Berberine Abstracts 3

© 2010

Berberine alters the processing of Alzheimer's amyloid precursor protein to decrease Abeta secretion

            (Asai, Iwata et al. 2007) Download

Berberine is an isoquinoline alkaloid isolated from Coptidis rhizoma, a major herb widely used in Chinese herbal medicine. Berberine's biological activity includes antidiarrheal, antimicrobial, and anti-inflammatory effects. Recent findings show that berberine prevents neuronal damage due to ischemia or oxidative stress and that it might act as a novel cholesterol-lowering compound. The accumulation of amyloid-beta peptide (Abeta) derived from amyloid precursor protein (APP) is a triggering event leading to the pathological cascade of Alzheimer's disease (AD); therefore the inhibition of Abeta production should be a rational therapeutic strategy in the prevention and treatment of AD. Here, we report that berberine reduces Abeta levels by modulating APP processing in human neuroglioma H4 cells stably expressing Swedish-type of APP at the range of berberine concentration without cellular toxicity. Our results indicate that berberine would be a promising candidate for the treatment of AD.

Genetic evidence for inhibition of bacterial division protein FtsZ by berberine

            (Boberek, Stach et al. 2010) Download

BACKGROUND: Berberine is a plant alkaloid that is widely used as an anti-infective in traditional medicine. Escherichia coli exposed to berberine form filaments, suggesting an antibacterial mechanism that involves inhibition of cell division. Berberine is a DNA ligand and may induce filamentation through induction of the SOS response. Also, there is biochemical evidence for berberine inhibition of the cell division protein FtsZ. Here we aimed to assess possible berberine mechanism(s) of action in growing bacteria using genetics tools. METHODOLOGY/PRINCIPAL FINDINGS: First, we tested whether berberine inhibits bacterial growth through DNA damage and induction of the SOS response. The SOS response induced by berberine was much lower compared to that induced by mitomycin C in an SOS response reporter strain. Also, cell filamentation was observed in an SOS-negative E. coli strain. To test whether berberine inhibits FtsZ, we assessed its effects on formation of the cell division Z-rings, and observed a dramatic reduction in Z-rings in the presence of berberine. We next used two different strategies for RNA silencing of ftsZ and both resulted in sensitisation of bacteria to berberine, visible as a drop in the Minimum Inhibitory Concentration (MIC). Furthermore, Fractional Inhibitory Concentration Indices (FICIs) showed a high level of synergy between ftsZ silencing and berberine treatment (FICI values of 0.23 and 0.25 for peptide nucleic acid- and expressed antisense RNA-based silencing of ftsZ, respectively). Finally, over-expression of ftsZ led to a mild rescue effect in berberine-treated cells. CONCLUSIONS: The results argue against DNA binding as the primary mechanism of action of berberine and support the hypothesis that its antibacterial properties are due to inhibition of the cell division protein FtsZ. In addition, the genetic approach used here provides a means to rapidly test the activity of other putative FtsZ inhibitors.

Berberine reduces methylation of the MTTP promoter and alleviates fatty liver induced by a high-fat diet in rats

            (Chang, Yan et al. 2010) Download

High-calorie food leads to nonalcoholic fatty liver disease (NAFLD) through dysregulation of genes involved in lipid metabolism, but the precise mechanism remains unclear. DNA methylation represents one of the mechanisms that contributes to dysregulation of gene expression via interaction with environmental factors. Berberine can alleviate fatty liver in db/db and ob/ob mice. Here, we investigated whether DNA methylation is involved in the pathogenesis of NAFLD induced by a high-fat diet (HFD) and whether berberine improves NAFLD through influencing the methylation status of promoters of key genes. HFD markedly decreased the mRNA levels encoding CPT-1alpha, MTTP, and LDLR in the liver. In parallel, DNA methylation levels in the MTTP promoter of rats with NAFLD were elevated in the liver. Interestingly, berberine reversed the downregulated expression of these genes and selectively inhibited HFD-induced increase in the methylation of MTTP. Consistently, berberine increased hepatic triglyceride (TG) export and ameliorated HFD-induced fatty liver. Furthermore, a close negative correlation was observed between the MTTP expression and its DNA methylation (at sites -113 and -20). These data indicate that DNA methylation of the MTTP promoter likely contributes to its downregulation during HFD-induced NAFLD and, further, that berberine can partially counteract the HFD-elicited dysregulation of MTTP by reversing the methylation state of its promoter, leading to reduced hepatic fat content.

Berberine inhibits p53-dependent cell growth through induction of apoptosis of prostate cancer cells

            (Choi, Oh et al. 2009) Download

Berberine has anti-tumor properties in some cancer cells including prostate cancer, but the exact mechanisms and in vivo effects are unclear. We investigated anti-cancer activity of berberine in vitro and in vivo, and possible mechanisms in prostate cancer cells. Berberine treatment inhibited cell cancer growth in a concentration (0-50 microM) and time- (0-48 h) dependent manner without any growth inhibition in normal human prostate epithelial PWR-1E cells. However, the p53 expressing LNCaP cells were more susceptible against berberine than the p53 lacking PC-3 cells. The cell arrest in G0/G1 phase, apoptotic cell death and the expression of apoptotic cell death proteins Bax and caspase-3 was much higher in berberine-treated LNCaP cells than those in PC-3 cells. Exploration of p53 siRNA or pifithrin-alpha, a p53 inhibitor to the LNCaP cells, suppressed berberine-induced cell death and expression of apoptosis-related proteins. In xenograft in vivo studies, berberine reduced tumor weights and volumes accompanied with apoptotic cell death and increased expression of apoptotic cell death proteins, however, the extent of inhibitory effect was more significant in LNCaP cell-bearing mice. Therefore, these results indicated that berberine inhibited p53-dependent prostate cancer cell death.

Hepatoprotective effects of berberine on carbon tetrachloride-induced acute hepatotoxicity in rats

            (Feng, Siu et al. 2010) Download

BACKGROUND: Berberine is an active compound in Coptidis Rhizoma (Huanglian) with multiple pharmacological activities including antimicrobial, antiviral, anti-inflammatory, cholesterol-lowering and anticancer effects. The present study aims to determine the hepatoprotective effects of berberine on serum and tissue superoxide dismutase (SOD) levels, the histology in tetrachloride (CCl4)-induced liver injury. METHODS: Sprague-Dawley rats aged seven weeks were injected intraperitoneally with 50% CCl4 in olive oil. Berberine was orally administered before or after CCl4 treatment in various groups. Twenty-four hours after CCl4 injection, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, serum and liver superoxide dismutase (SOD) activities were measured. Histological changes of liver were examined with microscopy. RESULTS: Serum ALT and AST activities significantly decreased in a dose-dependent manner in both pre-treatment and post-treatment groups with berberine. Berberine increased the SOD activity in liver. Histological examination showed lowered liver damage in berberine-treated groups. CONCLUSION: The present study demonstrates that berberine possesses hepatoprotective effects against CCl4-induced hepatotoxicity and that the effects are both preventive and curative. Berberine should have potential for developing a new drug to treat liver toxicity.

Quaternary protoberberine alkaloids

            (Grycova, Dostal et al. 2007) Download

This contribution reviews some general aspects of the quaternary iminium protoberberine alkaloids. The alkaloids represent a very extensive group of secondary metabolites with diverse structures, distribution in nature, and biological effects. The quaternary protoberberine alkaloids (QPA), derived from the 5,6-dihydrodibenzo[a,g]quinolizinium system, belong to a large class of isoquinoline alkaloids. Following a general introduction, the plant sources of QPA, their biosynthesis, and procedures for their isolation are discussed. Analytical methods and spectral data are summarized with emphasis on NMR spectroscopy. The reactivity of QPA is characterized by the sensitivity of the iminium bond CN(+) to nucleophilic attack. The addition of various nucleophiles to the protoberberine skeleton is discussed. An extended discussion of the principal chemical reactivity is included since this governs interactions with biological targets. Quaternary protoberberine alkaloids and some related compounds exhibit considerable biological activities. Recently reported structural studies indicate that the QPA interact with nucleic acids predominantly as intercalators or minor groove binders. Currently, investigations in many laboratories worldwide are focused on the antibacterial and antimalarial activity, cytotoxicity, and potential genotoxicity of QPA.

The therapeutic potential of Berberis darwinii stem-bark: quantification of berberine and in vitro evidence for Alzheimer's disease therapy

            (Habtemariam 2011) Download

Berberis darwinii is native to South America but has been widely distributed in Europe and other continents following its discovery by Charles Darwin. Herewith, the therapeutic potential of stem-bark of the plant for treating Alzheimer's disease was studied using an in vitro acetylcholinesterase inhibition assay. It was found that the methanolic extract of the stem-bark was a potent inhibitor of the enzyme with an IC50 value of 1.23 +/- 0.05 microg/mL. An HPLC-based berberine quantification study revealed an astonishing 38% yield of the dried methanolic extract.

Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine

            (Imanshahidi and Hosseinzadeh 2008) Download

Barberry (Berberis vulgaris L. family Berberidaceae) is well known in Iran and various parts of this plant including its root, bark, leaf and fruit have been used as folk medicine. The two decades of research has demonstrated different pharmacological and therapeutic effects of B. vulgaris and its isoquinoline alkaloids (particularly berberine). Studies carried out on the chemical composition of the plant show that the most important constituents of this plant are isoquinoline alkaloids such as berberine, berbamine and palmatine. Berberine represents one of the most studied among the naturally occurring protoberberine alkaloids. In addition to B. vulgaris (barberry), berberine is present in many other plants and is used for the treatment of different diseases. This article reviews the traditional uses and pharmacological effects of total extract and the most active ingredient of B. vulgaris (berberine).

Inhibitory activities of the alkaloids from Coptidis Rhizoma against aldose reductase

            (Jung, Yoon et al. 2008) Download

As part of our ongoing search of natural sources for therapeutic and preventive agents for diabetic complications, the rat lens aldose reductase (RLAR) inhibitory effect of Coptidis Rhizoma (the rhizome of Coptis chinensis Franch) was evaluated. Its extract and fractions exhibited broad and moderate RLAR inhibitory activities of 38.9 approximately 67.5 microg/mL. In an attempt to identify bioactive components, six quaternary protoberberine-type alkaloids (berberine, palmatine, jateorrhizine, epiberberine, coptisine, and groenlandicine) and one quaternary aporphine-type alkaloid (magnoflorine) were isolated from the most active n-BuOH fraction, and the chemical structures therein were elucidated on the basis of spectroscopic evidence and comparison with published data. The anti-diabetic complications capacities of seven C. chinensis-derived alkaloids were evaluated via RLAR and human recombinant AR (HRAR) inhibitory assays. Although berberine and palmatine were previously reported as prime contributors to AR inhibition, these two major components exhibited no AR inhibitory effects at a higher concentration of 50 microg/ml in the present study. Conversely, epiberberine, coptisine, and groenlandicine exhibited moderate inhibitory effects with IC(50) values of 100.1, 118.4, 140.1 microM for RLAR and 168.1, 187.3, 154.2 microM for HRAR. The results clearly indicated that the presence of the dioxymethylene group in the D ring and the oxidized form of the dioxymethylene group in the A ring were partly responsible for the AR inhibitory activities of protoberberine-type alkaloids. Therefore, Coptidis Rhizoma, and the alkaloids contained therein, would clearly have beneficial uses in the development of therapeutic and preventive agents for diabetic complications and diabetes mellitus.

Berberine inhibits human hepatoma cell invasion without cytotoxicity in healthy hepatocytes

            (Liu, Wang et al. 2011) Download

Conventional chemotherapy fails to cure metastatic hepatoma mainly due to its high hepatotoxicity. Many plant-derived agents have been accepted to effectively inhibit hepatoma cell invasion. However, the investigation that whether effectual plant-derived agents against invasive hepatoma cells exert unexpected cytotoxicity in healthy hepatocytes has been ignored. This study demonstrated that berberine exhibited significant cytotoxicity in HepG2 cells mainly through upregulation of reactive oxygen species (ROS) production but was ineffective in normal Chang liver cells. Berberine exerted anti-invasive effect on HepG2 cells through suppression of matrix metalloproteinase-9 (MMP-9) expression. Moreover, berberine could significantly inhibit the activity of PI3K-AKT and ERK pathways. Combination treatment of ERK pathway inhibitor PD98059 or AKT pathway inhibitor LY294002 and berberine could result in a synergistic reduction on MMP-9 expression along with an inhibition of cell invasion. Enhancement of ROS production by berberine had no influence on its suppressive effects on the activity of PI3K-AKT and ERK pathways, as well as MMP-9 expression and HepG2 cell invasion. In conclusion, our results suggest that berberine may be a potential alternative against invasive hepatoma cells through PI3K-AKT and ERK pathways-dependent downregulation of MMP-9 expression. This study also provides a previously neglected insight into the investigation of plant-derived agents-based therapy against tumor invasion with the consideration of damage to healthy cells.

Polymorphic nucleic Acid binding of bioactive isoquinoline alkaloids and their role in cancer

            (Maiti and Kumar 2010) Download

Bioactive alkaloids occupy an important position in applied chemistry and play an indispensable role in medicinal chemistry. Amongst them, isoquinoline alkaloids like berberine, palmatine and coralyne of protoberberine group, sanguinarine of the benzophenanthridine group, and their derivatives represent an important class of molecules for their broad range of clinical and pharmacological utility. In view of their extensive occurrence in various plant species and significantly low toxicities, prospective development and use of these alkaloids as effective anticancer agents are matters of great current interest. This review has focused on the interaction of these alkaloids with polymorphic nucleic acid structures (B-form, A-form, Z-form, H(L)-form, triple helical form, quadruplex form) and their topoisomerase inhibitory activity reported by several research groups using various biophysical techniques like spectrophotometry, spectrofluorimetry, thermal melting, circular dichroism, NMR spectroscopy, electrospray ionization mass spectroscopy, viscosity, isothermal titration calorimetry, differential scanning calorimetry, molecular modeling studies, and so forth, to elucidate their mode and mechanism of action for structure-activity relationships. The DNA binding of the planar sanguinarine and coralyne are found to be stronger and thermodynamically more favoured compared to the buckled structure of berberine and palmatine and correlate well with the intercalative mechanism of sanguinarine and coralyne and the partial intercalation by berberine and palmatine. Nucleic acid binding properties are also interpreted in relation to their anticancer activity.

Berberine-induced apoptosis in human prostate cancer cells is initiated by reactive oxygen species generation

            (Meeran, Katiyar et al. 2008) Download

Phytochemicals show promise as potential chemopreventive or chemotherapeutic agents against various cancers. Here we report the chemotherapeutic effects of berberine, a phytochemical, on human prostate cancer cells. The treatment of human prostate cancer cells (PC-3) with berberine induced dose-dependent apoptosis but this effect of berberine was not seen in non-neoplastic human prostate epithelial cells (PWR-1E). Berberine-induced apoptosis was associated with the disruption of the mitochondrial membrane potential, release of apoptogenic molecules (cytochrome c and Smac/DIABLO) from mitochondria and cleavage of caspase-9,-3 and PARP proteins. This effect of berberine on prostate cancer cells was initiated by the generation of reactive oxygen species (ROS) irrespective of their androgen responsiveness, and the generation of ROS was through the increased induction of xanthine oxidase. Treatment of cells with allopurinol, an inhibitor of xanthine oxidase, inhibited berberine-induced oxidative stress in cancer cells. Berberine-induced apoptosis was blocked in the presence of antioxidant, N-acetylcysteine, through the prevention of disruption of mitochondrial membrane potential and subsequently release of cytochrome c and Smac/DIABLO. In conclusion, the present study reveals that the berberine-mediated cell death of human prostate cancer cells is regulated by reactive oxygen species, and therefore suggests that berberine may be considered for further studies as a promising therapeutic candidate for prostate cancer.

Neuropharmacological and pharmacokinetic properties of berberine: a review of recent research

            (Ye, Fu et al. 2009) Download

OBJECTIVES: This review summarizes recent research on the neuropharmacological and pharmacokinetic properties of berberine, an isoquinoline alkaloid extracted from Coptidis rhizoma. KEY FINDINGS: Berberine has multiple neuropharmacological properties, such as neuroprection, anti-neuronal apoptosis, improvement of cerebral microcirculation and anti-Alzheimer's disease, and so on. The pharmacokinetic characteristics of berberine are that it is not easily absorbed and it is not stable in the gastrointestinal tract of animals or humans. SUMMARY: Further studies need to be carried out to develop berberine as a drug for nervous system diseases, such as brain ischaemia and Alzheimer's disease, that has favorable pharmacokinetic properties.


Asai, M., N. Iwata, et al. (2007). "Berberine alters the processing of Alzheimer's amyloid precursor protein to decrease Abeta secretion." Biochem Biophys Res Commun 352(2): 498-502.

Boberek, J. M., J. Stach, et al. (2010). "Genetic evidence for inhibition of bacterial division protein FtsZ by berberine." PLoS One 5(10): e13745.

Chang, X., H. Yan, et al. (2010). "Berberine reduces methylation of the MTTP promoter and alleviates fatty liver induced by a high-fat diet in rats." J Lipid Res 51(9): 2504-15.

Choi, M. S., J. H. Oh, et al. (2009). "Berberine inhibits p53-dependent cell growth through induction of apoptosis of prostate cancer cells." Int J Oncol 34(5): 1221-30.

Feng, Y., K. Y. Siu, et al. (2010). "Hepatoprotective effects of berberine on carbon tetrachloride-induced acute hepatotoxicity in rats." Chin Med 5: 33.

Grycova, L., J. Dostal, et al. (2007). "Quaternary protoberberine alkaloids." Phytochemistry 68(2): 150-75.

Habtemariam, S. (2011). "The therapeutic potential of Berberis darwinii stem-bark: quantification of berberine and in vitro evidence for Alzheimer's disease therapy." Nat Prod Commun 6(8): 1089-90.

Imanshahidi, M. and H. Hosseinzadeh (2008). "Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine." Phytother Res 22(8): 999-1012.

Jung, H. A., N. Y. Yoon, et al. (2008). "Inhibitory activities of the alkaloids from Coptidis Rhizoma against aldose reductase." Arch Pharm Res 31(11): 1405-12.

Liu, B., G. Wang, et al. (2011). "Berberine inhibits human hepatoma cell invasion without cytotoxicity in healthy hepatocytes." PLoS One 6(6): e21416.

Maiti, M. and G. S. Kumar (2010). "Polymorphic nucleic Acid binding of bioactive isoquinoline alkaloids and their role in cancer." J Nucleic Acids 2010.

Meeran, S. M., S. Katiyar, et al. (2008). "Berberine-induced apoptosis in human prostate cancer cells is initiated by reactive oxygen species generation." Toxicol Appl Pharmacol 229(1): 33-43.

Ye, M., S. Fu, et al. (2009). "Neuropharmacological and pharmacokinetic properties of berberine: a review of recent research." J Pharm Pharmacol 61(7): 831-7.