Berberine, a plant alkaloid with lipid- and glucose-lowering properties: From in vitro evidence to clinical studies

Atherosclerosis

Volumn 243, Issue 2, 2015, Pages 449-461

  Pirillo, Angela ^a,b   Catapano, Alberico Luigi ^b,c  

^a Bassini Hospital   (Italy)

^b IRCCS MULTIMEDICA   (Italy)

^c UNIVERSITY OF MILAN   (Italy)

Author keywords

AMP activated protein kinase; Berberine; Glucose lowering; LDL receptor; Lipid lowering

Indexed keywords

BERBERINE; CHOLESTEROL; GLUCOSE; HIGH DENSITY LIPOPROTEIN; LIPID; LOW DENSITY LIPOPROTEIN; TRIACYLGLYCEROL; ANTIDIABETIC AGENT; BIOLOGICAL MARKER; GLUCOSE BLOOD LEVEL; HYPOCHOLESTEROLEMIC AGENT;

ADIPOCYTE; ADIPOSE TISSUE; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIDIABETIC ACTIVITY; ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; ARTICLE; BODY MASS; BONE CELL; CELL PROLIFERATION; CELLS BY BODY ANATOMY; CHOLESTEROL BLOOD LEVEL; CLINICAL STUDY; CONTROLLED STUDY; DIABETES MELLITUS; DIABETIC PATIENT; DRUG ABSORPTION; DRUG ACTIVITY; DRUG METABOLISM; DRUG TOLERABILITY; ENDOTHELIUM CELL; GLUCOSE ABSORPTION; GLUCOSE BLOOD LEVEL; GLUCOSE INTAKE; GLUCOSE TOLERANCE; GLUCOSE UTILIZATION; HEART MUSCLE CELL; HYPERCHOLESTEROLEMIA; IN VITRO STUDY; INSULIN DEPENDENT DIABETES MELLITUS; INTESTINE ABSORPTION; INTESTINE CELL; LIVER CELL; MACROPHAGE; MESANGIUM CELL; METABOLIC SYNDROME X; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OXIDATIVE STRESS; PANCREAS ISLET BETA CELL; PRIORITY JOURNAL; RAT; VASCULAR SMOOTH MUSCLE CELL; WAIST CIRCUMFERENCE; WEIGHT GAIN; ANIMAL; BLOOD; DISEASE MODEL; DRUG EFFECTS; HUMAN; METABOLISM; TREATMENT OUTCOME;

ANIMALS; ANTICHOLESTEREMIC AGENTS; BERBERINE; BIOMARKERS; BLOOD GLUCOSE; CHOLESTEROL; DIABETES MELLITUS; DISEASE MODELS, ANIMAL; HUMANS; HYPERCHOLESTEROLEMIA; HYPOGLYCEMIC AGENTS; TREATMENT OUTCOME;

EID: 84946073493     PISSN: 00219150     EISSN: 18791484     Source Type: Journal    
DOI: 10.1016/j.atherosclerosis.2015.09.032     Document Type: Review

References (134)

1. Imanshahidi M., Hosseinzadeh H. Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine. Phytother. Res. 2008, 22:999-1012.
2. Qiu F., Zhu Z., Kang N., Piao S., Qin G., Yao X. Isolation and identification of urinary metabolites of berberine in rats and humans. Drug Metab. Dispos. 2008, 36:2159-2165.
3. Liu Y.T., Hao H.P., Xie H.G., Lai L., Wang Q., Liu C.X., Wang G.J. Extensive intestinal first-pass elimination and predominant hepatic distribution of berberine explain its low plasma levels in rats. Drug Metab. Dispos. 2010, 38:1779-1784.
4. Tan X.S., Ma J.Y., Feng R., Ma C., Chen W.J., Sun Y.P., Fu J., Huang M., He C.Y., Shou J.W., He W.Y., Wang Y., Jiang J.D. Tissue distribution of berberine and its metabolites after oral administration in rats. PLoS One 2013, 8:e77969.
5. Liu Y., Hao H., Xie H., Lv H., Liu C., Wang G. Oxidative demethylenation and subsequent glucuronidation are the major metabolic pathways of berberine in rats. J. Pharm. Sci. 2009, 98:4391-4401.
6. Maeng H.J., Yoo H.J., Kim I.W., Song I.S., Chung S.J., Shim C.K. P-glycoprotein-mediated transport of berberine across Caco-2 cell monolayers. J. Pharm. Sci. 2002, 91:2614-2621.
7. Shitan N., Tanaka M., Terai K., Ueda K., Yazaki K. Human MDR1 and MRP1 recognize berberine as their transport substrate. Biosci. Biotechnol. Biochem. 2007, 71:242-245.
8. Pan G.Y., Wang G.J., Liu X.D., Fawcett J.P., Xie Y.Y. The involvement of P-glycoprotein in berberine absorption. Pharmacol. Toxicol. 2002, 91:193-197.
9. Kwon M., Choi Y.A., Choi M.K., Song I.S. Organic cation transporter-mediated drug-drug interaction potential between berberine and metformin. Arch. Pharm. Res. 2015, 38:849-856.
10. Cui H.M., Zhang Q.Y., Wang J.L., Chen J.L., Zhang Y.L., Tong X.L. In vitro studies of berberine metabolism and its effect of enzyme induction on HepG2 cells. J. Ethnopharmacol. 2014, 158(Pt A):388-396.
11. Guo Y., Chen Y., Tan Z.R., Klaassen C.D., Zhou H.H. Repeated administration of berberine inhibits cytochromes P450 in humans. Eur. J. Clin. Pharmacol. 2011, 68:213-217.
12. Colombo D., Lunardon L., Bellia G. Cyclosporine and herbal supplement interactions. J. Toxicol. 2014, 2014:145325.
13. Hou Q., Han W., Fu X. Pharmacokinetic interaction between tacrolimus and berberine in a child with idiopathic nephrotic syndrome. Eur. J. Clin. Pharmacol. 2013, 69:1861-1862.
14. Krishan S., Richardson D.R., Sahni S. Adenosine monophosphate-activated kinase and its key role in catabolism: structure, regulation, biological activity, and pharmacological activation. Mol. Pharmacol. 2015, 87:363-377.
15. Kong W., Wei J., Abidi P., Lin M., Inaba S., Li C., Wang Y., Wang Z., Si S., Pan H., Wang S., Wu J., 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.
16. Li Z., Jiang J.D., Kong W.J. Berberine up-regulates hepatic low-density lipoprotein receptor through Ras-independent but AMP-activated protein kinase-dependent Raf-1 activation. Biol. Pharm. Bull. 2014, 37:1766-1775.
17. Lee S., Lim H.J., Park J.H., Lee K.S., Jang Y., Park H.Y. Berberine-induced LDLR up-regulation involves JNK pathway. Biochem. Biophys. Res. Commun. 2007, 362:853-857.
18. Seidah N.G., Awan Z., Chretien M., Mbikay M. PCSK9: a key modulator of cardiovascular health. Circ. Res. 2014, 114:1022-1036.
19. Sahebkar A., Simental-Mendia L.E., Guerrero-Romero F., Golledge J., Watts G.F. Effect of statin therapy on plasma PCSK9 concentrations: a systematic review and meta-analysis of clinical trials. Diabetes Obes. Metab. 2015, 10.1111/dom.12536.
20. Cameron J., Ranheim T., Kulseth M.A., Leren T.P., Berge K.E. Berberine decreases PCSK9 expression in HepG2 cells. Atherosclerosis 2008, 201:266-273.
21. 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.
22. 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.
23. Cao S., Zhou Y., Xu P., Wang Y., Yan J., Bin W., Qiu F., Kang N. Berberine metabolites exhibit triglyceride-lowering effects via activation of AMP-activated protein kinase in Hep G2 cells. J. Ethnopharmacol. 2013, 149:576-582.
24. Cheng C.C., Hsueh C.M., Liang K.W., Ting C.T., Wen C.L., Hsu S.L. Role of JNK and c-Jun signaling pathway in regulation of human serum paraoxonase 1 gene transcription by berberine in human HepG2 cells. Eur. J. Pharmacol. 2011, 650:519-525.
25. Cheng W.E., Ying Chang M., Wei J.Y., Chen Y.J., Maa M.C., Leu T.H. Berberine reduces Toll-like receptor-mediated macrophage migration by suppression of Src enhancement. Eur. J. Pharmacol. 2015, 757:1-10.
26. Li Z., Geng Y.N., Jiang J.D., Kong W.J. Antioxidant and anti-inflammatory activities of berberine in the treatment of diabetes mellitus. Evid. Based Complement. Altern. Med. 2014, 2014:289264.
27. Sarna L.K., Wu N., Hwang S.Y., Siow Y.L., O K. Berberine inhibits NADPH oxidase mediated superoxide anion production in macrophages. Can. J. Physiol. Pharmacol. 2010, 88:369-378.
28. Lee D., Bae J., Kim Y.K., Gil M., Lee J.Y., Park C.S., Lee K.J. 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.
29. Mo C., Wang L., Zhang J., Numazawa S., Tang H., Tang X., Han X., Li J., Yang M., Wang Z., Wei D., Xiao H. The crosstalk between Nrf2 and AMPK signal pathways is important for the anti-inflammatory effect of berberine in LPS-stimulated macrophages and endotoxin-shocked mice. Antioxid. Redox. Signal 2014, 20:574-588.
30. Fan X., Wang J., Hou J., Lin C., Bensoussan A., Chang D., Liu J., Wang B. Berberine alleviates ox-LDL induced inflammatory factors by up-regulation of autophagy via AMPK/mTOR signaling pathway. J. Transl. Med. 2015, 13:450.
31. Huang Z., Meng S., Wang L., Wang Y., Chen T., Wang C. Suppression of oxLDL-induced MMP-9 and EMMPRIN expression by berberine via inhibition of NF-kappaB activation in human THP-1 macrophages. Anat. Rec. Hob. 2012, 295:78-86.
32. Huang Z., Wang L., Meng S., Wang Y., Chen T., Wang C. Berberine reduces both MMP-9 and EMMPRIN expression through prevention of p38 pathway activation in PMA-induced macrophages. Int. J. Cardiol. 2011, 146:153-158.
33. Guan S., Wang B., Li W., Guan J., Fang X. Effects of berberine on expression of LOX-1 and SR-BI in human macrophage-derived foam cells induced by ox-LDL. Am. J. Chin. Med. 2010, 38:1161-1169.
34. Lee T.S., Pan C.C., Peng C.C., Kou Y.R., Chen C.Y., Ching L.C., Tsai T.H., Chen S.F., Lyu P.C., Shyue S.K. Anti-atherogenic effect of berberine on LXRalpha-ABCA1-dependent cholesterol efflux in macrophages. J. Cell Biochem. 2010, 111:104-110.
35. Zimetti F., Adorni M.P., Ronda N., Gatti R., Bernini F., Favari E. The natural compound berberine positively affects macrophage functions involved in atherogenesis. Nutr. Metab. Cardiovasc Dis. 2015, 25:195-201.
36. Cho B.J., Im E.K., Kwon J.H., Lee K.H., Shin H.J., Oh J., Kang S.M., Chung J.H., Jang Y. Berberine inhibits the production of lysophosphatidylcholine-induced reactive oxygen species and the ERK1/2 pathway in vascular smooth muscle cells. Mol. Cells 2005, 20:429-434.
37. Lee S., Lim H.J., Park H.Y., Lee K.S., Park J.H., Jang Y. Berberine inhibits rat vascular smooth muscle cell proliferation and migration in vitro and improves neointima formation after balloon injury in vivo. Berberine improves neointima formation in a rat model. Atherosclerosis 2006, 186:29-37.
38. Mordi I., Tzemos N. Is reversal of endothelial dysfunction still an attractive target in modern cardiology?. World J. Cardiol. 2014, 6:824-835.
39. Ko Y.J., Lee J.S., Park B.C., Shin H.M., Kim J.A. Inhibitory effects of zoagumhwan water extract and berberine on angiotensin II-induced monocyte chemoattractant protein (MCP)-1 expression and monocyte adhesion to endothelial cells. Vasc. Pharmacol. 2007, 47:189-196.
40. Wu Y.H., Chuang S.Y., Hong W.C., Lai Y.J., Chang G.J., Pang J.H. 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.
41. Zhang M., Wang C.M., Li J., Meng Z.J., Wei S.N., Bucala R., Li Y.L., Chen L. Berberine protects against palmitate-induced endothelial dysfunction: involvements of upregulation of AMPK and eNOS and downregulation of NOX4. Mediat. Inflamm. 2013, 2013:260464.
42. 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.
43. Tian P., Ge H., Liu H., Kern T.S., Du L., Guan L., Su S., Liu P. Leukocytes from diabetic patients kill retinal endothelial cells: effects of berberine. Mol. Vis. 2013, 19:2092-2105.
44. Pirro M., Schillaci G., Paltriccia R., Bagaglia F., Menecali C., Mannarino M.R., Capanni M., Velardi A., Mannarino E. Increased ratio of CD31+/CD42- microparticles to endothelial progenitors as a novel marker of atherosclerosis in hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol. 2006, 26:2530-2535.
45. Xu M.G., Wang J.M., Chen L., Wang Y., Yang Z., Tao J. Berberine-induced mobilization of circulating endothelial progenitor cells improves human small artery elasticity. J. Hum. Hypertens. 2008, 22:389-393.
46. Xu M.G., Wang J.M., Chen L., Wang Y., Yang Z., Tao J. Berberine-induced upregulation of circulating endothelial progenitor cells is related to nitric oxide production in healthy subjects. Cardiology 2009, 112:279-286.
47. Xiao M., Men L.N., Xu M.G., Wang G.B., Lv H.T., Liu C. Berberine protects endothelial progenitor cell from damage of TNF-alpha via the PI3K/AKT/eNOS signaling pathway. Eur. J. Pharmacol. 2014, 743:11-16.
48. 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, 171:3246-3254.
49. 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.
50. Shen N., Huan Y., Shen Z.F. Berberine inhibits mouse insulin gene promoter through activation of AMP activated protein kinase and may exert beneficial effect on pancreatic beta-cell. Eur. J. Pharmacol. 2012, 694:120-126.
51. 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:E148-E156.
52. Kim S.H., Shin E.J., Kim E.D., Bayaraa T., Frost S.C., Hyun C.K. Berberine activates GLUT1-mediated glucose uptake in 3T3-L1 adipocytes. Biol. Pharm. Bull. 2007, 30:2120-2125.
53. Zhang Q., Xiao X., Feng K., Wang T., Li W., Yuan T., Sun X., Sun Q., Xiang H., Wang H. Berberine moderates glucose and lipid metabolism through multipathway mechanism. Evid. Based Complement. Altern. Med. 2011, 2011.
54. Pan G.Y., Huang Z.J., Wang G.J., Fawcett J.P., Liu X.D., Zhao X.C., Sun J.G., Xie Y.Y. The antihyperglycaemic activity of berberine arises from a decrease of glucose absorption. Planta Med. 2003, 69:632-636.
55. 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-E964.
56. 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, 1812:527-535.
57. Zhang J., Tang H., Deng R., Wang N., Zhang Y., Wang Y., Liu Y., Li F., Wang X., Zhou L. Berberine suppresses adipocyte differentiation via decreasing CREB transcriptional activity. PLoS One 2015, 10:e0125667.
58. Hu Y., Davies G.E. Berberine increases expression of GATA-2 and GATA-3 during inhibition of adipocyte differentiation. Phytomedicine 2009, 16:864-873.
59. Huang C., Zhang Y., Gong Z., Sheng X., Li Z., Zhang W., Qin Y. Berberine inhibits 3T3-L1 adipocyte differentiation through the PPARgamma pathway. Biochem. Biophys. Res. Commun. 2006, 348:571-578.
60. 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.
61. Wang M., Wang J., Tan R., Wu Q., Qiu H., Yang J., Jiang Q. Effect of berberine on PPAR alpha/NO activation in high glucose- and insulin-induced cardiomyocyte hypertrophy. Evid. Based Complement. Altern. Med. 2013, 2013:285489.
62. Chang W., Zhang M., Li J., Meng Z., Wei S., Du H., Chen L., Hatch G.M. Berberine improves insulin resistance in cardiomyocytes via activation of 5'-adenosine monophosphate-activated protein kinase. Metabolism 2013, 62:1159-1167.
63. Chen K., Li G., Geng F., Zhang Z., Li J., Yang M., Dong L., Gao F. Berberine reduces ischemia/reperfusion-induced myocardial apoptosis via activating AMPK and PI3K-Akt signaling in diabetic rats. Apoptosis 2014, 19:946-957.
64. Yu L., Li F., Zhao G., Yang Y., Jin Z., Zhai M., Yu W., Zhao L., Chen W., Duan W., Yu S. Protective effect of berberine against myocardial ischemia reperfusion injury: role of Notch1/Hes1-PTEN/Akt signaling. Apoptosis 2015, 20:796-810.
65. Liu W., Tang F., Deng Y., Li X., Lan T., Zhang X., Huang H., Liu P. Berberine reduces fibronectin and collagen accumulation in rat glomerular mesangial cells cultured under high glucose condition. Mol. Cell Biochem. 2009, 325:99-105.
66. Liu W., Liu P., Tao S., Deng Y., Li X., Lan T., Zhang X., Guo F., Huang W., Chen F., Huang H., Zhou S.F. Berberine inhibits aldose reductase and oxidative stress in rat mesangial cells cultured under high glucose. Arch. Biochem. Biophys. 2008, 475:128-134.
67. Rahigude A.B., Kaulaskar S.V., Bhutada P.S. Possible therapeutic potential of berberine in diabetic osteopathy. Med. Hypotheses 2012, 79:440-444.
68. Wei P., Jiao L., Qin L.P., Yan F., Han T., Zhang Q.Y. Effects of berberine on differentiation and bone resorption of osteoclasts derived from rat bone marrow cells. Zhong Xi Yi Jie He Xue Bao 2009, 7:342-348.
69. Lee H.W., Suh J.H., Kim H.N., Kim A.Y., Park S.Y., Shin C.S., Choi J.Y., Kim J.B. Berberine promotes osteoblast differentiation by Runx2 activation with p38 MAPK. J. Bone Min. Res. 2008, 23:1227-1237.
70. Jeyabalan J., Shah M., Viollet B., Chenu C. AMP-activated protein kinase pathway and bone metabolism. J. Endocrinol. 2012, 212:277-290.
71. Wang Q., Zhang M., Liang B., Shirwany N., Zhu Y., Zou M.H. Activation of AMP-activated protein kinase is required for berberine-induced reduction of atherosclerosis in mice: the role of uncoupling protein 2. PLoS One 2011, 6:e25436.
72. 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, 63:1167-1177.
73. Chang X.X., Yan H.M., Xu Q., Xia M.F., Bian H., Zhu T.F., Gao X. The effects of berberine on hyperhomocysteinemia and hyperlipidemia in rats fed with a long-term high-fat diet. Lipids Health Dis. 2012, 11:86.
74. 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.
75. 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.
76. Wan X., Chen X., Liu L., Zhao Y., Huang W.J., Zhang Q., Miao G.G., Chen W., Xie H.G., Cao C.C. Berberine ameliorates chronic kidney injury caused by atherosclerotic renovascular disease through the suppression of NFkappaB signaling pathway in rats. PLoS One 2013, 8:e59794.
77. Tisch R., McDevitt H. Insulin-dependent diabetes mellitus. Cell 1996, 85:291-297.
78. Chueh W.H., Lin J.Y. Protective effect of berberine on serum glucose levels in non-obese diabetic mice. Int. Immunopharmacol. 2012, 12:534-538.
79. Chueh W.H., Lin J.Y. Berberine, an isoquinoline alkaloid in herbal plants, protects pancreatic islets and serum lipids in nonobese diabetic mice. J. Agric. Food Chem. 2011, 59:8021-8027.
80. Leng S.H., Lu F.E., Xu L.J. Therapeutic effects of berberine in impaired glucose tolerance rats and its influence on insulin secretion. Acta Pharmacol. Sin. 2004, 25:496-502.
81. Liu C., Wang Z., Song Y., Wu D., Zheng X., Li P., Jin J., Xu N., Li L. Effects of berberine on amelioration of hyperglycemia and oxidative stress in high glucose and high fat diet-induced diabetic hamsters in vivo. Biomed. Res. Int. 2015, 2015:313808.
82. Lu S.S., Yu Y.L., Zhu H.J., Liu X.D., Liu L., Liu Y.W., Wang P., Xie L., Wang G.J. Berberine promotes glucagon-like peptide-1 (7-36) amide secretion in streptozotocin-induced diabetic rats. J. Endocrinol. 2009, 200:159-165.
83. 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.
84. 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.
85. 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.
86. 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, 5:5493.
87. Zhao H.L., Sui Y., Qiao C.F., Yip K.Y., Leung R.K., Tsui S.K., Lee H.M., Wong H.K., Zhu X., Siu J.J., He L., Guan J., Liu L.Z., Xu H.X., Tong P.C., Chan J.C. Sustained antidiabetic effects of a berberine-containing Chinese herbal medicine through regulation of hepatic gene expression. Diabetes 2012, 61:933-943.
88. 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-E819.
89. Dong S.F., Hong Y., Liu M., Hao Y.Z., Yu H.S., Liu Y., Sun J.N. Berberine attenuates cardiac dysfunction in hyperglycemic and hypercholesterolemic rats. Eur. J. Pharmacol. 2011, 660:368-374.
90. Ni W.J., Ding H.H., Tang L.Q. Berberine as a promising anti-diabetic nephropathy drug: an analysis of its effects and mechanisms. Eur. J. Pharmacol. 2015, 760:103-112.
91. Ni W.J., Ding H.H., Zhou H., Qiu Y.Y., Tang L.Q. Renoprotective effects of berberine through regulation of the MMPs/TIMPs system in streptozocin-induced diabetic nephropathy in rats. Eur. J. Pharmacol. 2015, 764:448-456.
92. Gupta D., Krueger C.B., Lastra G. Over-nutrition, obesity and insulin resistance in the development of beta-cell dysfunction. Curr. Diabetes Rev. 2012, 8:76-83.
93. Hu Y., Davies G.E. Berberine inhibits adipogenesis in high-fat diet-induced obesity mice. Fitoterapia 2010, 81:358-366.
94. Gu J.J., Gao F.Y., Zhao T.Y. A preliminary investigation of the mechanisms underlying the effect of berberine in preventing high-fat diet-induced insulin resistance in rats. J. Physiol. Pharmacol. 2012, 63:505-513.
95. Han J., Lin H., Huang W. Modulating gut microbiota as an anti-diabetic mechanism of berberine. Med. Sci. Monit. 2011, 17:RA164-RA167.
96. 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.
97. Xie W., Gu D., Li J., Cui K., Zhang Y. Effects and action mechanisms of berberine and Rhizoma coptidis on gut microbes and obesity in high-fat diet-fed C57BL/6J mice. PLoS One 2011, 6:e24520.
98. Dong H., Zhao Y., Zhao L., Lu F. The effects of berberine on blood lipids: a systemic review and meta-analysis of randomized controlled trials. Planta Med. 2013, 79:437-446.
99. 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, 13:475-482.
100. Affuso F., Ruvolo A., Micillo F., Sacca L., Fazio S. Effects of a nutraceutical combination (berberine, red yeast rice and policosanols) on lipid levels and endothelial function randomized, double-blind, placebo-controlled study. Nutr. Metab. Cardiovasc Dis. 2010, 20:656-661.
101. Marazzi G., Cacciotti L., Pelliccia F., Iaia L., Volterrani M., Caminiti G., Sposato B., Massaro R., Grieco F., Rosano G. Long-term effects of nutraceuticals (berberine, red yeast rice, policosanol) in elderly hypercholesterolemic patients. Adv. Ther. 2011, 28:1105-1113.
102. Pisciotta L., Bellocchio A., Bertolini S. Nutraceutical pill containing berberine versus ezetimibe on plasma lipid pattern in hypercholesterolemic subjects and its additive effect in patients with familial hypercholesterolemia on stable cholesterol-lowering treatment. Lipids Health Dis. 2012, 11:123.
103. Weng T.C., Yang Y.H., Lin S.J., Tai S.H. A systematic review and meta-analysis on the therapeutic equivalence of statins. J. Clin. Pharm. Ther. 2010, 35:139-151.
104. Cicero A.F., Tartagni E., Ferroni A., De Sando V., Grandi E., Borghi C. Combined nutraceutical approach to postmenopausal syndrome and vascular remodeling biomarkers. J. Altern. Complement. Med. 2013, 19:582-587.
105. Yin J., Xing H., Ye J. Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism 2008, 57:712-717.
106. 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. Altern. Med. 2012, 2012:591654.
107. Perez-Rubio K.G., Gonzalez-Ortiz M., Martinez-Abundis E., Robles-Cervantes J.A., Espinel-Bermudez M.C. Effect of berberine administration on metabolic syndrome, insulin sensitivity, and insulin secretion. Metab. Syndr. Relat. Disord. 2013, 11:366-369.
108. Yang J., Yin J., Gao H., Xu L., Wang Y., Li M. Berberine improves insulin sensitivity by inhibiting fat store and adjusting adipokines profile in human preadipocytes and metabolic syndrome patients. Evid. Based Complement. Altern. Med. 2012, 2012:363845.
109. Affuso F., Mercurio V., Ruvolo A., Pirozzi C., Micillo F., Carlomagno G., Grieco F., Fazio S. A nutraceutical combination improves insulin sensitivity in patients with metabolic syndrome. World J. Cardiol. 2012, 4:77-83.
110. Hua W., Ding L., Chen Y., Gong B., He J., Xu G. Determination of berberine in human plasma by liquid chromatography-electrospray ionization-mass spectrometry. J. Pharm. Biomed. Anal. 2007, 44:931-937.
111. 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.
112. Derosa G., Bonaventura A., Bianchi L., Romano D., D'Angelo A., Fogari E., Maffioli P. Berberis aristata/Silybum marianum fixed combination on lipid profile and insulin secretion in dyslipidemic patients. Expert Opin. Biol. Ther. 2013, 13:1495-1506.
113. Derosa G., Bonaventura A., Bianchi L., Romano D., D Angelo A., Fogari E., Maffioli P. Effects of Berberis aristata/Silybum marianum association on metabolic parameters and adipocytokines in overweight dyslipidemic patients. J. Biol. Regul. Homeost. Agents 2013, 27:717-728.
114. Di Pierro F., Bellone I., Rapacioli G., Putignano P. Clinical role of a fixed combination of standardized Berberis aristata and Silybum marianum extracts in diabetic and hypercholesterolemic patients intolerant to statins. Diabetes Metab. Syndr. Obes. 2015, 8:89-96.
115. Di Pierro F., Putignano P., Villanova N., Montesi L., Moscatiello S., Marchesini G. Preliminary study about the possible glycemic clinical advantage in using a fixed combination of Berberis aristata and Silybum marianum standardized extracts versus only Berberis aristata in patients with type 2 diabetes. Clin. Pharmacol. 2013, 5:167-174.
116. Lv X.Y., Li J., Zhang M., Wang C.M., Fan Z., Wang C.Y., Chen L. Enhancement of sodium caprate on intestine absorption and antidiabetic action of berberine. AAPS Pharm. Sci. Tech. 2010, 11:372-382.
117. Zhang M., Lv X., Li J., Meng Z., Wang Q., Chang W., Li W., Chen L., Liu Y. Sodium caprate augments the hypoglycemic effect of berberine via AMPK in inhibiting hepatic gluconeogenesis. Mol. Cell Endocrinol. 2012, 363:122-130.
118. Zhaojie M., Ming Z., Shengnan W., Xiaojia B., Hatch G.M., Jingkai G., Li C. Amorphous solid dispersion of berberine with absorption enhancer demonstrates a remarkable hypoglycemic effect via improving its bioavailability. Int. J. Pharm. 2014, 467:50-59.
119. Chen W., Fan D., Meng L., Miao Y., Yang S., Weng Y., He H., Tang X. Enhancing effects of chitosan and chitosan hydrochloride on intestinal absorption of berberine in rats. Drug Dev. Ind. Pharm. 2012, 38:104-110.
120. Chen W., Miao Y.Q., Fan D.J., Yang S.S., Lin X., Meng L.K., Tang X. Bioavailability study of berberine and the enhancing effects of TPGS on intestinal absorption in rats. AAPS Pharm. Sci. Tech. 2011, 12:705-711.
121. Wang Z., Wu J., Zhou Q., Wang Y., Chen T. Berberine nanosuspension enhances hypoglycemic efficacy on streptozotocin induced diabetic C57BL/6 mice. Evid. Based Complement. Altern. Med. 2015, 2015:239749.
122. Patil S., Dash R.P., Anandjiwala S., Nivsarkar M. Simultaneous quantification of berberine and lysergol by HPLC-UV: evidence that lysergol enhances the oral bioavailability of berberine in rats. Biomed. Chromatogr. 2011, 26:1170-1175.
123. Zhang Y., Cui Y.L., Gao L.N., Jiang H.L. Effects of beta-cyclodextrin on the intestinal absorption of berberine hydrochloride, a P-glycoprotein substrate. Int. J. Biol. Macromol. 2013, 59:363-371.
124. Gui S.Y., Wu L., Peng D.Y., Liu Q.Y., Yin B.P., Shen J.Z. Preparation and evaluation of a microemulsion for oral delivery of berberine. Pharmazie 2008, 63:516-519.
125. Wang T., Wang N., Song H., Xi X., Wang J., Hao A., Li T. Preparation of an anhydrous reverse micelle delivery system to enhance oral bioavailability and anti-diabetic efficacy of berberine. Eur. J. Pharm. Sci. 2011, 44:127-135.
126. Zhu J.X., Tang D., Feng L., Zheng Z.G., Wang R.S., Wu A.G., Duan T.T., He B., Zhu Q. Development of self-microemulsifying drug delivery system for oral bioavailability enhancement of berberine hydrochloride. Drug Dev. Ind. Pharm. 2013, 39:499-506.
127. Xue M., Yang M.X., Zhang W., Li X.M., Gao D.H., Ou Z.M., Li Z.P., Liu S.H., Li X.J., Yang S.Y. Characterization, pharmacokinetics, and hypoglycemic effect of berberine loaded solid lipid nanoparticles. Int. J. Nanomed. 2013, 8:4677-4687.
128. 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.
129. Shan Y.Q., Ren G., Wang Y.X., Pang J., Zhao Z.Y., Yao J., You X.F., Si S.Y., Song D.Q., Kong W.J., Jiang J.D. Berberine analogue IMB-Y53 improves glucose-lowering efficacy by averting cellular efflux especially P-glycoprotein efflux. Metabolism 2013, 62:446-456.
130. Wei S.C., Dong S., Xu L.J., Zhang C.Y. Intestinal absorption of berberine and 8-hydroxy dihydroberberine and their effects on sugar absorption in rat small intestine. J. Huazhong Univ. Sci. Technol. Med. Sci. 2014, 34:186-189.
131. Liu D.L., Xu L.J., Dong H., Chen G., Huang Z.Y., Zou X., Wang K.F., Luo Y.H., Lu F.E. Inhibition of proprotein convertase subtilisin/kexin type 9: a novel mechanism of berberine and 8-hydroxy dihydroberberine against hyperlipidemia. Chin. J. Integr. Med. 2015, 21:132-138.
132. Turner N., Li J.Y., Gosby A., To S.W., Cheng Z., Miyoshi H., Taketo M.M., Cooney G.J., Kraegen E.W., James D.E., Hu L.H., Li J., Ye J.M. 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, 57:1414-1418.
133. Cheng Z., Chen A.F., Wu F., Sheng L., Zhang H.K., Gu M., Li Y.Y., Zhang L.N., Hu L.H., Li J.Y., Li J. 8,8-Dimethyldihydroberberine with improved bioavailability and oral efficacy on obese and diabetic mouse models. Bioorg. Med. Chem. 2010, 18:5915-5924.
134. Chen J., Cao J., Fang L., Liu B., Zhou Q., Sun Y., Wang Y., Li Y., Meng S. Berberine derivatives reduce atherosclerotic plaque size and vulnerability in apoE(-/-) mice. J. Transl. Med. 2014, 12:326.