tissue inflammation in mice with diet-induced obesity. Sci Rep 2016; 6(1): 22612-22622

[28] Hwang JM, Wang CJ, Chou FP, Tseng YS, Lin WL, Chu CY. Inhibitory effect of berberine on tert-butyl hydroperoxide-induced oxidative damage in rat liver. Arch Toxicol 2002; 76(11): 664–670

[29] Zhao Z, Wei Q, Hua W, Liu Y, Liu X, Zhu Y. Hepatoprotective effects of berberine on acetaminophen-induced hepatotoxicity in mice. Biomed Pharmacother 2018; 103: 1319–1326

[30] Rafiei H, Omidian K, Bandy B. Comparison of dietary polyphenols for protection against molecular mechanisms underlying nonalcoholic fatty liver disease in a cell model of steatosis. Mol Nutr Food Res 2017; 61(9): 1600781

[31] Qin C, Zhang H, Zhao L, Zeng M, Huang W, Fu G, Zhou W, Wang H, Yan H. Microbiota transplantation reveals beneficial impact of berberine on hepatotoxicity by improving gut homeostasis. Sci China Life Sci 2018; 61(12): 1537–1544

[32] Sun Y, Xia M, Yan H, Han Y, Zhang F, Hu Z, Cui A, Ma F, Liu Z, Gong Q, Chen X, Gao J, Bian H, Tan Y, Li Y, Gao X. Berberine attenuates hepatic steatosis and enhances energy expenditure in mice by inducing autophagy and fibroblast growth factor 21. Br J Pharmacol 2018; 175(2): 374–387

[33] Zhang D, Ke L, Ni Z, Chen Y, Zhang LH, Zhu SH, Li CJ, Shang L, Liang J, Shi YQ. Berberine containing quadruple therapy for initial Helicobacter pylori eradication: an open-label randomized phase IV trial. Medicine (Baltimore) 2017; 96(32): e7697

[34] Bae FA, Han MJ, Kim NJ, Kim DH. Anti-Helicobacter pylori activity of herbal medicines. Biol Pharm Bull 1998; 21(9): 990–992

[35] Chung JG, Wu LT, Chang SH, Lo HH, Hsieh SE, Li YC, Hung CF. Inhibitory actions of ellagic acid on growth and arylamine N-acetyltransferase activity in strains of Helicobacter pylori from peptic ulcer patients. Microbios 1998; 93(375): 115–127

[36] Li C, Huang P, Wong K, Xu Y, Tan L, Chen H, Lu Q, Luo C, Tam C, Zhu L, Su Z, Xie J. Coptisine-induced inhibition of Helicobacter pylori: elucidation of specific mechanisms by probing urease active site and its maturation process. J Enzyme Inhib Med Chem 2018; 33(1): 1362–1375

[37] Jiang X, Jiang C, Huang C, Chen G, Jiang K, Huang B, Liu F. Berberine combined with triple therapy versus triple therapy for Helicobacter pylori eradication: a meta-analysis of randomized controlled trials. Evid Based Complement Alternat Med 2018; 2018: 8716910

[38] Huang YQ, Huang GR, Wu MH, Tang HY, Huang ZS, Zhou XH, Yu WQ, Su JW, Mo XQ, Chen BP, Zhao LJ, Huang XF, Wei HY, Wei LD. Inhibitory effects of emodin, baicalin, schizandrin and berberine on hefA gene: treatment of Helicobacter pylori-induced multidrug resistance. World J Gastroenterol 2015; 21(14): 4225–4231

[39] Zhang X, Yang Y, Gang S, Yang C, Lu M, Zhi J. Berberine-, allicin- or clarithromycin-based triple therapy for the first-line treatment of Helicobacter pylori infection: an open-label, randomizedt trial. Gastroenterology 2014; 146(5): S398

[40] Lu JS, Liu YQ, Li M, Li BS, Xu Y. Protective effects and its mechanisms of total alkaloids from rhizoma Coptis chinensis on Helicobacter pylori LPS induced gastric lesion in rats. China J Chin Mater Med (Zhongguo Zhong Yao Za Zhi) 2007; 32(13): 1333–1336 (in Chinese)

[41] Wu X, Li X, Dang Z, Jia Y. Berberine demonstrates anti-inflammatory properties in Helicobacter pylori-infected mice with chronic gastritis by attenuating the Th17 response triggered by the B cell-activating factor. J Cell Biochem 2018; 119(7): 5373–5381

[42] Kuo CL, Chou CC, Yung BY. Berberine complexes with DNA in the berberine-induced apoptosis in human leukemic HL-60 cells. Cancer Lett 1995; 93(2): 193–200

[43] Li L, Wang X, Sharvan R, Gao J, Qu S. Berberine could inhibit thyroid carcinoma cells by inducing mitochondrial apoptosis, G0/G1 cell cycle arrest and suppressing migration via PI3K-AKT and MAPK signaling pathways. Biomed Pharmacother 2017; 95: 1225–1231

[44] Mantena SK, Sharma SD, Katiyar SK. Berberine, a natural product, induces G1-phase cell cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells. Mol Cancer Ther 2006; 5(2): 296–308

[45] Lin CC, Yang JL, Lu CC, Chung JG. Berberine induces cell cycle arrest and apoptosis in human HSC-3 oral cancer cells. FASEB J 2007, 27(5A):3371–3378

[46] Kang JX, Liu J, Wang J, He C, Li FP. The extract of huanglian, a medicinal herb, induces cell growth arrest and apoptosis by upregulation of interferon-β and TNF-α in human breast cancer cells. Carcinogenesis 2005; 26(11): 1934–1939

[47] Zheng F, Tang Q, Wu J, Zhao S, Liang Z, Li L, Wu W, Hann S. p38α MAPK-mediated induction and interaction of FOXO3a and p53 contribute to the inhibited-growth and induced-apoptosis of human lung adenocarcinoma cells by berberine. J Exp Clin Cancer Res 2014; 33(1): 36

[48] Liu Q, Xu X, Zhao M, Wei Z, Li X, Zhang X, Liu Z, Gong Y, Shao C. Berberine induces senescence of human glioblastoma cells by downregulating the EGFR-MEK-ERK signaling pathway. Mol Cancer Ther 2015; 14(2): 355–363

[49] Peng PL, Kuo WH, Tseng HC, Chou FP. Synergistic tumor-killing effect of radiation and berberine combined treatment in lung cancer: the contribution of autophagic cell death. Int J Radiat Oncol Biol Phys 2008; 70(2): 529–542

[50] Wu HL, Hsu CY, Liu WH, Yung BY. Berberine-induced apoptosis of human leukemia HL-60 cells is associated with down-regulation of nucleophosmin/B23 and telomerase activity. Int J Cancer 1999; 81(6): 923–929

[51] Franceschin M, Rossetti L, D’Ambrosio A, Schirripa S, Bianco A, Ortaggi G, Savino M, Schultes C, Neidle S. Natural and synthetic G-quadruplex interactive berberine derivatives. Bioorg Med Chem Lett 2006; 16(6): 1707–1711

[52] Rocca R, Moraca F, Costa G, Alcaro S, Distinto S, Maccioni E, Ortuso F, Artese A, Parrotta L. Structure-based virtual screening of novel natural alkaloid derivatives as potential binders of h-telo and c-myc DNA G-quadruplex conformations. Molecules 2014; 20(1): 206–223

[53] Moraca F, Amato J, Ortuso F, Artese A, Pagano B, Novellino E, Alcaro S, Parrinello M, Limongelli V. Ligand binding to telomeric G-quadruplex DNA investigated by funnel-metadynamics simulations. Proc Natl Acad Sci USA 2017; 114(11): E2136–E2145

[54] Hwang JM, Kuo HC, Tseng TH, Liu JY, Chu CY. Berberine induces apoptosis through a mitochondria/caspases pathway in human hepatoma cells. Arch Toxicol 2006; 80(2): 62–73

[55] Hou D, Xu G, Zhang C, Li B, Qin J, Hao X, Liu Q, Zhang X, Liu J, Wei J, Gong Y, Liu Z, Shao C. Berberine induces oxidative DNA damage and impairs homologous recombination repair in ovarian cancer cells to confer increased sensitivity to PARP inhibition. Cell Death Dis 2017; 8(10): e3070

[56] Shukla S, Rizvi F, Raisuddin S, Kakkar P. FoxO proteins’ nuclear retention and BH3-only protein Bim induction evoke mitochondrial dysfunction-mediated apoptosis in berberine-treated HepG2 cells. Free Radic Biol Med 2014; 76: 185–199

[57] Zhang X, Gu L, Li J, Shah N, He J, Yang L, Hu Q, Zhou M. Degradation of MDM2 by the interaction between berberine and DAXX leads to potent apoptosis in MDM2-overexpressing cancer cells. Cancer Res 2010; 70(23): 9895–9904

[58] Li J, Gu L, Zhang H, Liu T, Tian D, Zhou M, Zhou S. Berberine represses DAXX gene transcription and induces cancer cell apoptosis. Lab Invest 2013; 93(3): 354–364

[59] Hsu WH, Hsieh YS, Kuo HC, Teng CY, Huang HI, Wang CJ, Yang SF, Liou YS, Kuo WH. Berberine induces apoptosis in SW620 human colonic carcinoma cells through generation of reactive oxygen species and activation of JNK/p38 MAPK and FasL. Arch Toxicol 2007; 81(10): 719–728

[60] Xiong J, Wang L, Fei XC, Jiang XF, Zheng Z, Zhao Y, Wang CF, Li B, Chen SJ, Janin A, Gale RP, Zhao WL. MYC is a positive regulator of choline metabolism and impedes mitophagy-dependent necroptosis in diffuse large B-cell lymphoma. Blood Cancer J 2017; 7(7): e582

[61] Kuo CL, Chi CW, Liu TY. The anti-inflammatory potential of berberine in vitro and in vivo. Cancer Lett 2004; 203(2): 127–137

[62] Ho YT, Yang JS, Li TC, Lin JJ, Lin JG, Lai KC, Ma CY, Wood WG, Chung JG. Berberine suppresses in vitro migration and invasion of human SCC-4 tongue squamous cancer cells through the inhibitions of FAK, IKK, NF-κB, u-PA and MMP-2 and -9. Cancer Lett 2009; 279(2): 155–162

[63] Pandey MK, Sung B, Kunnumakkara AB, Sethi G, Chaturvedi MM, Aggarwal BB. Berberine modifies cysteine 179 of IκBα kinase, suppresses nuclear factor-κB-regulated antiapoptotic gene products, and potentiates apoptosis. Cancer Res 2008; 68(13): 5370–5379

[64] Li D, Zhang Y, Liu K, Zhao Y, Xu B, Xu L, Tan L, Tian Y, Li C, Zhang W, Cao H, Zhan YY, Hu T. Berberine inhibits colitis-associated tumorigenesis via suppressing inflammatory responses and the consequent EGFR signaling-involved tumor cell growth. Lab Invest 2017; 97(11): 1343–1353

[65] Han X, Tai H, Wang X, Wang Z, Zhou J, Wei X, Ding Y, Gong H, Mo C, Zhang J, Qin J, Ma Y, Huang N, Xiang R, Xiao H. AMPK activation protects cells from oxidative stress-induced senescence via autophagic flux restoration and intracellular NAD(+) elevation. Aging Cell 2016; 15(3): 416–427

[66] Ruan H, Zhan YY, Hou J, Xu B, Chen B, Tian Y, Wu D, Zhao Y, Zhang Y, Chen X, Mi P, Zhang L, Zhang S, Wang X, Cao H, Zhang W, Wang H, Li H, Su Y, Zhang XK, Hu T. Berberine binds RXRα to suppress β-catenin signaling in colon cancer cells. Oncogene 2017; 36(50): 6906–6918

[67] Li J, Cao B, Liu X, Fu X, Xiong Z, Chen L, Sartor O, Dong Y, Zhang H. Berberine suppresses androgen receptor signaling in prostate cancer. Mol Cancer Ther 2011; 10(8): 1346–1356

[68] Ayati SH, Fazeli B, Momtazi-Borojeni AA, Cicero AFG, Pirro M, Sahebkar A. Regulatory effects of berberine on microRNome in cancer and other conditions. Crit Rev Oncol Hematol 2017; 116: 147–158

[69] Kim S, Oh SJ, Lee J, Han J, Jeon M, Jung T, Lee SK, Bae SY, Kim J, Gil WH, Kim SW, Lee JE, Nam SJ. Berberine suppresses TPA-induced fibronectin expression through the inhibition of VEGF secretion in breast cancer cells. Cell Physiol Biochem 2013; 32(5): 1541–1550

[70] Qi HW, Xin LY, Xu X, Ji XX, Fan LH. Epithelial-to-mesenchymal transition markers to predict response of berberine in suppressing lung cancer invasion and metastasis. J Transl Med 2014; 12(1): 22

[71] Yu CS, Kuo HM, Chung JG. The role of cyclooxygenase-2 in berberine induced apoptosis and inhibited cell migration of human gastric adenocarcinoma RF-1 and RF-48 cell lines. FASEB J 2006; 20(5):A1131

[72] Kim HS, Kim MJ, Kim EJ, Yang Y, Lee MS, Lim JS. Berberine-induced AMPK activation inhibits the metastatic potential of melanoma cells via reduction of ERK activity and COX-2 protein expression. Biochem Pharmacol 2012; 83(3): 385–394

[73] Lin JP, Yang JS, Wu CC, Chung JG. Berberine induced down-regulation of matrix metalloproteinases-1, -2, and -7 expressions were associated with levels of reactive oxygen species in human gastric cancer cells (SNU-5) in vitro. FASEB J 2006; 20(5): A1145

[74] Kim S, Lee J, You D, Jeong Y, Jeon M, Yu J, Kim SW, Nam SJ, Lee JE. Berberine suppresses cell motility through downregulation of TGF-β1 in triple negative breast cancer cells Cell. Physiol Biochem 2018; 45(2): 795–807

[75] Liu SJ, Sun YM, Tian DF, He YC, Zeng L, He Y, Ling CQ, Sun SH. Downregulated NM23-H1 expression is associated with intracranial invasion of nasopharyngeal carcinoma. Br J Cancer 2008; 98(2): 363–369

[76] Tang F, Wang D, Duan C, Huang D, Wu Y, Chen Y, Wang W, Xie C, Meng J, Wang L, Wu B, Liu S, Tian D, Zhu F, He Z, Deng F, Cao Y. Berberine inhibits metastasis of nasopharyngeal carcinoma 5-8F cells by targeting Rho kinase-mediated Ezrin phosphorylation at threonine 567. J Biol Chem 2009; 284(40): 27456–27466

[77] Yang X, Yang B, Cai J, Zhang C, Zhang Q, Xu L, Qin Q, Zhu H, Ma J, Tao G, Cheng H, Sun X. Berberine enhances radiosensitivity of esophageal squamous cancer by targeting HIF-1α in vitro and in vivo. Cancer Biol Ther 2013; 14(11): 1068–1073

[78] Pan Y, Shao D, Zhao Y, Zhang F, Zheng X, Tan Y, He K, Li J, Chen L. Berberine reverses hypoxia-induced chemoresistance in breast cancer through the inhibition of AMPK-HIF-1α. Int J Biol Sci 2017; 13(6): 794–803

[79] Chen Q, Qin R, Fang Y, Li H. Berberine sensitizes human ovarian cancer cells to cisplatin through miR-93/PTEN/Akt signaling pathway. Cell Physiol Biochem 2015; 36(3): 956–965

[80] Mitani N, Murakami K, Yamaura T, Ikeda T, Saiki I. Inhibitory effect of berberine on the mediastinal lymph node metastasis produced by orthotopic implantation of Lewis lung carcinoma. Cancer Lett 2001; 165(1): 35–42

[81] Fan XX, Leung EL, Xie Y, Liu ZQ, Zheng YF, Yao XJ, Lu LL, Wu JL, He JX, Yuan ZW, Fu J, Wei CL, Huang J, Xiao DK, Luo LX, Jiang ZB, Zhou YL. Kam RK, Liu L. Suppression of lipogenesis via reactive oxygen species-AMPK signaling for treating malignant and proliferative diseases. Antioxid Redox Signal 2018; 28(5): 339–357

[82] Zhao Y, Cui L, Pan Y, Shao D, Zheng X, Zhang F, Zhang H, He K, Chen L. Berberine inhibits the chemotherapy-induced repopulation by suppressing the arachidonic acid metabolic pathway and phosphorylation of FAK in ovarian cancer. Cell Prolif 2017; 50(6): e12393

[83] Yin J, Gao Z, Liu D, Liu Z, Ye J. Berberine improves glucose metabolism through induction of glycolysis. Am J Physiol Endocrinol Metab 2008; 294(1): E148–E156

[84] Zhou L, Yang Y, Wang X, Liu S, Shang W, Yuan G, Li F, Tang J, Chen M, Chen J. Berberine stimulates glucose transport through a mechanism distinct from insulin. Metabolism 2007; 56(3): 405–412

[85] Ma X, Egawa T, Kimura H, Karaike K, Masuda S, Iwanaka N, Hayashi T. Berberine-induced activation of 5′-adenosine monophosphate-activated protein kinase and glucose transport in rat skeletal muscles. Metabolism 2010; 59(11): 1619–1627

[86] Lee YS, Kim WS, Kim KH, Yoon MJ, Cho HJ, Shen Y, Ye JM, Lee CH, Oh WK, Kim CT, Hohnen-Behrens C, Gosby A, Kraegen EW, James DE, Kim JB. Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes 2006; 55(8): 2256–2264

[87] Kong WJ, Zhang H, Song DQ, Xue R, Zhao W, Wei J, Wang YM, Shan N, Zhou ZX, Yang P, You XF, Li ZR, Si SY, Zhao LX, Pan HN, Jiang JD. Berberine reduces insulin resistance through protein kinase C-dependent up-regulation of insulin receptor expression. Metabolism 2009; 58(1): 109–119

[88] Zhang H, Wei J, Xue R, Wu JD, Zhao W, Wang ZZ, Wang SK, Zhou ZX, Song DQ, Wang YM, Pan HN, Kong WJ, Jiang JD. Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression. Metabolism 2010; 59(2): 285–292

[89] Jeong HW, Hsu KC, Lee JW, Ham M, Huh JY, Shin HJ, Kim WS, Kim JB. Berberine suppresses proinflammatory responses through AMPK activation in macrophages. Am J Physiol Endocrinol Metab 2009; 296(4): E955–E964

[90] Turner N, Li JY, Gosby A, To SW, Cheng Z, Miyoshi H, Taketo MM, Cooney GJ, Kraegen EW, James DE, Hu LH, Li J, Ye JM. Berberine and its more biologically available derivative, dihydroberberine, inhibit mitochondrial respiratory complex I: a mechanism for the action of berberine to activate AMP-activated protein kinase and improve insulin action. Diabetes 2008; 57(5): 1414–1418

[91] Gomes AP, Duarte FV, Nunes P, Hubbard BP, Teodoro JS, Varela AT, Jones JG, Sinclair DA, Palmeira CM, Rolo AP. Berberine protects against high fat diet-induced dysfunction in muscle mitochondria by inducing SIRT1-dependent mitochondrial biogenesis. Biochim Biophys Acta 2012; 1822(2): 185–195

[92] Wang Y, Shou JW, Li XY, Zhao ZX, Fu J, He CY, Feng R, Ma C, Wen BY, Guo F, Yang XY, Han YX, Wang LL, Tong Q, You XF, Lin Y, Kong WJ, Si SY, Jiang JD. Berberine-induced bioactive metabolites of the gut microbiota improve energy metabolism. Metabolism 2017; 70: 72–84

[93] Deng Y, Xu J, Zhang X, Yang J, Zhang D, Huang J, Lv P, Shen W, Yang Y. Berberine attenuates autophagy in adipocytes by targeting BECN1. Autophagy 2014; 10(10): 1776–1786

[94] Chen Y, Li Y, Wang Y, Wen Y, Sun C. Berberine improves free-fatty-acid-induced insulin resistance in L6 myotubes through inhibiting peroxisome proliferator-activated receptor gamma and fatty acid transferase expressions. Metabolism 2009; 58(12): 1694–1702

[95] Li A, Liu Q, Li Q, Liu B, Yang Y, Zhang N. Berberine reduces pyruvate-driven hepatic glucose production by limiting mitochondrial import of pyruvate through mitochondrial pyruvate carrier 1. EBioMedicine 2018; 34: 243–255

[96] Yin J, Hu R, Chen M, Tang J, Li F, Yang Y, Chen J. Effects of berberine on glucose metabolism in vitro. Metabolism 2002; 51(11): 1439–1443

[97] Liu L, Liu J, Gao Y, Yu X, Xu G, Huang Y. Uncoupling protein-2 mediates the protective action of berberine against oxidative stress in rat insulinoma INS-1E cells and in diabetic mouse islets. Br J Pharmacol 2014; 171(13): 3246–3254

[98] Dong L, Geng FH, Zhang Z, Zhang P, Xing WJ, Dong MQ, Chen KK, Yan WJ, Li J, Fu F, Zhao ZJ, Gao F. GW24-e2332 Berberine alleviates mesenteric artery endothelial dysfunction by improving insulin sensitivity in type 2 diabetic rats. Heart 2013; 99(Suppl 3): A100–A101

[99] Geng FH, Li GH, Zhang X, Zhang P, Dong MQ, Zhao ZJ, Zhang Y, Dong L, Gao F. Berberine improves mesenteric artery insulin sensitivity through up-regulating insulin receptor-mediated signalling in diabetic rats. Br J Pharmacol 2016; 173(10): 1569–1579

[100] Ma YG, Zhang YB, Bai YG, Dai ZJ, Liang L, Liu M, Xie MJ, Guan HT. Berberine alleviates the cerebrovascular contractility in streptozotocin-induced diabetic rats through modulation of intracellular Ca²⁺ handling in smooth muscle cells. Cardiovasc Diabetol 2016; 15(1): 63

[101] Moghaddam HK, Baluchnejadmojarad T, Roghani M, Khaksari M, Norouzi P, Ahooie M, Mahboobi F. Berberine ameliorate oxidative stress and astrogliosis in the hippocampus of STZ-induced diabetic rats. Mol Neurobiol 2014; 49(2): 820–826

[102] Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, Wang Y, Wang Z, Si S, Pan H, Wang S, Wu J, Wang Y, Li Z, Liu J, Jiang JD. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med 2004; 10(12): 1344–1351

[103] Banach M, Patti AM, Giglio RV, Cicero AFG, Atanasov AG, Bajraktari G, Bruckert E, Descamps O, Djuric DM, Ezhov M, Fras Z, von Haehling S, Katsiki N, Langlois M, Latkovskis G, Mancini GBJ, Mikhailidis DP, Mitchenko O, Moriarty PM, Muntner P, Nikolic D, Panagiotakos DB, Paragh G, Paulweber B, Pella D, Pitsavos C, Reiner Ž, Rosano GMC, Rosenson RS, Rysz J, Sahebkar A, Serban MC, Vinereanu D, Vrablík M, Watts GF, Wong ND, Rizzo M. The role of nutraceuticals in statin intolerant patients. J Am Coll Cardiol 2018; 72(1): 96–118

[104] Singh AB, Li H, Kan CF, Dong B, Nicolls MR, Liu J. The critical role of mRNA destabilizing protein heterogeneous nuclear ribonucleoprotein D in 3′ untranslated region-mediated decay of low-density lipoprotein receptor mRNA in liver tissue. Arterioscler Thromb Vasc Biol 2014; 34(1): 8–16

[105] Kim WS, Lee YS, Cha SH, Jeong HW, Choe SS, Lee MR, Oh GT, Park HS, Lee KU, Lane MD, Kim JB. Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity. Am J Physiol Endocrinol Metab 2009; 296(4): E812–E819

[106] Zhou L, Wang X, Yang Y, Wu L, Li F, Zhang R, Yuan G, Wang N, Chen M, Ning G. Berberine attenuates cAMP-induced lipolysis via reducing the inhibition of phosphodiesterase in 3T3-L1 adipocytes. Biochim Biophys Acta 2011; 1812(4): 527–535

[107] Wang Y, Yi X, Ghanam K, Zhang S, Zhao T, Zhu X. Berberine decreases cholesterol levels in rats through multiple mechanisms, including inhibition of cholesterol absorption. Metabolism 2014; 63(9): 1167–1177

[108] Sun R, Yang N, Kong B, Cao B, Feng D, Yu X, Ge C, Huang J, Shen J, Wang P, Feng S, Fei F, Guo J, He J, Aa N, Chen Q, Pan Y, Schumacher JD, Yang CS, Guo GL, Aa J, Wang G. Orally administered berberine modulates hepatic lipid metabolism by altering microbial bile acid metabolism and the intestinal FXR signaling pathway. Mol Pharmacol 2017; 91(2): 110–122

[109] Choi BH, Ahn IS, Kim YH, Park JW, Lee SY, Hyun CK, Do MS. Berberine reduces the expression of adipogenic enzymes and inflammatory molecules of 3T3-L1 adipocyte. Exp Mol Med 2006; 38(6): 599–605

[110] Zhang Z, Zhang H, Li B, Meng X, Wang J, Zhang Y, Yao S, Ma Q, Jin L, Yang J, Wang W, Ning G. Berberine activates thermogenesis in white and brown adipose tissue. Nat Commun 2014; 5(1): 5493

[111] Zhang X, Zhao Y, Xu J, Xue Z, Zhang M, Pang X, Zhang X, Zhao L. Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats. Sci Rep 2015; 5(1): 14405

[112] Sun H, Liu Q, Hu H, Jiang Y, Shao W, Wang Q, Jiang Z, Gu A. Berberine ameliorates blockade of autophagic flux in the liver by regulating cholesterol metabolism and inhibiting COX2-prostaglandin synthesis. Cell Death Dis 2018; 9(8): 824

[113] Marin-Neto JA, Maciel BC, Secches AL, Gallo Júnior L. Cardiovascular effects of berberine in patients with severe congestive heart failure. Clin Cardiol 1988; 11(4): 253–260

[114] Tsui H, Zi M, Wang S, Chowdhury SK, Prehar S, Liang Q, Cartwright EJ, Lei M, Liu W, Wang X. Smad3 couples Pak1 with the antihypertrophic pathway through the E3 ubiquitin ligase, Fbxo32. Hypertension 2015; 66(6): 1176–1183

[115] Salehi S, Filtz TM. Berberine possesses muscarinic agonist-like properties in cultured rodent cardiomyocytes. Pharmacol Res 2011; 63(4): 335–340

[116] Huang WM, Wu ZD, Gan YQ. Effects of berberine on ischemic ventricular arrhythmia. Chin J Cardiovasc Med (Zhonghua Xin Xue Guan Bing Za Zhi) 1989; 17(5): 300–319 (in Chinses)

[117] Sánchez-Chapula J. Increase in action potential duration and inhibition of the delayed rectifier outward current IK by berberine in cat ventricular myocytes. Br J Pharmacol 1996; 117(7): 1427–1434

[118] Li BX, Yang BF, Zhou J, Xu CQ, Li YR. Inhibitory effects of berberine on IK1, IK, and HERG channels of cardiac myocytes. Acta Pharmacol Sin 2001; 22(2): 125–131

[119] Wang LH, Yu CH, Fu Y, Li Q, Sun YQ. Berberine elicits anti-arrhythmic effects via IK1/Kir2.1 in the rat type 2 diabetic myocardial infarction model. Phytother Res 2011; 25(1): 33–37

[120] Wang LH, Li XL, Li Q, Fu Y, Yu HJ, Sun YQ, Zhang L, Shan HL. Berberine alleviates ischemic arrhythmias via recovering depressed Ito and ICa currents in diabetic rats. Phytomedicine 2012; 19(3-4): 206–210

[121] Derosa G, D’Angelo A, Bonaventura A, Bianchi L, Romano D, Maffioli P. Effects of berberine on lipid profile in subjects with low cardiovascular risk. Expert Opin Biol Ther 2013; 13(4): 475–482

[122] Ruscica M, Gomaraschi M, Mombelli G, Macchi C, Bosisio R, Pazzucconi F, Pavanello C, Calabresi L, Arnoldi A, Sirtori CR, Magni P. Nutraceutical approach to moderate cardiometabolic risk: results of a randomized, double-blind and crossover study with Armolipid Plus. J Clin Lipidol 2014; 8(1): 61–68

[123] Fogacci F, Grassi D, Rizzo M, Cicero AFG. Metabolic effect of berberine-silymarin association: a meta-analysis of randomized, double-blind, placebo-controlled clinical trials. Phytother Res 2019; 33(4): 862–870

[124] Wang Y, Huang Y, Lam KS, Li Y, Wong W, Ye H, Lau CW, Vanhoutte PM, Xu A. Berberine prevents hyperglycemia-induced endothelial injury and enhances vasodilatation via adenosine monophosphate-activated protein kinase and endothelial nitric oxide synthase. Cardiovasc Res 2009; 82(3): 484–492

[125] Cicero AFG, Fogacci F, Colletti A. Food and plant bioactives for reducing cardiometabolic disease risk: an evidence based approach. Food Funct 2017; 8(6): 2076–2088

[126] Cicero AF, Baggioni A. Berberine and its role in chronic disease. Adv Exp Med Biol 2016; 928: 27–45

[127] Caliceti C, Franco P, Spinozzi S, Roda A, Cicero AF. Berberine: new insights from pharmacological aspects to clinical evidences in the management of metabolic disorders. Curr Med Chem 2016; 23(14): 1460–1476

[128] Caliceti C, Rizzo P, Cicero AF. Potential benefits of berberine in the management of perimenopausal syndrome. Oxid Med Cell Longev 2015; 2015: 723093

[129] Yu L, Li Q, Yu B, Yang Y, Jin Z, Duan W, Zhao G, Zhai M, Liu L, Yi D, Chen M, Yu S. Berberine attenuates myocardial ischemia/reperfusion injury by reducing oxidative stress and inflammation response: role of silent information regulator 1. Oxid Med Cell Longev 2016; 2016: 1689602

[130] Huang ZQ，Ye BZ，Huang WJ. GW24-e1352 Berberine mitigated cardiac hypoxiareoxygenation injury by suppressed autophagy and reduced cell death via inhibition of the activation of AMPK-mTOR signalling pathway in rat H9c2 cells. Heart 2013; 99(Suppl 3): A93

[131] Kang DGA, Sohn EJA, Kwon EKA, Han JHA, Oh H, Lee HSAR. Effects of berberine on angiotensin-converting enzyme and NO/cGMP system in vessels. Vascul Pharmacol 2002; 39(6): 281–286

[132] Kang DG, Sohn EJ, Kwon EK, Han JH, Oh H, Lee HS. Effects of berberine on angiotensin-converting enzyme and NO/cGMP system in vessels. Vascul Pharmacol 2002; 39(6): 281–286

[133] Caliceti C, Rizzo P, Ferrari R, Fortini F, Aquila G, Leoncini E, Zambonin L, Rizzo B, Calabria D, Simoni P, Mirasoli M, Guardigli M, Hrelia S, Roda A, Cicero AFG. Novel role of the nutraceutical bioactive compound berberine in lectin-like OxLDL receptor 1-mediated endothelial dysfunction in comparison to lovastatin. Nutr Metab Cardiovasc Dis 2017; 27(6): 552–563

[134] Mazza A, Lenti S, Schiavon L, Zuin M, D’Avino M, Ramazzina E, Casiglia E. Nutraceuticals for serum lipid and blood pressure control in hypertensive and hypercholesterolemic subjects at low cardiovascular risk. Adv Ther 2015; 32(7): 680–690

[135] Wang J, Guo T, Peng QS, Yue SW, Wang SX. Berberine via suppression of transient receptor potential vanilloid 4 channel improves vascular stiffness in mice. J Cell Mol Med 2015; 19(11): 2607–2616

[136] Luo J, Gu Y, Liu P, Jiang X, Yu W, Ye P, Chao Y, Yang H, Zhu L, Zhou L, Chen S. Berberine attenuates pulmonary arterial hypertension via protein phosphatase 2A signaling pathway both in vivo and in vitro. J Cell Physiol 2018; 233(12): 9750–9762

[137] Liu X, Zhang X, Ye L, Yuan H. Protective mechanisms of berberine against experimental autoimmune myocarditis in a rat model. Biomed Pharmacother 2016; 79: 222–230

[138] Coelho AR, Martins TR, Couto R, Deus C, Pereira CV, Simões RF, Rizvanov AA, Silva F, Cunha-Oliveira T, Oliveira PJ, Serafim TL. Berberine-induced cardioprotection and Sirt3 modulation in doxorubicin-treated H9c2 cardiomyoblasts. Biochim Biophys Acta Mol Basis Dis 2017; 1863(11): 2904–2923

[139] Zhang C, Li C, Chen S, Li Z, Jia X, Wang K, Bao J, Liang Y, Wang X, Chen M, Li P, Su H, Wan JB, Lee SMY, Liu K, He C. Berberine protects against 6-OHDA-induced neurotoxicity in PC12 cells and zebrafish through hormetic mechanisms involving PI3K/AKT/Bcl-2 and Nrf2/HO-1 pathways. Redox Biol 2017; 11: 1–11

[140] Zhuang W, Li T, Wang C, Shi X, Li Y, Zhang S, Zhao Z, Dong H, Qiao Y. Berberine exerts antioxidant effects via protection of spiral ganglion cells against cytomegalovirus-induced apoptosis. Free Radic Biol Med 2018; 121: 127–135

[141] Zhu JR, Lu HD, Guo C, Fang WR, Zhao HD, Zhou JS, Wang F, Zhao YL, Li YM, Zhang YD, Yang CQ, Sun JG. Berberine attenuates ischemia-reperfusion injury through inhibiting HMGB1 release and NF-kB nuclear translocation. Acta Pharmacol Sin 2018; 39(11): 1706–1715

[142] Wang F, Zhao G, Cheng L, Zhou HY, Fu LY, Yao WX. Effects of berberine on potassium currents in acutely isolated CA1 pyramidal neurons of rat hippocampus. Brain Res 2004; 999(1): 91–97

[143] Sun SWang K, Lei H, Li L, Tu M, Zeng S, Zhou H, Jiang H. Inhibition of organic cation transporter 2 and 3 may be involved in the mechanism of the antidepressant-like action of berberine. Prog Neuropsychopharmacol Biol Psychiatry 2014; 49: 1–6

[144] Fan J, Li B, Ge T, Zhang Z, Lv J, Zhao J, Wang P, Liu W, Wang X, Mlyniec K, Cui R. Berberine produces antidepressant-like effects in ovariectomized mice. Sci Rep 2017; 7(1): 1310

[145] Liu YM, Niu L, Wang LL, Bai L, Fang XY, Li YC, Yi LT. Berberine attenuates depressive-like behaviors by suppressing neuro-inflammation in stressed mice. Brain Res Bull 2017; 134: 220–227

[146] Wang B, Xu X, He X, Wang Z, Yang M. Berberine improved aldo-induced podocyte injury via inhibiting oxidative stress and endoplasmic reticulum stress pathways both in vivo and in vitro. Cell Physiol Biochem 2016; 39(1): 217–228

[147] Kim BH, Kim M, Yin CH, Jee JG, Sandoval C, Lee H, Bach EA, Hahm DH, Baeg GH. Inhibition of the signalling kinase JAK3 alleviates inflammation in monoarthritic rats. Br J Pharmacol 2011; 164(1): 106–118

[148] Lee HW, Suh JH, Kim HN, Kim AY, Park SY, Shin CS, Choi JY, Kim JB. Berberine promotes osteoblast differentiation by Runx2 activation with p38 MAPK. J Bone Miner Res 2008; 23(8): 1227–1237

[149] Robinson CL, Chong ACN, Ashbrook AW, Jeng G, Jin J, Chen H, Tang EI, Martin LA, Kim RS, Kenyon RM, Do E, Luna JM, Saeed M, Zeltser L, Ralph H, Dudley VL, Goldstein M, Rice CM, Cheng CY, Seandel M, Chen S. Male germ cells support long-term propagation of Zika virus. Nat Commun 2018; 9(1): 2090

Acknowledgements

The author thanks the Xinjuan Liu from the Department of Gastroenterology, Beijing Chaoyang Hospital for the help.

Compliance with ethics guidelines

Danyang Song, Jianyu Hao, and Daiming Fan declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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