Berberine
Encyclopedia
Berberine is a quaternary ammonium
salt from the protoberberine group of isoquinoline
alkaloid
s. It is found in such plants as Berberis
(e.g. Berberis aquifolium (Oregon grape), Berberis vulgaris
(Barberry), and Berberis aristata
(Tree Turmeric)),Hydrastis canadensis (Goldenseal
), Phellodendron amurense
(Amur Cork Tree, Huang Bai, Huang Po, Po Mu) and Coptis chinensis
(Chinese Goldthread, Huang-Lian, Huang-Lien), and Tinospora cordifolia
, and to a smaller extent in Argemone mexicana
(Prickly Poppy) and Eschscholzia californica (Californian Poppy). Berberine is usually found in the roots, rhizome
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 ultraviolet light, berberine shows a strong yellow fluorescence
. Because of this it is used in histology
for staining heparin
in mast cell
s. As a natural dye, berberine has a Colour Index
(CI) of 75160.
, 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 antibiotic., When applied in vitro and in combination with methoxyhydnocarpin, an inhibitor of multidrug resistance pump
s, berberine inhibits growth of Staphylococcus aureus
. and Microcystis aeruginosa. a toxic cyanobacterium
Berberine is a component of some eye drop
formulations. There is some evidence 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.
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
.
and human diabetes mellitus.
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 incretin
s.
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
(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, 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
(THZ), 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.
, LDL cholesterol, triglyceride
s and aterogenic apolipoprotein
s (apo B) (Apo B), but the mechanism of action is distinct from statin
s.
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.
Berberine also prevents proliferation of hepatic stellate cells (HSCs), which are central for the development of fibrosis during liver injury.
Anti-atherosclerosis properties.
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.
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.
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 its use in clinical development may be more as a cytostatic agent than a cytotoxic compound.
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 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. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=12456
Berberine may also act in a manner comparable to Tianeptine
by increasing the number of serotonin transporter
s available in the brain, enhacing the reuptake of serotonin.
damage in vitro, and berberine may be one of the targeted therapeutic agents that can restore barrier function in intestinal disease states.
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 syndromes, including HIV PI-associated atherosclerosis. The report shows the potential application of berberine as a complementary therapeutic agent for HIV infection.
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.
Quaternary ammonium cation
Quaternary ammonium cations, also known as quats, are positively charged polyatomic ions of the structure NR4+, R being an alkyl group or an aryl group. Unlike the ammonium ion and the primary, secondary, or tertiary ammonium cations, the quaternary ammonium cations are permanently charged,...
salt from the protoberberine group of isoquinoline
Isoquinoline
Isoquinoline is a heterocyclic aromatic organic compound. It is a structural isomer of quinoline. Isoquinoline and quinoline are benzopyridines, which are composed of a benzene ring fused to a pyridine ring. In a broader sense, the term isoquinoline is used to make reference to isoquinoline...
alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
s. It is found in such plants as Berberis
Berberis
Berberis , the barberries or pepperidge bushes, is a genus of about 450-500 species of deciduous and evergreen shrubs from 1-5 m tall with thorny shoots, native to the temperate and subtropical regions of Europe, Asia, Africa, North America and South America. They are closely related to the genus...
(e.g. Berberis aquifolium (Oregon grape), Berberis vulgaris
Berberis vulgaris
Berberis vulgaris /// is a shrub in the family Berberidaceae, native to central and southern Europe, northwest Africa and western Asia; it is also naturalised in northern Europe, including the British Isles and Scandinavia, and North America.It is a deciduous shrub growing up to 4 m high...
(Barberry), and Berberis aristata
Berberis aristata
Berberis aristata, also known as Indian Barberry or Tree Turmeric, belongs to the family Berberidaceae and the genus Berberis . The genus comprises approximately 450-500 species of deciduous evergreen shrubs and is found in the temperate and sub-tropical regions of Asia, Europe, and America. B....
(Tree Turmeric)),Hydrastis canadensis (Goldenseal
Goldenseal
Goldenseal is a perennial herb in the buttercup family Ranunculaceae, native to southeastern Canada and the northeastern United States. It may be distinguished by its thick, yellow knotted rootstock. The stem is purplish and hairy above ground and yellow below ground where it connects to the...
), Phellodendron amurense
Phellodendron amurense
Phellodendron amurense Rupr. is a species of tree in the family Rutaceae, commonly called the Amur cork tree. It is a major source of huáng bò , one of the 50 fundamental herbs used in traditional Chinese medicine...
(Amur Cork Tree, Huang Bai, Huang Po, Po Mu) and Coptis chinensis
Coptis chinensis
The Chinese goldthread is a species of goldthread native to China.-Etymology:*Coptis chinensis Franch. var. chinensis**The Chinese goldthread (Coptis chinensis) is a species of goldthread native to China.-Etymology:*Coptis chinensis Franch. var. chinensis**The Chinese goldthread (Coptis chinensis)...
(Chinese Goldthread, Huang-Lian, Huang-Lien), and Tinospora cordifolia
Tinospora cordifolia
Tinospora cordifolia, which is known by the common name Guduchi, is an herbaceous vine of the family Menispermaceae indigenous to the tropical areas of India, Myanmar and Sri Lanka....
, and to a smaller extent in Argemone mexicana
Argemone mexicana
Argemone mexicana is a species of poppy found in Mexico and now widely naturalized in the United States, India and Ethiopia...
(Prickly Poppy) and Eschscholzia californica (Californian Poppy). Berberine is usually found in the roots, rhizome
Rhizome
In botany and dendrology, a rhizome is a characteristically horizontal stem of a plant that is usually found underground, often sending out roots and shoots from its nodes...
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 ultraviolet light, berberine shows a strong yellow fluorescence
Fluorescence
Fluorescence is the emission of light by a substance that has absorbed light or other electromagnetic radiation of a different wavelength. It is a form of luminescence. In most cases, emitted light has a longer wavelength, and therefore lower energy, than the absorbed radiation...
. Because of this it is used in histology
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...
for staining heparin
Heparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...
in mast cell
Mast cell
A mast cell is a resident cell of several types of tissues and contains many granules rich in histamine and heparin...
s. As a natural dye, berberine has a Colour Index
Colour Index International
Colour Index International is a reference database jointly maintained by the Society of Dyers and Colourists and the American Association of Textile Chemists and Colorists. It was first printed in 1925 but is now published exclusively on the web...
(CI) of 75160.
Traditional use
As a traditional medicine or dietary supplement, berberine has shown some activity against fungal infections, Candida albicansCandida albicans
Candida albicans is a diploid fungus that grows both as yeast and filamentous cells and a causal agent of opportunistic oral and genital infections in humans. Systemic fungal infections including those by C...
, yeast, parasites, and bacterial/viral infections.
Berberine seems to exert synergistic effects with fluconazole
Fluconazole
Fluconazole is a triazole antifungal drug used in the treatment and prevention of superficial and systemic fungal infections. In a bulk powder form, it appears as a white crystalline powder, and it is very slightly soluble in water and soluble in alcohol. It is commonly marketed under the trade...
even in drug-resistant Candida albicans infections.
Some research has been undertaken into possible use against MRSA infection.
Berberine is considered antibiotic., When applied in vitro and in combination with methoxyhydnocarpin, an inhibitor of multidrug resistance pump
ABCC2
Multidrug resistance-associated protein 2 also called canalicular multispecific organic anion transporter 1 or ATP-binding cassette sub-family C member 2 is a protein that in humans is encoded by the ABCC2 gene....
s, berberine inhibits growth of Staphylococcus aureus
Staphylococcus aureus
Staphylococcus aureus is a facultative anaerobic Gram-positive coccal bacterium. It is frequently found as part of the normal skin flora on the skin and nasal passages. It is estimated that 20% of the human population are long-term carriers of S. aureus. S. aureus is the most common species of...
. and Microcystis aeruginosa. a toxic cyanobacterium
Berberine is a component of some eye drop
Eye drop
Eye drops are saline-containing drops used as a route to administer medication in the eye. Depending on the condition being treated, they may contain steroids, antihistamines, sympathomimetics, beta receptor blockers, parasympathomimetics, parasympatholytics, prostaglandins, non-steroidal...
formulations. There is some evidence it is useful in the treatment of trachoma
Trachoma
Trachoma is an infectious disease causing a characteristic roughening of the inner surface of the eyelids. Also called granular conjunctivitis and Egyptian ophthalmia, it is the leading cause of infectious blindness in the world...
, and it has been a standard treatment for leishmaniasis
Leishmaniasis
Leishmaniasis is a disease caused by protozoan parasites that belong to the genus Leishmania and is transmitted by the bite of certain species of sand fly...
.
Berberine prevents and suppresses proinflammatory cytokines, E-selectin
E-selectin
E-selectin, also known as CD62 antigen-like family member E , endothelial-leukocyte adhesion molecule 1 , or leukocyte-endothelial cell adhesion molecule 2 , is a cell adhesion molecule expressed only on endothelial cells activated by cytokines. Like other selectins, it plays an important part in...
, and genes, and increases adiponectin
Adiponectin
Adiponectin is a protein which in humans is encoded by the ADIPOQ gene.- Structure :...
expression which partly explains its versatile health effects. Berberine is a nucleic acid-binding isoquinolone alkaloid with wide potential therapeutic properties.
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
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...
.
Diabetes mellitus
Berberine has been tested and used successfully in experimentaland human diabetes mellitus.
Berberine has been shown to lower elevated blood glucose as effectively as metformin
Metformin
Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...
. The mechanisms of action include inhibition of aldose reductase
Aldose reductase
Aldose reductase is an NADPH-dependent oxidoreductase that catalyzes the reduction of a variety of aldehydes and carbonyls, including monosaccharides...
, inducing glycolysis, preventing insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
through increasing insulin receptor expression and acting like incretin
Incretin
Incretins are a group of gastrointestinal hormones that cause an increase in the amount of insulin released from the beta cells of the islets of Langerhans after eating, even before blood glucose levels become elevated. They also slow the rate of absorption of nutrients into the blood stream by...
s.
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
Hepatocyte nuclear factor 4 alpha
Hepatocyte nuclear factor 4 alpha also known as NR2A1 is a nuclear receptor that in humans is encoded by the HNF4A gene.- Function :...
, 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
Dipeptidyl peptidase-4
Dipeptidyl peptidase-4 , also known as adenosine deaminase complexing protein 2 or CD26 is a protein that, in humans, is encoded by the DPP4 gene.-Function:...
(DPP IV), as well as the pro-diabetic target human protein tyrosine phosphatase
Protein tyrosine phosphatase
Protein tyrosine phosphatases are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins. Protein tyrosine phosphorylation is a common post-translational modification that can create novel recognition motifs for protein interactions and cellular...
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, 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
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
. 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
Metformin
Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...
and 2,4-thiazolidinedione
Thiazolidinedione
The thiazolidinediones , also known as glitazones, are a class of medications used in the treatment of diabetes mellitus type 2. They were introduced in the late 1990s.- Mechanism of action :...
(THZ), 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.
Lipids
Berberine lowers elevated blood total cholesterolCholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
, LDL cholesterol, triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
s and aterogenic apolipoprotein
Apolipoprotein
Apolipoproteins are proteins that bind lipids to form lipoproteins and transport the lipids through the lymphatic and circulatory systems....
s (apo B) (Apo B), but the mechanism of action is distinct from statin
Statin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
s.
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
LDL receptor
The Low-Density Lipoprotein Receptor is a mosaic protein of ~840 amino acids that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognizes the apoprotein B100 which is embedded in the phospholipid outer layer of LDL particles...
(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
AMP-activated protein kinase
5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis. It consists of three proteins that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of...
(AMPK),
specifically extracellular signal-regulated kinases
Extracellular signal-regulated kinases
In molecular biology, extracellular-signal-regulated kinases or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells...
(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.
Liver
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.
Congestive heart failure
Experimental and clinical studies suggest berberine may be useful for patients with severe congestive heart failure.Anti-atherosclerosis properties.
Transplants
According to a Chinese report, combined use of berberine with ciclosporinCiclosporin
Ciclosporin , cyclosporine , cyclosporin , or cyclosporin A is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the immune system, and therefore the risk of organ rejection...
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.
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 and gastric carcinoma. Animal studies have shown that berberine can suppress chemical-induced carcinogenesis, clastogenesis ,
tumor promotion, tumor invasion, prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
,
neuroblastoma,
and leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
.
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.
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 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 receptorSigma receptor
The sigma receptors σ1 and σ2 bind to ligands such as 4-PPBP, SA 4503, ditolylguanidine, dimethyltryptamine and siramesine.- Classification :...
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 Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
(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. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=12456
Berberine may also act in a manner comparable to Tianeptine
Tianeptine
Tianeptine was discovered by The French Society of Medical Research in the 1960s. Under the trade-names it is a drug used for treating major depressive episodes ....
by increasing the number of serotonin transporter
Serotonin transporter
The serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...
s available in the brain, enhacing the reuptake of serotonin.
Intestinal disorders
Berberine can ameliorate proinflammatory cytokines-induced intestinal epithelial tight junctionTight junction
Tight junctions, or zonula occludens, are the closely associated areas of two cells whose membranes join together forming a virtually impermeable barrier to fluid. It is a type of junctional complex present only in vertebrates...
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 HIVHIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
PI-induced inflammatory response in macrophages. Modulation of the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
(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.
Biosynthesis
The alkaloidAlkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
berberine has a tetracyclic skeleton derived from a benzyltetrahydroisoquinoline system with the incorporation of an extra carbon atom provided by S-adenosyl methionine
S-Adenosyl methionine
S-Adenosyl methionine is a common cosubstrate involved in methyl group transfers. SAM was first discovered in Italy by G. L. Cantoni in 1952. It is made from adenosine triphosphate and methionine by methionine adenosyltransferase . Transmethylation, transsulfuration, and aminopropylation are the...
(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
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
. L-DOPA and 4-hydroxypyruvic acid both come from L-Tyr. Although two tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
molecules are used in the biosynthetic pathway, only the phenylethylamine fragment of the tetrahydroisoquinoline
Tetrahydroisoquinoline
Tetrahydroisoquinoline is a secondary amine with the chemical formula C9H11N.-Reactions:Like other secondary amines, tetrahydroisoquinoline can be oxidized to the corresponding nitrone using hydrogen peroxide, catalyzed by selenium dioxide....
ring system is formed via DOPA, the remaining carbon atoms come from tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
via 4-hydroxyphenylacetaldehyde. L-DOPA loses carbon dioxide to form dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
1. Likewise, 4-hydroxypyruvic acid also loses carbon dioxide to form 4-hydroxyphenyl-acetaldehyde 2. Dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
1 then reacts with 4-hydroxy-phenylacetaldehyde 2 to form (S)-norcolaurine 3 in a reaction similar to the Mannich reaction
Mannich reaction
The Mannich reaction is an organic reaction which consists of an amino alkylation of an acidic proton placed next to a carbonyl functional group with formaldehyde and ammonia or any primary or secondary amine. The final product is a β-amino-carbonyl compound also known as a Mannich base...
. After oxidation and methylation by SAM
S-Adenosyl methionine
S-Adenosyl methionine is a common cosubstrate involved in methyl group transfers. SAM was first discovered in Italy by G. L. Cantoni in 1952. It is made from adenosine triphosphate and methionine by methionine adenosyltransferase . Transmethylation, transsulfuration, and aminopropylation are the...
, (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
Keto-enol tautomerism
In organic chemistry, keto-enol tautomerism refers to a chemical equilibrium between a keto form and an enol . The enol and keto forms are said to be tautomers of each other...
to form (S)-scoulerine, which is then methylated by SAM to form (S)-tetrahydrocolumbamine 7. Product 7 is then oxidized to form the methylenedioxy
Methylenedioxy
Methylenedioxy in the field of chemistry, particularly in organic chemistry, is the name for a functional group with the structural formula R-O-CH2-O-R' which is connected to the rest of a molecule by two chemical bonds. The methylenedioxy group consists of two oxygen atoms connected to a methylene...
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.
See also
- SanguinarineSanguinarineSanguinarine is a quaternary ammonium salt from the group of benzylisoquinoline alkaloids. It is extracted from some plants, including bloodroot , Mexican prickly poppy Argemone mexicana, Chelidonium majus and Macleaya cordata. It is also found in the root, stem and leaves of the opium poppy but...
, a plant based compound with very similar chemical classification as berberine - CoptisineCoptisineCoptisine is an alkaloid found in Chinese goldthread . Famous for the bitter taste that it produces, it is used in Chinese herbal medicine along with the related compound berberine for treating digestive disorders caused by bacterial infections.Also found in Greater Celandine and has also been...
for a related pharmacological discussion - GoldensealGoldensealGoldenseal is a perennial herb in the buttercup family Ranunculaceae, native to southeastern Canada and the northeastern United States. It may be distinguished by its thick, yellow knotted rootstock. The stem is purplish and hairy above ground and yellow below ground where it connects to the...
for a related pharmacological discussion - JatrorrhizineJatrorrhizineJatrorrhizine is a protoberberine alkaloid isolated from Enantia chlorantha and other species. Synonyms that may be encountered include jateorrhizine, neprotin, jatrochizine, jatrorhizine, or yatrorizine. It has been reported to have antiinflammatory effect, and to improve blood flow and mitotic...
another protoberberine alkaloid