Abstract
Although advances have been made, chemotherapy for chronic, multifactorial diseases such as cancers, Alzheimer’s disease, cardiovascular diseases and diabetes is far from satisfactory. Agents with different mechanisms of action are required. The botanic compound berberine (BBR) has been used as an over-the-counter antibacterial for diarrhea in China for many decades. Recent clinical studies have shown that BBR may be therapeutic in various types of chronic diseases. This review addresses BBR’s molecular mechanisms of action and clinical efficacy and safety in patients with type 2 diabetes, hyperlipidemia, heart diseases, cancers and inflammation. One of the advantages of BBR is its multiple-target effects in each of these diseases. The therapeutic efficacy of BBR may reflect a synergistic regulation of these targets, resulting in a comprehensive effect against these various chronic disorders. The safety of BBR may be due to its harmonious distribution into those targets. Although the single-target concept is still the principle for drug discovery and research, this review emphasizes the concept of a multiple target strategy, which may be an important approach toward the successful treatment of multifactorial chronic diseases.
Article PDF
References
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 J D. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med, 2004, 10: 1344–1351
Huang Z J, Zeng Y, Lan P, Sun P H, Chen W M. Advances in structural modifications and biological activities of berberine: An active compound in traditional Chinese medicine. Mini Rev Med Chem, 2011, 11: 1122–1129
Xie Q, Johnson B R, Wenckus C S, Fayad M I, Wu C D. Efficacy of berberine, an antimicrobial plant alkaloid, as an endodontic irrigant against a mixed-culture biofilm in an in vitro tooth model. J Endod, 2012, 38: 1114–1117
Chen Q M, Xie M Z. Studies on the hypoglycemic effect of Coptis chinensis and berberine (in Chinese). Yao Xue Xue Bao, 1986, 21: 401–406
Lee Y S, Kim W S, Kim K H, Yoon M J, Cho H J, Shen Y, Ye J M, Lee C H, Oh W K, Kim C T, Hohnen-Behrens C, Gosby A, Kraegen E W, James D E, Kim J B. Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes, 2006, 55: 2256–2264
Zhang H, Kong W J, Shan Y Q, Song D Q, Li Y, Wang Y M, You X F, Jiang J D. Protein kinase D activation stimulates the transcription of the insulin receptor gene. Mol Cell Endocrinol, 2010, 330: 25–32
Chen C, Zhang Y, Huang C. Berberine inhibits PTP1B activity and mimics insulin action. Biochem Biophys Res Commun, 2010, 397: 543–547
Xia X, Yan J, Shen Y, Tang K, Yin J, Zhang Y, Yang D, Liang H, Ye J, Weng J. Berberine improves glucose metabolism in diabetic rats by inhibition of hepatic gluconeogenesis. PLoS ONE, 2011, 6: e16556
Han J, Lin H, Huang W. Modulating gut microbiota as an antidiabetic mechanism of berberine. Med Sci Monit, 2011, 17: RA164–167
Zhang X, Zhao Y, Zhang M, Pang X, Xu J, Kang C, Li M, Zhang C, Zhang Z, Zhang Y, Li X, Ning G, Zhao L. Structural changes of gut microbiota during berberine-mediated prevention of obesity and insulin resistance in high-fat diet-fed rats. PLoS ONE, 2012, 7: e42529
Dong H, Wang N, Zhao L, Lu F. Berberine in the treatment of type 2 diabetes mellitus: A systemic review and meta-analysis. Evid Based Complement Alternat Med, 2012, 2012: 591654
di Pierro F, Villanova N, Agostini F, Marzocchi R, Soverini V, Marchesini G. Pilot study on the additive effects of berberine and oral type 2 diabetes agents for patients with suboptimal glycemic control. Diabetes Metab Syndr Obes, 2012, 5: 213–217
Zhang H, Wei J, Xue R, Wu J D, Zhao W, Wang Z Z, Wang S K, Zhou Z X, Song D Q, Wang Y M, Pan H N, Kong W J, Jiang J D. Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression. Metabolism, 2010, 59: 285–292
Lan T, Shen X, Liu P, Liu W, Xu S, Xie X, Jiang Q, Li W, Huang H. Berberine ameliorates renal injury in diabetic C57BL/6 mice: Involvement of suppression of SphK-S1P signaling pathway. Arch Biochem Biophys, 2010, 502: 112–120
Li H, Dong B, Park S W, Lee H S, Chen W, Liu J. Hepatocyte nuclear factor 1alpha plays a critical role in PCSK9 gene transcription and regulation by the natural hypocholesterolemic compound berberine. J Biol Chem, 2009, 284: 28885–28895
Kim W S, Lee Y S, Cha S H, Jeong H W, Choe S S, Lee M R, Oh G T, Park H S, Lee K U, Lane M D, Kim J B. Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity. Am J Physiol Endocrinol Metab, 2009, 296: E812–819
Brusq J M, Ancellin N, Grondin P, Guillard R, Martin S, Saintillan Y, Issandou M. Inhibition of lipid synthesis through activation of AMP kinase: An additional mechanism for the hypolipidemic effects of berberine. J Lipid Res, 2006, 47: 1281–1288
Winiarska M, Bil J, Wilczek E, Wilczynski G M, Lekka M, Engelberts P J, Mackus W J, Gorska E, Bojarski L, Stoklosa T, Nowis D, Kurzaj Z, Makowski M, Glodkowska E, Issat T, Mrowka P, Lasek W, Dabrowska-Iwanicka A, Basak G W, Wasik M, Warzocha K, Sinski M, Gaciong Z, Jakobisiak M, Parren P W, Golab J. Statins impair antitumor effects of rituximab by inducing conformational changes of CD20. PLoS Med, 2008, 5: e64
Antons K A, Williams C D, Baker S K, Phillips P S. Clinical perspectives of statin-induced rhabdomyolysis. Am J Med, 2006, 119: 400e9
Zhao W, Xue R, Zhou Z X, Kong W J, Jiang J D. Reduction of blood lipid by berberine in hyperlipidemic patients with chronic hepatitis or liver cirrhosis. Biomed Pharmacother, 2008, 62: 730–731
Beltowski J, Wójcicka G, Jamroz-Wisniewska A. Adverse effects of statins—mechanisms and consequences. Curr Drug Saf, 2009, 4: 209–228
Kong W J, Wei J, Zuo Z Y, Wang Y M, Song D Q, You X F, Zhao L X, Pan H N, Jiang J D. Combination of simvastatin with berberine improves the lipid-lowering efficacy. Metabolism, 2008, 57: 1029–1037
Kong W J, Zhang H, Song D Q, Xue R, Zhao W, Wei J, Wang Y M, Shan N, Zhou Z X, Yang P, You X F, Li Z R, Si S Y, Zhao L X, Pan H N, Jiang J D. Berberine reduces insulin resistance through protein kinase C-dependent up-regulation of insulin receptor expression. Metabolism, 2009, 58: 109–119
Lau C W, Yao X Q, Chen Z Y, Ko W H, Huang Y. Cardiovascular actions of berberine. Cardiovasc Drug Rev, 2001, 19: 234–244
Rodriguez-Menchaca A, Ferrer-Villada T, Lara J, Fernandez D, Navarro-Polanco R A, Sanchez-Chapula J A. Block of HERG channels by berberine: Mechanisms of voltage- and state-dependence probed with site-directed mutant channels. J Cardiovasc Pharmacol, 2006, 47: 21–29
Wang Y, Huang Y, Lam K S, Li Y, Wong W T, Ye H, Lau C W, Vanhoutte P M, 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: 484–492
Zeng X H, Zeng X J, Li Y Y. Efficacy and safety of berberine for congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol, 2003, 92: 173–176
Marin-Neto J A, Maciel B C, Secches A L, Gallo Júnior L. Cardiovascular effects of berberine in patients with severe congestive heart failure. Clin Cardiol, 1988, 11: 253–260
Huang W M. Treating ventricular fast arrhythmias with berberine (in Chinese). Zhong Hua Xin Xue Guan Za Zhi, 1990, 18: 156
Jiang C G, Kuang Y T. Therapeutic efficacy of berberine in 32 arrhythmic patients (in Chinese). Zhong Guo Zhong Xi Yi Jie He Ji Jiu Za Zhi, 1998, 5: 402
Tillhon M, Guamán Ortiz L M, Lombardi P, Scovassi A I. Berberine: New perspectives for old remedies. Biochem Pharmacol, 2012, 84: 1260–1267
Li G H, Wang D L, Hu Y D, Pu P, Li D Z, Wang W D, Zhu B, Hao P, Wang J, Xu X Q, Wan J Q, Zhou Y B, Chen Z T. Berberine inhibits acute radiation intestinal syndrome in human with abdomen radiotherapy. Med Oncol, 2010, 27: 919–925
Liu Y, Yu H, Zhang C, Cheng Y, Hu L, Meng X, Zhao Y. Protective effects of berberine on radiation-induced lung injury via intercellular adhesion molecular-1 and transforming growth factor-beta-1 in patients with lung cancer. Eur J Cancer, 2008, 44: 2425–2432
Zanardi M, Quirico E, Benvenuti C, Pezzana A. Use of a lipidlowering food supplement in patients on hormone therapy following breast cancer. Minerva Ginecol, 2012, 64: 431–435
Lou T, Zhang Z, Xi Z, Liu K, Li L, Liu B, Huang F. Berberine inhibits inflammatory response and ameliorates insulin resistance in hepatocytes. Inflammation, 2011, 34: 659–667
Choi B H, Ahn I S, Kim Y H, Park J W, Lee S Y, Hyun C K, Do M S. Berberine reduces the expression of adipogenic enzymes and inflammatory molecules of 3T3-L1 adipocyte. Exp Mol Med, 2006, 38: 599–605
Wu M, Wang J, Liu L T. Advance of studies on anti-atherosclerosis mechanism of berberine. Chin J Integr Med, 2010, 16: 188–192
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. J Infect Dis, 2011, 203: 1602–1612
Jeong H W, Hsu K C, Lee J W, Ham M, Huh J Y, Shin H J, Kim W S, Kim J B. Berberine suppresses proinflammatory responses through AMPK activation in macrophages. Am J Physiol Endocrinol Metab, 2009, 296: E955–964
Jiang Q, Liu P, Wu X, Liu W, Shen X, Lan T, Xu S, Peng J, Xie X, Huang H. Berberine attenuates lipopolysaccharide-induced extracellular matrix accumulation and inflammation in rat mesangial cells: Involvement of NF-κB signaling pathway. Mol Cell Endocrinol, 2011, 331: 34–40
Pickup J C. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care, 2004, 27: 813–823
Cui G, Qin X, Zhang Y, Gong Z, Ge B, Zang Y Q. Berberine differentially modulates the activities of ERK, p38 MAPK, and JNK to suppress Th17 and Th1 T cell differentiation in type 1 diabetic mice. J Biol Chem, 2009, 284: 28420–28429
Sheng Z X, Xie D H. The pro-inflammatory cytokine levels of type 2 diabetic patients and the impact of berberine therapy. New Med, 2010, 41: 177–180
Meng S, Wang L S, Huang Z Q, Zhou Q, Sun Y G, Cao J T, Li Y G, Wang C Q. Berberine ameliorates inflammation in patients with acute coronary syndrome following percutaneous coronary intervention. Clin Exp Pharmacol Physiol, 2012, 39: 406–411
Vuddanda P R, Chakraborty S, Singh S. Berberine: A potential phytochemical with multispectrum therapeutic activities. Expert Opin Investig Drugs, 2010, 19: 1297–1307
Kulkarni S K, Dhir A. Berberine: A plant alkaloid with therapeutic potential for central nervous system disorders. Phytother Res, 2010, 24: 317–324
Ye M Z, Fu S, Pi R B, He F. Neuropharmacological and pharmacokinetic properties of berberine: A review of recent research. J Pharm Pharmacol, 2009, 61: 831–837
Yki-Järvinen H. Thiazolidinediones. N Engl J Med, 2004, 351: 1106–1118
Tolman K G. The safety of thiazolidinediones. Expert Opin Drug Saf, 2011, 10: 419–428
Kung J, Henry R R. Thiazolidinedione safety. Expert Opin Drug Saf, 2012, 11: 565–579
Cariou B, Charbonnel B, Staels B. Thiazolidinediones and PPARγ agonists: Time for a reassessment. Trends Endocrinol Metab, 2012, 23: 205–215
Fitzgerald G A. Coxibs and cardiovascular disease. N Engl J Med, 2004, 351: 1709–1711
McAdam B F, Catella-Lawson F, Mardini I A, Kapoor S, Lawson J A, FitzGerald G A. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: The human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci USA, 1999, 96: 272–277
Psaty B M, Furberg C D. COX-2 inhibitors—lessons in drug safety. N Engl J Med, 2005, 352: 1133–1135
Kumar G S. RNA targeting by small molecules: Binding of protoberberine, benzophenanthridine and aristolochia alkaloids to various RNA structures. J Biosci, 2012, 37: 539–552
Maiti M, Kumar G S. Polymorphic nucleic acid binding of bioactive isoquinoline alkaloids and their role in cancer. J Nucleic Acids, 2010, 2010: 593408
Li Y H, Yang P, Kong W J, Wang Y X, Hu C Q, Zuo Z Y, Wang Y M, Gao H, Gao L M, Feng Y C, Du N N, Liu Y, Song D Q, Jiang J D. Berberine analogues as a novel class of the low-density-lipoprotein receptor up-regulators: Synthesis, structure-activity relationships, and cholesterol-lowering efficacy. J Med Chem, 2009, 52: 492–501
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is published with open access at Springerlink.com
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 2.0 International License ( https://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
About this article
Cite this article
Yao, J., Kong, W. & Jiang, J. Learning from berberine: Treating chronic diseases through multiple targets. Sci. China Life Sci. 58, 854–859 (2015). https://doi.org/10.1007/s11427-013-4568-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11427-013-4568-z