Berberine

Berberine
File:Berberin.svg
style="background: #F8EABA; text-align: center;" colspan="2" | Identifiers
CAS number	633-66-9
PubChem	2353
ChemSpider	2263
SMILES
InChI
InChI key	YBHILYKTIRIUTE-UHFFFAOYAJ
style="background: #F8EABA; text-align: center;" colspan="2" | Properties
Molecular formula	C20H18NO4+
Molar mass	336.36122 g/mol
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Berberine is a quaternary ammonium salt from the group of isoquinoline alkaloids. It is found in such plants as Berberis, goldenseal (Hydrastis canadensis), and Coptis chinensis, usually in the roots, rhizomes, 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 ultraviolet light, berberine shows a strong yellow fluorescence. Because of this it is used in histology for staining heparin in mast cells. As a natural dye berberin has a Colour Index (CI) of 75160.

Traditional use

As a traditional medicine or dietary supplement, berberine has showed some activity against fungal infections, Candida albicans, yeast, parasites, and bacterial/viral infections. Berberine seems to exert synergistic effects with fluconazole even in drug-resistant Candida albicans infections. Some research has been undertaken into possible use against MRSA infection.

Berberine is considered an ineffective antibiotic. However, when applied in vitro and in combination with methoxyhydnocarpin, an inhibitor of multidrug resistance pumps, berberine inhibits growth of Staphylococcus aureus.

Berberine is a component of some eye drop formulations. There is some evidence that it is useful in the treatment of trachoma, and it has been a standard treatment for leishmaniasis. Berberine prevents and suppresses proinflammatory cytokines, E-selectin, and genes, and increases adiponectin expression which partly explains its versatile health effects. Berberine is a nucleic acid-binding isoquinolone alkaloid with wide potential therapeutic properties.

Biosynthesis

File:Biosynthesis of berberine.gif

Biosynthesis of Berberine

The alkaloid berberine has a tetracyclic skeleton that is 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.

It is known that the immediate precursor of protoberberine alkaloids in plants is (S)-reticuline. 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.

Diabetes, dyslipidemias and cardiovascular conditions

During the last few decades, many studies have shown that berberine has various beneficial effects on the cardiovascular system and significant anti-inflammatory activities. A Canadian report suggests that 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. Berberine exerts up-regulating activity on both low-density-lipoprotein receptor (LDLR) and insulin receptor (InsR). This one-drug-multiple-target characteristic might be suitable for the treatment of metabolic syndrome. Berberine has been tested and used successfully in experimental and human diabetes mellitus. Berberine has been shown to lower elevated blood glucose as effectively as metformin. The mechanisms of action include activation of PPAR-gamma , inhibition of aldose reductase, inducing glycolysis, preventing insulin resistance through increasing insulin receptor expression and acting like incretins. A new study suggest that berberine may overcome insulin resistance via modulating key molecules in insulin signaling pathway, leading to increased glucose uptake in insulin resistant cells. Berberine inhibits Foxo1, which integrates insulin signaling with mitochondrial function. Inhibition of Foxo1 can improve hepatic metabolism during insulin resistance and the metabolic syndrome. 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 cell more sensitive to glucose fluctuation and response more effectively to glucose challenge. Berberine seems to inhibit human dipeptidyl peptidase-4 (DPP IV) as well as the pro-diabetic target human protein tyrosine phosphatase 1B (h-PTP 1B), which explain at least some of its anti-hyperglycemic activities. Berberine suppresses intestinal disaccharidases with beneficial metabolic effects in diabetic states. A recent comprehensive metabonomics method, applied to 60 type 2 diabetics, suggests that 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 that berberine might play a pivotal role in the treatment of type 2 diabetes, conclude the authors.

Berberine has been shown to boost the effects of metformin and 2,4-thiazolodinedione (THZ) and can partly replace the commercial drugs, which could lead to a reduction in toxicity and side effects of the latter.

Berberine lowers elevated blood total cholesterol, LDL cholesterol, triglycerides and aterogenic apolipoproteins (apo B) (Apo B), but the mechanism of action is distinct from statins. 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), and increasing in the liver the expression of LDL receptors through extracellular signal-regulated kinase (ERK) signaling pathway, 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 plant stanols synergistically inhibit cholesterol absorption in hamsters. Berberin seems to improve the arterial endothelial function in humans. Berberine activates AMP-activated protein kinase (AMPK), specifically extracellular signal-regulated kinases (ERK), which plays a central role in glucose and lipid metabolism, suppresses proinflammatory cystokines, and reduces MMP-9 and EMMPRIN expression, which are all beneficial changes for heart health. Morevover, berberine reduces hepatic fat content in the rats of non-alcoholic fatty liver disease (NAFLD). Berberine also prevents proliferation of hepatic stellate cells (HSCs), which are central for the development of fibrosis during liver injury.

Experimental and clinical studies suggest that berberine may be useful for patients with severe congestive heart failure.

According to a Chinese report, combined use of berberine with ciclosporin A (CsA) could markedly increase the blood concentration of CsA in heart transplanted recipients and reduce the dosage of CsA required, save the cost for medical service, and shows no obvious adverse reaction.

Cancer

Berberine has drawn extensive attention towards its antineoplastic effects. It seems to suppress the growth of a wide variety of tumor cells including breast cancer, leukemia, melanoma, epidermoid carcinoma, hepatoma, pancreatic cancer, oral carcinoma, tongue carcinoma, glioblastoma, prostate carcinoma, gastric carcinoma. Animal studies have shown that berberine can suppress chemical-induced carcinogenesis, clastogenesis , tumor promotion, tumor invasion, prostate cancer, neuroblastoma, and leukemia. It is a radiosensitzer 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, 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 that this pathway plays a major role in the action of berberine. 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. Berberine, 300 mg three times a day orally, also seems to inhibit complication of abdominal or pelvic radiation, called radiation-induced acute intestinal symptoms (RIAISs). The studies suggest that 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. 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 that berberine may have a potential of inhibition and prevention of Alzheimer's disease (AD) mainly through both cholinesterase (ChEs)inhibitory and β-amyloids pathways, and additionally through antioxidant capacities.

Intestinal disorders

Berberine can ameliorate pro-inflammatory cytokines induced intestinal epithelia tight junction damage in vitro, and berberine may be one of the targeted therapeutic agents that can restore barrier function in intestinal disease states.

HIV

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(ER) stress response represents a potential therapeutic target for various inflammatory diseases and metabolic syndrome including HIV PI-associated atherosclerosis. The report shows the potential application of berberine as a complementary therapeutic agent for HIV infection.

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.

References

da:Berberin zh:小檗鹼