Hyperlipidemia
Isoproterenol
RosuvastatinEllagic acid a b s t r a c t Hyperlipidemia (HL) with subsequent coronary atherosclerosis is the major trigger of ischemia and hence, myocardial infarction (MI) occurs. The present study aimed to elucidate the effects of pretreatment with rosuvastatin and ellagic acid, as well as their combination on isoproterenol-induced MI in hyperlipidemic rats. Adult rats were fed with a cholesterol-rich diet for seven weeks and received rosuvastatin (10 mg/kg) and/or ellagic acid (30 mg/kg) by oral gavage daily starting from the fifth week then subcutaneously injected with two doses 24-h apart of 100 mg/kg isoproterenol in the last two days. ECG pattern was monitored and both cardiac biomarkers (cTnI, CK-MB, LDH and AST) and lipid profile (TC, TG, HDL-c and LDL-c) were measured in serum. MDA and GSH levels were quantified in cardiac homogenates and heart tissue damage was examined by histopathology. Furthermore, the expression levels of iNOS, eNOS, Bax and Bcl-2 in heart samples were assessed by western blotting. Three-week pretreatment with rosuvastatin and/or ellagic acid markedly ameliorated HL-and isoproterenol-induced alterations in ECG, cardiac markers, oxidation markers, lipid profile and heart architecture. Both drugs downregulated iNOS and upregulated eNOS, while only rosuvastatin and the combination downregulated Bax. This study provides evidence that rosuvastatin and ellagic acid possess cardioprotective effect on the hyperlipidemic-myocardial infarction rat model and the combination does not offer extra protection than monotherapy.
A set
of
meta
-substituted 3-arylisoquinolinones
have been identified that show substantial cytotoxicity in breast,
liver, lung and colon cancer cell lines; these are up to 700-fold
more active than the corresponding
para
analogues.
These compounds were initially proposed as inhibitors of
N
-ribosyl dihydronicotinamide (NRH): quinone oxidoreductase 2 (NQO2)
but were found to be inactive against the enzyme. Instead, COMPARE
analysis suggested that 6-fluoro-3-(
meta
-fluorophenyl)isoquinolin-1(2
H
)-one (
4
) could mimic colchicine and interact
with microtubules, a recognized target for cancer therapy. Subsequent
docking, molecular dynamics simulations, and free energy analysis
further suggested that compound
4
bound well into the
colchicine-binding pocket of tubulin. Indeed,
4
suppressed
tubulin polymerization, caused
G
2
/
M
cell cycle arrest, and induced apoptosis. Also,
4
inhibited the formation of endothelial cell capillary-like
tubes and further disrupted the structure of preestablished tubes;
the effects were not observed with
para
analogue
5
. In accordance with this, the computed free energy of binding
of
5
to tubulin was lower in magnitude than that for
4
and appeared to arise in part from the inability of the
para
substituent to occupy a tubulin subpocket, which is
possible in the
meta
orientation. In conclusion,
the antiproliferative potential of the novel 3-arylisoquinolinones
is markedly influenced by a subtle change in the structure (
meta
versus
para
). The
meta
-substituted isoquinolinone
4
is a microtubule-destabilizing
agent with potential tumor-selectivity and antiangiogenic and vascular
disrupting features.
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