Inhibition of mouse liver respiration by Chelidonium majus isoquinoline alkaloids

Barreto, Maria Carmo; Pinto, Ruy E.; Arrabaça, João Daniel; Pavão, Maria Leonor

doi:10.1016/j.toxlet.2003.09.007

Cited by 56 publications

(33 citation statements)

References 18 publications

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“…These data suggest that berberine is able to reduce oxygen-dependent glucose oxidation in mitochondria. This observation is consistent with berberine activity in the purified mitochondria, in which berberine inhibited NADlinked respiration (1,11,12). The reduction in oxygen consumption was associated with an increase in glycolysis, suggesting that berberine stimulates ATP production through glycolysis.…”

Section: Discussionsupporting

confidence: 86%

See 1 more Smart Citation

Berberine improves glucose metabolism through induction of glycolysis

Yin¹,

Gao²,

Liu³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

341

224

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Berberine, a botanical alkaloid used to control blood glucose in type 2 diabetes in China, has recently been reported to activate AMPK. However, it is not clear how AMPK is activated by berberine. In this study, activity and action mechanism of berberine were investigated in vivo and in vitro. In dietary obese rats, berberine increased insulin sensitivity after 5-wk administration. Fasting insulin and HOMA-IR were decreased by 46 and 48%, respectively, in the rats. In cell lines including 3T3-L1 adipocytes, L6 myotubes, C2C12 myotubes, and H4IIE hepatocytes, berberine was found to increase glucose consumption, 2-deoxyglucose uptake, and to a less degree 3-O-methylglucose (3-OMG) uptake independently of insulin. The insulin-induced glucose uptake was enhanced by berberine in the absence of change in IRS-1 (Ser 307/312 ), Akt, p70 S6, and ERK phosphorylation. AMPK phosphorylation was increased by berberine at 0.5 h, and the increase remained for Ն16 h. Aerobic and anaerobic respiration were determined to understand the mechanism of berberine action. The long-lasting phosphorylation of AMPK was associated with persistent elevation in AMP/ATP ratio and reduction in oxygen consumption. An increase in glycolysis was observed with a rise in lactic acid production. Berberine exhibited no cytotoxicity, and it protected plasma membrane in L6 myotubes in the cell culture. These results suggest that berberine enhances glucose metabolism by stimulation of glycolysis, which is related to inhibition of glucose oxidation in mitochondria. Berberine-induced AMPK activation is likely a consequence of mitochondria inhibition that increases the AMP/ATP ratio. type 2 diabetes; insulin sensitivity; oxygen consumption; mitochondrial function; adenosine 5Ј-monophosphate-activated protein kinase BERBERINE IS A BOTANICAL ALKALOID in the roots and bark of several plants, including Coptis chinensis French, an ancient Chinese herb that has been used to treat diabetes for thousands of years in China. Berberine is the main active compound of the herb. In addition to its metabolic activities, berberine has well-established antimicrobial activities in the control of infection by bacteria, viruses, fungi, protozoans, and helminthes (8,14). It is an over-the-counter drug for the treatment of gastrointestinal infections in China. In 1988, the hypoglycemic effect of berberine was found when berberine was used to treat diarrhea in diabetic patients in China (13). Since then, berberine has been used as an antihyperglycemic agent by many physicians in China. There are many clinical reports about the hypoglycemic action of berberine in Chinese literature.Regarding the mechanism of berberine action, we found that berberine increased glucose metabolism in cultured cells, and this activity was comparable to that observed for metformin in 2002 (20). This activity was confirmed later in other studies, and AMPK was proposed to mediate the metabolic activities of berberine (2, 3, 9, 22). In 2006, it was reported that berberine was able to activate AMPK for inh...

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Section: Discussionsupporting

confidence: 86%

“…Although AMPK is activated by berberine, the metabolic conditions that lead to this effect require further investigation. Berberine was shown to inhibit the citric acid cycle in isolated mitochondria (1,11,12). However, it is not clear whether this activity can be observed in living cells for AMPK activation.…”

mentioning

confidence: 99%

Berberine improves glucose metabolism through induction of glycolysis

Yin¹,

Gao²,

Liu³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

341

224

View full text Add to dashboard Cite

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“…Previous studies in fact have shown that berberine inhibits NADH dehydrogenase and respiratory activity [23,37]. In addition, mitochondrial participation in berberine-induced apoptosis has been demonstrated in a number of studies [2,6,11,38].…”

Section: Discussionmentioning

confidence: 90%

Different concentrations of berberine result in distinct cellular localization patterns and cell cycle effects in a melanoma cell line

Serafim

Oliveira

Sardão

et al. 2007

Cancer Chemother Pharmacol

117

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Purpose Natural products represent a rich reservoir of potential small molecule inhibitors exhibiting antiproliferative and tumoricidal properties. An example is the isoquinoline alkaloid berberine, which is found in plants such as goldenseal (Hydrastis canadensis). Studies have shown that berberine is able to trigger apoptosis in diVerent malignant cell lines, and can also lead to cell cycle arrest at sub-apoptotic doses. A particularly interesting feature of berberine is the fact that it is a Xuorescent molecule, and its uptake and distribution in cells can be studied by Xow cytometry and epiXuorescence microscopy. To test the relationships between berberine uptake, distribution and cellular eVect in melanoma cells, K1735-M2 mouse and WM793 human melanoma cells were treated with diVerent concentrations of berberine, and alterations in cell cycle progression, DNA synthesis, cell proliferation, and cell death measured. Methods Cell proliferation was measured by sulforhodamine B assays, cell death by Xow cytometry, berberine uptake and distribution by laser scanning confocal microscopy and Xow cytometry, cell cycle progression by Xow cytometry, and DNA synthesis, M-phase, and mitochondrial eVects by immunolabeling and epiXuorescence microscopy methods. Results In these melanoma cell lines, berberine at low doses (12.5-50 M) is concentrated in mitochondria and promotes G1 arrest. In contrast, higher doses (over 50 M) result in cytoplasmic and nuclear berberine accumulation, and G2 arrest. DNA synthesis is not markedly aVected by low doses of berberine, but 100 M is strongly inhibitory. Even at 100 M, berberine inhibits cell growth with relatively little induction of apoptosis. Conclusion Berberine displays multiphasic eVects in these malignant cell lines, which are correlated with the concentration and intracellular distribution of this alkaloid. These results help explain some of the conXicting information in the literature regarding the eVects of berberine, and suggest that its use in clinical development may be more as a cytostatic agent than a cytotoxic compound.

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“…It was shown that sanguinarine induced a programmed the other type of cell death in the erythroleukemia K562 cell line by causing a significant increase in the expression of proapoptotic Bax protein and activation of caspase cascade [1,29]. Some alkaloids were found to block the respiration processes in mitochondria [2]. We have demonstrated (in a submitted article), that the intercalating properties of specific celandine alkaloids correlated with their ability to induce dissipation of trans-membrane potential and caused alteration in the permeability of the inner mitochondrial membrane; in turn, this may have led to a release of the pro-apoptotic proteins from mitochondria to cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

“…Chelidonine was shown to interact with tubulin in target cells and cause their mitotic arrest [18]. The molecules of chelerythrine, sanguinarine, berberine and coptisine possess a positive charge due to the presence of quaternary nitrogen, and exhibit a significant inhibitory effect on the mitochondrial respiration [2]. Sanguinarine and chelerythrine contain reactive imine groups and are capable of inhibiting the activity of enzymes and other proteins which possess the nucleophilic groups [8].…”

Section: Introductionmentioning

confidence: 99%

Correlation of the cytotoxic activity of four different alkaloids, from Chelidonium majus (greater celandine), with their DNA intercalating properties and ability to induce breaks in the DNA of NK/Ly murine lymphoma cells

Kaminskyy¹,

Lootsik

Stoika³

2006

Open Life Sciences

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Abstract:The purpose of this study was to examine the relationship between the DNA intercalating characteristics and the DNA damaging capacity of four alkaloids extracted from Chelidonium majus L, as well as their toxicity towards murine NK/Ly lymphoma cells. Chelerythrine, sanguinarine and coptisine were found to be intercalated into the DNA isolated from NK/Ly cells, meanwhile, chelidonine exhibited no affinity to DNA. Sanguinarine exhibited the greatest toxicity toward NK/Ly cells, and the toxicity of the other three decreased in descending order: chelerythrine, coptisine and chelidonine. Chelerythrine and sanguinarine caused DNA damage, illustrated by the formation of comets of the third class. Coptisine was less toxic than chelerythrine and sanguinarine, and affected the formation the same class of comets in higher concentration. The quantity of comets induced by chelidonine were negligible, a finding consistent with its inability to intercalate into DNA structure. The ability of four main alkaloids of Chelidonium majus L., to intercalate into DNA isolated from murine NK/Ly lymphoma cells, correlated with their ability to induce breaks in cellular DNA and with their toxic effect towards those cells.

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Inhibition of mouse liver respiration by Chelidonium majus isoquinoline alkaloids

Cited by 56 publications

References 18 publications

Berberine improves glucose metabolism through induction of glycolysis

Berberine improves glucose metabolism through induction of glycolysis

Different concentrations of berberine result in distinct cellular localization patterns and cell cycle effects in a melanoma cell line

Correlation of the cytotoxic activity of four different alkaloids, from Chelidonium majus (greater celandine), with their DNA intercalating properties and ability to induce breaks in the DNA of NK/Ly murine lymphoma cells

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