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Adaptogens that act predominantly on the Biologic Intelligence
Hydrastis Canadensis
Goldenseal
 

It is a small plant, native from the North American forests. Its roots and rhizomes were traditionally used by the Indians as a disinfectant and to treat skin diseases, digestive and hepatic problems, diarrhea and eye irritations. Today, it is used in modern phytotherapy for the treatment of infections of the gastrointestinal, urogenital and respiratory tract.

The root of Hydrastis Canadensis is one of the most popular herbs and holds the fourth sales position of medicinal plants in the United States.

Press the bottle to see a photo of this plant

Active Elements:

Its principal active elements are isocincholine alkaloids: Berberine (3-6%), hydrastine (2-4%), hydrastanine, canadine and canadaline (in minor proportions) that provide anti-inflammatory and bacteriostatic properties when taken in small doses and bactericidal properties when ingested in higher doses; that is where its deserved fame as “natural antibiotic” comes from.

Berberine is its principal active element and is found in the roots, rhizomes and in the bark of the plant. This substance has a long history of medical use in Indian (Ayurvedic) and Chinese medicine. It has shown a significant anti-microbial activity against a variety of bacteria, viruses, fungus, protozoa, and other microorganisms. At present, its main uses include: bacterial or parasitic intestinal infections, oropharyngeal and respiratory infections, urogenital infections, and trachoma eye infection.
Berberine
Pharmacology:

The pharmacological actions of Berberine include:

• Antibacterial action:

- Metabolic inhibition of certain microorganisms.

- Inhibition of the formation of enterotoxins.

- Inhibition of bacterial adherence (inhibits a bacterial lipase which permits the colonizing of skin and mucous membranes).

• Anti-diarrheal action: Inhibition of the ionic intestinal secretion.

• Anti-spasmodic action: Inhibition of the contraction of smooth muscles.

• Anti-inflammatory, immunomodulating, and anti-tumoral action.

• Increase of the platelet count in certain cases of thrombocytopenia.

• Cardiovascular effects: positive inotropic, negative chronotropic, anti-arrhythmia, vessels dilator.

• Hypoglycemic action: inhibits the alpha-glycosidase, decreasing the transport of glucose through the intestinal epithelium. Furthermore, increases the glucose consumption of the cells without increasing the insulin secretion.

Clinical Applications:

Intestinal Infections:

Numerous studies have shown the effectiveness of berberine in cases of diarrhea caused by vibrio cholera and enteropathogenical and enterotoxiological Escherichia coli. The results of these studies indicate that it improves the cases of diarrhea by means of different mechanisms. One study has shown that Berberine reduces the intestinal secretion of water and electrolytes induced by the choleric toxin. Other studies show that it inhibits some enterotoxins of Vibrio cholera and Escherichia coli, decreases significantly the intestinal peristalsis reducing the contraction of smooth muscles and slows down the intestinal transit in humans. It has also shown antibacterial effects on Vibrio cholera. In cases of Escherichia coli infection, berberine inhibits the bacterial adherence to the intestinal mucous membranes which is the first step of the infectional process, probably as a result of its inhibitory effect on the fimbriae formation on the bacterial surface.

Berberine has proven to inhibit the growth of Giardia lamblia and Entamoeba histolytica. In tropical countries, the giardisis is a frequent disease, particularly in the pediatric population. Clinical studies have shown that the administration of Berberine improves the gastrointestinal symptoms and achieves a reduction of the examinations of faeces positive to Giardia. Compared with metronidazol, smaller doses of Berberina have shown the same effectivity.

In vitro and in vivo studies on the effects of Berberine on Entamoeba histolytica indicate that it was quickly amoebicide and caused embeddlement, degeneration and finally the break-up of the trophozoits.

Berberine has also shown effectivity against intestinal pathogens, like Salmonella enteritidis, Shigella, and Helicobacter pilorii.

Oral-Pharyngeal and Respiratory Infections:

Its anti-microbial spectrum is of special importance at mucous level as it acts on pathogens that cause infections of the oropharynx and respiratory ways like: Streptococcus pyogenes group A, Staphylococcus aurous, Pneumococcus, Neisseria meningitidis, Proteus, Klebsiella, Pseudomona aeruginosa, Corinebacterium difteriae and Micobacterium tuberculosis, including resistant strains to conventional anti-tuberculosis therapy. A study reports that Berberine blocks the adherence of Streptococcus group A to the cells of the host. Considering its anti-microbial spectrum, it can be used in cases of infection of the tonsils, pharynx, gingivitis, pyorrhea, sinusitis, etc.

Anti-Tooth Decay Action:

Studies in vitro have shown that Berberine has a bactericidal action against Streptococcus mutans, a cariogenic microorganism.

Urinary Infections:

Given that Berberine concentrates in the bladder, it can be useful for the treatment of urinary infections caused by susceptible germs.

Vaginal Infections:

Berberine quickly inhibits the growth of Trichomonas vaginalis, forming big autophagic spaces that finally lead to maimed trophozoits. It has also shown to be effective against other vaginal pathogens like Candida albicans, Neisseria gonorrea, Treponema pallidum and Chlamydia.

Malaria:

In vitro studies show that Berberine acts against Plasmodium falciparum. Apparently it interferes with the cell division of the parasite by inhibition of the enzyme telomerase.

Leishmaniasis:

In the case of infection by Leishmaniasis donovani, Berberina reduces significantly the parasite charge and quickly improves the hematological parameters in infected animals, with less secondary effects than pentamidine. Test results in vitro indicate that it inhibits the multiplication of the amastigots and their transformation into promastigots. It also inhibits the incorporation of the nucleotides in the nucleic acids of the amastigots, interfering in the DNA synthesis and other macromolecules. It also inhibits the respiration of this parasite and inhibits its maturation.

Eye Infection:

A clinical study on 51 patients was done, comparing the use of Berberine versus sulfacetamide in the treatment of eyes infected by Chlamydia tracomatis (Trachoma), determining that, although the sulfacetamide drops achieved slightly superior clinical results, the conjunctive scraping of those patients continued positive and relapses occurred. The conjunctive scraping of patients who had received beberine containing drops were negative and no relapses occurred, even one year after the treatment. This study concluded that, although the Berberine did not produce any direct anti-chlamydia effects, it cured the infection stimulating some defensive mechanisms of the host. Another clinical study showed that Berberine was superior to sulfacetamide, improving the clinical course of the eye trachoma and achieving a decrease of the serum antibodies against Clamidia tracomatis.

Cardiovascular Effects:

Clinical studies on humans and animals indicate that Berberine has positive inotropic, negative chronotropic, anti-arrhythmic and vessel dilatory effects. It prevents taquiarrhythmias induced by ischemia, stimulates the myocardic contractibility and decreases the peripheral vascular resistance and, therefore, the arterial pressure. These effects are ascribed to the blocking of the potassium channels and the interchange of sodium and calcium. Furthermore, it extends the duration of the potential of ventricular action.

Anti-Inflammatory Action:

In vitro studies on human cells show that Berberine inhibits the activating protein 1 (AP-1), a key factor of the transcription during inflammation and carcinogenesis. Another study, using human lymphocites, showed that Berberine has a significant inhibitory effect on the lymphocitical transformation and it concluded that its anti-inflammatory action could be due to an inhibition of the DNA synthesis in the activated lymphocites. A third study concluded that during the platelet activation, in response to tissue damage, Berberine has a direct effect on different aspects of the inflammatory process. It inhibits the liberation of the archidonic acid of the phospholipids of the cellular membrane, inhibits the liberation of the platelet tromboxane A2, and it inhibits the formation of thrombus.

Other Effects:

Berberine has shown various beneficial effects, including: anti-pyretic effect; immunostimulation to increase the production of the anti-genoespecific immunoglobulins G and M and the stimulation of the macrophages; increase of platelet count in cases of primary or secondary thrombocytopenia and increase of the excretion of bilirubin combined in experimental hyperbilirubinemia. In addition, it has anti-tumor properties as is shown by the inhibition of the transcription of COX-2 and the activity of N-acetyltransferase in cellular lines of colon cancer and bladder cancer.
Doses and Toxicity:

The therapeutic dose for most clinical situations is 1 capsule, taken orally, 2 to 4 times per day during up to 3 weeks. In serious cases 2 to 3 capsules, 4 times per day.

It is considered that Hydrastis canadensis is not toxic at doses used in normal clinical situations and has not shown any cytoxic or mutagenic effects.

Hydrastis canadensis does not produce any intestinal dysbacteriosis.

High doses may produce some secondary effects like: gastrointestinal discomfort, dyspnoea or decrease of blood pressure.
Contraindications:

Hydrastis canadense should be avoided during pregnancy as it may cause uterine contractions and premature birth.

It should not be administered to newborns with jaundice as it may interfere with the metabolism of the bilirubin.

The safety of this product with regard to the period of lactation or patients with serious hepatic or renal disease has not been established yet.
References

1: J Agric Food Chem. 2003 Dec 3 ;51 (25):7352-8.
Chemical comparison of goldenseal (Hydrastis canadensis L.) root powder from three commercial suppliers.

Weber HA, Zart MK, Hodges AE, Molloy HM, O'Brien BM, Moody LA.
Midwest Research Institute, 425 Volker Boulevard , Kansas City , Missouri 64110 .

The characterization of herbal materials is a significant challenge to analytical chemists. Goldenseal (Hydrastis canadensis L.), which has been chosen for toxicity evaluation by NIEHS, is among the top 15 herbal supplements currently on the market and contains a complex mixture of indigenous components ranging from carbohydrates and amino acids to isoquinoline alkaloids. One key component of herbal supplement production is botanical authentication, which is also recommended prior to initiation of efficacy or toxicological studies. To evaluate material available to consumers, goldenseal root powder was obtained from three commercial suppliers and a strategy was developed for characterization and comparison that included Soxhlet extraction, HPLC, GC-MS, and LC-MS analyses. HPLC was used to determine the weight percentages of the goldenseal alkaloids berberine, hydrastine, and canadine in the various extract residues. Palmatine, an isoquinoline alkaloid native to Coptis spp. and other common goldenseal adulterants, was also quantitated using HPLC. GC-MS was used to identify non-alkaloid constituents in goldenseal root powder, whereas LC-MS was used to identify alkaloid components. After review of the characterization data, it was determined that alkaloid content was the best biomarker for goldenseal. A 20-min ambient extraction method for the determination of alkaloid content was also developed and used to analyze the commercial material. All three lots of purchased material contained goldenseal alkaloids hydrastinine, berberastine, tetrahydroberberastine, canadaline, berberine, hydrastine, and canadine. Material from a single supplier also contained palmatine, coptisine, and jatrorrhizine, thus indicating that the material was not pure goldenseal. Comparative data for three commercial sources of goldenseal root powder are presented.

2: J Pharm Pharmacol. 2003 Aug ;55 (8):1143-9.
Effect of berberine on proliferation, cell cycle and apoptosis in HeLa and L1210 cells.

Jantova S, Cipak L, Cernakova M, Kost'alova D.
Department of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology, SK-81237 Bratislava, Slovak Republic.
Previous studies on the anticancer activity of protoberberine alkaloids against a variety of cancer cell lines were extended to human tumour HeLa and murine leukemia L1210 cell lines. An attempt was also made to investigate the relationship between the cytotoxic activity of berberine and its molecular mechanism of action. Cytotoxicity was measured in-vitro using a primary biochemical screening according to Oyama and Eagle, and the growth inhibition assay. The in-vitro cytotoxic techniques were complemented by cell cycle analysis and determination of apoptotic DNA fragmentation in L1210 cells. Berberine acted cytotoxically on both tumour cell lines. The sensitivity of leukemia L1210 cells to the berberine was higher than that of HeLa cells. The IC( 100) was below 100 microg mL(-1) for HeLa cells and approached a 10 microg mL(-1) limit for the leukemia L1210 cells. For both cell lines the IC( 50) was found to be less than 4 microg mL(-1), a limit put forward by the National Cancer Institute (NCI) for classification of the compound as a potential anticancer drug. In L1210 cells treated with 10-50 microg mL( -1) berberine, G(0)/G(1) cell cycle arrest was observed. Furthermore, a concentration-dependent decrease of cells in S phase and increase in G( 2)/M phase was detected. In addition, apoptosis detected as sub- G( 0) cell population in cell cycle measurement was proved in 25-100 microg mL(-1) berberine-treated cells by monitoring the apoptotic DNA fragmentation (DNA ladder) using agarose gel electrophoresis.

3: Planta Med. 2003 Jul ;69 (7):632-6.
The antihyperglycaemic activity of berberine arises from a decrease of glucose absorption.

Pan GY, Huang ZJ, Wang GJ, Fawcett JP, Liu XD, Zhao XC, Sun JG, Xie YY.
Center of Pharmacokinetics , China Pharmaceutical University, Nanjing , China .

The mechanism of action of berberine as an antihyperglycaemic agent was investigated in the Caco-2 cell line. Berberine was found to effectively inhibit the activity of disaccharidases in Caco-2 cells. It also decreased sucrase activity after preincubation with Caco-2 cells for 72 hours. However gluconeogenesis and glucose consumption of Caco-2 cells were not influenced. 2-Deoxyglucose transporting through Caco-2 cell monolayers was decreased by berberine but the effect was not statistically significant. These results suggest that the antihyperglycaemic activity of berberine is at least partly due to its ability to inhibit alpha-glucosidase and decrease glucose transport through the intestinal epithelium.

4: Planta Med. 2003 Jul ;69 (7):623-7.
Antimicrobial constituents from goldenseal (the Rhizomes of Hydrastis canadensis) against selected oral pathogens.

Hwang BY, Roberts SK, Chadwick LR, Wu CD, Kinghorn AD.
Program for Collaborative Research in the Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
Two new C-methyl flavonoids, 6,8-di- C-methylluteolin 7-methyl ether (1) and 6- C-methylluteolin 7-methyl ether (2), were isolated from a commercially available sample of the roots of Hydrastis canadensis, along with seven known compounds, berberine (3), beta-hydrastine (4), canadine (5), canadaline (6), isocorypalmine (7), canadinic acid (8), and beta-sitosterol 3- O-beta- D-glucoside (9). The structures of the new compounds 1 and 2 were elucidated on the basis of their spectral data including 1D and 2D NMR techniques. Of these isolates, berberine (3) and, to a lesser extent, 1 and 2, showed antimicrobial activity when evaluated against the oral pathogens Streptococcus mutans and Fusobacterium nucleatum. Berberine (3) exhibited an additive antimicrobial effect when tested against S. mutans in combination with 1.

5: Am J Cardiol. 2003 Jul 15 ;92 (2):173-6.
Efficacy and safety of berberine for congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

Zeng XH, Zeng XJ, Li YY.
Section of Cardiology, Department of Medicine, Chengdu Second Municipal Hospital , China .

This study was designed to assess the efficacy and safety of berberine for chronic congestive heart failure (CHF). One hundred fifty-six patients with CHF and >90 ventricular premature complexes (VPCs) and/or nonsustained ventricular tachycardia (VT) on 24-hour Holter monitoring were randomly divided into 2 groups. All patients were given conventional therapy for CHF, consisting of angiotensin-converting enzyme inhibitors, digoxin, diuretics, and nitrates. Patients in the treatment group (n = 79) were also given berberine 1.2 to 2.0 g/day. The remaining 77 patients were given placebo. Symptoms, a 6-minute walk test, left ventricular ( LV ) ejection fraction (EF), frequency and complexity of VPCs, and quality of life were assessed after 8 weeks of treatment and during a mean 24-month follow-up. After treatment with berberine, there was a significantly greater increase in LVEF, exercise capacity, improvement of the dyspnea-fatigue index, and a decrease of frequency and complexity of VPCs compared with the control group. There was a significant decrease in mortality in the berberine-treated patients during long-term follow-up (7 patients receiving treatment died vs 13 on placebo, p <0.02). Proarrhythmia was not observed, and there were no apparent side effects. Thus, berberine improved quality of life and decreased VPCs and mortality in patients with CHF.

6: Nat Prod Res. 2003 Aug ;17 (4):269-74.
Microbial transformation of the phthalideisoquinoline alkaloid, (-)-beta-hydrastine.

Herath WH, Ferreira D, Khan IA.
National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, USA .

The phthalideisoquinoline alkaloid (-)-beta-hydrastine is one of the main active constituents of the medicinal plant, Hydrastis canadensis, which is used in many dietary supplements intended to enhance the immune system. Treatment of hydrastine with the fermentation broth of Polyporous brumalis (ATCC 34487) as a model for mammalian metabolism, gave a new alkaloid, (1S)-hydroxyhydrastine. Structure elucidation was based primarily on NMR and chiroptical studies.

7: Phytother Res. 2003 Mar ;17 (3):217-21.
In vitro susceptibility of Helicobacter pylori to isoquinoline alkaloids from Sanguinaria canadensis and Hydrastis canadensis.

Mahady GB. Program for Collaborative Research in the Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
Methanol extracts of the rhizomes of Sanguinaria canadensis, and the roots and rhizomes of Hydrastis canadensis, two plants used traditionally for the treatment of gastrointestinal ailments, were screened for in vitro antibacterial activity against 15 strains of Helicobacter pylori. The rhizome extracts, as well as a methanol extract of S. canadensis suspension-cell cultures inhibited the growth of H. pylori in vitro, with a MIC50 range of 12.5-50.0 microg/ml. Three isoquinoline alkaloids were identified in the active fraction. Sanguinarine and chelerythrine, two benzophenanthridine alkaloids, inhibited the growth of the bacterium, with an MIC50 of 50.0 and 100.0 microg/ml, respectively . Protopine, a protopine alkaloid, also inhibited the growth of the bacterium, with a MIC50 of 100 microg/ml . The crude methanol extract of H. canadensis rhizomes was very active, with an MIC50 of 12.5 microg/ml . Two isoquinoline alkaloids, berberine and beta-hydrastine, were identified as the active constituents, and having an MIC50 of 12.5 and 100.0 microg/ml, respectively.

8: Pharmacol Toxicol. 2002 Oct ;91 (4):193-7.
The involvement of P-glycoprotein in berberine absorption.

Pan GY, Wang GJ, Liu XD, Fawcett JP, Xie YY.
Center of Pharmacokinetics , China Pharmaceutical University, Nanjing , China .
Berberine is an important ingredient in a number of traditional Chinese medicines but has been shown to have poor bioavailability in the dog. The aim of this study was to use the P-glycoprotein (P-glycoprotein) inhibitors cyclosporin A , verapamil and the monoclonal antibody C219 in in vivo and in vitro models of intestinal absorption to determine the role of P-glycoprotein in berberine absorption. In the rat recirculating perfusion model, berberine absorption was improved 6-times by P-glycoprotein inhibitors. In the rat everted intestinal sac model, berberine serosal-to-mucosal transport was significantly decreased by cyclosporin A. In Ussing-type chambers, the rate of serosal-to-mucosal transport across rat ileum was 3-times greater than in the reverse direction and was significantly decreased by cyclosporin A. In Caco-2 cells, berberine uptake was significantly increased by P-glycoprotein inhibitors and by monoclonal antibody C219. P-glycoprotein appears to contribute to the poor intestinal absorption of berberine which suggests P-glycoprotein inhibitors could be of therapeutic value by improving its bioavailability.


9: J Pharm Sci. 2002 Dec ;91 (12):2614-21.
P-glycoprotein-mediated transport of berberine across Caco-2 cell monolayers.

Maeng HJ, Yoo HJ, Kim IW, Song IS, Chung SJ, Shim CK.
Department of Pharmaceutics, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
The objective of this study was to investigate the mechanisms by which berberine is transported in the secretory and absorptive directions across Caco-2 cell monolayers. The basolateral-to-apical (B-A) flux was 30-fold greater than the apical-to-basolateral flux and temperature dependent (i.e., drastic decrease at 4 degrees C compared with 37 degrees C). The above results suggest the involvement of a carrier-mediated active transport mechanism for the B-A transport of berberine. However, no significant concentration dependency for the permeability ( P( app)) of berberine was observed for B-A transport over a concentration range of 5-300 microM, indicating that the K(m) value of berberine for the carrier system is greater than 300 microM. Well-documented P-glycoprotein (P-gp) substrates such as verapamil, daunomycin, and rhodamine123 inhibited the B-A flux of berberine, whereas tetraethylammonium and taurocholate did not, suggesting that P-gp is involved in the transport. For the case of daunomycin, the B-A flux, but not the apical-to-basolateral flux, was significantly increased after pretreatment of the cell monolayers with berberine. In addition, the uptake of 1 microM daunomycin into Caco-2 cells was decreased as a result of this pretreatment. These results suggest that the repeated administration of berberine may up-regulate P-gp functions in Caco-2 cells. If this occurs in the gastrointestinal epithelial cells, the repeated administration of berberine may reduce the gastrointestinal absorption of P-gp substrates including chemotherapeutic agents such as daunomycin.

10: Metabolism. 2002 Nov ;51 (11):1439-43.
Effects of berberine on glucose metabolism in vitro.

Yin J, Hu R, Chen M, Tang J, Li F, Yang Y, Chen J.
Shanghai Institute of Endocrinology, Ruijin Hospital, Shanghai Second Medical University, Shanghai, China.

The action of berberine was compared with metformin and troglitazone (TZD) with regard to the glucose-lowering action in vitro. HepG2 cell line, phenotypically similar to human hepatocytes, was used for glucose consumption (GC) studies. Cell proliferation was measured by methylthiotetrazole (MTT) assay. In moderate high glucose concentration (11.1 mmol/L), GC of HepG2 cells was increased by 32% to 60% (P <.001 to P <.0001) with 5 x 10(-6) mol/L to 1 x 10(-4) mol/L berberine, which was comparable to that with 1 x 10(-3) mol/L metformin. The glucose-lowering effect of berberine decreased as the glucose concentration increased. The maximal potency was reached in the presence of 5.5 mmol/L glucose, and it was abolished when the glucose concentration increased to 22.2 mmol/L. The effect was not dependent on insulin concentration, which was similar to that of metformin and was different from that of TZD, whose glucose-lowering effect is insulin dependent. TZD had a better antihyperglycemic potency than metformin when insulin was added (P <.001). In the meantime, a significant toxicity of the drug to HepG2 cells was also observed. The betaTC3 cell line was used for insulin release testing, and no secretogogue effect of berberine was observed. These observations suggest that berberine is able to exert a glucose-lowering effect in hepatocytes, which is insulin independent and similar to that of metformin, but has no effect on insulin secretion.

11: Neurochem Res. 2002 Sep ;27 (9):883-9.
Berberine inhibited arylamine N-acetyltransferase activity and gene expression and DNA adduct formation in human malignant astrocytoma (G9T/VGH) and brain glioblastoma multiforms (GBM 8401) cells.

Wang DY, Yeh CC, Lee JH, Hung CF, Chung JG.
Department of Orthopaedics, China Medical College Hospital , Taichung , Taiwan , People's Republic of China .

Studies have demonstrated that berberine exhibits the antineoplastic action in rat model. Rat glial tumor cells also have been shown to have N-acetyltransferase activity. In this study, we reported the effects of berberine on arylamine N-acetyltransferase (NAT) activity, gene expression, and DNA adduct formation in human brain tumor cell lines (G95/VGH and GBM 8401). The activity of NAT (N-acetylation of substrate) was measured and determined by high-performance liquid chromatography (HPLC) assaying for the amounts of acetylated 2-aminofluorene (AF) and nonacetylated AF. Human brain tumor cells (G9T/VGH and GBM 8401) were used for examining NAT activity and gene expression and AF-DNA adduct formation. NAT gene expression was determined by polymerase chain reaction (PCR) for the levels of mRNA NAT in both examined cells lines. The amounts of AF-DNA adducts were also determined and quantities by HPLC. The results demonstrated that NAT activity, levels of mRNA NAT1 and AF-DNA adduct formation in both examined cell were inhibited and decreased by berberine in a dose-dependent manner. The apparent values of Km and Vmax from NAT of both examined cells were also determined with or without berberine cotreatment. The data also indicated that berberine decreased the apparent values of Km and Vmax. These effects also indicate that berberine is a uncompetitive inhibitor.


12: Acta Pharmacol Sin. 2002 Jan ;23 (1):77-82.
Identification of three sulfate-conjugated metabolites of berberine chloride in healthy volunteers' urine after oral administration.

Pan JF, Yu C, Zhu DY, Zhang H, Zeng JF, Jiang SH, Ren JY.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031,China.

AIM: To identify the structure of unknown metabolites of berberine (Ber) in human urine after oral administration. METHODS: Urine samples were obtained from 5 volunteers after they orally took Ber chloride 0.9 g per day for three days. Metabolites in urine samples were isolated and purified by polyporous resin column chromatography. The individual metabolites were identified mainly using electrospray ionization mass spectroscopy (ESI-MS) and proton nuclear magnetic resonance (1H NMR) spectroscopy. RESULTS: Three unknown metabolites (M1, M2, and M3) were isolated. They were susceptible to arylsufatase. ESI-MS measurements of M1, M2, and M3 produced quasimolecular ions [M+H ]+ , m/z 17.9, 404.0, and 402.0 respectively. Especially, each of them produced a characteristic protonated ion [M-80+H ]+ , which can be ascribed as quasimolecular ions lost a SO3 fragment. 1H NMR spectra of the metabolites were also obtained and each of 1H signals was assigned. CONCLUSION: Structures of M1, M2, and M3 were firmly identified as jatrorrhizine-3-sulfate, demethyleneberberine-2-sulfate, and thalifendine-10-sulfate, and the major metabolite was M2.

13: J Prosthet Dent. 1995 Jun ;73 (6):530-3.
In vitro study on the effects of trial denture cleansers with berberine hydrochloride.

Nakamoto K, Tamamoto M, Hamada T .
Department of Prosthetic Dentistry, Hiroshima University , School of Dentistry , Hiroshima , Japan .

The antifungal activity of trial denture cleansers prepared with berberine hydrochloride was examined against Candida albicans, C. tropicalis, and C. glabrata. A commercial denture cleanser and a trial denture cleanser that exhibited strong antifungal activity were tested for their effects on Candida spp., the color stability of the dental material, and the surface roughness of acrylic resin plates. The results of these tests revealed that the trial denture cleanser removed 64% to 89% of adhered cells from acrylic resin surfaces and had little effect on the other physical properties tested.
 

14: J Egypt Soc Parasitol. 2001 Dec ;31 (3):893-904 + 1p plate.
Evaluation of the effect of a plant alkaloid (berberine derived from Berberis aristata) on Trichomonas vaginalis in vitro.

Soffar SA, Metwali DM, Abdel-Aziz SS, el-Wakil HS, Saad GA.
Department of Parasitology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.

Berberine is a quaternary alkaloid derived from the plant Berberis aristata having antibacterial, antiamoebic, antifungal, antihelminthic, leishmanicidal and tuberculostatic properties. The effect of berberine sulphate salt on the growth of Trichomonas vaginalis in vitro was compared to the efficacy of metronidazole as a reference drug. Results showed that berberine sulphate was comparable to metronidazole as regards potency with the advantage of being more safe and possible replacement in metronidazole resistant cases.


15: Cardiovasc Drug Rev. 2001 Fall ;19 (3):234-44.
Cardiovascular actions of berberine.

Lau CW, Yao XQ, Chen ZY, Ko WH, Huang Y.
Department of Physiology, Chinese University of Hong Kong, Shatin, Hong Kong, China.

Berberine, is an alkaloid from Hydrastis canadensis L., Chinese herb Huanglian, and many other plants. It is widely used in traditional Chinese medicine as an antimicrobial in the treatment of dysentery and infectious diarrhea. This manuscript describes cardiovascular effects of berberine and its derivatives, tetrahydroberberine and 8-oxoberberine. Berberine has positive inotropic, negative chronotropic, antiarrhythmic, and vasodilator properties. Both derivatives of berberine have antiarrhythmic activity. Some cardiovascular effects of berberine and its derivatives are attributed to the blockade of K+ channels (delayed rectifier and K( ATP)) and stimulation of Na+ -Ca(2+) exchanger. Berberine has been shown to prolong the duration of ventricular action potential. Its vasodilator activity has been attributed to multiple cellular mechanisms. The cardiovascular effects of berberine suggest its possible clinical usefulness in the treatment of arrhythmias and/or heart failure.

16: Planta Med. 2001 Oct ;67 (7):609-13.
Effects of hydrastine derivatives on dopamine biosynthesis in PC12 cells.

Kim SH, Shin JS, Lee JJ, Yin SY, Kai M, Lee MK.
College of Pharmacy , Chungbuk National University , Kaeshin-Dong, Heungduk-Ku, Cheongju 361-763, Republic of Korea .
The effects of hydrastine derivatives on dopamine biosynthesis in PC12 cells were investigated. Treatments of PC12 cells with (1R ,9S )-beta-hydrastine hydrochloride [(+)-beta-hydrastine HCl] and (1R,9S)-beta-hydrastine [(-)-beta-hydrastine] showed 50.6 % and 33.1 % inhibition of dopamine content at a concentration of 10 microM for 48 h. However, (1S ,9R )-beta-hydrastine [(+)-beta-hydrastine] and hydrastinine hydrochloride did not reduce dopamine content. The IC( 50) values of (1R,9S)-beta-hydrastine hydrochloride and (1R,9S)-beta-hydrastine were 9.3 microM and 20.7 microM , respectively. Next, the intracellular mechanisms of (1R ,9S )-beta-hydrastine hydrochloride in PC12 cells were investigated. Dopamine content decreased at 6 h and reached a minimal level at 24 h after the exposure of PC12 cells to 20 microM (1R,9S)-beta-hydrastine hydrochloride. Tyrosine hydroxylase (TH) activity was inhibited at 6 h following the treatment with (1R,9S)-beta-hydrastine hydrochloride, and was maintained at a reduced level for up to 36 h in PC12 cells (17 - 27 % inhibition at 20 microM), whereas TH mRNA level was not found to alter for 24 h. However, the level of intracellular Ca++ concentration decreased by treatment with (1R ,9S )-beta-hydrastine hydrochloride at 20 microM by 18.4 % inhibition relative to the control level in PC12 cells. These results suggest that (1R ,9S )-beta-hydrastine hydrochloride contributes partially to the decrease in dopamine content by the inhibition of TH activity in PC12 cells.

17: Planta Med. 2001 Aug ;67 (6):561-4.
Antibacterial activity of Hydrastis canadensis extract and its major isolated alkaloids.

Scazzocchio F, Cometa MF, Tomassini L, Palmery M.

The effects of hydrastine derivatives on dopamine biosynthesis in PC12 cells were The antibacterial activity of extract and isolated major alkaloids (berberine, beta-hydrastine, canadine and canadaline) of Hydrastis canadensis L. (Ranunculaceae) was evaluated against 6 strains of microorganism: Staphylococcus aureus (ATCC 25 993 and ATCC 6538P), Streptococcus sanguis (ATCC 10 556), Escherichia coli (ATCC 25 922), Pseudomonas aeruginosa (ATCC 27 853). Bactericidal activity was evaluated by contact test by measuring the "killing time" on a low density bacterial inoculum, and bacteriostatic activity in liquid medium by M.I.C. values. The results provide a rational basis for the traditional antibacterial use of Hydrastis canadensis.

18: J Pharm Sci. 2001 Jul ;90 (7):817-22.
High-performance liquid chromatography determination of hydrastine and berberine in dietary supplements containing goldenseal.

Abourashed EA, Khan IA.
National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy , University of Mississippi , University , Mississippi 38677 , USA .

Goldenseal (Hydrastis canadensis L., Ranunculaceae) is an ingredient of various dietary supplements intended for enhancing general body immunity. Many goldenseal products are currently available in the United States , either alone or in combination with echinacea. In most products, the content of the main active alkaloids of goldenseal, hydrastine and berberine, is not indicated on the label. A high-performance liquid chromatography (HPLC) method has been developed for the detection and quantification of hydrastine and berberine in a number of products obtained from the United States market. The method uses a Phenomenex Luna C( 18) column, a mobile phase consisting of solvent A ( 100 mM sodium acetate/acetic acid, pH 4.0) and solvent B (acetonitrile/methanol; 90/10, v/v). Elution was run at a flow rate of 1.0 mL/min, with a linear gradient of 80- 40% A in B over 20 min and ultraviolet detection at 290 nm. A wide range of content variation was observed for both alkaloids in the tested samples.

19: Anticancer Drug Des. 2000 Aug ;15 (4):255-64.
The 9-position in berberine analogs is an important determinant of DNA topoisomerase II inhibition.

Krishnan P, Bastow KF.
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina at Chapel Hill 27599, USA.

A current model suggests that the intercalative and minor groove binding components of protoberberines and related compounds are important for DNA topoisomerase I and/or II inhibition. The significance of the 9-substituent in berberine on drug-topoisomerase II interactions is reported here and is based on a comparison of 9-ethoxycarbonyl berberine (compound 1), 9-N,N-dimethylcarbamoyl berberine (compound 2) and 12-bromo berberine (methoxy group at 9-position; compound 3) as enzyme inhibitors. Compound 1 selectively inhibited topoisomerase II and stabilized cleavage complexes predominantly at unique sites and some background sites (depending on the concentration). This agent also allowed partial dissociation of enzyme from the DNA in the absence of religation, indicating unique interactions between 1, enzyme and DNA in the ternary complexes. Compound 2, which had similar DNA binding properties to 1, was not a topoisomerase II poison in the tested concentration range. In contrast, compound 3 was a stronger DNA binding agent but a much weaker enzyme poison both in vitro and in cell-based assays. The results show that the proposed drug domain for DNA intercalation is not a major determinant of enzyme inhibition for simple berberine analogs. Rather, the 9-substituent within the domain has a major influence, presumably by facilitating drug interaction with enzyme and/or enzyme-DNA complexes.


20: Pharmacol Toxicol. 2000 Nov ;87 (5):218-22.
Relaxant effects of Hydrastis canadensis L. and its major alkaloids on guinea pig isolated trachea.

Abdel-Haq H, Cometa MF, Palmery M, Leone MG, Silvestrini B, Saso L.
Department of Pharmacology of Natural Substances and General Physiology, University of Rome La Sapienza, Italy.

Hydrastis or goldenseal, one of the most popular medicinal herbs in the U.S.A. , is used in mild pathological conditions like cold and flu, based on the pharmacological properties of its active components, berberine (anticholinergic, antisecretory, and antimicrobial) and beta-hydrastine (astringent). We previously reported the relaxant effect of a total ethanolic extract of hydrastis on carbachol precontracted isolated guinea pig trachea, and with the present study, using the same experimental model, we aimed at evaluating the contribution of its major alkaloids, berberine, beta-hydrastine, canadine and canadaline to the total effect. Furthermore, using specific pharmacological tools, like timolol and xanthine amine congener, we attempted to elucidate its mechanism of action. The EC50 of berberine, beta-hydrastine, canadine and canadaline, were 34.2+/-0.6, 72.8+/-0.6, 11.9+/-1.2 and 2.4+/-0.8 microg/ml, respectively. Timolol effectively antagonized the effect of canadine (EC50 = 19.7+/-3.0 microg/ml) and canadaline (EC50 = 17.1+/-1.2 microg/ml) but not that of berberine and beta-hydrastine, while xanthine amine congener antagonized the effect of beta-hydrastine (EC50 = 149.9+/-35.3 microg/ml) and canadaline (EC50 = 26.1+/-3.0 microg/ml) but not that of berberine and canadine. Besides, the hydrastis extract, at concentrations between 0.01 and 0.1 microg/ml, potentiated the relaxant effect of isoprenaline on carbachol-precontracted isolated guinea pig trachea. These data, which are insufficient to draw definite mechanistic conclusions, indicate that the aforementioned alkaloids may act by interacting with adrenergic and adenosinic receptors.

21: Phytother Res. 2000 Dec ;14 (8):612-6.
Antioxidants in medicinal plant extracts. A research study of the antioxidant capacity of Crataegus, Hamamelis and Hydrastis.

Periera da Silva A, Rocha R, Silva CM, Mira L, Duarte MF, Florencio MH.
Laboratorio de Genetica da Faculdade de Medicina de Lisboa, 1600 Lisboa, Portugal.

The antioxidant capacity of extracts of Crataegus oxyacantha, Hamamelis virginiana, Hydrastis canadensis, plants native to Europe and North America which have long been used in herbal medicine for the treatment of cardiac and circulatory functions, has been investigated. The total antioxidant potential conferred by all hydrogen donating antioxidants present in these extracts has been assessed by the ABTS assay and the relative order of antioxidant potential has been established. Gas chromatography coupled to mass spectrometry (GC-MS) has been used for the chemical identification of the antioxidant volatile compounds present in the extracts. The GC-MS data were related to the results obtained using the ABTS assay.

22: Am J Chin Med. 2000 ;28 (2):227-38.
Effects of berberine on arylamine N-acetyltransferase activity and 2-aminofluorene-DNA adduct formation in human leukemia cells.

Chung JG, Chen GW, Hung CF, Lee JH, Ho CC, Ho HC, Chang HL, Lin WC, Lin JG.
Department of Microbiology, China Medical College , Taichung , Taiwan .
Berberine is an alkaloid occurring in the plant genera Berberis and Coptis. Although berberine had been demonstrated to have antineoplastic function by inhibiting DNA-synthesis in activated lymphocytes, there is no available information to address berberine affects on human leukemia cell N-acetyltransferase (NAT) activity and 2-aminofluorene (AF)-DNA adduct formation. Thus, berberine was tested for inhibition of arylamine NAT activity and AF-DNA adduct formation in human leukemia cells. The NAT activity was measured by a high performance liquid chromatography assaying for the amounts of N-acetyl-2-aminofluorene (AAF) and N-acetyl-p-aminobenzoic acid (N-Ac-PABA) and the remaining AF and p-aminobenzoic acid (PABA). The NAT activity and AF-DNA adduct formation in human leukemia cells were inhibited by berberine in a dose-dependent manner, i.e. the higher the concentration of berberine, the higher the inhibition of NAT activity and AF-DNA adduct. The data also indicate that berberine decreased the apparent values of Km and Vmax from human leukemia cells in both cytosol and intact cells.

23: J Ethnopharmacol. 2000 Aug ;71 (3):449-56.
Structural modification of berberine alkaloids in relation to cytotoxic activity in vitro.

Orfila L. Unidad de Cultivo Celular-Toxicologia, Instituto de Investigaciones Farmaceuticas, Universidad Central de Venezuela, Caracas, Venezuela.
The cytotoxicity of two protoberberine alkaloids: berberine and lincangenine, their 8-hydroxy-7 ,8 -dihydro-derivatives and tetrahydroprotoberberine:thaicanine, was evaluated. The cellular responses through the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] (MTT) method were measured in Hela (uterus carcinoma), SVKO3 (ovary carcinoma), Hep-2 (larynx carcinoma), primary culture from mouse embryon, and human fibroblast cells at the concentration: 10-1000 ppm (microg/ml) for 24 h. Berberine showed the highest cytotoxicity among the compounds tested, giving LC50 values for all cell lines at the concentration of 10 ppm. The results indicated that the cytotoxicity was notably decreased by structural changes, i.e. by modulation of the planarity caused by the introduction of hydroxyl group at C-8 and concomitant saturation of double bond between N-C8 in protoberberine molecules. In the case of berberine, the cytotoxic effect changed from 98.8 (berberine) to 39% for 8-hydroxydihydroberberine at the concentration of 100 ppm in Hela cells line. The same effect was observed with lincangenine and 8-OH-lincangenine (cytotoxicities 70 and 25%, respectively, at 1000 ppm in SVKO3 cells). On the other hand, these compounds showed a low selectivity for the different human cancer cell lines tested.

24: Proc Natl Acad Sci U S A. 2000 Feb 15 ;97 (4):1433-7.
Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 5'-methoxyhydnocarpin, a multidrug pump inhibitor.

Stermitz FR. Department of Chemistry, Colorado State University, Fort Collins , CO 80523 , USA .


Multidrug resistance pumps (MDRs) protect microbial cells from both synthetic and natural antimicrobials. Amphipathic cations are preferred substrates of MDRs. Berberine alkaloids, which are cationic antimicrobials produced by a variety of plants, are readily extruded by MDRs. Several Berberis medicinal plants producing berberine were found also to synthesize an inhibitor of the NorA MDR pump of a human pathogen Staphylococcus aureus. The inhibitor was identified as 5'-methoxyhydnocarpin (5'-MHC), previously reported as a minor component of chaulmoogra oil, a traditional therapy for leprosy. 5'-MHC is an amphipathic weak acid and is distinctly different from the cationic substrates of NorA. 5'-MHC had no antimicrobial activity alone but strongly potentiated the action of berberine and other NorA substrates against S. aureus. MDR-dependent efflux of ethidium bromide and berberine from S. aureus cells was completely inhibited by 5'-MHC. The level of accumulation of berberine in the cells was increased strongly in the presence of 5'-MHC, indicating that this plant compound effectively disabled the bacterial resistance mechanism against the berberine antimicrobial.

25: Cancer Lett. 2000 Jan 1 ;148 (1):19-25.
Inhibitory effect of Coptidis Rhizoma and berberine on the proliferation of human esophageal cancer cell lines.

Iizuka N, Miyamoto K, Okita K, Tangoku A, Hayashi H, Yosino S, Abe T, Morioka T, Department of Bioregulatory Function, Yamaguchi University School of Medicine, Ube, Japan.
Our previous study demonstrated that the herbal medicine, Oren-to, had antitumor effects on esophageal cancer cells (ECCs) in vitro. The purpose of this study was to examine which of the seven constituents of Oren-to had antitumor effects on esophageal cancer cells. MTT assay showed that, of the seven constituents, only the aqueous extract of Coptidis Rhizoma had potent inhibitory effect on the proliferation of two types of ECC lines, YES-3 and YES- 4. In addition, the proliferation of all six types of ECC lines (YES-1 to YES-6) was inhibited in a dose-dependent manner (P<0.001 for all), when co-cultured at each concentration of Coptidis Rhizoma for 72 h. The ID50 of Coptidis Rhizoma for YES-1 to YES-6 was 2.2 microg/ml, 3.0 microg/ml, 0.25 microg/ml, 2.8 microg/ml, 2.5 microg/ml, and 0.5 microg/ml, respectively, berberine, one of protoberberine components of Coptidis Rhizoma, showed potent antitumor effects on all six types of ECC lines as well as Coptidis Rhizoma. In addition, the ID50 of berberine showed a positive correlation with that of Coptidis Rhizoma in six types of ECC lines examined (r2 = 0.763, P = 0.023). Cell cycle analysis of Coptidis Rhizoma-treated cancer cells showed the accumulation of cells in the G0/G1 phase and relative decrease of the S phase. These results support the possibility that the use of Coptidis Rhizoma containing abundant berberine may be useful as one of alternative therapies for esophageal cancers.

26: Biosci Biotechnol Biochem. 1999 Sep ;63 (9):1557-62.
Inhibition of Candida rugosa lipase by berberine and structurally related alkaloids, evaluated by high-performance liquid chromatography.

Grippa E, Valla R, Battinelli L, Mazzanti G, Saso L, Silvestrini B.
Department of Pharmacology of Natural Substances and General Physiology, University of Rome La Sapienza, Italy.

It is known that certain microorganisms produce extracellular lipase to better colonize the skin and mucosal surfaces. Since different extracts from medicinal plants have anti-lipase activity (Shimura et al., Biosci. Biotechnol. Biochem., 56: 1478-1479, 1992), we examined the effects of selected natural substances on Candida rugosa lipase. In the presence of the compounds under examination, the enzyme was incubated with beta-naphthyl laurate, and beta-naphthol, produced by the enzymatic reaction, was extracted with ethyl acetate and analyzed by reversed phase HPLC, using a C-18 column. Thus, the inhibitory activity was calculated by a proper formula based on the variations of the area under the chromatographic peak of beta-naphthol. The method was validated by analyzing substances with known anti-lipase activity such as saturated fatty acids (C10-16) and tetracycline. Berberine and a number of structurally related alkaloids such as chelidonine, chelerythrine, and sanguinarine appeared active. This property of berberine and sanguinarine is of interest because they are used in pathological conditions in which microbial lipases could play a pathogenic role.


27: Biomed Chromatogr. 1999 Nov ;13 (7):442-4.
Relationship between the clinical effects of berberine on severe congestive heart failure and its concentration in plasma studied by HPLC.

Zeng X, Zeng X.
Chengdu University and Section of Cardiology, Chengdu Second Municipul Hospital, Chengdu, Sichuan 610081, People's Republic of China.
It has been reported that berberine is valuable for long-term treatment of ventricular premature beats (VPBs) and leads to a decrease in mortality for patients with congestive heart failure (CHF). In order to improve its therapeutic value and reduce its side effects, it is necessary to study the relationship between its activity and plasma concentration in patients with CHF. Patients with CHF were treated with conventional therapy for 2 weeks. Immediately after the data from a dynamic electrocardiogram (DCG) and left ventricular ejection fraction (LVEF) were obtained, 1.2 g/day of oral berberine was given. After 2 weeks of berberine therapy, the DCG data and LVEF were reassessed and the plasma berberine concentration was measured by HPLC. Plasma samples were pretreated by extraction with chloroform. Berberine in all samples was determined using a mu Bondapak C( 18) column, a mobile phase of acetonitrile:0.02 mol/L phosphoric acid (45:55, v/v), and a UV detector at 346 nm. The mean recovery was 96.5%. The linear range was 40-1600 ng/mL. The detection limit for berberine in plasma was 0. 4 ng. The decrease in frequency and complexity of VPBs and the increase in LVEF in patients with plasma berberine concentrations higher than 0.11 mg/L (n = 31, group B) were more significant than at concentrations lower than 0.11 mg/L (p < 0.01 vs p < 0.05). Copyright 1999 John Wiley & Sons, Ltd.

28: Br J Cancer. 1999 Oct ;81 (3):416-22.
Berberine modulates expression of mdr1 gene product and the responses of digestive track cancer cells to Paclitaxel.

Lin HL, Liu TY, Wu CW, Chi CW.
Department of Medical Research and Education, Veterans General Hospital-Taipei, Taiwan, ROC.

It has been reported that berberine is valuable for long-term treatment of ventricular Berberine is the major constituent of Coptis chinese and is commonly used in Chinese herbal medicine to treat patients with gastrointestinal disorders. In this study, using flow cytometry, we have found that a 24-h berberine treatment up-regulated the multidrug-resistant transporter (pgp-170) expression in two oral (KB, OC2), two gastric (SC-M1, NUGC-3) and two colon (COLO 205, CT 26) cancer cell lines. Decreased retention of rhodamine 123 was observed in berberine-treated cells as compared to vehicle control. To examine whether the berberine modulated pgp-170 expression in cancer cells is associated with changes in drug resistance, we determined the cytotoxicity, cell cycle progression and cell morphology of Paclitaxel-treated cells. Paclitaxel (1 nM-10 microM) treatment for 24 h induced cytotoxicity in OC2, SC-M1 and COLO 205 cells in a dose-dependent manner. Pretreatment of cells with 32 microM berberine for 24 h prior to Paclitaxel treatment resulted in increased viability as compared to that of Paclitaxel-treated cells. In addition, Paclitaxel-induced apoptosis and/or G2/M arrest in these three cancer cell lines. Pretreatment of cells with berberine prior to Paclitaxel blocked the Paclitaxel-induced cell cycle responses and morphological changes. These results together suggest that berberine modulated the expression and function of pgp-170 that leads to reduced response to Paclitaxel in digestive track cancer cells.

29: Am J Chin Med. 1999 ;27 (2):265-75.
Effects of berberine on arylamine N-acetyltransferase activity in human colon tumor cells.

Lin JG, Chung JG, Wu LT, Chen GW, Chang HL, Wang TF.
Institute of Chinese Medical Science, China Medical College , Taichung , Taiwan
It has been reported that berberine is valuable for long-term treatment of ventricular Berberine is the major constituent of Coptis chinese and is commonly used in Chinese Berberine was used to determine loss of viable cells and inhibition of arylamine Nacetyltransferase (NAT) activity in a human colon tumor (adenocarcinoma) cell line. The viable cells were determined by trypan blue exclusion under a light microscope. The NAT activity was measured by high performance liquid chromatography for the amounts of N-acetyl-2-aminofluorene (AAF), N-acetyl-p-aminobenzoic acid (N-Ac-PABA), and the remaining 2-aminofluorene (AF) and p-aminobenzoic acid (PABA). The viability and NAT activity in a human colon tumor cell line was inhibited by berberine in a dose-dependent manner, i.e., the higher the concentration of berberine, the higher the inhibition of NAT activity and cell death. The NAT activities measured in the intact human colon tumor cells were decreased over 50% by AAF and NAc-PABA production from acetylation of AF and PABA. The apparent values of Kmoff and Vmax of NAT from colon tumor cells were also inhibited by berberine in cytosols and in intact cells. This report is the first to show that berberine did affect human colon tumor cell NAT activity.

30: J Ethnopharmacol. 1999 Aug ;66 (2):227-33.
Inhibition by berberine of cyclooxygenase-2 transcriptional activity in human colon cancer cells.

Fukuda K, Hibiya Y, Mutoh M, Koshiji M, Akao S, Fujiwara H.
Department of Oriental Medicine, Gifu University School of Medicine, Japan.
It has been reported that berberine is valuable for long-term treatment of ventricular Berberine is the major constituent of Coptis chinese and is commonly used in Chinese

The enzyme cyclooxygenase-2 (COX-2) is abundantly expressed in colon cancer cells and plays a key role in colon tumorigenesis. Compounds inhibiting COX-2 transcriptional activity have therefore potentially a chemopreventive property against colon tumor formation. An assay method for estimating COX-2 transcriptional activity in human colon cancer cells was established using a beta-galactosidase reporter gene system, and examination was made of various medicinal herbs and their ingredients for an inhibitory effect on COX-2 transcriptional activity. We found that berberine, an isoquinoline alkaloid present in plants of the genera Berberis and Coptis, effectively inhibits COX-2 transcriptional activity in colon cancer cells in a dose- and time-dependent manner at concentrations higher than 0.3 microM. The present findings may further explain the mechanism of anti-inflammatory and anti-tumor promoting effects of berberine.


31: Immunol Lett. 1999 Jun 1 ;68 (2-3):391-5.
Increased production of antigen-specific immunoglobulins G and M following in vivo treatment with the medicinal plants Echinacea angustifolia and Hydrastis canadensis.

Rehman J. Department of Internal Medicine, Veterans Affairs Medical Center and University of California , San Diego 92161 , USA

It has been reported that berberine is valuable for long-term treatment of ventricular Berberine is the major constituent of Coptis chinese and is commonly used in Chinese

A number of immunomodulatory effects have been attributed to the medicinal plants Echinacea angustifolia and Goldenseal (Hydrastis canadensis); however, little is known about whether treatment with these plants can enhance antigen-specific immunity. We investigated the antigen-specific in vivo immunomodulatory potential of continuous treatment with Echinacea and Goldenseal root extract over a period of 6 weeks using rats that were injected with the novel antigen keyhole limpet hemocyanin (KLH) and re-exposed to KLH after the initial exposure. Immunoglobulin production was monitored via ELISA continuously over a period of 6 weeks. The Echinacea-treated group showed a significant augmentation of their primary and secondary IgG response to the antigen, whereas the Goldenseal-treated group showed an increase in the primary IgM response during the first 2 weeks of treatment. Our results suggest that medicinal plants like Echinacea or Goldenseal may enhance immune function by increasing antigen-specific immunoglobulin production.


32: Food Chem Toxicol. 1999 Apr ;37 (4):319-26.
Effects of berberine on arylamine N-acetyltransferase activity in human bladder tumour cells.

Chung JG, Wu LT, Chu CB, Jan JY, Ho CC, Tsou MF, Lu HF, Chen GW, Lin JG, Wang TF.
Department of Microbiology, China Medical College , Taichung , Taiwan , Republic of China .

Berberine was used to determine inhibition of arylamine N-acetyltransferase (NAT) activity in human bladder tumour cells. The NAT activity was measured by HPLC assaying for the amounts of N-acetyl-2-aminofluorene (AAF) and N-acetyl-p-aminobenzoic acid (N-Ac-PABA) and remaining 2-aminofluorene (AF) and p-aminobenzoic acid (PABA). Two assay systems were performed, one with cellular cytosols, the other with intact bladder tumour cell suspensions. The NAT activity in human bladder tumour cells was inhibited by berberine in a dose-dependent manner, that is, the higher the concentration of berberine, the higher the inhibition of NAT activity. The values of apparent Km and Vmax calculated from cytosol NAT and intact cells were also decreased by berberine. This report is the first demonstration to show berberine did affect human bladder tumour cell NAT activity.

33: Planta Med. 1999 May ;65 (4):381-3.
Inhibition of activator protein 1 activity by berberine in human hepatoma cells.

Fukuda K, Hibiya Y, Mutoh M, Koshiji M, Akao S, Fujiwara H.
Activator protein 1 (AP-1) is a transcription factor which plays a critical role in inflammation and carcinogenesis. The present study was conducted to investigate the effect of berberine, an isoquinoline alkaloid present in plants of the genera Berberis and Coptis, on the activity of AP-1 using a reporter gene assay in human hepatoma cells. Berberine was shown to inhibit AP-1 activity in a dose- and time-dependent manner at concentrations higher than 0.3 microM. Berberine inhibited AP-1 activity almost completely as low as 10 microM after 48 h treatment. The inhibitory effect on AP-1 activity in cancer cells may further explain the anti-tumor promoting activity of berberine.

34: Int J Cancer. 1999 Jun 11 ;81 (6):923-9.
Berberine-induced apoptosis of human leukemia HL-60 cells is associated with down-regulation of nucleophosmin/B23 and telomerase activity.

Wu HL, Hsu CY, Liu WH, Yung BY.
Department of Pharmacology, College of Medicine , Chang Gung University , Taiwan , China .
The steady-state level of nucleophosmin/B23 mRNA decreased during berberine-induced (25 microg/ml, 24 to 96 hr) apoptosis of human leukemia HL-60 cells. A decline in telomerase activity was also observed in HL-60 cells treated with berberine. A stable clone of nucleophosmin/B23 overexpressed in HL-60 cells was selected and found to be less responsive to berberine-induced apoptosis. About 35% to 63% of control vector-transfected cells (pCR3) exhibited morphological characteristics of apoptosis, while about 8% to 45% of nucleophosmin/B23-over-expressed cells (pCR3-B23) became apoptotic after incubation with 15 microg/ml berberine for 48 to 96 hr. DNA extracted from pCR3 cells contained more fragmented DNA than pCR3-B23 cells during treatment with 15 microg/ml berberine for 24 to 48 hr. Our results indicate that berberine-induced apoptosis is associated with down-regulation of nucleophosmin/B23 and telomerase activity. We also suggest that nucleophosmin/B23 may play an important role in the control of the cellular response to apoptosis induction.

35: Cancer. 1999 May 1 ;85 (9):1937-42.
Up-regulation of multidrug resistance transporter expression by berberine in human and murine hepatoma cells.

Lin HL, Liu TY, Lui WY, Chi CW.
Department of Medical Research and Education, Veterans General Hospital-Taipei, Taiwan, Republic of China.
BACKGROUND: Berberine, one of the major constitutents of alkaloids of Coptis chinensis is frequently utilized in the treatment of inflammation and liver-related diseases. In Chinese herbal medicine, Coptis chinensis is used as a prophylactic drug to treat gastrointestinal disorders. In a previous study, the authors found that berberine reduced cell proliferation and alpha-fetoprotein expression in human hepatoma HepG2 cells. Multidrug resistance transporter (pgp-170) is known to be overexpressed in HepG2 cells. Whether berberine regulates the expression of pgp- 170 in HepG2 and other hepatoma cell lines is unknown and worthy of investigation. METHODS: Human and murine hepatoma cells were treated with berberine (0.32, 3.2, 32, and 320 microM), tamoxifen (1 microM), or verapamil (10 microM) for 24 hours. Flow cytometry was used to measure retention of a fluorescence dye, rhodamine 123, and the level of immunoreactive pgp- 170 in berberine-treated hepatoma cells. RESULTS: Berberine up-regulated the expression of pgp- 170 in three human hepatoma cell lines. The function of pgp-170 was blocked by tamoxifen and verapamil, resulting in increased retention of rhodamine 123. Retention of rhodamine 123 was significantly reduced in berberine-treated hepatoma cells. CONCLUSIONS: Berberine modulates the expression and function of pgp- 170 in hepatoma cells. These results suggest that treatment of tumor cells with berberine may result in reduced retention of chemotherapeutic agents.

36: Eur J Pharmacol. 1999 Feb 26 ;368 (1):111-8.
Berberine inhibits ion transport in human colonic epithelia.

Taylor CT , Winter DC, Skelly MM, O'Donoghue DP, O'Sullivan GC, Harvey BJ, Baird AW.
Department of Pharmacology, University College Dublin , Belfield , Ireland .
The effects of berberine on ion transport in both human colonic mucosal epithelia and an intestinal epithelial cell line (T84) were examined. Berberine (concentration range 0-500 microM) reduced both basal and stimulated ion transport responses in human colonic mucosae in a manner which was non-specific for Ca2+ -or cAMP-mediated signals. Similarly, in cultured intestinal epithelial monolayers, berberine inhibited Ca2+ -and cAMP-mediated responses indicating an inhibitory activity directly at the level of the epithelium rather than an indirect effect through other mucosal element(s). Berberine did not alter the rate of generation of cAMP by adenylyl cyclase or the activity of protein kinase A, the effector enzyme of the cAMP pathway. Berberine inhibited carbachol-stimulated 86Rb+ efflux from T84 monolayers. Berberine also inhibited K+ conductance in apically-permeabilised re-sected mucosae. These results indicate i) that berberine exerts an anti-secretory action directly upon epithelial cells and ii) the mechanism of action may be at the level of blockade of K+ channels.

37: J Nat Prod. 1998 Oct ;61 (10):1187-93.
Antitubercular natural products: berberine from the roots of commercial Hydrastis canadensis powder. Isolation of inactive 8-oxotetrahydrothalifendine, canadine, beta-hydrastine, and two new quinic acid esters, hycandinic acid esters-1 and -2.

Gentry EJ, Jampani HB, Keshavarz-Shokri A, Morton MD, Velde DV, Telikepalli H.
PathoGenesis Corporation, 201 Elliott Avenue West, Suite 150, Seattle, Washington 98119, USA.


Berberine (4) is responsible for the activity of an extract of a commercial root sample of Hydrastis canadensis against multiply drug resistant Mycobacterium tuberculosis. Two new quinic acid feruloyl esters, compounds 2 and 3, have been isolated from the same source along with canadine (1c), 8-oxotetrahydrothalifendine (1), and beta-hydrastine (5). These were found to be inactive. The structures of the new compounds were elucidated from spectral (1H, 13C , HMQC, HMBC, and H-H COSY) and chemical evidences.

38: Life Sci. 1998 ;62 (25):2283-94.
Inhibitory effects of berberine on voltage- and calcium-activated potassium currents in human myeloma cells.

Wu SN, Yu HS, Jan CR, Li HF, Yu CL .
Department of Medical Education and Research, Veterans General Hospital , Kaohsiung , Taiwan .
The effects of berberine, an isoquinoline alkaloid, were investigated in human myeloma cells. In cells with intracellular Ca2+ concentration ([Ca2+ ]i ) = 10 nM, the depolarizing square pulses from -80 mV elicited an instantaneous outward current with an inactivation. This outward current was voltage dependent, activating at -30 mV and showed inactivation with repetitive depolarization, and was hence believed to be n type voltage-activated K+ current ( IK( V)). Berberine (30 microM) produced a prolongation in the recovery of IK( V) inactivation. In cells with [Ca2+ ]i = 1 microM, berberine also inhibited A23187-induced IK(Ca). Berberine (1-300 microM) caused the inhibition of IK( V) and IK(Ca) in the concentration-dependent manners. The IC50 values of berberine-induced inhibition of IK( V) and IK(Ca) were approximately 15 microM and 50 microM, respectively. In inside-out configurations, berberine inside the pipette suppressed the activity of K( Ca) channels without changing the single channel conductance. Berberine also inhibited the proliferation of this cell line and the IC50 value of berberine-induced inhibition of cell proliferation was 5 microM. Thus, the cytotoxic effect of berberine in cancer cells may be partially explained by its direct blockade of these K+ channels.

39: East Afr Med J. 1997 May ;74 (5):283-4.
Treatment of chloroquine-resistant malaria using pyrimethamine in combination with berberine, tetracycline or cotrimoxazole.

Sheng WD, Jiddawi MS, Hong XQ, Abdulla SM .
Jiang Yin Peoples Hospital , Jiangsu , China .

Two hundred and fifteen patients with chloroquine-resistant malaria were randomised into three groups. The first group of 82 patients were given pyrimethamine and berberine (berberine group), the second group of 64 patients, pyrimethamine and tetracycline (tetracycline group) and the third group of 69 patients were given pyrimethamine and cotrimoxazole (cotrimoxazole group). In the berberine group, the clearance, rate of asexual parasitaemia was 74.4% after treatment, while in the tetracycline group it was 67.2% and in the cotrimoxazole group 47.8%. These results indicate that berberine is more effective in clearing the parasite than both tetracycline and cotrimoxazole, and that the combination of pyrimethamine and berberine gives the best results for chloroquine resistant malaria.

40: J Pharm Pharmacol. 1995 Dec ;47 (12A):1029-31.
Inhibition of in-vitro lymphocyte transformation by the isoquinoline alkaloid berberine.

Ckless K, Schlottfeldt JL, Pasqual M, Moyna P, Henriques JA, Wajner M.
Departamento de Bioquimica, UFRGS, Porto Alegre, Brasil.
The effects of berberine, an isoquinoline alkaloid, were investigated in human myeloma cells. In cells with intracellular Ca2+ concentration ([Ca2+ ]i ) = 10 nM, the depolarizing Berberine is an isoquinoline alkaloid with multiple pharmacological actions, including an anti-inflammatory activity. The effects of berberine on in-vitro cellular proliferation of human peripheral lymphocytes stimulated with phytohaemagglutinin, concanavalin A and pokeweed mitogen were studied. Mononuclear cells were cultured in flat-bottomed 96-well microplates at 37 degrees C for 96-144 h in the presence of one mitogen at different concentrations and the alkaloid at doses of 2.5 to 20 microg mL-1 . The mitogen-induced response of lymphocytes was evaluated from the extent of the incorporation of [3H ]thymidine into cells in-vitro. A consistent and progressive inhibitory influence of berberine with increasing concentrations in culture was identified with all mitogens and was more pronounced with pokeweed mitogen. The effect of berberine was observed in phytohaemagglutinin (PHA)-and concanavalin A-activated lymphocytes when the drug was added during the first 24 h of culture, whereas the same effect occurred throughout the incubation period in pokeweed mitogen-stimulated cells. The viability of lymphocytes following treatment with the drug, as assessed by the trypan blue exclusion test, revealed no change when compared with the same untreated lymphocytes, indicating no lymphocytotoxic activity. We conclude that some effects of berberine, especially its anti-inflammatory action, may arise in part from the inhibition of DNA-synthesis in activated lymphocytes.

41: Cancer Lett. 1995 Jul 13 ;93 (2):193-200.

Berberine complexes with DNA in the berberine-induced apoptosis in human leukemic HL-60 cells.

Kuo CL, Chou CC, Yung BY.
Graduate Institute of Pharmacology, Yang Ming Medical College , Taiwan , ROC.
The effects of berberine, an isoquinoline alkaloid, were investigated in human myeloma cells. In cells with intracellular Ca2+ concentration ([Ca2+ ]i ) = 10 nM, the depolarizing Berberine, an alkaloid initially isolated from Chinese herbal medicine exhibited the ability to induce morphological changes and internucleosomal DNA fragmentation, characteristic of apoptosis in promyelocytic leukemia HL-60 cells. Cell cycle studies showed that only about 20% of the cells underwent apoptosis at the early time (6 h) of berberine (25 micrograms/ml) treatment; these appeared to be cells in S phase at the time of berberine treatment. At extended time (6-48 h), cells were cell cycle arrested, the number of cells of each phase, particularly the cells of S phase decreased and much more (> 50%) of the cells appeared with DNA content less than G1. Attempts were also made to isolate possible berberine-DNA complexes from cell cultures treated with berberine (25 micrograms/ml; 2-24 h). Shifts of absorption maxima of berberine in the direction of longer wavelengths were observed in the isolated berberine-DNA complexes. Palmatine, an analog of berberine, which was not able to induce apoptosis, also complexed with DNA in cells treated with palmatine (25 micrograms/ml; 2-24 h). Our results suggest that some important cellular processes other than the intracellular DNA-interacting action of berberine may be involved in the berberine-induced apoptosis in HL-60 cells.

42: Zhongguo Zhong Xi Yi Jie He Za Zhi. 1994 Dec ;14 (12):718-20.
[Effect of berberine on transit time of human small intestine]

Yuan J, Shen XZ, Zhu XS.
Third People's Hospital of Suzhou , Jiangsu .

Sorbitol was used as a test sugar for the determination of small intestinal transit time (SITT) by means of breath hydrogen test (BHT). After oral administration of 15g sorbitol, breath hydrogen increased markedly (delta H2 > 5 mumol/L) in 26 of 30 subjects. Following ingestion of a mixture of meglucamine diatrizoate and sorbitol by 18 subjects, SITT measured by BHT correlated closely with the simultaneously determined time for the meglucamine diatrizoate in reaching ileo-cecum. The BHT was used to investigate the effect of berberine on SITT in human. SITT in 20 healthy subjects was 71.10 +/- 22.04 min, SITT was significantly delayed to 98.25 +/- 29.03 min after oral administration of the 1.2g of berberine (P < 0.01). This result suggested that the antidiarrheal property of berberine might be mediated, at least in part, by its ability to delay the small intestinal transit.


43: Gematol Transfuziol. 1994 Sep-Oct ;39 (5):33-5.
[Effect of berb