Coptisine

The herbs of Chelidonium majus L.

Coptisine is an alkaloid from Chinese goldthread, and acts as an efficient uncompetitive IDO inhibitor with a Ki value of 5.8 μM and an IC50 value of 6.3 μM.

In Vitro:Coptisine is an efficient uncompetitive IDO inhibitor with a Ki value of 5.8 μM and an IC50 value of 6.3 μM[1]. Coptisine (0.1-100 μM) inhibits the proliferation of A549, H460, H2170, MDA-MB-231 and HT-29 cells, with IC50s of 18.09, 29.50, 21.60, 20.15 and 26.60 µM, respectively. Coptisine (12.5, 25, 50 μM) upregulates the expression of pH2AX and p21, reduces expression of cyclin B1, cdc2, and cdc25C, and induces G2/M arrest and apoptosis of A549 cells in a concentration-dependent manner. Coptisine (12.5, 25, 50 μM) also induces mitochondrial dysfunction and activates caspases activities in A549 cells. Furthermore, Coptisine (50 μM) increases ROS levels in a time-dependent manner (0.5, 1, 2, 4, 12, and 24 h)[3].

In Vivo:Coptisine shows increased toxicity in mice in a concentration dependent manner, with LD50 value of 880.18 mg/kg. Coptisine (154 mg/kg/day, 90 days) shows no toxicity on SD rats. Coptisine (23.35, 46.7, 70.05 mg/kg, p.o.) dose-dependently decreases the levels of TC, TG, and LDL-c and increases HDL-c content in serum of hamsters to different degree, slows down weight gain induced by the HFHC diet, and raises the level of cholesterol and TBA in feces dose-dependently in hamsters. Coptisine (70.05 mg/kg, p.o.) suppresses HMGCR protein expression level and induces the protein expression of SREBP-2, LDLR, and CYP7A1 involved in cholesterol metabolism[2].

References:
[1]. Yu D, et al. The IDO inhibitor coptisine ameliorates cognitive impairment in a mouse model of Alzheimer's disease. J Alzheimers Dis. 2015;43(1):291-302. [2]. He K, et al. The safety and anti-hypercholesterolemic effect of coptisine in Syrian golden hamsters. Lipids. 2015 Feb;50(2):185-94. [3]. Rao PC, et al. Coptisine-induced cell cycle arrest at G2/M phase and reactive oxygen species-dependent mitochondria-mediated apoptosis in non-small-cell lung cancer A549 cells. Tumour Biol. 2017 Mar;39(3):1010428317694565.

Coptisine protects rat heart against myocardial ischemia/reperfusion injury by suppressing myocardial apoptosis and inflammation.[Pubmed:24267256]

Atherosclerosis. 2013 Dec;231(2):384-91.

OBJECTIVE: Protecting the heart from myocardial ischemia and reperfusion (I/R) damage is the focus of intense research. Coptisine is an isoquinoline alkaloid isolated from Coptidis Rhizoma. The present study investigated the potential effect of Coptisine on myocardial I/R damage in rats and the underlying mechanisms. METHODS AND RESULTS: Electrocardiogram examination showed that the administration of Coptisine 10 min before ischemia significantly decreased I/R-induced arrhythmia after 30 min ischemia followed by 3 h reperfusion. The release of cardiac markers was also limited. Echocardiography was performed before ischemia and 24 h post-I/R, separately. The M-mode records showed that the reductions of ejection fraction (EF) and fractional shortening (FS) were attenuated in Coptisine-treated rats compared with the I/R rats. Similar results were obtained with Evans Blue/triphenyl tetrazolium chloride (TTC) staining, in which Coptisine notably reduced infarct size. Moreover, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay demonstrated Coptisine suppressed myocardial apoptosis, which may be related to the upregulation of Bcl-2 protein and inhibition of caspase-3 activation. Coptisine treatment also attenuated the proinflammatory cytokines including interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha in heart tissue. Additionally, Western blot and immunohistochemical analysis showed that Coptisine markedly reduced Rho, Rho-kinase 1 (ROCK1), and ROCK2 expression and attenuated the phosphorylation of myosin phosphatase targeting subunit-1, a downstream target of ROCK. CONCLUSIONS: Coptisine exerts pronounced cardioprotection in rats subjected to myocardial I/R likely through suppressing myocardial apoptosis and inflammation by inhibiting the Rho/ROCK pathway.

Cytotoxic effects of Coptis chinensis and Epimedium sagittatum extracts and their major constituents (berberine, coptisine and icariin) on hepatoma and leukaemia cell growth.[Pubmed:14756686]

Clin Exp Pharmacol Physiol. 2004 Jan-Feb;31(1-2):65-9.

1. The present study was conducted to evaluate the cytotoxic effects of Coptis chinensis and Epimedium sagittatum extracts and their major constituents on hepatoma and leukaemia cells in vitro. 2. Four human liver cancer cell lines, namely HepG2, Hep3B, SK-Hep1 and PLC/PRF/5, and four leukaemia cell lines, namely K562, U937, P3H1 and Raji, were used in the present study. 3. Of the two crude drugs, C. chinensis exhibited the strongest activity against SK-Hep1 (IC50 = 7 microg/mL) and Raji (IC50 = 4 microg/mL) cell lines. The IC50 values for C. chinensis on HepG2, Hep3B and PLC/PRF/5 cell lines were 20, 55 and 35 microg/mL, respectively. The IC50 values for C. chinensis on K562, U937 and P3H1 cell lines were 29, 29 and 31 microg/mL, respectively. 4. With the exception of HepG2 and Hep3B, the E. sagittatum extract inhibited the proliferation of all cell lines (SK-Hep1, PLC/PRF/5, K562, U937, P3H1 and Raji), with IC50 values of 15, 57, 74, 221, 40 and 80 microg/mL, respectively. 5. Interestingly, the two major compounds of C. chinensis, berberine and Coptisine, showed a strong inhibition on the proliferation of both hepatoma and leukaemia cell lines, with IC50 values varying from 1.4 to 15.2 microg/mL and from 0.6 to 14.1 microg/mL, respectively. However, icariin (the major compound of E. sagittatum) showed no inhibition of either the hepatoma or leukaemia cell lines. 6. The results of the present study suggest that the C. chinensis extract and its major constituents berberine and Coptisine possess active antihepatoma and antileukaemia activities.

The IDO inhibitor coptisine ameliorates cognitive impairment in a mouse model of Alzheimer's disease.[Pubmed:25079795]

J Alzheimers Dis. 2015;43(1):291-302.

Indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme in the kynurenine pathway (KP) of tryptophan catabolism, was recently established as one of the potential players involved in the pathogenesis of Alzheimer's disease (AD). Coptisine is a main pharmacological active constituent of the traditional Chinese medicinal prescription Oren-gedoku-to (OGT) which has therapeutic potential for the treatment of AD. Our recent studies have demonstrated that OGT significantly inhibited recombinant human IDO activity, which shed light on the possible mechanism of OGT's action on AD. Here, we characterized the effects of Coptisine in an AD mouse model on the basis of its IDO inhibitory ability. Coptisine was found to be an efficient uncompetitive IDO inhibitor with a Ki value of 5.8 muM and an IC50 value of 6.3 muM. In AbetaPP/PS1 transgenic mice, oral administration of Coptisine inhibited IDO in the blood and decreased the activation of microglia and astrocytes, consequently prevented neuron loss, reduced amyloid plaque formation, and ameliorated impaired cognition. Neuronal pheochromocytoma (PC12) cells induced with amyloid-beta peptide 1-42 and interferon-gamma showed reduction of cell viability and enhancement of IDO activity, while Coptisine treatment increased cell viability based on its reversal effect on the enhanced activity of IDO. In conclusion, our present findings provide further evidence supporting the critical links between IDO, KP, and AD, and demonstrate Coptisine, a novel IDO inhibitor, as a potential new class of drugs for AD treatment.

Unraveling the novel anti-osteosarcoma function of coptisine and its mechanisms.[Pubmed:24607417]

Toxicol Lett. 2014 May 2;226(3):328-36.

Uncontrolled cell proliferation and robust angiogenesis play critical roles in osteosarcoma growth and metastasis. In this study we explored novel agents derived from traditional Chinese medicinal herbs that potently inhibit osteosarcoma growth and metastasis. Coptisine, an active component of the herb Coptidis rhizoma, markedly inhibited aggressive osteosarcoma cell proliferation. Coptisine induced cell cycle arrest at the G0/G1 phase through downregulation of CDK4 and cyclin D1 expression and effectively suppressed tumor growth in a xenografted mouse model. Coptisine significantly impeded osteosarcoma cell migration, invasion, and capillary-like network formation by decreasing the expression of VE-cadherin and integrin ss3, and diminishing STAT3 phosphorylation. Coptisine significantly elevated blood erythrocyte and hemoglobin levels while still remaining within the normal range. It also moderately increased white blood cell and platelet counts. These data suggest that Coptisine exerts a strong anti-osteosarcoma effect with very low toxicity and is a potential anti-osteosarcoma drug candidate.

The safety and anti-hypercholesterolemic effect of coptisine in Syrian golden hamsters.[Pubmed:25547428]

Lipids. 2015 Feb;50(2):185-94.

Current work was conducted to evaluate the cholesterol-lowering effect of Coptisine extracted from Rhizoma coptidis in Syrian golden hamsters. The safety results indicated that Coptisine was a safe and low-toxic compound. Coptisine showed a beneficial effect in the abnormal serum lipid levels induced by a high-fat and high-cholesterol diet (HFHC): at a concentration of 70.05 mg/kg, Coptisine significantly led to a decrease in total cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-c) levels by 26.70, 15.38, and 22.22 %, respectively, and high-density lipoprotein cholesterol (HDL-c) was increased by 41.74 % in serum of hamsters (p < 0.01). In addition, total bile acid (TBA) levels in feces of hamsters were elevated after Coptisine administration. Further investigation has suggested that the mRNA and protein expression of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) in the liver of hamsters was down-regulated by high-dosage Coptisine treatment (p < 0.05); mRNA and protein expression of low-density lipoprotein receptor (LDLR) and cholesterol 7alpha-hydroxylase (CYP7A1) were dramatically up-regulated by Coptisine administration. The apical sodium-dependent bile salt transporter expression was down-regulated in the Coptisine-treated animals, but showed no significant differences from the HFHC groups. Taken together, our results demonstrate that a high dosage of Coptisine could inhibit cholesterol synthesis via suppressing the HMGCR expression and promoting the use and excretion of cholesterol via up-regulating LDLR and CYP7A1 expression. These findings suggest a critical role for Coptisine in anti- hypercholesterolemia, and thus it needs to be considered as a potential natural cholesterol lowering agent.

Antispasmodic and relaxant activity of chelidonine, protopine, coptisine, and Chelidonium majus extracts on isolated guinea-pig ileum.[Pubmed:9933996]

Planta Med. 1998 Dec;64(8):758-60.

Two ethanolic dry extracts from the herb Chelidonium majus L. with a defined content of the main alkaloids (chelidonine, protopine, and coptisisine) and the alkaloids themselves were studied in three different antispasmodic test models on isolated ileum of guinea-pigs. In the BaCl2-stimulated ileum, chelidonine and protopine exhibited the known papaverine-like musculotropic action, whereas Coptisine (up to 3.0 x 10(-5) g/ml) was ineffective in this model. Both extracts were active with 53.5% and 49.0% relaxation at 5 x 10(-4) g/ml. The carbachol and the electric field stimulated contractions were antagonized by all three alkaloids. Coptisine showed competitive antagonist behaviour with a pA2 value of 5.95. Chelidonine and protopine exhibited a certain degree of non-competitive antagonism. In the electric field the antagonist activities decreased in the order protopine > Coptisine > chelidonine. The concentrations of the chelidonium herb extracts for 50% inhibition of the carbachol and electrical field induced spasms were in the range of 2.5 to 5 x 10(-4) g/ml.

Investigation of the anti-fungal activity of coptisine on Candida albicans growth by microcalorimetry combined with principal component analysis.[Pubmed:19426275]

J Appl Microbiol. 2009 Oct;107(4):1072-80.

AIMS: This study investigated the anti-fungal activity of Coptisine on Candida albicans growth. METHODS AND RESULTS: The metabolic power-time curves of Candida albicans growth at 37 degrees C affected by Coptisine were measured by microcalorimetry using an LKB-2277 Bioactivity Monitor with stop-flow mode. Then, the diameter of inhibitory zones in the agar layer was observed using agar cup method, and the minimal inhibitory concentration (MIC) of Coptisine on Candida albicans growth was determined by serial dilution method. From the principal component analysis on nine quantitative parameters obtained from the power-time curves, we could easily evaluate the anti-fungal activity of Coptisine by analysing the change of values of the main two parameters, growth rate constant k and maximum power output in the log phase P(m, log). The results showed that Coptisine had strong anti-fungal activity: at a low concentration (45 microg ml(-1)) began to inhibit the growth of Candida albicans and at a high concentration (500 microg ml(-1)) completely inhibited Candida albicans growth. Coptisine gave big inhibitory zones with diameters between 11 and 43 mm within test range, and the MIC of it was 1000 microg ml(-1). CONCLUSIONS: Coptisine had strong anti-fungal activity on Candida albicans growth. The method of microcalorimetry applied for the assay of anti-fungal activity of Coptisine was quantitative, sensitive and simple. SIGNIFICANCE AND IMPACT OF THE STUDY: This work will provide useful information for the development of chemical biology policy in the use of anti-microbials in food and drug production.

Coptisine is an alkaloid from Chinese goldthread, and acts as an efficient uncompetitive IDO inhibitor with a Ki value of 5.8 μM and an IC50 value of 6.3 μM.

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