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Revision as of 08:04, 28 October 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,071 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'ChEMBL', 'CASNo').← Previous edit		Latest revision as of 23:53, 27 December 2024 edit undoMaxim Masiutin (talk | contribs)Extended confirmed users, IP block exemptions, Pending changes reviewers31,058 edits →Research: ceTags: Mobile edit Mobile app edit Android app edit App select source
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			{{short description|Quaternary ammonium cation}}
	{{chembox
			{{cs1 config|name-list-style=vanc}}{{chembox
	| Verifiedfields = changed		| Verifiedfields = changed
			| Watchedfields = changed
	| verifiedrevid = 399353403
			| verifiedrevid = 457785306
	| ImageFile_Ref = {{chemboximage|correct|??}}
			| ImageFile1_Ref = {{chemboximage|correct|??}}
	| ImageFile=Berberin.svg
			| ImageFile1 =Berberin.svg
	|ImageSize=200px
			| ImageSize1 =
	|IUPACName=
			| ImageFile2_Ref = {{chemboximage|correct|??}}
	|OtherNames=
			| ImageFile2 =Berberine 3D.png
	|Section1= {{Chembox Identifiers
			| ImageSize2 =
	| InChI = 1/C20H18NO4/c1-22-17-4-3-12-7-16-14-9-19-18(24-11-25-19)8-13(14)5-6-21(16)10-15(12)20(17)23-2/h3-4,7-10H,5-6,11H2,1-2H3/q+1
			| IUPACName = 9,10-Dimethoxy-7,8,13,13a-tetradehydro-2′''H''-dioxoloberbin-7-ium
			| SystematicName = 9,10-Dimethoxy-5,6-dihydro-2''H''-7λ<sup>5</sup>-dioxoloisoquinolinoisoquinolin-7-ylium<ref>{{BlueBook2013|rec=73.3.1}}</ref>
			| OtherNames =Umbellatine;<ref name="merck14"/><br />5,6-Dihydro-9,10-dimethoxybenzo-1,3-benzodioxoloquinolizinium;<ref name="merck14"/><br />7,8,13,13a-Tetradehydro-9,10-dimethoxy-2,3-(methylenedioxy)berbinium<ref name="merck14">The Merck Index, 14th ed., 1154. Berberine</ref>
			|Section1={{Chembox Identifiers
			| InChI = 1/C20H18NO4/c1-22-17-4-3-12-7-16-14-9-19-18(24-11-25-19)8-13(14)5-6-21(16)10-15(12)20(17)23-2/h3-4,7-10H,5-6,11H2,1-2H3/q+1
	| InChIKey = YBHILYKTIRIUTE-UHFFFAOYAJ		| InChIKey = YBHILYKTIRIUTE-UHFFFAOYAJ
	| StdInChI_Ref = {{stdinchicite|correct|chemspider}}		| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
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	| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}		| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChIKey = YBHILYKTIRIUTE-UHFFFAOYSA-N		| StdInChIKey = YBHILYKTIRIUTE-UHFFFAOYSA-N
	| CASNo_Ref = {{cascite|correct|??}}		| CASNo_Ref = {{cascite|changed|??}}
	| CASNo = <!-- blanked - oldvalue: 633-66-9 -->		| CASNo =2086-83-1
	| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}		| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
	| ChemSpiderID = 2263		| ChemSpiderID = 2263
	| ChEMBL_Ref = {{ebicite|changed|EBI}}		| ChEMBL_Ref = {{ebicite|changed|EBI}}
	| ChEMBL = <!-- blanked - oldvalue: 12089 -->		| ChEMBL = 12089
	| PubChem=2353		| PubChem =2353
			| EC_number = 218-229-1
	| UNII_Ref = {{fdacite|changed|FDA}}
			| KEGG = C00757
			| 3DMet =
			| Beilstein = 3570374
			| UNII_Ref = {{fdacite|correct|FDA}}
	| UNII = 0I8Y3P32UF		| UNII = 0I8Y3P32UF
	| ChEBI_Ref = {{ebicite|changed|EBI}}		| ChEBI_Ref = {{ebicite|correct|EBI}}
	| ChEBI = 16118		| ChEBI = 16118
	| DrugBank_Ref = {{drugbankcite|changed|drugbank}}		| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
	| DrugBank = DB04115		| DrugBank = DB04115
	| SMILES = O1c2c(OC1)cc5c(c2)c4cc3ccc(OC)c(OC)c3c4CC5		| SMILES = O1c2c(OC1)cc5c(c2)c4cc3ccc(OC)c(OC)c3c4CC5
	}}		}}
	|Section2= {{Chembox Properties		|Section2={{Chembox Properties
			| C=20|H=18|N=1|O=4
	| Formula=C<sub>20</sub>H<sub>18</sub>NO<sub>4</sub>+
			| Formula_Charge =+
	| MolarMass=336.36122 g/mol
	| Appearance=		| Appearance =Yellow solid
	| Density=		| Density =
			| MeltingPtC = 145
	| MeltingPt=
			| MeltingPt_ref = <ref name = Merck>'']'', 10th Ed. (1983), p.165, Rahway: Merck & Co.</ref>
	| BoilingPt=
			| BoilingPt =
	| Solubility=
			| Solubility =Slowly soluble<ref name = Merck/>
	}}
	|Section3= {{Chembox Hazards
	| MainHazards=
	| FlashPt=
	| Autoignition=
	}}		}}
			|Section3={{Chembox Hazards
			| MainHazards =
			| FlashPt =
			| AutoignitionPt =
			}}
	}}		}}
			'''Berberine''' is a ] salt from the protoberberine group of ], occurring naturally as a ] in some plants including species of '']'', from which its name is derived.
	'''Berberine''' is a ] salt from the ] group of ] ]s. It is found in such plants as '']'' (e.g. ] (Oregon grape), ](Barberry), and ] (Tree Turmeric)),''Hydrastis canadensis'' (]), ]<ref>Zhang Q. Cai L. Zhong G. Luo W. Zhongguo, "Simultaneous determination of jatrorrhizine, palmatine, berberine, and obacunone in Phellodendron amurense Cortex by RP-HPLC" ''China Journal of Chinese Materia Medica''. 35(16):2061-4, 2010 Aug.</ref> (Amur Cork Tree, Huang Bai, Huang Po, Po Mu) and '']'' (Chinese Goldthread, Huang-Lian, Huang-Lien), and ], and to a smaller extent in ] (Prickly Poppy) and ] (Californian Poppy).
	Berberine is usually found in the roots, ]s, stems, and bark.
	Berberine is strongly yellow colored, which is why in earlier times ''Berberis'' species were used to dye wool, leather and wood. Wool is still today dyed with berberine in northern India. Under ], berberine shows a strong yellow ].<ref name="unijena">{{cite web |title=Fluoreszenzfarbstoffe in der Natur |url=http://www.chemie.uni-jena.de/institute/oc/weiss/naturstoffe.htm |first=Dieter |last=Weiß |year=2008 |accessdate=17 July 2009 |language=German}}</ref> Because of this it is used in ] for ] ] in ]s.<ref name="sigma2">{{cite web |title=B3251 Berberine chloride form |url=http://www.sigmaaldrich.com/catalog/ProductDetail.do?N4=B3251 |publisher=] |year=2009 |accessdate=17 July 2009 |unused_data=SIGMA&N5=SEARCH_CONCAT_PNO|BRAND_KEY&F=SPEC}}</ref> As a natural dye, berberin has a ] (CI) of 75160.		Due to their yellow ]ation, raw ''Berberis'' materials were once commonly used to dye wool, leather, and wood.<ref>{{cite journal|vauthors=Gulrajani ML|date=2001|title=Present status of natural dyes|url=http://nopr.niscair.res.in/handle/123456789/24928|journal=Indian Journal of Fibre & Textile Research|language=en-US|volume=26|pages=191–201|via=NISCAIR Online Periodicals Repository|access-date=2017-12-28|archive-date=2021-11-20|archive-url=https://web.archive.org/web/20211120183428/http://nopr.niscair.res.in/handle/123456789/24928|url-status=live}}</ref> Under ], berberine shows a strong yellow ],<ref name="unijena">{{cite web |title=Fluoreszenzfarbstoffe in der Natur |url=http://www.chemie.uni-jena.de/institute/oc/weiss/naturstoffe.htm |vauthors=Weiß D |year=2008 |access-date=17 July 2009 |language=de |archive-date=9 March 2007 |archive-url=https://web.archive.org/web/20070309172021/http://www.chemie.uni-jena.de/institute/oc/weiss/naturstoffe.htm |url-status=live }}</ref> making it useful in ] for ] ] in ]s.<ref name="sigma2">{{cite web |title=B3251 Berberine chloride form |url=http://www.sigmaaldrich.com/catalog/product/sigma/b3251?lang=en&region=US |publisher=] |year=2013 |access-date=2 Aug 2013 |archive-date=7 September 2012 |archive-url=https://web.archive.org/web/20120907195333/http://www.sigmaaldrich.com/catalog/product/sigma/b3251?lang=en&region=US |url-status=live }}</ref> As a natural dye, berberine has a ] of 75160.
	==Traditional use==		==Research==
			Studies on the pharmacological effects of berberine, including its potential use as a medicine, are preliminary ]: some studies are conducted on cell cultures or animal models, whereas ]s investigating the use of berberine in humans are limited.<ref name="pmid32335802">{{cite journal |vauthors=Song D, Hao J, Fan D |title=Biological properties and clinical applications of berberine |journal=Front Med |volume=14 |issue=5 |pages=564–582 |date=October 2020 |pmid=32335802 |doi=10.1007/s11684-019-0724-6 |s2cid=216111561 |url=}}</ref> A 2023 review study stated that berberine may improve lipid concentrations.<ref name="pmid37183391">{{cite journal | vauthors=Hernandez AV, Hwang J, Nasreen I, Sicignano D, Pasupuleti V, Snow-Caroti K | display-authors=3 | title=Impact of Berberine or Berberine Combination Products on Lipoprotein, Triglyceride and Biological Safety Marker Concentrations in Patients with Hyperlipidemia: A Systematic Review and Meta-Analysis. | journal=J Diet Suppl | year=2023 | volume= 21| issue= 2| pages=242–259 | pmid=37183391 | doi=10.1080/19390211.2023.2212762 | pmc= | s2cid=258687419 | url=https://pubmed.ncbi.nlm.nih.gov/37183391 | access-date=2023-08-28 | archive-date=2023-06-01 | archive-url=https://web.archive.org/web/20230601233652/https://pubmed.ncbi.nlm.nih.gov/37183391/ | url-status=live }}</ref> High-quality, large clinical studies are needed to properly evaluate the effectiveness and safety of berberine in various health conditions, because existing studies are insufficient to draw reliable conclusions.<ref name="pmid32335802"/>
	As a traditional medicine or dietary supplement, berberine has shown some activity against fungal infections, '']'', yeast, parasites, and bacterial/viral infections.<ref>{{cite journal |author=Birdsall TC, Kelly GS |title=Berberine: Therapeutic potential of an alkaloid found in several medicinal plants |journal=Alternative Medicine Reviews |volume=2 |issue=2 |pages=94–103 |year=1997 |url=http://www.thorne.com/media/berberine.pdf |format=PDF}}</ref><ref name="pmid10767672">{{cite journal |title=Berberine |journal=Alternative Medicine Review |volume=5 |issue=2 |pages=175–7 |year=2000 |month=April |pmid=10767672 |url=http://www.thorne.com/altmedrev/.fulltext/5/2/175.pdf |isbn=0712306498 |author=Peter J. Gibbs and Kenneth R. Seddon. |publisher=British Library |location=London }}</ref>
	Berberine seems to exert synergistic effects with ] even in drug-resistant ''Candida albicans'' infections.<ref>{{cite journal |author=Xu Y, Wang Y, Yan L, ''et al.'' |title=Proteomic analysis reveals a synergistic mechanism of fluconazole and berberine against fluconazole-resistant Candida albicans: endogenous ROS augmentation |journal=Journal of Proteome Research |volume=8 |issue=11 |pages=5296–304 |year=2009 |month=November |pmid=19754040 |doi=10.1021/pr9005074}}</ref>
			Berberine supplements are widely available in the U.S. but have not been approved by the U.S. ] (FDA) for any specific medical use. Researchers publicly warn that studies linking berberine to supposed health benefits are limited. Furthermore, the quality of berberine supplements can vary between different brands. A study conducted in 2017 found that out of 15 different products sold in the U.S., only six contained at least 90% of specified berberine amount.<ref name="pmid28792254">{{cite journal |vauthors=Funk RS, Singh RK, Winefield RD, Kandel SE, Ruisinger JF, Moriarty PM, Backes JM |title=Variability in Potency Among Commercial Preparations of Berberine |journal=J Diet Suppl |volume=15 |issue=3 |pages=343–351 |date=May 2018 |pmid=28792254 |pmc=5807210 |doi=10.1080/19390211.2017.1347227 |url=}}</ref><ref>{{cite news |url=https://www.wsj.com/articles/berberine-natures-ozempic-weight-loss-902e097 |title=The Cheaper Weight-Loss Alternative Riding the Ozempic Wave |newspaper=Wall Street Journal |date=14 June 2023 |last1=Subbaraman |first1=Nidhi |access-date=29 December 2023 |archive-date=29 December 2023 |archive-url=https://web.archive.org/web/20231229164947/https://www.wsj.com/articles/berberine-natures-ozempic-weight-loss-902e097 |url-status=live }}</ref>
	Some research has been undertaken into possible use against ] infection.<ref>{{cite journal |author=Yu HH, Kim KJ, Cha JD, ''et al.'' |title=Antimicrobial activity of berberine alone and in combination with ampicillin or oxacillin against methicillin-resistant ''Staphylococcus aureus'' |journal=Journal of Medicinal Food |volume=8 |issue=4 |pages=454–61 |year=2005 |pmid=16379555 |doi=10.1089/jmf.2005.8.454}}</ref>
			==Biological sources==
	Berberine is considered antibiotic.,<ref>Ozbalci C., Karaosmanoglu K., Aksan Kurnaz I., Kazan D., Sariyar Akbulut B., 'Comparative transcriptome and proteome analysis for the effect of berberine' FEBS Journal 2010 277 SUPPL. 1 (184-185)</ref><ref>Li Y., Zuo G.-Y. 'Advances in studies on antimicrobial activities of alkaloids" Chinese Traditional and Herbal Drugs 2010 41:6 (1006-1014)</ref> When applied in vitro and in combination with methoxyhydnocarpin, an inhibitor of ]s, berberine inhibits growth of '']''.<ref>{{cite journal |author=Stermitz FR, Lorenz P, Tawara JN, Zenewicz LA, Lewis K |title=Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 5'-methoxyhydnocarpin, a multidrug pump inhibitor |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=97 |issue=4 |pages=1433–7 |year=2000 |month=February |pmid=10677479 |pmc=26451 |doi=10.1073/pnas.030540597}}</ref> and Microcystis aeruginosa.<ref>Zhang S., Zhang B., Xing K., Zhang X., Tian X., Dai W.," Inhibitory effects of golden thread (Coptis chinensis) and berberine on Microcystis aeruginosa Water Science and Technology 2010 61:3 (763-769)</ref> a toxic ]
			* '']'' (barberry)
			* '']'' (tree turmeric)
			* '']''
			* '']''
			* '']'' (Oregon grape)
			* '']'' (goldenseal)
			* '']'' (yellowroot)
			* '']'' (Amur cork tree)<ref name="Cicero Baggioni 2016 pp. 27–45">{{cite book | last1=Cicero | first1=Arrigo F. G. | last2=Baggioni | first2=Alessandra | title=Anti-inflammatory Nutraceuticals and Chronic Diseases | series=Advances in Experimental Medicine and Biology | chapter=Berberine and Its Role in Chronic Disease | publisher=Springer International Publishing | publication-place=Cham | year=2016 | volume=928 | isbn=978-3-319-41332-7 | issn=0065-2598 | doi=10.1007/978-3-319-41334-1_2 | pages=27–45| pmid=27671811 }}</ref>
			* '']'' (Chinese goldthread)
			* '']''
			* '']'' (prickly poppy)
			* '']'' (California poppy)
			Berberine is usually found in the roots, ]s, stems, and bark.<ref name="pubchem">{{cite web|url=https://pubchem.ncbi.nlm.nih.gov/compound/2353|title=Berberine|publisher=PubChem, National Library of Medicine, US National Institutes of Health|date=March 9, 2020|access-date=March 10, 2020|archive-date=March 5, 2016|archive-url=https://web.archive.org/web/20160305223654/https://pubchem.ncbi.nlm.nih.gov/compound/2353|url-status=live}}</ref>
	Berberine is a component of some ] formulations.{{Citation needed|reason=needs to be a more reliable source that actually lists some information. was:<ref>{{cite web |title=Drugs (Listed by Trade Name) &gt; Murine Eye Drops |url=http://www.virtualmedicalcentre.com/drugs.asp?drugid=1241&title=Murine-Eye-Drops |publisher=Bigpond.com |accessdate=2009-01-01}}</ref>|date=August 2010}} There is some evidence it is useful in the treatment of ],<ref>{{cite journal |author=Babbar OP, Chhatwal VK, Ray IB, Mehra MK |title=Effect of berberine chloride eye drops on clinically positive trachoma patients |journal=The Indian Journal of Medical Research |volume=76 |issue=Suppl |pages=83–8 |year=1982 |month=December |pmid=7185757}}</ref> and it has been a standard treatment for ].<ref>{{cite journal |title=Cutaneous leishmaniasis in Jodhpur district |journal=Indian Journal of Dermatology, Venereology and Leprology |volume=62 |issue=3 |pages=149–51
	|year=1996 |url=http://www.doaj.org/doaj?func=abstract&id=229883 |author1=Kalla, G. |author2=Singhi, M.K. |author3=Kalla, Gyaneshwar}}</ref>
	Berberine prevents and suppresses proinflammatory cytokines, ],<ref>{{cite journal |author=Hu Y, Chen X, Duan H, Hu Y, Mu X |title=Chinese herbal medicinal ingredients inhibit secretion of IL-6, IL-8, E-selectin and TXB(2) in LPS-induced rat intestinal microvascular endothelial cells |journal=Immunopharmacology and Immunotoxicology |year=2009 |month=April |pmid=19555212 |doi=10.3109/08923970902814129 |volume=31 |issue=4 |pages=550–555}}</ref> and genes, and increases ] expression<ref>{{cite journal |author=Choi BH, Kim YH, Ahn IS, Ha JH, Byun JM, Do MS |title=The inhibition of inflammatory molecule expression on 3T3-L1 adipocytes by berberine is not mediated by leptin signaling |journal=Nutrition Research and Practice |volume=3 |issue=2 |pages=84–8 |year=2009 |pmid=20016706 |pmc=2788178 |doi=10.4162/nrp.2009.3.2.84}}</ref> which partly explains its versatile health effects. Berberine is a nucleic acid-binding isoquinolone alkaloid with wide potential therapeutic properties.<ref name=Bhadra2010>{{cite journal |author=Bhadra K, Kumar GS |title=Therapeutic potential of nucleic acid-binding isoquinoline alkaloids: Binding aspects and implications for drug design |journal=Medicinal Research Reviews |year=2010 |month=January |pmid=20077560 |doi=10.1002/med.20202 |pages=n/a}}</ref>
	==Newer and experimental uses==
	===Diabetes, dyslipidemias and cardiovascular conditions===
	During the last few decades, many studies have shown berberine has various beneficial effects on the cardiovascular system and significant anti-inflammatory activities.<ref>{{cite journal |author=Kuo CL, Chi CW, Liu TY |title=The anti-inflammatory potential of berberine in vitro and in vivo |journal=Cancer Lett |volume=203 |pages=127–137 |month=January |year=2004 |url=http://www.cancerletters.info/article/S0304-3835%2803%2900594-9/abstract |doi=10.1016/j.canlet.2003.09.002 |pmid=14732220 |issue=2}}</ref> 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.<ref>{{cite journal |author=Sarna LK, Wu N, Hwang SY, Siow YL |title=Berberine inhibits NADPH oxidase mediated superoxide anion production in macrophages |journal=Can J Physiol Pharmacol. |volume=88 |issue=3 |pages=369–78 |year=2010 |doi=10.1139/Y09-136 |url=http://rparticle.web-p.cisti.nrc.ca/rparticle/AbstractTemplateServlet?calyLang=eng&journal=cjpp&volume=88&year=2010&issue=3&msno=y09-136 |pmid=20393601}}</ref>
	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 ].<ref>{{cite journal |author=Yin J, Zhang H, Ye J |title=Traditional chinese medicine in treatment of metabolic syndrome |journal=Endocrine, Metabolic & Immune Disorders Drug Targets |volume=8 |issue=2 |pages=99–111 |year=2008 |month=June |pmid=18537696 |pmc=2467395 |url=http://www.bentham-direct.org/pages/content.php?EMIDDT/2008/00000008/00000002/0005V.SGM |doi=10.2174/187153008784534330}}</ref><ref>{{cite journal |doi=10.1016/j.bmcl.2009.09.059 |title=Synthesis and biological evaluation of berberine analogues as novel up-regulators for both low-density-lipoprotein receptor and insulin receptor |pmid=19800225 |month=November |year=2009 |first1=Yan-Xiang |last1=Wang |first2=Yu-Ping |last2=Wang |first3=Hao |last3=Zhang |first4=Wei-Jia |last4=Kong |first5=Ying-Hong |last5=Li |first6=Fei |last6=Liu |first7=Rong-Mei |last7=Gao |first8=Ting |last8=Liu |first9=Jian-Dong |last9=Jiang |journal=Bioorganic & Medicinal Chemistry Letters |volume=19 |issue=21 |pages=6004–8}}</ref>
	====Diabetes mellitus====
	Berberine has been tested and used successfully in experimental<ref>{{cite journal |author=Wang Y, Campbell T, Perry B, Beaurepaire C, Qin L |title=Hypoglycemic and insulin-sensitizing effects of berberine in high-fat diet- and streptozotocin-induced diabetic rats |journal=Metabolism: Clinical and Experimental |year=2010 |month=March |pmid=20304443 |doi=10.1016/j.metabol.2010.02.005 |volume=60 |issue=2 |pages=298–305}}</ref><ref>{{cite journal |author=Wang C, Li J, Lv X, ''et al.'' |month=August |year=2009 |title=Ameliorative effect of berberine on endothelial dysfunction in diabetic rats induced by high fat diet and streptozotocin |pmid=19686728 |doi=10.1016/j.ejphar.2009.07.027 |journal=European journal of pharmacology |volume=620 |issue=1–3 |pages=131–7}}</ref>
	and human ] mellitus.<ref name=GuY10>{{cite journal |author=Gu Y, Zhang Y, Shi X, ''et al.'' |title=Effect of traditional Chinese medicine berberine on type 2 diabetes based on comprehensive metabonomics |journal=Talanta |volume=81 |issue=3 |pages=766–72 |year=2010 |month=May |pmid=20298851 |doi=10.1016/j.talanta.2010.01.015}}</ref><ref name=pmid19800084>{{cite journal |author=Zhang H, Wei J, Xue R, ''et al.'' |title=Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression |journal=Metabolism: Clinical and Experimental |volume= 59|issue= 2|pages= 285–92|year=2009 |month=September |pmid=19800084 |doi=10.1016/j.metabol.2009.07.029}}</ref><ref name=pmid19401197>{{cite journal |author=Wang JM, Yang Z, Xu MG, ''et al.'' |title=Berberine-induced decline in circulating CD31+/CD42- microparticles is associated with improvement of endothelial function in humans |journal=European Journal of Pharmacology |volume=614 |issue=1–3 |pages=77–83 |year=2009 |month=July |pmid=19401197 |doi=10.1016/j.ejphar.2009.04.037 }}</ref><ref>{{cite journal |author=Zhang Y, Li X, Zou D, ''et al.'' |title=Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine |journal=The Journal of Clinical Endocrinology and Metabolism |volume=93 |issue=7 |pages=2559–65 |year=2008 |month=July |pmid=18397984 |doi=10.1210/jc.2007-2404 |last12=Ning |first12=G}}</ref>
	Berberine has been shown to lower elevated blood glucose as effectively as ].<ref>{{cite journal |author=Yin J, Xing H, Ye J |title=Efficacy of berberine in patients with type 2 diabetes mellitus |journal=Metabolism: Clinical and Experimental |volume=57 |issue=5 |pages=712–7 |year=2008 |month=May |pmid=18442638 |pmc=2410097 |doi=10.1016/j.metabol.2008.01.013 }}</ref> The mechanisms of action include inhibition of ],<ref>{{cite journal |author=Wu LY, Ma ZM, Fan XL, ''et al.'' |title=The anti-necrosis role of hypoxic preconditioning after acute anoxia is mediated by aldose reductase and sorbitol pathway in PC12 cells |journal=Cell Stress & Chaperones |year=2009 |month=November |pmid=19902381 |doi=10.1007/s12192-009-0153-6 |volume=15 |issue=4 |pages=387–94 |pmc=3082650}}</ref> inducing glycolysis,<ref>{{cite journal |author=Yin J, Gao Z, Liu D, Liu Z, Ye J |title=Berberine improves glucose metabolism through induction of glycolysis |journal=American Journal of Physiology. Endocrinology and Metabolism |volume=294 |issue=1 |pages=E148–56 |year=2008 |month=January |pmid=17971514 |pmc=2464622 |doi=10.1152/ajpendo.00211.2007}}</ref> preventing ]<ref>{{cite journal |author=Kong WJ, Zhang H, Song DQ, ''et al.'' |title=Berberine reduces insulin resistance through protein kinase C-dependent up-regulation of insulin receptor expression |journal=Metabolism |volume=58 |issue=1 |pages=109–19 |year=2009 |month=January |pmid=19059538 |doi=10.1016/j.metabol.2008.08.013 |last12=Li |first12=ZR |last13=Si |first13=SY |last14=Zhao |first14=LX |last15=Pan |first15=HN |last16=Jiang |first16=JD }}</ref><ref>Lou T, Zhang Z, Xi Z, ''et al.'' "Berberine Inhibits Inflammatory Response and Ameliorates Insulin Resistance in Hepatocytes." Inflammation. 2010 Nov 26.</ref> through increasing insulin receptor expression<ref name=pmid19800084/> and acting like ]s.<ref>{{cite journal |author=Lu SS, Yu YL, Zhu HJ, ''et al.'' |title=Berberine promotes glucagon-like peptide-1 (7-36) amide secretion in streptozotocin-induced diabetic rats |journal=The Journal of Endocrinology |volume=200 |issue=2 |pages=159–65 |year=2009 |month=February |pmid=18996945 |doi=10.1677/JOE-08-0419 }}</ref>
	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.<ref>{{cite journal |author=Liu LZ, Cheung SC, Lan LL, ''et al.'' |title=Berberine Modulates Insulin Signaling Transduction in Insulin-resistant Cells |journal=Molecular and Cellular Endocrinology |volume= 317|issue= 1–2|pages= 148–53|year=2009 |month=December |pmid=20036710 |doi=10.1016/j.mce.2009.12.027}}</ref>
	Berberine might exert its insulinotropic effect in isolated rat islets by up-regulating the expression of ], 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.<ref>{{cite journal |pmid=18932278 |year=2008 |month= October|last1=Wang |first1=ZQ |last2=Lu |last3=Leng |last4=Fang |last5=Chen |last6=Wang |last7=Dong |last8=Yan |title=Facilitating effects of berberine on rat pancreatic islets through modulating hepatic nuclear factor 4 α expression and glucokinase activity |volume=14 |issue=39 |pages=6004–11 |journal=World journal of gastroenterology |url=http://www.wjgnet.com/1007-9327/14/6004.asp |doi=10.3748/wjg.14.6004 |author2=Lu |author3=Leng |author4=Fang |author5=Chen |author6=Wang |author7=Dong |author8=Yan |pmc=2760199}}</ref>
	Berberine seems to inhibit human ] (DPP IV), as well as the pro-diabetic target human ] 1B (h-PTP 1B), which explain at least some of its anti-hyperglycemic activities.<ref>{{cite journal |author=Al-Masri IM, Mohammad MK, Tahaa MO |title=Inhibition of dipeptidyl peptidase IV (DPP IV) is one of the mechanisms explaining the hypoglycemic effect of berberine |journal=] |volume= 0|issue= 5|pages= 090729101626017|year=2009 |month=July |pmid=19640223 |doi=10.1080/14756360802610761 }}</ref> Berberine suppresses intestinal disaccharidases with beneficial metabolic effects in diabetic states.<ref>{{cite journal |author=Liu L, Yu YL, Yang JS, ''et al.'' |title=Berberine suppresses intestinal disaccharidases with beneficial metabolic effects in diabetic states, evidences from in vivo and in vitro study |journal=Naunyn-Schmiedeberg's Archives of Pharmacology |year=2010 |month=March |pmid=20229011 |doi=10.1007/s00210-010-0502-0 |volume=381 |issue=4 |pages=371–81}}</ref>
	A recent comprehensive ] method, applied to 60 type 2 diabetics, suggested administration of berberine down-regulates the high level of ] which are known to be toxic to the pancreas and cause ]. These results suggest berberine might play a pivotal role in the treatment of type 2 diabetes, concluded the authors.<ref name=GuY10/>
	Berberine has been shown to boost the effects of ] and 2,4-] (THZ), and can partly replace the commercial drugs, which could lead to a reduction in toxicity and side effects of the latter.<ref>{{cite journal |author=Prabhakar PK, Doble M |month=August |year=2009 |title=Synergistic effect of phytochemicals in combination with hypoglycemic drugs on glucose uptake in myotubes |journal=Phytomedicine |doi=10.1016/j.phymed.2009.05.021 |pmid=19660925 |last1=Prabhakar |first1=PK |last2=Doble |first2=M |volume= 16|issue= 12|pages= 1119–26}}</ref>
	Berberine inhibits Foxo1,<ref name=pmid19721228>{{cite journal |author=Sun X, Zhang X, Hu H, ''et al.'' |title=Berberine inhibits hepatic stellate cell proliferation and prevents experimental liver fibrosis |journal=Biological & Pharmaceutical Bulletin |volume=32 |issue=9 |pages=1533–7 |year=2009 |month=September |pmid=19721228 |doi=10.1248/bpb.32.1533}}</ref> which integrates insulin signaling with mitochondrial function. Inhibition of Foxo1 can improve hepatic metabolism during insulin resistance and the metabolic syndrome.<ref>{{cite journal |author=Cheng Z, Guo S, Copps K, ''et al.'' |title=Foxo1 integrates insulin signaling with mitochondrial function in the liver |journal=Nature Medicine |volume=15 |issue=11 |pages=1307–11 |year=2009 |month=November |pmid=19838201 |doi=10.1038/nm.2049}}</ref>
	====Lipids====
	Berberine lowers elevated blood total ], LDL cholesterol, ]s and aterogenic ]s (apo B) (Apo B),<ref>{{cite journal |author=Zhou JY, Zhou SW, Zhang KB, ''et al.'' |title=Chronic effects of berberine on blood, liver glucolipid metabolism and liver PPARs expression in diabetic hyperlipidemic rats |journal=Biological & Pharmaceutical Bulletin |volume=31 |issue=6 |pages=1169–76 |year=2008 |month=June |pmid=18520050 |doi=10.1248/bpb.31.1169}}</ref> but the mechanism of action is distinct from ]s.<ref>{{cite journal |author=Holy EW, Akhmedov A, Lüscher TF, Tanner FC |title=Berberine, a natural lipid-lowering drug, exerts prothrombotic effects on vascular cells |journal=Journal of Molecular and Cellular Cardiology |volume=46 |issue=2 |pages=234–40 |year=2009 |month=February |pmid=19014947 |doi=10.1016/j.yjmcc.2008.10.011 }}</ref><ref>{{cite journal |author=Kong W, Wei J, Abidi P, ''et al.'' |title=Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins |journal=Nature Medicine |volume=10 |issue=12 |pages=1344–51 |year=2004 |month=December |pmid=15531889 |doi=10.1038/nm1135 |last12=Wu |first12=J |last13=Wang |first13=Y |last14=Li |first14=Z |last15=Liu |first15=J |last16=Jiang |first16=JD }}</ref><ref>{{cite journal |author=Kim WS, Lee YS, Cha SH, ''et al.'' |title=Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity |journal=American Journal of Physiology– Endocrinology and Metabolism |volume=296 |issue=4 |pages=E812–9 |year=2009 |month=April |pmid=19176354 |doi=10.1152/ajpendo.90710.2008 }}</ref>
	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 ] (LDLR),<ref>{{cite journal |author=Li H, Dong B, Park SW, ''et al.'' |month=August |year=2009 |title=HNF1α plays a critical role in PCSK9 gene transcription and regulation by a natural hypocholesterolemic compound berberine |pmid=19687008 |doi=10.1074/jbc.M109.052407 |volume=284 |issue=42 |pages=28885–95 |journal=The Journal of biological chemistry |pmc=2781434}}</ref>
	and increasing in the liver the expression of LDL receptors through extracellular signal-regulated kinase (ERK) signaling pathway,<ref>{{cite journal |author=Abidi P, Zhou Y, Jiang JD, Liu J |title=Extracellular signal-regulated kinase-dependent stabilization of hepatic low-density lipoprotein receptor mRNA by herbal medicine berberine |journal=Arteriosclerosis, Thrombosis, and Vascular Biology |volume=25 |issue=10 |pages=2170–6 |year=2005 |month=October |pmid=16100034 |doi=10.1161/01.ATV.0000181761.16341.2b}}</ref>
	while statins inhibit cholesterol synthesis in the liver by blocking HMG-CoA-reduktase. This explains why berberine does not cause side effects typical to statins. Berberine and ]s synergistically inhibit cholesterol absorption in hamsters.<ref>{{cite journal |doi=10.1016/j.atherosclerosis.2009.08.050 |title=Berberine and plant stanols synergistically inhibit cholesterol absorption in hamsters |year=2009 |first1=Yanwen |last1=Wang |first2=Xiaoming |last2=Jia |first3=Khadija |last3=Ghanam |first4=CéCile |last4=Beaurepaire |first5=Jeffrey |last5=Zidichouski |first6=Lisa |last6=Miller |journal=Atherosclerosis |volume=209 |pages=111–7 |pmid=19782362 |issue=1}}</ref>
	Berberin seems to improve the arterial endothelial function in humans.<ref name=pmid19401197/><ref name="Wang Y, Huang Y, Lam KS, et al. 2009 484–92">{{cite journal |author=Wang Y, Huang Y, Lam KS, ''et al.'' |title=Berberine prevents hyperglycemia-induced endothelial injury and enhances vasodilatation via adenosine monophosphate-activated protein kinase and endothelial nitric oxide synthase |journal=Cardiovascular Research |volume=82 |issue=3 |pages=484–92 |year=2009 |month=June |pmid=19251722 |doi=10.1093/cvr/cvp078 }}</ref> Berberine activates ] (AMPK),<ref>{{cite journal |author=Turner N, Li JY, Gosby A, ''et al.'' |title=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 |journal=Diabetes |volume=57 |issue=5 |pages=1414–8 |year=2008 |month=May |pmid=18285556 |doi=10.2337/db07-1552}}</ref>
	specifically ] (ERK),<ref>{{cite journal |author=Cui G, Qin X, Zhang Y, Gong Z, Ge B, Zang YQ |title=Berberine differentially modulates the activities of Erk, p38 MAPK and JNK to suppress Th17 and Th1 T cell differentiation in type 1 diabetic mice |journal=The Journal of Biological Chemistry |volume= 284|issue= 41|pages= 28420–9|year=2009 |month=August |pmid=19661066 |doi=10.1074/jbc.M109.012674 |pmc=2788891}}</ref>
	which plays a central role in glucose and lipid metabolism,<ref>{{cite journal |author=Lamontagne J, Pepin E, Peyot ML, ''et al.'' |title=Pioglitazone acutely reduces insulin secretion and causes metabolic deceleration of the pancreatic β-cell at submaximal glucose concentrations |journal=Endocrinology |year=2009 |month=April |pmid=19406947 |doi=10.1210/en.2008-1557 |volume=150 |issue=8 |pages=3465–74 |pmc=2717855}}</ref><ref>{{cite journal |author=Lee YS, Kim WS, Kim KH, ''et al.'' |title=Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states |journal=Diabetes |volume=55 |issue=8 |pages=2256–64 |year=2006 |month=August |pmid=16873688 |doi=10.2337/db06-0006}}</ref>
	suppresses proinflammatory cystokines,<ref>{{cite journal |author=Jeong HW, Hsu KC, Lee JW, ''et al.'' |title=Berberine suppresses proinflammatory responses through AMPK activation in macrophages |journal=American Journal of Physiology– Endocrinology and Metabolism |volume=296 |issue=4 |pages=E955–64 |year=2009 |month=April |pmid=19208854 |doi=10.1152/ajpendo.90599.2008 }}</ref> and reduces MMP-9 and EMMPRIN expression,<ref>{{cite journal |author=Huang Z, Wang L, Meng S, Wang Y, Chen T, Wang C |title=Berberine reduces both MMP-9 and EMMPRIN expression through prevention of p38 pathway activation in PMA-induced macrophages |journal=International Journal of Cardiology |year=2009 |month=July |pmid=19576641 |doi=10.1016/j.ijcard.2009.06.023 |volume=146 |issue=2 |pages=153–158 }}</ref>
	which are all beneficial changes for heart health.
	====Liver====
	Morevover, berberine reduces hepatic fat content in the rats of non-alcoholic fatty liver disease (NAFLD).<ref>{{cite web |author=Chang XX, Gao X, Liu M, ''et al.'' |title=BBR reduces hepatic fat content in the rats of NAFLD by decreasing the methylation of MTP promoter |url=http://www.abstractsonline.com/viewer/viewAbstractPrintFriendly.asp?CKey={28AA66ED-CC72-498F-973D-928A0C143093}&SKey={7229ACEF-CE60-4AD0-93F4-CD86A4A2AF74}&MKey={B3E385FB-2CC7-4F7C-8766-2F743C19F069}&AKey={3B7B2FB4-D207-4884-AE88-132BE0AFCDBB} |accessdate=17 July 2009}}{{Self-published inline|date=November 2009}}</ref>
	Berberine also prevents proliferation of hepatic stellate cells (HSCs), which are central for the development of fibrosis during liver injury.<ref name=pmid19721228/>
	====Congestive heart failure====
	Experimental<ref>{{cite journal |author=Qi MY, Feng Y, Dai DZ, Li N, Cheng YS, Dai Y |title=CPU86017, a berberine derivative, attenuates cardiac failure through normalizing calcium leakage and downregulated phospholamban and exerting antioxidant activity |journal=Acta Pharmacol Sin |volume=31 |issue=2 |pages=165–74 |month=February |year=2010 |url=http://www.nature.com/aps/journal/v31/n2/abs/aps2009180a.html |doi=10.1038/aps.2009.180 |pmid=20139899}}</ref><ref>{{cite journal |author=Huang WM, Yan H, Jin JM, Yu C, Zhang H |title=Beneficial effects of berberine on hemodynamics during acute ischemic left ventricular failure in dogs |journal=Chinese Medical Journal |volume=105 |issue=12 |pages=1014–9 |year=1992 |month=December |pmid=1299549}}</ref><ref>{{cite journal |author=Riccioppo Neto F |title=Electropharmacological effects of berberine on canine cardiac Purkinje fibres and ventricular muscle and atrial muscle of the rabbit |journal=British Journal of Pharmacology |volume=108 |issue=2 |pages=534–7 |year=1993 |month=February |pmid=8448600 |pmc=1908004}}</ref> and clinical studies<ref>{{cite journal |author=Marin-Neto JA, Maciel BC, Secches AL, Gallo Júnior L |title=Cardiovascular effects of berberine in patients with severe congestive heart failure |journal=Clinical Cardiology |volume=11 |issue=4 |pages=253–60 |year=1988 |month=April |pmid=3365876 |doi=10.1002/clc.4960110411}}</ref><ref>{{cite journal |author=Zeng XH, Zeng XJ, Li YY |title=Efficacy and safety of berberine for congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy |journal=The American Journal of Cardiology |volume=92 |issue=2 |pages=173–6 |year=2003 |month=July |pmid=12860219 |doi=10.1016/S0002-9149(03)00533-2}}</ref> suggest berberine may be useful for patients with severe congestive ].
	Anti-atherosclerosis properties.<ref>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)</ref>
	====Transplants====
	According to a Chinese report, combined use of berberine with ] 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.<ref>{{cite journal |author=Huang XS, Yang GF, Pan YC |title= |language=Chinese |journal=Zhongguo Zhong Xi Yi Jie He Za Zhi Zhongguo Zhongxiyi Jiehe Zazhi |volume=28 |issue=8 |pages=702–4 |year=2008 |month=August |pmid=18928093}}</ref>
	===Cancer===
	Berberine has drawn extensive attention towards its antineoplastic effects.<ref>{{cite journal |author=Sun Y, Xun K, Wang Y, Chen X |date=20 August 2009 |title=A systematic review of the anticancer properties of berberine, a natural product from Chinese herbs |journal=Anticancer Drugs |pmid=19704371 |month=Oct |volume=20 |issue=9 |pages=757–69 |doi=10.1097/CAD.0b013e328330d95b}}</ref><ref>{{cite journal |author=Tang J, Feng Y, Tsao S, ''et al.'' |month=August |year=2009 |title=Berberine and Coptidis Rhizoma as novel antineoplastic agents: a review of traditional use and biomedical investigations |pmid=19686830 |doi=10.1016/j.jep.2009.08.009 |journal=Journal of ethnopharmacology |volume=126 |issue=1 |pages=5–17}}</ref> It seems to suppress the growth of a wide variety of tumor cells, including breast cancer,<ref>{{cite journal |author=Kim JB, Yu JH, Ko E, ''et al.'' |title=The alkaloid Berberine inhibits the growth of Anoikis-resistant MCF-7 and MDA-MB-231 breast cancer cell lines by inducing cell cycle arrest |journal=Phytomedicine |volume= 17 |pages= 436–40|year=2009 |month=October |pmid=19800775 |doi=10.1016/j.phymed.2009.08.012 |issue=6}}</ref> leukemia, melanoma,<ref>{{cite journal |author=Serafim TL, Oliveira PJ, Sardao VA, Perkins E, Parke D, Holy J |title=Different concentrations of berberine result in distinct cellular localization patterns and cell cycle effects in a melanoma cell line |journal=Cancer Chemotherapy and Pharmacology |volume=61 |issue=6 |pages=1007–18 |year=2008 |month=May |pmid=17661039 |doi=10.1007/s00280-007-0558-9}}</ref> epidermoid carcinoma, hepatoma, pancreatic cancer,<ref>{{cite journal |author=Pinto-Garcia L, Efferth T, Torres A, Hoheisel JD, Youns M |title=Berberine Inhibits Cell Growth and Mediates Caspase-Independent Cell Death in Human Pancreatic Cancer Cells |journal=Planta Medica |month=May |volume=76 |issue=11 |pages=1155–61 |year=2010 |pmid=20455200 |doi=10.1055/s-0030-1249931 }}</ref>
	oral carcinoma, tongue carcinoma,<ref>{{cite journal |author=Ho YT, Lu CC, Yang JS, ''et al.'' |title=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 |journal=Anticancer Research |volume=29 |issue=10 |pages=4063–70 |year=2009 |month=October |pmid=19846952 |url=http://ar.iiarjournals.org/cgi/pmidlookup?view=long&pmid=19846952}}</ref> glioblastoma, prostate carcinoma and gastric carcinoma.<ref>{{cite journal |author=Auyeung KK, Ko JK |title=Coptis chinensis inhibits hepatocellular carcinoma cell growth through nonsteroidal anti-inflammatory drug-activated gene activation |month=October |year=2009 |volume=24 |issue=4 |pages=571–7 |pmid=19724899 |journal=International journal of molecular medicine}}</ref><ref>{{cite journal |author=Tang F, Wang D, Duan C, ''et al.'' |title=Berberine inhibits metastasis of nasopharyngeal carcinoma 5-8F cells by targeting Rho kinase-mediated Ezrin phosphorylation at threonine 567 |journal=The Journal of Biological Chemistry |volume=284 |issue=40 |pages=27456–66 |year=2009 |month=October |pmid=19651779 |doi=10.1074/jbc.M109.033795 |pmc=2785675}}</ref> Animal studies have shown that berberine can suppress chemical-induced carcinogenesis, clastogenesis ,<ref>{{cite journal |doi=10.1111/j.1742-7843.2010.00579.x |author=Sindhu G, Manoharan S |pmid=20406204 |title=Anti-Clastogenic Effect of Berberine against DMBA-Induced Clastogenesis |journal=Basic Clin Pharmacol Toxicol. |month=April |volume=107 |issue=4 |pages=818–24 |year=2010 |url=http://www3.interscience.wiley.com/journal/123352730/abstract?CRETRY=1&SRETRY=0}}</ref>
	tumor promotion, tumor invasion,<ref>{{cite journal |author=Pandey MK, Sung B, Kunnumakkara AB, Sethi G, Chaturvedi MM, Aggarwal BB |title=Berberine modifies cysteine 179 of IκBα kinase, suppresses nuclear factor-κB-regulated antiapoptotic gene products, and potentiates apoptosis |journal=Cancer Research |volume=68 |issue=13 |pages=5370–9 |year=2008 |month=July |pmid=18593939 |doi=10.1158/0008-5472.CAN-08-0511}}</ref><ref>{{cite journal |author=Kim JB, Ko E, Han W, Shin I, Park SY, Noh DY |title=Berberine diminishes the side population and ABCG2 transporter expression in MCF-7 breast cancer cells |journal=Planta Medica |volume=74 |issue=14 |pages=1693–700 |year=2008 |month=November |pmid=18951337 |doi=10.1055/s-0028-1088313 }}</ref><ref>{{cite journal |author=Kim S, Choi JH, Kim JB, ''et al.'' |title=Berberine suppresses TNF-α-induced MMP-9 and cell invasion through inhibition of AP-1 activity in MDA-MB-231 human breast cancer cells |journal=Molecules |volume=13 |issue=12 |pages=2975–85 |year=2008 |pmid=19052522 |doi=10.3390/molecules13122975}}</ref><ref>{{cite journal |author=Liu J, He C, Zhou K, Wang J, Kang JX |title=Coptis extracts enhance the anticancer effect of estrogen receptor antagonists on human breast cancer cells |journal=Biochemical and Biophysical Research Communications |volume=378 |issue=2 |pages=174–8 |year=2009 |month=January |pmid=19000652 |doi=10.1016/j.bbrc.2008.10.169 }}</ref><ref>{{cite journal |author=Thirupurasundari CJ, Padmini R, Devaraj SN |title=Effect of berberine on the antioxidant status, ultrastructural modifications and protein bound carbohydrates in azoxymethane-induced colon cancer in rats |journal=Chemico-biological Interactions |volume=177 |issue=3 |pages=190–5 |year=2009 |month=February |pmid=18951886 |doi=10.1016/j.cbi.2008.09.027 }}</ref> ],<ref name="pmid16505103">{{cite journal |author=Mantena SK, Sharma SD, Katiyar SK |title=Berberine, a natural product, induces G1-phase cell cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells |journal=Molecular Cancer Therapeutics |volume=5 |issue=2 |pages=296–308 |year=2006 |month=February |pmid=16505103 |doi=10.1158/1535-7163.MCT-05-0448}}</ref><ref>{{cite journal |author=Muralimanoharan SB, Kunnumakkara AB, Shylesh B, ''et al.'' |title=Butanol fraction containing berberine or related compound from nexrutine inhibits NFκB signaling and induces apoptosis in prostate cancer cells |journal=The Prostate |volume=69 |issue=5 |pages=494–504 |year=2009 |month=April |pmid=19107816 |pmc=2674392 |doi=10.1002/pros.20899 }}</ref><ref>{{cite journal |author=Choi MS, Oh JH, Kim SM, ''et al.'' |title=Berberine inhibits p53-dependent cell growth through induction of apoptosis of prostate cancer cells |journal=International Journal of Oncology |volume=34 |issue=5 |pages=1221–30 |year=2009 |month=May |pmid=19360335 |url=http://www.spandidos-publications.com/ijo/article.jsp?article_id=ijo_34_5_1221 }}</ref><ref>{{cite journal |author=Wang GY, Lv QH, Dong Q, Xu RZ, Dong QH |title=Berbamine induces Fas-mediated apoptosis in human hepatocellular carcinoma HepG2 cells and inhibits its tumor growth in nude mice |journal=Journal of Asian Natural Products Research |volume=11 |issue=3 |pages=219–28 |year=2009 |pmid=19408145 |doi=10.1080/10286020802675076 }}</ref>
	neuroblastoma,<ref>{{cite journal |author=Choi MS, Yuk DY, Oh JH, ''et al.'' |title=Berberine inhibits human neuroblastoma cell growth through induction of p53-dependent apoptosis |journal=Anticancer Research |volume=28 |issue=6A |pages=3777–84 |year=2008 |pmid=19189664 |url=http://ar.iiarjournals.org/cgi/pmidlookup?view=long&pmid=19189664 |month= November}}</ref><ref>{{cite journal |author=Lin CC, Ng LT, Hsu FF, Shieh DE, Chiang LC |title=Cytotoxic effects of Coptis chinensis and Epimedium sagittatum extracts and their major constituents (berberine, coptisine and icariin) on hepatoma and leukaemia cell growth |journal=Clin. Exp. Pharmacol. Physiol. |volume=31 |issue=1–2 |pages=65–9 |year=2004 |pmid=14756686 |doi=10.1111/j.1440-1681.2004.03951.x |month= January}}</ref>
	and ].<ref name="Wang Y, Huang Y, Lam KS, et al. 2009 484–92"/><ref name="pmid16619512">{{cite journal |author=Lin CC, Lin SY, Chung JG, Lin JP, Chen GW, Kao ST |title=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 |journal=Anticancer Research |volume=26 |issue=2A |pages=1097–104 |year=2006 |pmid=16619512 |url=http://ar.iiarjournals.org/cgi/pmidlookup?view=long&pmid=16619512 |month= March}}</ref>
	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,<ref>{{cite journal |author=Khan M, Giessrigl B, Vonach C, ''et al.'' |title=Berberine and a Berberis lycium extract inactivate Cdc25A and induce α-tubulin acetylation that correlate with HL-60 cell cycle inhibition and apoptosis |journal=Mutation Research |volume=683 |issue=1–2 |pages=123–30 |year=2010 |month=January |pmid=19909759 |doi=10.1016/j.mrfmmm.2009.11.001}}</ref>
	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.<ref>{{cite journal |author=Lin S, Tsai SC, Lee CC, Wang BW, Liou JY, Shyu KG |title=Berberine inhibits HIF-1α expression via enhanced proteolysis |journal=Molecular Pharmacology |volume=66 |issue=3 |pages=612–9 |date=1 September 2004|pmid=15322253 |url=http://molpharm.aspetjournals.org/cgi/content/full/66/3/612 }}</ref>
	Berberine suppressed ] 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.<ref>{{cite journal |author=Liu Y, Yu H, Zhang C, ''et al.'' |title=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 |journal=European Journal of Cancer |volume=44 |issue=16 |pages=2425–32 |year=2008 |month=November |pmid=18789680 |doi=10.1016/j.ejca.2008.07.040 }}</ref>
	Berberine, 300&nbsp;mg three times a day orally, also seems to inhibit complication of abdominal or pelvic radiation, called radiation-induced acute intestinal symptoms (RIAISs).<ref>{{cite journal |author=Li GH, Wang DL, Hu YD, ''et al.'' |title=Berberine inhibits acute radiation intestinal syndrome in human with abdomen radiotherapy |journal=Medical Oncology (Northwood, London, England) |volume=27 |issue=3 |pages=919–25 |year=2009 |month=September |pmid=19757213 |doi=10.1007/s12032-009-9307-8}}</ref>
	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.<ref>{{cite journal |doi=10.1586/ern.09.40 |year=2009 |month= July|title=sigma-1 receptors in major depression and anxiety |volume=9 |issue=7 |pages=1021–34 |pmid=19589051 |journal=Expert review of neurotherapeutics |author1=Kulkarni, Sk |author2=Dhir, A}}</ref><ref>{{cite journal |author=Kulkarni SK, Dhir A |title=Current investigational drugs for major depression |journal=Expert Opinion on Investigational Drugs |volume=18 |issue=6 |pages=767–88 |year=2009 |month=June |pmid=19426122 |doi=10.1517/13543780902880850 }}</ref><ref>{{cite journal |author=Kulkarni SK, Dhir A |title=On the mechanism of antidepressant-like action of berberine chloride |journal=European Journal of Pharmacology |volume=589 |issue=1–3 |pages=163–72 |year=2008 |month=July |pmid=18585703 |doi=10.1016/j.ejphar.2008.05.043 }}</ref><ref>{{cite journal |author=Kulkarni SK, Dhir A |title=Berberine: a plant alkaloid with therapeutic potential for central nervous system disorders |journal=Phytotherapy Research |volume= 24|issue= 3 |year=2009 |month=December |pmid=19998323 |doi=10.1002/ptr.2968 |pages=317–24}}</ref> Berberine inhibits ] (POP) in a dose-dependent manner. Berberine is also known to bind to ]s 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 ] (AD), mainly through both cholinesterase (ChEs)inhibitory and β-amyloids pathways,<ref>{{cite journal |author=Xiang J, Yu C, Yang F |title=Conformation-activity studies on the interaction of berberine with acetylcholinesterase: Physical chemistry approach |journal=Progress in Natural Science |volume=19 |issue=12 |pages=1721–5 |month=December |year=2009 |doi=10.1016/j.pnsc.2009.07.010 }}</ref><ref>{{cite journal |author=Huang L, Shi A, He F, Li X |title=Synthesis, biological evaluation, and molecular modeling of berberine derivatives as potent acetylcholinesterase inhibitors |journal=Bioorganic & Medicinal Chemistry |volume= 18|issue= 3|pages= 1244–51|year=2009 |month=December |pmid=20056426 |doi=10.1016/j.bmc.2009.12.035}}</ref> and additionally through antioxidant capacities.<ref>{{cite journal |author=Jung HA, Min BS, Yokozawa T, Lee JH, Kim YS, Choi JS |title=Anti-Alzheimer and antioxidant activities of Coptidis Rhizoma alkaloids |journal=Biological & Pharmaceutical Bulletin |volume=32 |issue=8 |pages=1433–8 |year=2009 |month=August |pmid=19652386 |doi=10.1248/bpb.32.1433}}</ref>
	Other studies have shown berberine to increase noradrenaline and serotonin levels in the brain (rats) while inhibiting dopaminergic activity.<ref>{{cite journal |author=Peng WH, Lo KL, Lee YH, Hung TH, Lin YC |title=Berberine produces antidepressant-like effects in the forced swim test and in the tail suspension test in mice |journal=Life Sciences |volume= 81|issue= 11|pages= 933–938|year=2007 |month=August |doi=10.1016/j.lfs.2007.08.003 |pmid=17804020}}</ref><ref>{{cite journal |author=Lee B, Yang CH, Hahm DH, Choe ES, Lee HJ, Pyun KH, Shim I |title=Inhibitory Effects of Coptidis rhizoma and Berberine on Cocaine-induced Sensitization |journal=Evidence-based Complementary and Alternative Medicine |volume= 6|issue= 1|pages= 85–90|year=2007 |month=October |doi=10.1093/ecam/nem070 |pmid=18955248 |pmc=2644267}}</ref> The half-life of berberine ''in vivo'' seems to be three to four hours, thus requiring administration three times a day if steady levels are to be achieved.<ref>{{cite journal |author=Zhao YN, Ding Y, Wang RF, Xing DM, Cheng J, Du L |title=A new approach to investigate the pharmacokinetics of traditional chinese medicine YL2000 |journal=The American journal of Chinese Medicine |volume= 32|issue= 6|pages= 921–929|year=2004 |pmid=15673197 |doi=10.1142/S0192415X04002521}}</ref>
	Berberine seems to be able to antagonize orexin receptors, which may partly explain its metabolic, anti-Alzheimer and neurotransmitter modulating properties.
	===Intestinal disorders===
	Berberine can ameliorate proinflammatory cytokines-induced intestinal epithelial ] damage ''in vitro'', and berberine may be one of the targeted therapeutic agents that can restore barrier function in intestinal disease states.<ref>{{cite journal |author=Li N, Gu L, Qu L, ''et al.'' |title=Berberine attenuates pro-inflammatory cytokine-induced tight junction disruption in an in vitro model of intestinal epithelial cells |journal=European Journal of Pharmaceutical Sciences |year=2010 |month=February |pmid=20149867 |doi=10.1016/j.ejps.2010.02.001 |volume=40 |issue=1 |pages=1–8}}</ref><ref>{{cite journal |author=Gu L, Li N, Gong J, Li Q, Zhu W, Li J, ''et al.'' |title= Berberine Ameliorates Intestinal Epithelial Tight-Junction Damage and Down-regulates Myosin Light Chain Kinase Pathways in a Mouse Model of Endotoxinemia |journal= The Journal of Infectious Diseases |year=2011 |month=June |url=http://www.ncbi.nlm.nih.gov/pubmed/21592990 |volume=203|issue= 11|pages 602-12}}</ref>
	===HIV===
	A new study identified a key cellular mechanism underlying the protective effect of berberine on ] PI-induced inflammatory response in macrophages. Modulation of the ](ER) 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 infection.<ref>{{cite journal |author=Zha W, Liang G, Xiao J, ''et al.'' |title=Berberine inhibits HIV protease inhibitor-induced inflammatory response by modulating ER stress signaling pathways in murine macrophages |journal=PLoS ONE |volume=5 |issue=2 |pages=e9069 |year=2010 |pmid=20161729 |pmc=2817721 |doi=10.1371/journal.pone.0009069 |editor1-last=Luo |editor1-first=Yuan}}</ref>
	== Biosynthesis ==		== Biosynthesis ==
			]
	] The ] berberine has a tetracyclic skeleton derived from a benzyltetrahydroisoquinoline system with the incorporation of an extra carbon atom provided by ] (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 ], and a cyclization to the aromatic ring occurs by virtue of the phenolic group.<ref>{{cite book |author=Dewick, P. |title=Medicinal Natural Products: A Biosynthetic Approach |edition=3rd |publisher=Wiley |location=West Sussex, England |year=2009 |page=357 |isbn=0471496413}}</ref>
			The ] berberine has a tetracyclic skeleton derived from a benzyltetrahydroisoquinoline system with the incorporation of an extra carbon atom as a bridge. Formation of the berberine bridge is rationalized as an oxidative process in which the ''N''-], supplied by ] (SAM), is oxidized to an ], and a cyclization to the aromatic ring occurs by virtue of the phenolic group.<ref>{{cite book | vauthors = Dewick P |title=Medicinal Natural Products: A Biosynthetic Approach |url=https://archive.org/details/medicinalnatural00dewi_015 |url-access=limited |edition=3rd |publisher=Wiley |location=West Sussex, England |year=2009 |page= |isbn=978-0-471-49641-0}}</ref>
	] is known as the immediate precursor of protoberberine alkaloids in plants.<ref>{{cite journal |author=Park SU, Facchini PJ |title=Agrobacterium rhizogenes-mediated transformation of opium poppy, ''Papaver somniferum l.'', and California poppy, ''Eschscholzia californica cham.'', root cultures |journal=Journal of Experimental Botany |volume=51 |issue=347 |pages=1005–16 |year=2000 |month=June |pmid=10948228 |doi=10.1093/jexbot/51.347.1005}}</ref> Berberine is an alkaloid derived from ]. ] and 4-hydroxypyruvic acid both come from L-Tyr. Although two ] molecules are used in the biosynthetic pathway, only the ] fragment of the ] ring system is formed via DOPA, the remaining carbon atoms come from ] via 4-hydroxyphenylacetaldehyde. ] loses carbon dioxide to form ] '''1'''. Likewise, 4-hydroxypyruvic acid also loses carbon dioxide to form 4-hydroxyphenyl-acetaldehyde '''2'''. ] '''1''' then reacts with 4-hydroxy-phenylacetaldehyde '''2''' to form (S)-norcolaurine '''3''' in a reaction similar to the ]. After oxidation and methylation by ], ] '''4''' is formed. ] serves as a pivotal intermediate to other alkaloids. Oxidation of the ] then occurs and an ] 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 ] to form (S)-scoulerine, which is then methylated by SAM to form (S)-tetrahydrocolumbamine '''7'''. Product '''7''' is then oxidized to form the ] ring from the ''ortho''-methoxyphenol, via an O<sub>2</sub>-, 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 H<sub>2</sub>O<sub>2</sub> and H<sub>2</sub>O produced in the successive processes.<ref>{{cite book |author=Dewick, P. |title=Medicinal Natural Products: A Biosynthetic Approach |edition=3rd |publisher=Wiley |location=West Sussex, England |year=2009 |page=358 |isbn=0471496413}}</ref>		] is the immediate precursor of protoberberine alkaloids in plants.<ref>{{cite journal | vauthors = Park SU, Facchini PJ | title = Agrobacterium rhizogenes-mediated transformation of opium poppy, ''Papaver somniferum l.'', and California poppy, ''Eschscholzia californica cham.'', root cultures | journal = Journal of Experimental Botany | volume = 51 | issue = 347 | pages = 1005–16 | date = June 2000 | pmid = 10948228 | doi = 10.1093/jexbot/51.347.1005 | doi-access = }}</ref> Berberine is an alkaloid derived from ]. ] and 4-hydroxypyruvic acid both come from <small>L</small>-tyrosine. Although two tyrosine molecules are used in the biosynthetic pathway, only the ] fragment of the ] ring system is formed via DOPA; the remaining carbon atoms come from tyrosine via 4-hydroxyphenylacetaldehyde.<ref>{{cite book | vauthors = Dewick P |title=Medicinal Natural Products: A Biosynthetic Approach |url=https://archive.org/details/medicinalnatural00dewi_347 |url-access=limited |edition=3rd |publisher=Wiley |location=West Sussex, England |year=2009 |page= |isbn=978-0-471-49641-0}}</ref>
	==See also==		== References ==
			{{Reflist}}
	* ], a plant based compound with very similar chemical classification as berberine
	* ] for a related pharmacological discussion
	* ] for a related pharmacological discussion
	* ] another protoberberine alkaloid
			{{Other antibacterials}}
	==References==
			{{Muscarinic acetylcholine receptor modulators}}
	{{Reflist|2}}
			{{PPAR modulators}}
			{{Sigma receptor modulators}}
			{{Authority control}}
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