Chemico-biological interactions
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Chem. Biol. Interact. · Jan 2010
Local anesthetics structure-dependently interact with anionic phospholipid membranes to modify the fluidity.
While bupivacaine is more cardiotoxic than other local anesthetics, the mechanistic background for different toxic effects remains unclear. Several cardiotoxic compounds act on lipid bilayers to change the physicochemical properties of membranes. We comparatively studied the interaction of local anesthetics with lipid membranous systems which might be related to their structure-selective cardiotoxicity. ⋯ Bupivacaine significantly fluidized 2.5-12.5mol% cardiolipin-containing membranes at cardiotoxicologically relevant concentrations. Bupivacaine is considered to affect lipid bilayers by interacting electrostatically with negatively charged cardiolipin head groups and hydrophobically with phospholipid acyl chains. The structure-dependent interaction with lipid membranes containing cardiolipin, which is preferentially localized in cardiomyocyte mitochondrial membranes, may be a mechanistic clue to explain the structure-selective cardiotoxicity of local anesthetics.
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Chem. Biol. Interact. · Oct 2009
Potent growth suppressive activity of curcumin in human breast cancer cells: Modulation of Wnt/beta-catenin signaling.
Abnormal activation of the Wnt/beta-catenin signaling pathway and subsequent upregulation of beta-catenin driven downstream targets-c-Myc and cyclin D1 is associated with development of breast cancer. The objective of our study was to determine if curcumin could modulate the key elements of Wnt pathway in breast cancer cells; an effect that might underscore its usefulness for chemoprevention/treatment of this malignancy. Curcumin showed a cytotoxic effect on MCF-7 cells with 50% inhibitory concentration (IC(50)) of 35microM; while IC(50) for MDA-MB-231 cells was 30microM. ⋯ Further, the protein levels of the positively regulated beta-catenin targets-cyclin D1 and slug, were downregulated by curcumin treatment. The expression levels of two integral proteins of Wnt signaling, GSK3beta and E-cadherin were also altered by curcumin treatment. In conclusion, our data demonstrated that the efficacy of curcumin in inhibition of cell proliferation and induction of apoptosis might occur through modulation of beta-catenin pathway in human breast cancer cells.
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Chem. Biol. Interact. · Aug 2009
OX40-OX40 ligand interaction may activate phospholipase C signal transduction pathway in human umbilical vein endothelial cells.
Studies have recently supported the emerging role of OX40/OX40L interaction in atherosclerosis. The mechanism of OX40/OX40L interaction may be related to a variety of signal pathways. The most important signal pathway involves the activation of phospholipase C (PLC) which induces diacylglycerol-protein kinase C (DAG-PKC) and the inositol trisphosphate (IP(3))-intracellular free calcium ([Ca(2+)](i)) pathway. ⋯ Moreover, OX40 also induced peak [Ca(2+)](i) responses including the rapid transient phase and the sustained phase. Anti-OX40L antibody significantly suppressed OX40-induced DAG-PKC and IP(3)-[Ca(2+)](i) signal pathway activation in HUVEC. In conclusion, the data suggested that OX40-OX40L interaction induced a robust stimulation of phospholipase C signal transduction pathway in HUVEC.
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Chem. Biol. Interact. · Jul 2009
Cobalt protoporphyrin inhibition of lipopolysaccharide or lipoteichoic acid-induced nitric oxide production via blocking c-Jun N-terminal kinase activation and nitric oxide enzyme activity.
In the present study, low doses (0.5, 1, and 2 microM) of cobalt protoporphyrin (CoPP), but not ferric protoporphyrin (FePP) or tin protoporphyrin (SnPP), significantly inhibited lipopolysaccharide (LPS) or lipoteichoic acid (LTA)-induced inducible nitric oxide (iNOS) and nitric oxide (NO) production with an increase in heme oxygenase 1 (HO-1) protein in RAW264.7 macrophages under serum-free conditions. IC(50) values of CoPP inhibition of NO and iNOS protein individually induced by LPS and LTA were around 0.25 and 1.7 microM, respectively. This suggests that CoPP is more sensitive at inhibiting NO production than iNOS protein in response to separate LPS and LTA stimulation. ⋯ Furthermore, CoPP significantly reduced NO production in a cell-mediated, but not cell-free, iNOS enzyme activity assay accompanied by HO-1 induction. However, attenuation of HO-1 protein stimulated by CoPP via transfection of HO-1 siRNA did not affect NO's inhibition of CoPP against LPS stimulation. CoPP effectively suppressing LPS- and LTA-induced iNOS/NO production through blocking JNK activation and iNOS enzyme activity via a HO-1 independent manner is first demonstrated herein.
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Chem. Biol. Interact. · May 2009
Cardioprotective effect of gallic acid on cardiac troponin-T, cardiac marker enzymes, lipid peroxidation products and antioxidants in experimentally induced myocardial infarction in Wistar rats.
Currently there has been an increased interest globally to identify antioxidant compounds that are pharmacologically potent and have low or no side effects for use in preventive medicine. This study was designed to evaluate the protective effect of gallic acid on cardiac marker enzymes, troponin-T, LDH-isoenzyme pattern, lipid peroxidation products and antioxidant status in isoproterenol (ISO)-induced myocardial infarction in male Wistar rats. Male albino Wistar rats were pretreated with gallic acid (15 mg/kg) daily for a period of 10 days. ⋯ Gallic acid pretreatment showed significant protective effect on all the biochemical parameters studied. Histopathological findings of gallic acid pretreated myocardial infarcted heart confirmed the biochemical findings of this study. Thus, gallic acid protects the myocardium against isoproterenol-induced oxidative stress.