I just happened across this Wiki entry about Berberine
and thought Peatians might enjoy contemplating.
Peat has said how, in his college days,
he kept up a running side-study of dyes.
Maybe he said "brightly colored dyes" or was more specific? Can't recall. Think I heard him say this on the radio.
But you will note Berberine comes from the isoquinoline alkaloids,
so that chemical name looks a little like "quinone" if you squint.
And like methylene blue--another dye which is structurally similar to quinones--
it has antibiotic, antifungal, perhaps anti-cancer etc properties.
I put this under "Supplements"
not because I'm urging anyone to take it.
But, apparently it can be and long has been.
Berberine is a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids. It is found in such plants as Berberis [e.g. Berberis aquifolium (Oregon grape), Berberis vulgaris (barberry), Berberis aristata (tree turmeric)], Hydrastis canadensis (goldenseal), Xanthorhiza simplicissima (yellowroot), Phellodendron amurense[2] (Amur cork tree), Coptis chinensis (Chinese goldthread 黄连素 or Huang Lian Su), Tinospora cordifolia, Argemone mexicana (prickly poppy), and Eschscholzia californica (Californian poppy). Berberine is usually found in the roots, rhizomes, stems, and bark.[citation needed]
Berberine was supposedly used in China as a broad-spectrum anti-microbial medicine by Shennong around 3000 BC. This first recorded use of Berberine is described in the ancient Chinese medical book The Divine Farmer's Herb-Root Classic.
Due to Berberine's strong yellow color, Berberis species were used to dye wool, leather, and wood. Wool is still dyed with berberine today in northern India.[citation needed] Under ultraviolet light, berberine shows a strong yellow fluorescence,[3] so it is used in histology for staining heparin in mast cells.[4] As a natural dye, berberine has a colour index of 75160.
Traditional use]
As a Chinese traditional medicine or dietary supplement, berberine has shown some activity against fungal infections, Candida albicans, yeast, parasites, and bacterial/viral infections.[5][6] Berberine seems to exert synergistic effects with fluconazole even in drug-resistant C. albicans infections.[7]
Some research has been undertaken into possible use against MRSA infection.[8]
Berberine is considered antibiotic.[9][10] When applied in vitro and in combination with methoxyhydnocarpin, an inhibitor of multidrug resistance pumps, berberine inhibits growth of Staphylococcus aureus[11] and Microcystis aeruginosa,[12] a toxic cyanobacterium.
Berberine is a component of some eye drop formulations. There is some evidence it is useful in the treatment of trachoma,[13] and it has been a standard treatment for leishmaniasis.[14]
Berberine prevents and suppresses proinflammatory cytokines, E-selectin,[15] and genes, and increases adiponectin expression[16] which partly explains its versatile health effects. Berberine is a nucleic acid-binding isoquinoline alkaloid with wide potential therapeutic properties.[17]
Newer and experimental uses
Antiarrhythmia
The antiarrhythmic effect of Berberine has been demonstrated in animal models and clinical studies. Berberine increases the cardiac action potential duration by inhibiting potassium channels.[18] Berberine can be grouped as class III antiarrhythmic drug.
Diabetes, dyslipidemias and cardiovascular conditions[edit]
During the last few decades, many studies have shown berberine has various beneficial effects on the cardiovascular system and significant anti-inflammatory activities.[19] A Canadian report suggested berberine can effectively reduce intracellular superoxide levels in LPS-stimulated macrophages. Such a restoration of cellular redox by berberine is mediated by its selective inhibition of gp91phox expression and enhancement of SOD activity.[20]
Berberine exerts up-regulating activity on both the low-density-lipoprotein receptor (LDLR) and the insulin receptor (InsR). This one-drug-multiple-target characteristic might be suitable for the treatment of metabolic syndrome.[21][22]
Diabetes mellitus
Berberine has been tested and used successfully in experimental[23][24] and human diabetes mellitus.[25][26][27][28]
Berberine has been shown to lower elevated blood glucose as effectively as metformin.[29] The mechanisms of action include inhibition of aldose reductase,[30] inducing glycolysis,[31] preventing insulin resistance[32][33] through increasing insulin receptor expression[26] and acting like incretins.[34] A new study suggested berberine may overcome insulin resistance via modulating key molecules in insulin signaling pathway, leading to increased glucose uptake in insulin-resistant cells.[35]
Berberine might exert its insulinotropic effect in isolated rat islets by up-regulating the expression of hepatocyte nuclear factor 4 alpha, which probably acts solely or together with other HNFs to modulate glucokinase activity, rendering β cells more sensitive to glucose fluctuation and to respond more effectively to glucose challenge.[36]
Berberine seems to inhibit human dipeptidyl peptidase-4 (DPP4), as well as the prodiabetic target human protein tyrosine phosphatase 1B (h-PTP 1B), which explain at least some of its antihyperglycemic activities.[37] Berberine suppresses intestinal disaccharidases with beneficial metabolic effects in diabetic states.[38]
A recent comprehensive metabonomics method, applied to 60 type 2 diabetics, suggested administration of berberine down-regulates the high level of free fatty acids which are known to be toxic to the pancreas and cause insulin resistance. These results suggest berberine might play a pivotal role in the treatment of type 2 diabetes, concluded the authors.[25]
Berberine has been shown to boost the effects of metformin and 2,4-thiazolidinedione (TZD), and can partly replace the commercial drugs, which could lead to a reduction in toxicity and side effects of the latter.[39]
Berberine inhibits FOXO1,[40] which integrates insulin signaling with mitochondrial function. Inhibition of Foxo1 can improve hepatic metabolism during insulin resistance and the metabolic syndrome.[41]
Lipids
Berberine lowers elevated blood total cholesterol, LDL cholesterol, triglycerides and atherogenic apolipoproteins (apo B) (Apo B),[42] but the mechanism of action is distinct from that of statins.[43][44][45] Berberine reduces LDL cholesterol by upregulating LDLR mRNA expression posttranscriptionally while downregulating the transcription of proprotein convertase subtilisin/kexin type 9 (PCSK9), a natural inhibitor of LDL receptor (LDLR),[46] and increasing in the liver the expression of LDL receptors through extracellular signal-regulated kinase (ERK) signaling pathway,[47] while statins inhibit cholesterol synthesis in the liver by blocking HMG-CoA-reductase. This explains why berberine does not cause side effects typical of statins. Berberine and plant stanols synergistically inhibit cholesterol absorption in hamsters.[48]
Berberine seems to improve the arterial endothelial function in humans.[27][49] Berberine activates AMP-activated protein kinase (AMPK),[50] specifically extracellular signal-regulated kinases (ERK),[51] which plays a central role in glucose and lipid metabolism,[52][53] suppresses proinflammatory cytokines,[54] and reduces MMP-9 and EMMPRIN expression,[55] which are all beneficial changes for heart health.
Liver
Berberine reduces hepatic fat content in rats with nonalcoholic fatty liver disease.[56] Berberine also prevents proliferation of hepatic stellate cells (HSCs), which are central for the development of fibrosis during liver injury.[40]
Congestive heart failure
Experimental[57][58][59] and clinical studies[60][61] suggest berberine may be useful for patients with severe congestive heart failure.[62]
Transplants
According to a Chinese report, combined use of berberine with cyclosporin A (CsA) could markedly increase the blood concentration of CsA and reduce the dosage of CsA required, save the cost for medical service, and shows no obvious adverse reaction in heart-transplant recipients.[63]
Cancer
Berberine has drawn extensive attention towards its antineoplastic effects.[64][65] It seems to suppress the growth of a wide variety of tumor cells, including breast cancer,[66] leukemia, melanoma,[67] epidermoid carcinoma, hepatoma, pancreatic cancer,[68] oral carcinoma, tongue carcinoma,[69] glioblastoma, prostate carcinoma and gastric carcinoma.[70][71] Animal studies have shown that berberine can suppress chemical-induced carcinogenesis, clastogenesis,[72] tumor promotion, tumor invasion,[73][74][75][76][77] prostate cancer,[78][79][80][81] neuroblastoma,[82][83] and leukemia.[49][84]
It is a radiosensitizer of tumor cells, but not of normal cells. How berberine mediates these effects is not fully understood, but its ability to inhibit angiogenesis and to modulate Mcl-1, Bcl-xL, cyclooxygenase (COX)-2, MDR, tumor necrosis factor (TNF)- and IL-6, iNOS, IL-12, intercellular adhesion molecule-1 and ELAM-1 expression, MCP-1 and CINC-1, cyclin D1,[85] activator protein (AP-1), HIF-1, PPAR-, and topoisomerase II has been shown. By using yeast mutants, berberine was found to bind and inhibit stress-induced mitogen-activated protein kinase kinase activation. Because apoptotic, carcinogenic, and inflammatory effects and various gene products (such as TNF-α, IL-6, COX-2, adhesion molecules, cyclin D1, and MDR) modulated by berberine are regulated by the transcription factor nuclear factor- B (NF- B), it is postulated this pathway plays a major role in the action of berberine.[86] Berberine suppressed NF-κB activation induced by various inflammatory agents and carcinogens. This alkaloid also suppressed constitutive NF-κB activation found in certain tumor cells. It seems to protect against side effects of radiation therapy in lung cancer.[87] However, new studies suggest that while berberine decreases cell growth, it increases the side population (stem cell) fraction of H460 lung cancer cells.[88] In lung cancer it can also act through suppression of TGF-β1-induced epithelial-to-mesenchymal transition.[89] Berberine enhances chemosensitivity to some chemotherapeutic agents like irinotecan .[90]
Berberine, 300 mg three times a day orally, also seems to inhibit complication of abdominal or pelvic radiation, called radiation-induced acute intestinal symptoms.[91] The studies suggest its use in clinical development may be more as a cytostatic agent than a cytotoxic compound.
Mental health
Berberine seems to act as an herbal antidepressant and a neuroprotector against neurodegenerative disorders.[92][93][94][95] Berberine inhibits prolyl oligopeptidase (POP) in a dose-dependent manner. Berberine is also known to bind to sigma receptors like many synthetic antidepressant drugs. As berberine is a natural compound that has been safely administered to humans, preliminary results suggest the initiation of clinical trials in patients with depression, bipolar affective disorder, schizophrenia, or related diseases in which cognitive capabilities are affected, with either the extract or pure berberine. New experimental results suggest berberine may have a potential for inhibition and prevention of Alzheimer's disease (AD), mainly through both cholinesterase (ChEs) inhibitory and β-amyloids pathways,[96][97] and additionally through antioxidant capacities.[98]
Other studies have shown berberine to increase noradrenaline and serotonin levels in the brain (rats) while inhibiting dopaminergic activity.[99][100] The half-life of berberine in vivo seems to be three to four hours, thus suggesting administration three times a day if steady levels are to be achieved.[101]
Intestinal disorders
Berberine can ameliorate proinflammatory cytokines-induced intestinal epithelial tight junction damage in vitro, and berberine may be one of the targeted therapeutic agents that can restore barrier function in intestinal disease states.[102][103]
HIV/AIDS
A new study identified a key cellular mechanism underlying the protective effect of berberine on HIV PI-induced inflammatory response in macrophages. Modulation of the endoplasmic reticulum stress response represents a potential therapeutic target for various inflammatory diseases and metabolic syndromes, including HIV PI-associated atherosclerosis. The report shows the potential application of berberine as a complementary therapeutic agent for HIV/AIDS.[104]
Contraindications
Berberine use in newborns has been associated with kernicterus, a bilirubin-induced brain dysfunction.[105] Also, at dosages about 60-100 times as large as a human pharmacological dose, a small dose-response teratogenic effect was observed in rodents.[106] For these reasons, berberine is not usually recommended for use during pregnancy, although there are some reason to believe that this may not be harmful.[107]
Biosynthesis
Biosynthesis of berberine
The alkaloid berberine has a tetracyclic skeleton derived from a benzyltetrahydroisoquinoline system with the incorporation of an extra carbon atom provided by S-adenosyl methionine (SAM) via an N-methyl group. Formation of the berberine bridge is readily rationalized as an oxidative process in which the N-methyl group is oxidized to an iminium ion, and a cyclization to the aromatic ring occurs by virtue of the phenolic group.[108]
Reticuline is known as the immediate precursor of protoberberine alkaloids in plants.[109] Berberine is an alkaloid derived from tyrosine. L-DOPA and 4-hydroxypyruvic acid both come from L-Tyr. Although two tyrosine molecules are used in the biosynthetic pathway, only the phenylethylamine fragment of the tetrahydroisoquinoline ring system is formed via DOPA, the remaining carbon atoms come from tyrosine via 4-hydroxyphenylacetaldehyde. L-DOPA loses carbon dioxide to form dopamine 1. Likewise, 4-hydroxypyruvic acid also loses carbon dioxide to form 4-hydroxyphenyl-acetaldehyde 2. Dopamine 1 then reacts with 4-hydroxy-phenylacetaldehyde 2 to form (S)-norcolaurine 3 in a reaction similar to the Mannich reaction. After oxidation and methylation by SAM, (S)-reticuline 4 is formed. (S)-reticuline serves as a pivotal intermediate to other alkaloids. Oxidation of the tertiary amine then occurs and an iminium ion is formed 5. In a Mannich-like reaction the ortho position to the phenol is nucleophilic, and electrons are pushed to form 6. Product 6 then undergoes keto-enol tautomerism to form (S)-scoulerine, which is then methylated by SAM to form (S)-tetrahydrocolumbamine 7. Product 7 is then oxidized to form the methylenedioxy ring from the ortho-methoxyphenol, via an O2-, NADPH- and cytochrome P-450-dependent enzyme, giving (S)-canadine 8. (S)-canadine is then oxidized to give the quaternary isoquinolinium system of berberine. This happens in two separate oxidation steps, both requiring molecular oxygen, with H2O2 and H2O produced in the successive processes.[110]
See also
Sanguinarine, a plant-based compound with very similar chemical classification as berberine
Coptisine for a related pharmacological discussion
Goldenseal for a related pharmacological discussion
Jatrorrhizine another protoberberine alkaloid
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Jump up ^ Cui G, Qin X, Zhang Y, Gong Z, Ge B, Zang YQ (August 2009). "Berberine differentially modulates the activities of Erk, p38 MAPK and JNK to suppress Th17 and Th1 T cell differentiation in type 1 diabetic mice". The Journal of Biological Chemistry 284 (41): 28420–9. doi:10.1074/jbc.M109.012674. PMC 2788891. PMID 19661066.
Jump up ^ Lamontagne J, Pepin E, Peyot ML, Joly E, Ruderman NB, Poitout V, Madiraju SR, Nolan CJ, Prentki M (April 2009). "Pioglitazone acutely reduces insulin secretion and causes metabolic deceleration of the pancreatic β-cell at submaximal glucose concentrations". Endocrinology 150 (8): 3465–74. doi:10.1210/en.2008-1557. PMC 2717855. PMID 19406947.
Jump up ^ 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 (August 2006). "Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states". Diabetes 55 (8): 2256–64. doi:10.2337/db06-0006. PMID 16873688.
Jump up ^ Jeong HW, Hsu KC, Lee JW, Ham M, Huh JY, Shin HJ, Kim WS, Kim JB (April 2009). "Berberine suppresses proinflammatory responses through AMPK activation in macrophages". American Journal of Physiology– Endocrinology and Metabolism 296 (4): E955–64. doi:10.1152/ajpendo.90599.2008. PMID 19208854.
Jump up ^ Huang Z, Wang L, Meng S, Wang Y, Chen T, Wang C (July 2009). "Berberine reduces both MMP-9 and EMMPRIN expression through prevention of p38 pathway activation in PMA-induced macrophages". International Journal of Cardiology 146 (2): 153–158. doi:10.1016/j.ijcard.2009.06.023. PMID 19576641.
Jump up ^ Chang X, Yan H, Fei J, Jiang M, Zhu H, Lu D, Gao X (September 2010). "Berberine reduces methylation of the MTTP promoter and alleviates fatty liver induced by a high-fat diet in rats" (PDF). The Journal of Lipid Research 51 (9): 2504–2515. doi:10.1194/jlr.m001958. PMID 20567026.
Jump up ^ Qi MY, Feng Y, Dai DZ, Li N, Cheng YS, Dai Y (February 2010). "CPU86017, a berberine derivative, attenuates cardiac failure through normalizing calcium leakage and downregulated phospholamban and exerting antioxidant activity". Acta Pharmacol Sin 31 (2): 165–74. doi:10.1038/aps.2009.180. PMC 4002834. PMID 20139899.
Jump up ^ Huang WM, Yan H, Jin JM, Yu C, Zhang H (December 1992). "Beneficial effects of berberine on hemodynamics during acute ischemic left ventricular failure in dogs". Chinese Medical Journal 105 (12): 1014–9. PMID 1299549.
Jump up ^ Riccioppo Neto F (February 1993). "Electropharmacological effects of berberine on canine cardiac Purkinje fibres and ventricular muscle and atrial muscle of the rabbit". British Journal of Pharmacology 108 (2): 534–7. doi:10.1111/j.1476-5381.1993.tb12836.x. PMC 1908004. PMID 8448600.
Jump up ^ Marin-Neto JA, Maciel BC, Secches AL, Gallo Júnior L (April 1988). "Cardiovascular effects of berberine in patients with severe congestive heart failure". Clinical Cardiology 11 (4): 253–60. doi:10.1002/clc.4960110411. PMID 3365876.
Jump up ^ Zeng XH, Zeng XJ, Li YY (July 2003). "Efficacy and safety of berberine for congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy". The American Journal of Cardiology 92 (2): 173–6. doi:10.1016/S0002-9149(03)00533-2. PMID 12860219.
Jump up ^ Wu M., Wang J., Liu L.-T. "Advance of studies on anti-atherosclerosis mechanism of berberine", Chinese Journal of Integrative Medicine 2010 16:2 (188-192)
Jump up ^ Huang XS, Yang GF, Pan YC (August 2008). "[Effect of berberin hydrochloride on blood concentration of cyclosporine A in cardiac transplanted recipients]". Zhongguo Zhong Xi Yi Jie He Za Zhi Zhongguo Zhongxiyi Jiehe Zazhi (in Chinese) 28 (8): 702–4. PMID 18928093.
Jump up ^ Sun Y, Xun K, Wang Y, Chen X (October 2009). "A systematic review of the anticancer properties of berberine, a natural product from Chinese herbs". Anticancer Drugs 20 (9): 757–69. doi:10.1097/CAD.0b013e328330d95b. PMID 19704371.
Jump up ^ Tang J, Feng Y, Tsao S, Wang N, Curtain R, Wang Y (August 2009). "Berberine and Coptidis Rhizoma as novel antineoplastic agents: a review of traditional use and biomedical investigations". Journal of Ethnopharmacology 126 (1): 5–17. doi:10.1016/j.jep.2009.08.009. PMID 19686830.
Jump up ^ Kim JB, Yu JH, Ko E, Lee KW, Song AK, Park SY, Shin I, Han W, Noh DY (October 2009). "The alkaloid Berberine inhibits the growth of Anoikis-resistant MCF-7 and MDA-MB-231 breast cancer cell lines by inducing cell cycle arrest". Phytomedicine 17 (6): 436–40. doi:10.1016/j.phymed.2009.08.012. PMID 19800775.
Jump up ^ Serafim TL, Oliveira PJ, Sardao VA, Perkins E, Parke D, Holy J (May 2008). "Different concentrations of berberine result in distinct cellular localization patterns and cell cycle effects in a melanoma cell line". Cancer Chemotherapy and Pharmacology 61 (6): 1007–18. doi:10.1007/s00280-007-0558-9. PMID 17661039.
Jump up ^ Pinto-Garcia L, Efferth T, Torres A, Hoheisel JD, Youns M (May 2010). "Berberine Inhibits Cell Growth and Mediates Caspase-Independent Cell Death in Human Pancreatic Cancer Cells". Planta Medica 76 (11): 1155–61. doi:10.1055/s-0030-1249931. PMID 20455200.
Jump up ^ Ho YT, Lu CC, Yang JS, Chiang JH, Li TC, Ip SW, Hsia TC, Liao CL, Lin JG, Wood WG, Chung JG (October 2009). "Berberine induced apoptosis via promoting the expression of caspase-8, -9 and -3, apoptosis-inducing factor and endonuclease G in SCC-4 human tongue squamous carcinoma cancer cells". Anticancer Research 29 (10): 4063–70. PMID 19846952.
Jump up ^ Auyeung KK, Ko JK (October 2009). "Coptis chinensis inhibits hepatocellular carcinoma cell growth through nonsteroidal anti-inflammatory drug-activated gene activation". International journal of molecular medicine 24 (4): 571–7. doi:10.3892/ijmm_00000267. PMID 19724899.
Jump up ^ 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 (October 2009). "Berberine inhibits metastasis of nasopharyngeal carcinoma 5-8F cells by targeting Rho kinase-mediated Ezrin phosphorylation at threonine 567". The Journal of Biological Chemistry 284 (40): 27456–66. doi:10.1074/jbc.M109.033795. PMC 2785675. PMID 19651779.
Jump up ^ Sindhu G, Manoharan S (April 2010). "Anti-Clastogenic Effect of Berberine against DMBA-Induced Clastogenesis". Basic Clin Pharmacol Toxicol. 107 (4): 818–24. doi:10.1111/j.1742-7843.2010.00579.x. PMID 20406204.
Jump up ^ Pandey MK, Sung B, Kunnumakkara AB, Sethi G, Chaturvedi MM, Aggarwal BB (July 2008). "Berberine modifies cysteine 179 of IκBα kinase, suppresses nuclear factor-κB-regulated antiapoptotic gene products, and potentiates apoptosis". Cancer Research 68 (13): 5370–9. doi:10.1158/0008-5472.CAN-08-0511. PMID 18593939.
Jump up ^ Kim JB, Ko E, Han W, Shin I, Park SY, Noh DY (November 2008). "Berberine diminishes the side population and ABCG2 transporter expression in MCF-7 breast cancer cells". Planta Medica 74 (14): 1693–700. doi:10.1055/s-0028-1088313. PMID 18951337.
Jump up ^ Kim S, Choi JH, Kim JB, Nam SJ, Yang JH, Kim JH, Lee JE (2008). "Berberine suppresses TNF-α-induced MMP-9 and cell invasion through inhibition of AP-1 activity in MDA-MB-231 human breast cancer cells". Molecules 13 (12): 2975–85. doi:10.3390/molecules13122975. PMID 19052522.
Jump up ^ Liu J, He C, Zhou K, Wang J, Kang JX (January 2009). "Coptis extracts enhance the anticancer effect of estrogen receptor antagonists on human breast cancer cells". Biochemical and Biophysical Research Communications 378 (2): 174–8. doi:10.1016/j.bbrc.2008.10.169. PMC 3454467. PMID 19000652.
Jump up ^ Thirupurasundari CJ, Padmini R, Devaraj SN (February 2009). "Effect of berberine on the antioxidant status, ultrastructural modifications and protein bound carbohydrates in azoxymethane-induced colon cancer in rats". Chemico-biological Interactions 177 (3): 190–5. doi:10.1016/j.cbi.2008.09.027. PMID 18951886.
Jump up ^ Mantena SK, Sharma SD, Katiyar SK (February 2006). "Berberine, a natural product, induces G1-phase cell cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells". Molecular Cancer Therapeutics 5 (2): 296–308. doi:10.1158/1535-7163.MCT-05-0448. PMID 16505103.
Jump up ^ Muralimanoharan SB, Kunnumakkara AB, Shylesh B, Kulkarni KH, Haiyan X, Ming H, Aggarwal BB, Rita G, Kumar AP (April 2009). "Butanol fraction containing berberine or related compound from nexrutine inhibits NFκB signaling and induces apoptosis in prostate cancer cells". The Prostate 69 (5): 494–504. doi:10.1002/pros.20899. PMC 2674392. PMID 19107816.
Jump up ^ Choi MS, Oh JH, Kim SM, Jung HY, Yoo HS, Lee YM, Moon DC, Han SB, Hong JT (May 2009). "Berberine inhibits p53-dependent cell growth through induction of apoptosis of prostate cancer cells". International Journal of Oncology 34 (5): 1221–30. PMID 19360335.
Jump up ^ Wang GY, Lv QH, Dong Q, Xu RZ, Dong QH (2009). "Berbamine induces Fas-mediated apoptosis in human hepatocellular carcinoma HepG2 cells and inhibits its tumor growth in nude mice". Journal of Asian Natural Products Research 11 (3): 219–28. doi:10.1080/10286020802675076. PMID 19408145.
Jump up ^ Choi MS, Yuk DY, Oh JH, Jung HY, Han SB, Moon DC, Hong JT (November 2008). "Berberine inhibits human neuroblastoma cell growth through induction of p53-dependent apoptosis". Anticancer Research 28 (6A): 3777–84. PMID 19189664.
Jump up ^ Lin CC, Ng LT, Hsu FF, Shieh DE, Chiang LC (January 2004). "Cytotoxic effects of Coptis chinensis and Epimedium sagittatum extracts and their major constituents (berberine, coptisine and icariin) on hepatoma and leukaemia cell growth". Clin. Exp. Pharmacol. Physiol. 31 (1–2): 65–9. doi:10.1111/j.1440-1681.2004.03951.x. PMID 14756686.
Jump up ^ Lin CC, Lin SY, Chung JG, Lin JP, Chen GW, Kao ST (March 2006). "Down-regulation of cyclin B1 and up-regulation of Wee1 by berberine promotes entry of leukemia cells into the G2/M-phase of the cell cycle". Anticancer Research 26 (2A): 1097–104. PMID 16619512.
Jump up ^ Khan M, Giessrigl B, Vonach C, Madlener S, Prinz S, Herbaceck I, Hölzl C, Bauer S, Viola K, Mikulits W, Quereshi RA, Knasmüller S, Grusch M, Kopp B, Krupitza G (January 2010). "Berberine and a Berberis lycium extract inactivate Cdc25A and induce α-tubulin acetylation that correlate with HL-60 cell cycle inhibition and apoptosis". Mutation Research 683 (1–2): 123–30. doi:10.1016/j.mrfmmm.2009.11.001. PMID 19909759.
Jump up ^ Lin S, Tsai SC, Lee CC, Wang BW, Liou JY, Shyu KG (1 September 2004). "Berberine inhibits HIF-1α expression via enhanced proteolysis". Molecular Pharmacology 66 (3): 612–9. doi:10.1124/mol.66.3 (inactive 2015-01-10). PMID 15322253.
Jump up ^ Liu Y, Yu H, Zhang C, Cheng Y, Hu L, Meng X, Zhao Y (November 2008). "Protective effects of berberine on radiation-induced lung injury via intercellular adhesion molecular-1 and transforming growth factor-β-1 in patients with lung cancer". European Journal of Cancer 44 (16): 2425–32. doi:10.1016/j.ejca.2008.07.040. PMID 18789680.
Jump up ^ http://link.springer.com/article/10.100 ... 012-2119-0
Jump up ^ Qi HW, Xin LY, Xu X, Ji XX, Fan LH (Jan 2014). "Epithelial-to-mesenchymal transition markers to predict response of Berberine in suppressing lung cancer invasion and metastasis". J Transl Med. 12: 22. doi:10.1186/1479-5876-12-22. PMC 3944941. PMID 24456611.
Jump up ^ Yu M, Tong X, Qi B, Qu H, Dong S, Yu B, Zhang N, Tang N, Wang L, Zhang C (Jan 2014). "Berberine enhances chemosensitivity to irinotecan in colon cancer via inhibition of NF-κB". J Mol Med Rep 9 (1): 249–54. doi:10.3892/mmr.2013.1762. PMID 24173769.
Jump up ^ Li GH, Wang DL, Hu YD, Pu P, Li DZ, Wang WD, Zhu B, Hao P, Wang J, Xu XQ, Wan JQ, Zhou YB, Chen ZT (September 2009). "Berberine inhibits acute radiation intestinal syndrome in human with abdomen radiotherapy". Medical Oncology (Northwood, London, England) 27 (3): 919–25. doi:10.1007/s12032-009-9307-8. PMID 19757213.
Jump up ^ Kulkarni SK, Dhir A (July 2009). "sigma-1 receptors in major depression and anxiety". Expert Review of Neurotherapeutics 9 (7): 1021–34. doi:10.1586/ern.09.40. PMID 19589051.
Jump up ^ Kulkarni SK, Dhir A (June 2009). "Current investigational drugs for major depression". Expert Opinion on Investigational Drugs 18 (6): 767–88. doi:10.1517/13543780902880850. PMID 19426122.
Jump up ^ Kulkarni SK, Dhir A (July 2008). "On the mechanism of antidepressant-like action of berberine chloride". European Journal of Pharmacology 589 (1–3): 163–72. doi:10.1016/j.ejphar.2008.05.043. PMID 18585703.
Jump up ^ Kulkarni SK, Dhir A (December 2009). "Berberine: a plant alkaloid with therapeutic potential for central nervous system disorders". Phytotherapy Research 24 (3): 317–24. doi:10.1002/ptr.2968. PMID 19998323.
Jump up ^ Xiang J, Yu C, Yang F; Yu; Yang; Yang; Ding (December 2009). "Conformation-activity studies on the interaction of berberine with acetylcholinesterase: Physical chemistry approach". Progress in Natural Science 19 (12): 1721–5. doi:10.1016/j.pnsc.2009.07.010.
Jump up ^ Huang L, Shi A, He F, Li X (December 2009). "Synthesis, biological evaluation, and molecular modeling of berberine derivatives as potent acetylcholinesterase inhibitors". Bioorganic & Medicinal Chemistry 18 (3): 1244–51. doi:10.1016/j.bmc.2009.12.035. PMID 20056426.
Jump up ^ Jung HA, Min BS, Yokozawa T, Lee JH, Kim YS, Choi JS (August 2009). "Anti-Alzheimer and antioxidant activities of Coptidis Rhizoma alkaloids". Biological & Pharmaceutical Bulletin 32 (8): 1433–8. doi:10.1248/bpb.32.1433. PMID 19652386.
Jump up ^ Peng WH, Lo KL, Lee YH, Hung TH, Lin YC (August 2007). "Berberine produces antidepressant-like effects in the forced swim test and in the tail suspension test in mice". Life Sciences 81 (11): 933–938. doi:10.1016/j.lfs.2007.08.003. PMID 17804020.
Jump up ^ Lee B, Yang CH, Hahm DH, Choe ES, Lee HJ, Pyun KH, Shim I (October 2007). "Inhibitory Effects of Coptidis rhizoma and Berberine on Cocaine-induced Sensitization". Evidence-based Complementary and Alternative Medicine 6 (1): 85–90. doi:10.1093/ecam/nem070. PMC 2644267. PMID 18955248.
Jump up ^ Zhao YN, Ding Y, Wang RF, Xing DM, Cheng J, Du L (2004). "A new approach to investigate the pharmacokinetics of traditional chinese medicine YL2000". The American journal of Chinese Medicine 32 (6): 921–929. doi:10.1142/S0192415X04002521. PMID 15673197.
Jump up ^ Li N, Gu L, Qu L, Gong J, Li Q, Zhu W, Li J (2010). "Berberine attenuates pro-inflammatory cytokine-induced tight junction disruption in an in vitro model of intestinal epithelial cells". European Journal of Pharmaceutical Sciences 40 (1): 1–8. doi:10.1016/j.ejps.2010.02.001. PMID 20149867.
Jump up ^ Gu L, Li N, Gong J, Li Q, Zhu W, Li J (2011). "Berberine ameliorates intestinal epithelial tight-junction damage and down-regulates myosin light chain kinase pathways in a mouse model of endotoxinemia". The Journal of infectious diseases 203 (11): 1602–12. doi:10.1093/infdis/jir147. PMID 21592990.
Jump up ^ Zha W, Liang G, Xiao J, Studer EJ, Hylemon PB, Pandak WM, Wang G, Li X, Zhou H (2010). Luo Y, ed. "Berberine Inhibits HIV Protease Inhibitor-Induced Inflammatory Response by Modulating ER Stress Signaling Pathways in Murine Macrophages". PLoS ONE 5 (2): e9069. Bibcode:2010PLoSO...5.9069Z. doi:10.1371/journal.pone.0009069. PMC 2817721. PMID 20161729.
Jump up ^ Chan E (1993). "Displacement of bilirubin from albumin by berberine". Biology of the neonate 63 (4): 201–8. doi:10.1159/000243932. PMID 8513024.
Jump up ^ Jahnke GD, Price CJ, Marr MC, Myers CB, George JD (2006). "Developmental toxicity evaluation of berberine in rats and mice". Birth Defects Res B Dev Reprod Toxicol 77 (3): 201–8. doi:10.1002/bdrb.20075. PMID 16634078.
Jump up ^ Linn YC, Lu J, Lim LC, Sun H, Sun J, Zhou Y, Ng HS (2012). "Berberine-induced haemolysis revisited: safety of Rhizoma coptidis and Cortex phellodendri in chronic haematological diseases". Phytotherapy research 26 (5): 682–6. doi:10.1002/ptr.3617. PMID 22002596.
Jump up ^ Dewick, P. (2009). Medicinal Natural Products: A Biosynthetic Approach (3rd ed.). West Sussex, England: Wiley. p. 357. ISBN 0-471-49641-3.
Jump up ^ Park SU, Facchini PJ (June 2000). "Agrobacterium rhizogenes-mediated transformation of opium poppy, Papaver somniferum l., and California poppy, Eschscholzia californica cham., root cultures". Journal of Experimental Botany 51 (347): 1005–16. doi:10.1093/jexbot/51.347.1005. PMID 10948228.
Jump up ^ Dewick, P. (2009). Medicinal Natural Products: A Biosynthetic Approach (3rd ed.). West Sussex, England: Wiley. p. 358. ISBN 0-471-49641-3.
and thought Peatians might enjoy contemplating.
Peat has said how, in his college days,
he kept up a running side-study of dyes.
Maybe he said "brightly colored dyes" or was more specific? Can't recall. Think I heard him say this on the radio.
But you will note Berberine comes from the isoquinoline alkaloids,
so that chemical name looks a little like "quinone" if you squint.
And like methylene blue--another dye which is structurally similar to quinones--
it has antibiotic, antifungal, perhaps anti-cancer etc properties.
I put this under "Supplements"
not because I'm urging anyone to take it.
But, apparently it can be and long has been.
Berberine is a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids. It is found in such plants as Berberis [e.g. Berberis aquifolium (Oregon grape), Berberis vulgaris (barberry), Berberis aristata (tree turmeric)], Hydrastis canadensis (goldenseal), Xanthorhiza simplicissima (yellowroot), Phellodendron amurense[2] (Amur cork tree), Coptis chinensis (Chinese goldthread 黄连素 or Huang Lian Su), Tinospora cordifolia, Argemone mexicana (prickly poppy), and Eschscholzia californica (Californian poppy). Berberine is usually found in the roots, rhizomes, stems, and bark.[citation needed]
Berberine was supposedly used in China as a broad-spectrum anti-microbial medicine by Shennong around 3000 BC. This first recorded use of Berberine is described in the ancient Chinese medical book The Divine Farmer's Herb-Root Classic.
Due to Berberine's strong yellow color, Berberis species were used to dye wool, leather, and wood. Wool is still dyed with berberine today in northern India.[citation needed] Under ultraviolet light, berberine shows a strong yellow fluorescence,[3] so it is used in histology for staining heparin in mast cells.[4] As a natural dye, berberine has a colour index of 75160.
Traditional use]
As a Chinese traditional medicine or dietary supplement, berberine has shown some activity against fungal infections, Candida albicans, yeast, parasites, and bacterial/viral infections.[5][6] Berberine seems to exert synergistic effects with fluconazole even in drug-resistant C. albicans infections.[7]
Some research has been undertaken into possible use against MRSA infection.[8]
Berberine is considered antibiotic.[9][10] When applied in vitro and in combination with methoxyhydnocarpin, an inhibitor of multidrug resistance pumps, berberine inhibits growth of Staphylococcus aureus[11] and Microcystis aeruginosa,[12] a toxic cyanobacterium.
Berberine is a component of some eye drop formulations. There is some evidence it is useful in the treatment of trachoma,[13] and it has been a standard treatment for leishmaniasis.[14]
Berberine prevents and suppresses proinflammatory cytokines, E-selectin,[15] and genes, and increases adiponectin expression[16] which partly explains its versatile health effects. Berberine is a nucleic acid-binding isoquinoline alkaloid with wide potential therapeutic properties.[17]
Newer and experimental uses
Antiarrhythmia
The antiarrhythmic effect of Berberine has been demonstrated in animal models and clinical studies. Berberine increases the cardiac action potential duration by inhibiting potassium channels.[18] Berberine can be grouped as class III antiarrhythmic drug.
Diabetes, dyslipidemias and cardiovascular conditions[edit]
During the last few decades, many studies have shown berberine has various beneficial effects on the cardiovascular system and significant anti-inflammatory activities.[19] A Canadian report suggested berberine can effectively reduce intracellular superoxide levels in LPS-stimulated macrophages. Such a restoration of cellular redox by berberine is mediated by its selective inhibition of gp91phox expression and enhancement of SOD activity.[20]
Berberine exerts up-regulating activity on both the low-density-lipoprotein receptor (LDLR) and the insulin receptor (InsR). This one-drug-multiple-target characteristic might be suitable for the treatment of metabolic syndrome.[21][22]
Diabetes mellitus
Berberine has been tested and used successfully in experimental[23][24] and human diabetes mellitus.[25][26][27][28]
Berberine has been shown to lower elevated blood glucose as effectively as metformin.[29] The mechanisms of action include inhibition of aldose reductase,[30] inducing glycolysis,[31] preventing insulin resistance[32][33] through increasing insulin receptor expression[26] and acting like incretins.[34] A new study suggested berberine may overcome insulin resistance via modulating key molecules in insulin signaling pathway, leading to increased glucose uptake in insulin-resistant cells.[35]
Berberine might exert its insulinotropic effect in isolated rat islets by up-regulating the expression of hepatocyte nuclear factor 4 alpha, which probably acts solely or together with other HNFs to modulate glucokinase activity, rendering β cells more sensitive to glucose fluctuation and to respond more effectively to glucose challenge.[36]
Berberine seems to inhibit human dipeptidyl peptidase-4 (DPP4), as well as the prodiabetic target human protein tyrosine phosphatase 1B (h-PTP 1B), which explain at least some of its antihyperglycemic activities.[37] Berberine suppresses intestinal disaccharidases with beneficial metabolic effects in diabetic states.[38]
A recent comprehensive metabonomics method, applied to 60 type 2 diabetics, suggested administration of berberine down-regulates the high level of free fatty acids which are known to be toxic to the pancreas and cause insulin resistance. These results suggest berberine might play a pivotal role in the treatment of type 2 diabetes, concluded the authors.[25]
Berberine has been shown to boost the effects of metformin and 2,4-thiazolidinedione (TZD), and can partly replace the commercial drugs, which could lead to a reduction in toxicity and side effects of the latter.[39]
Berberine inhibits FOXO1,[40] which integrates insulin signaling with mitochondrial function. Inhibition of Foxo1 can improve hepatic metabolism during insulin resistance and the metabolic syndrome.[41]
Lipids
Berberine lowers elevated blood total cholesterol, LDL cholesterol, triglycerides and atherogenic apolipoproteins (apo B) (Apo B),[42] but the mechanism of action is distinct from that of statins.[43][44][45] Berberine reduces LDL cholesterol by upregulating LDLR mRNA expression posttranscriptionally while downregulating the transcription of proprotein convertase subtilisin/kexin type 9 (PCSK9), a natural inhibitor of LDL receptor (LDLR),[46] and increasing in the liver the expression of LDL receptors through extracellular signal-regulated kinase (ERK) signaling pathway,[47] while statins inhibit cholesterol synthesis in the liver by blocking HMG-CoA-reductase. This explains why berberine does not cause side effects typical of statins. Berberine and plant stanols synergistically inhibit cholesterol absorption in hamsters.[48]
Berberine seems to improve the arterial endothelial function in humans.[27][49] Berberine activates AMP-activated protein kinase (AMPK),[50] specifically extracellular signal-regulated kinases (ERK),[51] which plays a central role in glucose and lipid metabolism,[52][53] suppresses proinflammatory cytokines,[54] and reduces MMP-9 and EMMPRIN expression,[55] which are all beneficial changes for heart health.
Liver
Berberine reduces hepatic fat content in rats with nonalcoholic fatty liver disease.[56] Berberine also prevents proliferation of hepatic stellate cells (HSCs), which are central for the development of fibrosis during liver injury.[40]
Congestive heart failure
Experimental[57][58][59] and clinical studies[60][61] suggest berberine may be useful for patients with severe congestive heart failure.[62]
Transplants
According to a Chinese report, combined use of berberine with cyclosporin A (CsA) could markedly increase the blood concentration of CsA and reduce the dosage of CsA required, save the cost for medical service, and shows no obvious adverse reaction in heart-transplant recipients.[63]
Cancer
Berberine has drawn extensive attention towards its antineoplastic effects.[64][65] It seems to suppress the growth of a wide variety of tumor cells, including breast cancer,[66] leukemia, melanoma,[67] epidermoid carcinoma, hepatoma, pancreatic cancer,[68] oral carcinoma, tongue carcinoma,[69] glioblastoma, prostate carcinoma and gastric carcinoma.[70][71] Animal studies have shown that berberine can suppress chemical-induced carcinogenesis, clastogenesis,[72] tumor promotion, tumor invasion,[73][74][75][76][77] prostate cancer,[78][79][80][81] neuroblastoma,[82][83] and leukemia.[49][84]
It is a radiosensitizer of tumor cells, but not of normal cells. How berberine mediates these effects is not fully understood, but its ability to inhibit angiogenesis and to modulate Mcl-1, Bcl-xL, cyclooxygenase (COX)-2, MDR, tumor necrosis factor (TNF)- and IL-6, iNOS, IL-12, intercellular adhesion molecule-1 and ELAM-1 expression, MCP-1 and CINC-1, cyclin D1,[85] activator protein (AP-1), HIF-1, PPAR-, and topoisomerase II has been shown. By using yeast mutants, berberine was found to bind and inhibit stress-induced mitogen-activated protein kinase kinase activation. Because apoptotic, carcinogenic, and inflammatory effects and various gene products (such as TNF-α, IL-6, COX-2, adhesion molecules, cyclin D1, and MDR) modulated by berberine are regulated by the transcription factor nuclear factor- B (NF- B), it is postulated this pathway plays a major role in the action of berberine.[86] Berberine suppressed NF-κB activation induced by various inflammatory agents and carcinogens. This alkaloid also suppressed constitutive NF-κB activation found in certain tumor cells. It seems to protect against side effects of radiation therapy in lung cancer.[87] However, new studies suggest that while berberine decreases cell growth, it increases the side population (stem cell) fraction of H460 lung cancer cells.[88] In lung cancer it can also act through suppression of TGF-β1-induced epithelial-to-mesenchymal transition.[89] Berberine enhances chemosensitivity to some chemotherapeutic agents like irinotecan .[90]
Berberine, 300 mg three times a day orally, also seems to inhibit complication of abdominal or pelvic radiation, called radiation-induced acute intestinal symptoms.[91] The studies suggest its use in clinical development may be more as a cytostatic agent than a cytotoxic compound.
Mental health
Berberine seems to act as an herbal antidepressant and a neuroprotector against neurodegenerative disorders.[92][93][94][95] Berberine inhibits prolyl oligopeptidase (POP) in a dose-dependent manner. Berberine is also known to bind to sigma receptors like many synthetic antidepressant drugs. As berberine is a natural compound that has been safely administered to humans, preliminary results suggest the initiation of clinical trials in patients with depression, bipolar affective disorder, schizophrenia, or related diseases in which cognitive capabilities are affected, with either the extract or pure berberine. New experimental results suggest berberine may have a potential for inhibition and prevention of Alzheimer's disease (AD), mainly through both cholinesterase (ChEs) inhibitory and β-amyloids pathways,[96][97] and additionally through antioxidant capacities.[98]
Other studies have shown berberine to increase noradrenaline and serotonin levels in the brain (rats) while inhibiting dopaminergic activity.[99][100] The half-life of berberine in vivo seems to be three to four hours, thus suggesting administration three times a day if steady levels are to be achieved.[101]
Intestinal disorders
Berberine can ameliorate proinflammatory cytokines-induced intestinal epithelial tight junction damage in vitro, and berberine may be one of the targeted therapeutic agents that can restore barrier function in intestinal disease states.[102][103]
HIV/AIDS
A new study identified a key cellular mechanism underlying the protective effect of berberine on HIV PI-induced inflammatory response in macrophages. Modulation of the endoplasmic reticulum stress response represents a potential therapeutic target for various inflammatory diseases and metabolic syndromes, including HIV PI-associated atherosclerosis. The report shows the potential application of berberine as a complementary therapeutic agent for HIV/AIDS.[104]
Contraindications
Berberine use in newborns has been associated with kernicterus, a bilirubin-induced brain dysfunction.[105] Also, at dosages about 60-100 times as large as a human pharmacological dose, a small dose-response teratogenic effect was observed in rodents.[106] For these reasons, berberine is not usually recommended for use during pregnancy, although there are some reason to believe that this may not be harmful.[107]
Biosynthesis
Biosynthesis of berberine
The alkaloid berberine has a tetracyclic skeleton derived from a benzyltetrahydroisoquinoline system with the incorporation of an extra carbon atom provided by S-adenosyl methionine (SAM) via an N-methyl group. Formation of the berberine bridge is readily rationalized as an oxidative process in which the N-methyl group is oxidized to an iminium ion, and a cyclization to the aromatic ring occurs by virtue of the phenolic group.[108]
Reticuline is known as the immediate precursor of protoberberine alkaloids in plants.[109] Berberine is an alkaloid derived from tyrosine. L-DOPA and 4-hydroxypyruvic acid both come from L-Tyr. Although two tyrosine molecules are used in the biosynthetic pathway, only the phenylethylamine fragment of the tetrahydroisoquinoline ring system is formed via DOPA, the remaining carbon atoms come from tyrosine via 4-hydroxyphenylacetaldehyde. L-DOPA loses carbon dioxide to form dopamine 1. Likewise, 4-hydroxypyruvic acid also loses carbon dioxide to form 4-hydroxyphenyl-acetaldehyde 2. Dopamine 1 then reacts with 4-hydroxy-phenylacetaldehyde 2 to form (S)-norcolaurine 3 in a reaction similar to the Mannich reaction. After oxidation and methylation by SAM, (S)-reticuline 4 is formed. (S)-reticuline serves as a pivotal intermediate to other alkaloids. Oxidation of the tertiary amine then occurs and an iminium ion is formed 5. In a Mannich-like reaction the ortho position to the phenol is nucleophilic, and electrons are pushed to form 6. Product 6 then undergoes keto-enol tautomerism to form (S)-scoulerine, which is then methylated by SAM to form (S)-tetrahydrocolumbamine 7. Product 7 is then oxidized to form the methylenedioxy ring from the ortho-methoxyphenol, via an O2-, NADPH- and cytochrome P-450-dependent enzyme, giving (S)-canadine 8. (S)-canadine is then oxidized to give the quaternary isoquinolinium system of berberine. This happens in two separate oxidation steps, both requiring molecular oxygen, with H2O2 and H2O produced in the successive processes.[110]
See also
Sanguinarine, a plant-based compound with very similar chemical classification as berberine
Coptisine for a related pharmacological discussion
Goldenseal for a related pharmacological discussion
Jatrorrhizine another protoberberine alkaloid
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Jump up ^ http://link.springer.com/article/10.100 ... 012-2119-0
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Jump up ^ Dewick, P. (2009). Medicinal Natural Products: A Biosynthetic Approach (3rd ed.). West Sussex, England: Wiley. p. 358. ISBN 0-471-49641-3.
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