Where does berberine HCL come from?

06 May.,2024

 

BERBERINE - Uses, Side Effects, and More

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Carlomagno, G., Pirozzi, C., Mercurio, V., Ruvolo, A., and Fazio, S. Effects of a nutraceutical combination on left ventricular remodeling and vasoreactivity in subjects with the metabolic syndrome. Nutr Metab Cardiovasc.Dis 2012;22(5):e13-e14. View abstract.

Chae, S. H., Jeong, I. H., Choi, D. H., Oh, J. W., and Ahn, Y. J. Growth-inhibiting effects of Coptis japonica root-derived isoquinoline alkaloids on human intestinal bacteria. J Agric.Food Chem 1999;47(3):934-938. View abstract.

Chekalina, S. I., Umurzakova, R. Z., Saliev, K. K., and Abdurakhmanov, T. R. [Effect of berberine bisulfate on platelet hemostasis in thrombocytopenia patients]. Gematologiia i Transfuziologiia 1994;39(5):33-35. View abstract.

Cheng, Z., Pang, T., Gu, M., Gao, A. H., Xie, C. M., Li, J. Y., Nan, F. J., and Li, J. Berberine-stimulated glucose uptake in L6 myotubes involves both AMPK and p38 MAPK. Biochim.Biophys.Acta 2006;1760(11):1682-1689. View abstract.

Choudhry, V. P., Sabir, M., and Bhide, V. N. Berberine in giardiasis. Indian Pediatr. 1972;9(3):143-146. View abstract.

Chun YT, Yip TT, Lau KL, and et al. A biochemical study on the hypotensive effect of berberine in rats. Gen Pharmac 1979;10:177-182. View abstract.

Chung JG, Wu LT, Chang SH, and et al. Inhibitory actions of berberine on growth and arylamine N-acetyltransferase activity in strains of Helicobacter Pylori from peptic ulcer patients. International Journal of Toxicology 1999;18:35.

Chung, J. G., Chen, G. W., Hung, C. F., Lee, J. H., Ho, C. C., Ho, H. C., Chang, H. L., Lin, W. C., and Lin, J. G. Effects of berberine on arylamine N-acetyltransferase activity and 2-aminofluorene-DNA adduct formation in human leukemia cells. Am J Chin Med 2000;28(2):227-238. View abstract.

Chung, J. G., Wu, L. T., Chu, C. B., Jan, J. Y., Ho, C. C., Tsou, M. F., Lu, H. F., Chen, G. W., Lin, J. G., and Wang, T. F. Effects of berberine on arylamine N-acetyltransferase activity in human bladder tumour cells. Food Chem Toxicol 1999;37(4):319-326. View abstract.

Cianci, A., Cicero, A. F., Colacurci, N., Matarazzo, M. G., and De, Leo, V. Activity of isoflavones and berberine on vasomotor symptoms and lipid profile in menopausal women. Gynecol.Endocrinol. 2012;28(9):699-702. View abstract.

Desai, A. B., Shah, K. M., and Shah, D. M. Berberine in treatment of diarrhoea. Indian Pediatr. 1971;8(9):462-465. View abstract.

Dutta NK and Panse MV. Usefulness of berberine (an alkaloid from Berberis aristata) in the treatment of cholera (experimental). Indian J Med Res 1962;50(5):732-736.

Freile, M. L., Giannini, F., Pucci, G., Sturniolo, A., Rodero, L., Pucci, O., Balzareti, V., and Enriz, R. D. Antimicrobial activity of aqueous extracts and of berberine isolated from Berberis heterophylla. Fitoterapia 2003;74(7-8):702-705. View abstract.

Fukuda, K., Hibiya, Y., Mutoh, M., Koshiji, M., Akao, S., and Fujiwara, H. Inhibition by berberine of cyclooxygenase-2 transcriptional activity in human colon cancer cells. J Ethnopharmacol. 1999;66(2):227-233. View abstract.

Ghosh AK, Bhattacharyya FK, and Ghosh DK. Leishmania donovani: amastigote inhibition and mode of action of berberine. Experimental Parasitology 1985;60:404-413.

Guo, Y., Chen, Y., Tan, Z. R., Klaassen, C. D., and Zhou, H. H. Repeated administration of berberine inhibits cytochromes P450 in humans. Eur J Clin Pharmacol 2012;68(2):213-217. View abstract.

Hajnicka, V., Kost'alova, D., Svecova, D., Sochorova, R., Fuchsberger, N., and Toth, J. Effect of Mahonia aquifolium active compounds on interleukin-8 production in the human monocytic cell line THP-1. Planta Med 2002;68(3):266-268. View abstract.

Hayasaka, S., Kodama, T., and Ohira, A. Traditional Japanese herbal (kampo) medicines and treatment of ocular diseases: a review. Am J Chin Med 2012;40(5):887-904. View abstract.

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Holick, M. F., Lamb, J. J., Lerman, R. H., Konda, V. R., Darland, G., Minich, D. M., Desai, A., Chen, T. C., Austin, M., Kornberg, J., Chang, J. L., Hsi, A., Bland, J. S., and Tripp, M. L. Hop rho iso-alpha acids, berberine, vitamin D3 and vitamin K1 favorably impact biomarkers of bone turnover in postmenopausal women in a 14-week trial. J Bone Miner.Metab 2010;28(3):342-350. View abstract.

Hong, Y., Hui, S. S., Chan, B. T., and Hou, J. Effect of berberine on catecholamine levels in rats with experimental cardiac hypertrophy. Life Sci. 4-18-2003;72(22):2499-2507. View abstract.

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Hu, Y., Ehli, E. A., Kittelsrud, J., Ronan, P. J., Munger, K., Downey, T., Bohlen, K., Callahan, L., Munson, V., Jahnke, M., Marshall, L. L., Nelson, K., Huizenga, P., Hansen, R., Soundy, T. J., and Davies, G. E. Lipid-lowering effect of berberine in human subjects and rats. Phytomedicine. 7-15-2012;19(10):861-867. View abstract.

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Huang, W. M., Wu, Z. D., and Gan, Y. Q. [Effects of berberine on ischemic ventricular arrhythmia]. Zhonghua Xin.Xue.Guan.Bing.Za Zhi. 1989;17(5):300-1, 319. View abstract.

Hui, K. K., Yu, J. L., Chan, W. F., and Tse, E. Interaction of berberine with human platelet alpha 2 adrenoceptors. Life Sci. 1991;49(4):315-324. View abstract.

Iizuka, N., Miyamoto, K., Okita, K., Tangoku, A., Hayashi, H., Yosino, S., Abe, T., Morioka, T., Hazama, S., and Oka, M. Inhibitory effect of Coptidis Rhizoma and berberine on the proliferation of human esophageal cancer cell lines. Cancer Lett 1-1-2000;148(1):19-25. View abstract.

Iizuka, N., Oka, M., Yamamoto, K., Tangoku, A., Miyamoto, K., Miyamoto, T., Uchimura, S., Hamamoto, Y., and Okita, K. Identification of common or distinct genes related to antitumor activities of a medicinal herb and its major component by oligonucleotide microarray. Int J Cancer 11-20-2003;107(4):666-672. View abstract.

Inbaraj, J. J., Kukielczak, B. M., Bilski, P., Sandvik, S. L., and Chignell, C. F. Photochemistry and photocytotoxicity of alkaloids from Goldenseal (Hydrastis canadensis L.) 1. Berberine. Chem Res Toxicol 2001;14(11):1529-1534. View abstract.

Inoue, K., Kulsum, U., Chowdhury, S. A., Fujisawa, S., Ishihara, M., Yokoe, I., and Sakagami, H. Tumor-specific cytotoxicity and apoptosis-inducing activity of berberines. Anticancer Res 2005;25(6B):4053-4059. View abstract.

Jantova, S., Cipak, L., Cernakova, M., and Kost'alova, D. Effect of berberine on proliferation, cell cycle and apoptosis in HeLa and L1210 cells. J Pharm Pharmacol 2003;55(8):1143-1149. View abstract.

Jeong, H. W., Hsu, K. C., Lee, J. W., Ham, M., Huh, J. Y., Shin, H. J., Kim, W. S., and Kim, J. B. Berberine suppresses proinflammatory responses through AMPK activation in macrophages. Am J Physiol Endocrinol.Metab 2009;296(4):E955-E964. View abstract.

Kamat SA. Clinical trials with berberine hydrochloride for the control of diarrhea in acute gastroenteritis. J Assoc Physicians India 1967;15:525-529.

Kaneda Y, Tanaka T, and Saw T. Effects of berberine, a plant alkaloid, on the growth of anaerobic protozoa in axenic culture. Tokai J Exp Clin Med 1990;15(6):417-423.

Kaneda Y, Torii M, Tanaka T, and et al. In vitro effects of berberine sulphate on the growth and structure of Entamoeba histolytica, Giardia lamblia and Trichomonas vaginalis. Annals of Tropical Medicine and Parasitology 1991;85(4):417-425.

Khin, Maung U. and Nwe, Nwe Wai. Effect of berberine on enterotoxin-induced intestinal fluid accumulation in rats. J Diarrhoeal Dis Res 1992;10(4):201-204. View abstract.

Khin, Maung U., Myo, Khin, Nyunt, Nyunt Wai, and Tin, U. Clinical trial of high-dose berberine and tetracycline in cholera. J Diarrhoeal Dis Res 1987;5(3):184-187. View abstract.

Khin, Maung U., Myo, Khin, Nyunt, Nyunt Wai, Aye, Kyaw, and Tin, U. Clinical trial of berberine in acute watery diarrhoea. Br.Med.J.(Clin.Res.Ed) 12-7-1985;291(6509):1601-1605. View abstract.

Kim, H. S., Kim, M. J., Kim, E. J., Yang, Y., Lee, M. S., and Lim, J. S. Berberine-induced AMPK activation inhibits the metastatic potential of melanoma cells via reduction of ERK activity and COX-2 protein expression. Biochem.Pharmacol 2-1-2012;83(3):385-394. View abstract.

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., and Kim, J. B. Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity. Am J Physiol Endocrinol.Metab 2009;296(4):E812-E819. View abstract.

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., and Jiang, J. D. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med 2004;10(12):1344-1351. View abstract.

Krol R, Zalewski A, and Maroko PR. Beneficial effects of berberine, a new positive inotropic agent, on digitalis-induced ventricular arrhythmias. Circulation 1982;66(suppl 2):56.

Ksiezycka E, Cheung W, and Maroko PR. Antiarrhythmic effects of berberine on aconitine-induced ventricular and supraventricular arrhythmias. Clinical Research 1983;31(2):197A.

Kulkarni, S. K., Dandiya, P. C., and Varandani, N. L. Pharmacological investigations of berberine sulphate. Jpn.J Pharmacol. 1972;22(1):11-16. View abstract.

Kuo, C. L., Chi, C. W., and Liu, T. Y. Modulation of apoptosis by berberine through inhibition of cyclooxygenase-2 and Mcl-1 expression in oral cancer cells. In Vivo 2005;19(1):247-252. View abstract.

Kuo, C. L., Chou, C. C., and Yung, B. Y. Berberine complexes with DNA in the berberine-induced apoptosis in human leukemic HL-60 cells. Cancer Lett 7-13-1995;93(2):193-200. View abstract.

Lahiri S and Dutta NK. Berberine and chloramphenicol in the treatment of cholera and severe diarrhoea. Journal of the Indian Medical Association 1967;48(1):1-11.

Lamb, J. J., Holick, M. F., Lerman, R. H., Konda, V. R., Minich, D. M., Desai, A., Chen, T. C., Austin, M., Kornberg, J., Chang, J. L., Hsi, A., Bland, J. S., and Tripp, M. L. Nutritional supplementation of hop rho iso-alpha acids, berberine, vitamin D(3), and vitamin K(1) produces a favorable bone biomarker profile supporting healthy bone metabolism in postmenopausal women with metabolic syndrome. Nutr Res 2011;31(5):347-355. View abstract.

Lau, C. W., Yao, X. Q., Chen, Z. Y., Ko, W. H., and Huang, Y. Cardiovascular actions of berberine. Cardiovasc Drug Rev 2001;19(3):234-244. View abstract.

Lee, S., Lim, H. J., Park, H. Y., Lee, K. S., Park, J. H., and 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(1):29-37. View abstract.

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., and 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(8):2256-2264. View abstract.

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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., and Chen, Z. T. Berberine inhibits acute radiation intestinal syndrome in human with abdomen radiotherapy. Med Oncol. 2010;27(3):919-925. View abstract.

Li, H., Miyahara, T., Tezuka, Y., Namba, T., Suzuki, T., Dowaki, R., Watanabe, M., Nemoto, N., Tonami, S., Seto, H., and Kadota, S. The effect of kampo formulae on bone resorption in vitro and in vivo. II. Detailed study of berberine. Biol Pharm Bull 1999;22(4):391-396. View abstract.

Lin, C. C., Kao, S. T., Chen, G. W., Ho, H. C., and Chung, J. G. Apoptosis of human leukemia HL-60 cells and murine leukemia WEHI-3 cells induced by berberine through the activation of caspase-3. Anticancer Res 2006;26(1A):227-242. View abstract.

Lin, J. G., Chung, J. G., Wu, L. T., Chen, G. W., Chang, H. L., and Wang, T. F. Effects of berberine on arylamine N-acetyltransferase activity in human colon tumor cells. Am J Chin Med 1999;27(2):265-275. View abstract.

Lin, J. P., Yang, J. S., Lee, J. H., Hsieh, W. T., and Chung, J. G. Berberine induces cell cycle arrest and apoptosis in human gastric carcinoma SNU-5 cell line. World J Gastroenterol. 1-7-2006;12(1):21-28. View abstract.

Lin, S., Tsai, S. C., Lee, C. C., Wang, B. W., Liou, J. Y., and Shyu, K. G. Berberine inhibits HIF-1alpha expression via enhanced proteolysis. Mol Pharmacol 2004;66(3):612-619. View abstract.

Liu, Y., Yu, H., Zhang, C., Cheng, Y., Hu, L., Meng, X., and 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(16):2425-2432. View abstract.

Lu, S. S., Yu, Y. L., Zhu, H. J., Liu, X. D., Liu, L., Liu, Y. W., Wang, P., Xie, L., and Wang, G. J. Berberine promotes glucagon-like peptide-1 (7-36) amide secretion in streptozotocin-induced diabetic rats. J Endocrinol. 2009;200(2):159-165. View abstract.

Mahajan, V. M., Sharma, A., and Rattan, A. Antimycotic activity of berberine sulphate: an alkaloid from an Indian medicinal herb. Sabouraudia. 1982;20(1):79-81. View abstract.

Mantena, S. K., Sharma, S. D., and Katiyar, S. K. 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. View abstract.

Marazzi, G., Cacciotti, L., Pelliccia, F., Iaia, L., Volterrani, M., Caminiti, G., Sposato, B., Massaro, R., Grieco, F., and Rosano, G. Long-term effects of nutraceuticals (berberine, red yeast rice, policosanol) in elderly hypercholesterolemic patients. Adv.Ther 2011;28(12):1105-1113. View abstract.

Marin-Neto, J. A., Maciel, B. C., Secches, A. L., and Gallo, Junior L. Cardiovascular effects of berberine in patients with severe congestive heart failure. Clin.Cardiol. 1988;11(4):253-260. View abstract.

Meng, S., Wang, L. S., Huang, Z. Q., Zhou, Q., Sun, Y. G., Cao, J. T., Li, Y. G., and Wang, C. Q. Berberine ameliorates inflammation in patients with acute coronary syndrome following percutaneous coronary intervention. Clin Exp.Pharmacol Physiol 2012;39(5):406-411. View abstract.

Mitani, N., Murakami, K., Yamaura, T., Ikeda, T., and Saiki, I. Inhibitory effect of berberine on the mediastinal lymph node metastasis produced by orthotopic implantation of Lewis lung carcinoma. Cancer Lett. 4-10-2001;165(1):35-42. View abstract.

Miyazaki, H., Shirai, E., Ishibashi, M., Hosoi, K., Shibata, S., and Iwanaga, M. Quantitation of berberine chloride in human urine by use of selected ion monitoring in the field desorption mode. Biomed.Mass Spectrom. 1978;5(10):559-565. View abstract.

Mohan, M., Pant, C. R., Angra, S. K., and Mahajan, V. M. Berberine in trachoma. (A clinical trial). Indian J Ophthalmol. 1982;30(2):69-75. View abstract.

Muller, K., Ziereis, K., and Gawlik, I. The antipsoriatic Mahonia aquifolium and its active constituents; II. Antiproliferative activity against cell growth of human keratinocytes. Planta Med 1995;61(1):74-75. View abstract.

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Nishida, S., Kikuichi, S., Yoshioka, S., Tsubaki, M., Fujii, Y., Matsuda, H., Kubo, M., and Irimajiri, K. Induction of apoptosis in HL-60 cells treated with medicinal herbs. Am J Chin Med 2003;31(4):551-562. View abstract.

Ozaki, Y., Suzuki, H., and Satake, M. [Comparative studies on concentration of berberine in plasma after oral administration of coptidis rhizoma extract, its cultured cells extract, and combined use of these extracts and glycyrrhizae radix extract in rats]. Yakugaku Zasshi 1993;113(1):63-69. View abstract.

Palasuntheram C, Iyer KS, de Silva LB, and et al. Antibacterial activity of Coscinium fenestratum Colebr against Clostridium tetani. Ind J Med Res 1982;76(Suppl):71-76.

Pan, J. F., Yu, C., Zhu, D. Y., Zhang, H., Zeng, J. F., Jiang, S. H., and Ren, J. Y. Identification of three sulfate-conjugated metabolites of berberine chloride in healthy volunteers' urine after oral administration. Acta Pharmacol Sin. 2002;23(1):77-82. View abstract.

Peng, W. H., Hsieh, M. T., and Wu, C. R. Effect of long-term administration of berberine on scopolamine-induced amnesia in rats. Jpn J Pharmacol 1997;74(3):261-266. View abstract.

Pisciotta, L., Bellocchio, A., and 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. View abstract.

Purohit SK, Kochar DK, Lal BB, and et al. Cultivation of Leishmania tropica from untreated and treated cases of oriental sore. Indian Journal of Public Health 1982;26(1):34-37.

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Sack, R. B. and Froehlich, J. L. Berberine inhibits intestinal secretory response of Vibrio cholerae and Escherichia coli enterotoxins. Infect Immun. 1982;35(2):471-475. View abstract.

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Seow WK, Ferrante A, Summors A, and et al. Comparative effects of tetrandrine and berbamine on production of the inflammatory cytokines interleukin-1 and tumor necrosis factor. Life Sciences 1992;50(8):pl-53-pl-58.

Shaffer, J. E. Inotropic and chronotropic activity of berberine on isolated guinea pig atria. J Cardiovasc Pharmacol 1985;7(2):307-315. View abstract.

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Soffar, S. A., Metwali, D. M., Abdel-Aziz, S. S., el Wakil, H. S., and Saad, G. A. Evaluation of the effect of a plant alkaloid (berberine derived from Berberis aristata) on Trichomonas vaginalis in vitro. J Egypt.Soc Parasitol. 2001;31(3):893-904. View abstract.

Sriwilaijareon, N., Petmitr, S., Mutirangura, A., Ponglikitmongkol, M., and Wilairat, P. Stage specificity of Plasmodium falciparum telomerase and its inhibition by berberine. Parasitol.Int 2002;51(1):99-103. View abstract.

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Supek Z and Tomic D. Farmakološko-kemijsko istrazivanje zutike (

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Tai, Y. H., Feser, J. F., Marnane, W. G., and Desjeux, J. F. Antisecretory effects of berberine in rat ileum. Am J Physiol 1981;241(3):G253-G258. View abstract.

Thumm, H. W. and Tritschler, J. [The action of Berberin-drops on the intraocular pressure (IOP) (author's transl)]. Klin.Monbl.Augenheilkd. 1977;170(1):119-123. View abstract.

Trimarco, V., Cimmino, C. S., Santoro, M., Pagnano, G., Manzi, M. V., Piglia, A., Giudice, C. A., De, Luca N., and Izzo, R. Nutraceuticals for blood pressure control in patients with high-normal or grade 1 hypertension. High Blood Press Cardiovasc.Prev. 9-1-2012;19(3):117-122. View abstract.

Tripathi YB and Shukla SD. Berberis artistata inhibits PAF induced aggregation of rabbit platelets. Phytotherapy Research 1996;10:628-630.

Vik-Mo H, Faria DB, Cheung WM, and et al. Beneficial effects of berberine on left ventricular function in dogs with heart failure. Clinical Research 1983;31(2):224a.

Wang, D. Y., Yeh, C. C., Lee, J. H., Hung, C. F., and Chung, J. G. Berberine inhibited arylamine N-acetyltransferase activity and gene expression and DNA adduct formation in human malignant astrocytoma (G9T/VGH) and brain glioblastoma multiforms (GBM 8401) cells. Neurochem.Res 2002;27(9):883-889. View abstract.

Wang, N., Feng, Y., Cheung, F., Chow, O. Y., Wang, X., Su, W., and Tong, Y. A comparative study on the hepatoprotective action of bear bile and Coptidis Rhizoma aqueous extract on experimental liver fibrosis in rats. BMC.Complement Altern.Med 2012;12:239. View abstract.

Wang, Q., Zhang, M., Liang, B., Shirwany, N., Zhu, Y., and 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(9):e25436. View abstract.

Wang, Y., Jia, X., Ghanam, K., Beaurepaire, C., Zidichouski, J., and Miller, L. Berberine and plant stanols synergistically inhibit cholesterol absorption in hamsters. Atherosclerosis 2010;209(1):111-117. View abstract.

Wei, W., Zhao, H., Wang, A., Sui, M., Liang, K., Deng, H., Ma, Y., Zhang, Y., Zhang, H., and Guan, Y. A clinical study on the short-term effect of berberine in comparison to metformin on the metabolic characteristics of women with polycystic ovary syndrome. Eur J Endocrinol. 2012;166(1):99-105. View abstract.

Wright, C. W., Marshall, S. J., Russell, P. F., Anderson, M. M., Phillipson, J. D., Kirby, G. C., Warhurst, D. C., and Schiff, P. L. In vitro antiplasmodial, antiamoebic, and cytotoxic activities of some monomeric isoquinoline alkaloids. J Nat Prod 2000;63(12):1638-1640. View abstract.

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Berberine hydrochloride: anticancer activity and ...

Abstract

Background

Berberine hydrochloride is a conventional component in Chinese medicine, and is characterized by a diversity of pharmacological effects. However, due to its hydrophobic properties, along with poor stability and bioavailability, the application of berberine hydrochloride was hampered for a long time. In recent years, the pharmaceutical preparation of berberine hydrochloride has improved to achieve good prospects for clinical application, especially for novel nanoparticulate delivery systems. Moreover, anticancer activity and novel mechanisms have been explored, the chance of regulating glucose and lipid metabolism in cancer cells showing more potential than ever. Therefore, it is expected that appropriate pharmaceutical procedures could be applied to the enormous potential for anticancer efficacy, to give some new insights into anticancer drug preparation in Chinese medicine.

Methods and results

We accessed conventional databases, such as PubMed, Scope, and Web of Science, using “berberine hydrochloride”, “anti-cancer mechanism”, and “nanoparticulate delivery system” as search words, then summarized the progress in research, illustrating the need to explore reprogramming of cancer cell metabolism using nanoparticulate drug delivery systems.

Conclusion

With increasing research on regulation of cancer cell metabolism by berberine hydrochloride and troubleshooting of issues concerning nanoparticulate delivery preparation, berberine hydrochloride is likely to become a natural component of the nanoparticulate delivery systems used for cancer therapy. Meanwhile, the known mechanisms of berberine hydrochloride, such as decreased multidrug resistance and enhanced sensitivity of chemotherapeutic drugs, along with improvement in patient quality of life, could also provide new insights into cancer cell metabolism and nanoparticulate delivery preparation.

Keywords:

berberine hydrochloride, anticancer mechanisms, nanoparticulate drug progress

Introduction

Berberine hydrochloride is an isoquinoline alkaloid (see ) isolated from a variety of Chinese herbs, including Coptidis rhizoma, Phellodendron chinense schneid, and Phellodendron amurense, and has diverse pharmacological actions. It has antidiabetic and antilipid peroxidation activity, as well as an anti-atherosclerotic action, and also has neuroprotective properties and improves polycystic ovary syndrome.1–5 Berberine hydrochloride is widely used as an antibacterial, antifungal, and anti-inflammatory drug, and has been used as a gastrointestinal remedy for thousands of years in China.6,7

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Nowadays, the antiproliferative activity and sensitivity enhancement of berberine hydrochloride in various cancer cell lines8–14 have led to further research interest in this compound.15–17 Its antineoplastic properties include induction of apoptosis and cell cycle arrest, along with inhibition of cell migration and invasion via regulation of multiple pathways.18–21 The potential targets of berberine hydrochloride include reactive oxygen species generation, mitochondrial function, DNA topoisomerase inhibition, DNA or RNA binding, the estrogen receptor, matrix metalloproteinase regulation, p53 activation, and NF-kappa B signal activation.10,22–26 However, it has poor water solubility caused by a quarternary amine, resulting in a low effective concentration and limited absorption in the gastrointestinal tract, which seriously limits its application and development as a pharmaceutical preparation. Furthermore, it has a risk of adverse reactions associated with intramuscular and intravenous administration, such as anaphylactic shock and drug rash, so a novel drug delivery system to improve the solubility and bioavailability of berberine hydrochloride has become a matter of urgency.

During the rapid development of nanotechnology, increasing attention has been paid to nanoparticulate drug delivery systems.27–29 Modern nanoparticulate dosage forms including polymeric nanoparticles, nanocapsules, liposomes, solid lipid nanoparticles, and nanoemulsions, all of which can improve drug solubility. In general, nanoparticulate drug delivery enhances solubility and bioavailability, improving pharmacological activity and tissue macrophage distribution, while preventing physical and chemical degradation.30,31 Therefore, we combined the good anticancer efficacy of berberine hydrochloride with a novel nanoparticulate drug delivery system to obtain a promising anticancer agent.

This review discusses anticancer mechanisms, with particular reference to regulation of glucose and lipid metabolism, and describes a novel drug delivery system for berberine hydrochloride, aiming to provide new insights into Chinese medicine preparations with anticancer activity.

Anticancer mechanisms of berberine hydrochloride

The potential antitumor activity of berberine hydrochloride has always been a subject of considerable interest because of its known ability to interact with nucleic acids. Its ability to bind specifically to oligonucleotides and to stabilize DNA triplexes or G-quadruplexes via telomerase and topoisomerase inhibition accounts for its antiproliferative activity.32,33 The predominant interaction between berberine hydrochloride and double-stranded or single-stranded DNA is electrostatic, and can be quantified in terms of the Hill model of cooperative interactions.34 Recent novel mechanisms have a higher propensity for autophagy and autophagic regulators. Wang et al found that berberine hydrochloride induced autophagic cell death which was diminished by 3-methyladenine, a cell death inhibitor, in the human hepatic carcinoma cell lines HepG2 and MHCC97-L, through activation of beclin-1 and inhibition of the mTOR signaling pathway.35 In addition, the autophagic marker, microtubule-associated protein-1 light chain 3 (LC3) was modified after administration of berberine hydrochloride in the human A549 lung cancer cell line, accompanied by shrinkage of tumor volume in a Lewis lung carcinoma model in mice, all of which indicates that autophagy might be important in cancer cell death.36

In addition to autophagy and its interaction with nucleic acid, the hypoglycemic and hypolipidemic effects of berberine hydrochloride also point to a relationship between adipose tissue/adipocytes and tumorigenesis, through upregulation of mRNA and protein levels in adipose tissue, including peroxisome proliferator-activated receptor (PPAR) α, β, and γ, CDK9, and cyclin T1.3 Adipose tissue and adipocytes have a significant role in the tumor microenvironment,37 and SPARC (secreted protein acidic and rich in cysteine), an adiposity inhibitor, was suggested by Nagaraju and Sharma38 to be a potent anticancer molecule, and human adipose tissue-derived stem cells are known to be a source of carcinoma-associated fibroblasts in the presence of transforming growth factor β1.39 Further, adipose tissue-derived vascular endothelial growth factor and leptin promote adipogenesis in order to maintain the tumor microenvironment.40 Hirano et al have also suggested the existence of undefined factors derived from cancer cells which promote adipogenesis, further indicating a potential relationship between adipogenesis and development of cancer.41 In clinical lipofilling procedures undertaken for patients with breast cancer, there is an urgent need to clarify the issue of cancer recurrence and adipogenesis.42 The adipogenesis positive regulator, PPARγ, overexpressed in ERBB2-positive breast cancer cells, enables fatty acid synthesis, mainly to support energy demands and cell survival.43 Therefore, less toxic PPARγ agonists or antagonists, including berberine hydrochloride, are regarded as potential agents for improving adipose breast tissue and decreasing breast cancer risk, as well as suppressing proliferation and invasion of cancer cells.44 By inhibiting PPARγ protein expression and increasing PPARα mRNA levels, berberine hydrochloride has been shown to improve free fatty acid-induced insulin resistance in myotubes, and to suppress adipogenesis in white preadipocytes in humans and hepatic insulin resistance in diabetic hamsters.2,45,46 Berberine hydrochloride also prevented wasting of epididymal adipose tissue and ameliorated cancer cachexia in colon 26/clone 20-transplanted mice and colon 26/clone 20 cells,47 further highlighting the beneficial effect of this compound on adipose tissue in the tumor microenvironment.

Working as a potential natural compound in cancer therapy via its interaction with nucleic acid and regulation of cancer cells, as well as induction of autophagy, berberine hydrochloride augments the effects of chemotherapy/radiotherapy and has shown good prospects in cancer treatment.11 After the novel mechanisms by which it interferes with the development of adipose tissue and adipocyte metabolism in the tumor microenvironment were investigated, the efficacy and potential applications of berberine hydrochloride were highlighted and emphasized. Moreover, its extensive occurrence in various plant species and low toxicity suggest that berberine hydrochloride has the potential to become an effective antitumor agent in the future.

Nanoparticulate delivery systems

Reports on nanoparticulate delivery systems for berberine hydrochloride can be divided into three types, ie, solid lipid nanoparticles, nanoemulsions, and liposomes. Preparation, characterization, experimental design methods, and in vivo and in vitro studies are summarized here.

The first nanoparticulate delivery system uses a conventional rotary-evaporated film-ultrasonication method to make solid lipid nanoparticles of berberine hydrochloride (BH-SLN). These have good stability, a mean diameter of 60.5 nm, a zeta potential of 29.7 mV, drug loading of 8.69%, and an entrapment ratio of 97.58%.48 Certain other factors have a direct impact on actual amount and quality of liposome entrapment, including preparation and manufacturing methods, and types of excipients used and particle size. Entrapment is defined as the fraction of the initial solution remaining within the liposomes, which is the key factor in clinical application.49 Wang et al established the method of coagulation centrifugation to determine the entrapment efficiency of BH-SLN.50 A saturated aqueous solution of sodium chloride 0.05 mL in BH-SLN 0.5 mL was determined by high-pressure liquid chromatography, and then centrifuged at 12,000 rpm for 10 minutes to obtain the supernatant. The results show that coagulation centrifugation was rapid and accurate.

The second delivery system is berberine hydrochloride nanoemulsion, made by isopropyl myristate, EL40, and glycerin using pseudoternary phase diagrams. The nanoemulsion is a clear transparent solution with an average particle diameter of 56.8 nm.51 Small spherical drops are seen under electron microscopy, with a stable content and diameter even under high humidity and temperature conditions, along with strong light, 92.5% humidity, a temperature range of 40°C–60°C, and (4500 ± 500) LX.

The last system is a liposomal one, and there are several approaches used to prepare berberine hydrochloride liposomes, including the thin film evaporation method, the active loading method, and a combination of the thin film evaporation and active loading methods. The thin film evaporation process could achieve a higher encapsulation efficiency, and the optimum manufacturing processes are characterized by 60°C of hatched temperature, 30 minutes of time, and 3.3 mg/mL of cholesterol concentration.52 An active loading method is better than passive loading with a higher entrapment efficiency.53 There are several factors to be considered, including addition sequence, incubation time, incubation temperature, pH value of the external water phase, and the particle size of the liposome. Changing the addition sequence can also achieve different entrapment efficiencies, as can increasing incubation time and temperature and decreasing the particle size.53 Chen et al used different individual variables and an orthogonal design to obtain the optimal preparation conditions for berberine hydrochloride liposomes, including incubation time and incubation temperature, proportional weights of drug and lipids, soybean phosphatidylcholine, and cholesterol.54 The results indicated that the average encapsulation efficiency of the optimized liposome was 78.51% ± 2.45%, with a size range of 2.2–3.5 μm. Based on the uniform design, berberine hydrochloride liposomes were prepared by thin film evaporation and an active loading method.55 An optimal formulation was established and a high encapsulation efficiency of 79.33% was obtained with a drug loading ratio of 30.21 and a size range of 2.2–3.8 μm. In vivo and in vitro studies were carried out to investigate the way in which liposomal berberine hydrochloride works. Gou et al studied the effects of berberine hydrochloride liposomes on the combination of impaired glucose tolerance and hyperlipidemia, suggesting that glucose and lipid metabolism was interfered with and progression from hyperlipidemia to type 2 diabetes was also prevented.56

Conclusion

Studies of the molecular mechanisms by which berberine hydrochloride affects lipid and glucose metabolism warrant further attention. Additionally, with the increasing research on reprogramming of cancer cell metabolism, including inhibition of glycolysis, impairment of mitochondrial function, and suppression of cell anabolism, it could be possible to reverse abnormal cancer cell metabolism in various ways, including blocking formation of the cell membrane and synthesis of macromolecules, and inhibiting growth and proliferation of cancer cells. During the process of interfering with cancer cell reprogramming, because of the alteration in the physiological properties of the cell, multidrug resistance, sensitivity of chemotherapeutic drugs, and patient quality of life could be ameliorated, which indicates the potential of berberine hydrochloride as an adjuvant drug in antineoplastic treatment. With effective troubleshooting of issues such as the hydrophobic properties, poor stability, and bioavailability of berberine hydrochloride, research on nanoparticulate delivery systems for this compound is being vigorously pursued. Furthermore, investigations in this field are likely to provide new insights into anticancer drug preparation in Chinese medicine.

Acknowledgments

This study was supported by the Macao Science and Technology Development Fund (029/2007/A2) and University of Macau Research Fund (UL016A/09-Y2/CMS/WYT01/ICMS).

Footnotes

Disclosure

The authors report no conflicts of interest in this work.

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