|Jmol-3D images||Image 1|
|Molar mass||336.36122 g/mol|
|Solubility in water||slowly soluble|
| (what is: / ?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
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 (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.
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, so it is used in histology for staining heparin in mast cells. As a natural dye, berberine has a colour index of 75160.
- 1 Traditional use
- 2 Newer and experimental uses
- 3 Biosynthesis
- 4 See also
- 5 References
As a traditional medicine or dietary supplement, berberine has shown 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 C. albicans infections.
Berberine is considered antibiotic. When applied in vitro and in combination with methoxyhydnocarpin, an inhibitor of multidrug resistance pumps, berberine inhibits growth of Staphylococcus aureus and Microcystis aeruginosa, a toxic cyanobacterium.
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.
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. 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.
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.
Berberine has been shown to lower elevated blood glucose as effectively as metformin. The mechanisms of action include inhibition of aldose reductase, inducing glycolysis, preventing insulin resistance through increasing insulin receptor expression and acting like incretins. 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.
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.
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. Berberine suppresses intestinal disaccharidases with beneficial metabolic effects in diabetic states.
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.
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.
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 lowers elevated blood total cholesterol, LDL cholesterol, triglycerides and atherogenic 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-reductase. This explains why berberine does not cause side effects typical to statins. Berberine and plant stanols synergistically inhibit cholesterol absorption in hamsters.
Berberine 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 cytokines, and reduces MMP-9 and EMMPRIN expression, which are all beneficial changes for heart health.
Moreover, berberine reduces hepatic fat content in the rats of nonalcoholic fatty liver disease. Berberine also prevents proliferation of hepatic stellate cells (HSCs), which are central for the development of fibrosis during liver injury.
Congestive heart failure
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.
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 and 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 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, 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. 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. However, new studies suggest that while berberine decreases cell growth, it increases the side population (stem cell) fraction of H460 lung cancer cells.
Berberine, 300 mg three times a day orally, also seems to inhibit complication of abdominal or pelvic radiation, called radiation-induced acute intestinal symptoms. The studies suggest its use in clinical development may be more as a cytostatic agent than a cytotoxic compound.
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 berberine may have a potential for inhibition and prevention of Alzheimer's disease (AD), mainly through both cholinesterase (ChEs) inhibitory and β-amyloids pathways, and additionally through antioxidant capacities.
Other studies have shown berberine to increase noradrenaline and serotonin levels in the brain (rats) while inhibiting dopaminergic activity. 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.
Berberine seems to be able to antagonize orexin receptors, which may partly explain its metabolic, anti-Alzheimer and neurotransmitter modulating properties. 
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.
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 infection.
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.
(S)-Reticuline is known as the immediate precursor of protoberberine alkaloids in plants. 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.
- 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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