Worldwide, aspirin and ibuprofen are the most commonly used non-steroidal anti-inflammatory drugs (NSAIDs). Some adverse reactions, including gastrointestinal reactions, have been concerned extensively. Nevertheless, the mechanism of liver injury remains unclear. In the present study, we focused on the metabolism of liver cytochrome P450 (CYP450) and ultrastructural morphology of liver cells. A total of thirty rats were divided into three groups of 10. Rats in the aspirin and ibuprofen groups were given enteric-coated aspirin (15 mg/kg) and ibuprofen (15 mg/kg), respectively by gavage for four weeks. The body weights were recorded every two days. Liver function and metabolic capacity of CYP450 were studied on days 14 and 28. We then conducted ultrastructural examinations. Body weights in the Ibuprofen group were lower than those of the Control group, and ALT and AST levels were significantly higher (P < 0.05). There were no significant differences in terms of body weight, ALT or AST between the Aspirin and Control groups. The metabolic capacity of CYP450 was evaluated using five probe drugs, phenacetin, tolbutamide, metoprolol, midazolam, and bupropion. We found that ibuprofen and aspirin induced metabolism of the probe drugs. Moreover, according to the pharmacokinetic data, the Control, Aspirin and Ibuprofen groups could be discriminated accurately. Ultrastructural examination showed that the number of mitochondria was increased in both the Ibuprofen and Aspirin groups. Long-term administration of enteric-coated aspirin and ibuprofen induced the metabolic activity of the CYP450 enzyme. Aspirin had better tolerability than did ibuprofen, as reflected by pharmacokinetic data of probe drug metabolism.
Background: Recent studies have demonstrated a key role of vascular smooth muscle cell (VSMC) dysfunction in atherosclerosis. Cyclin-dependent kinases 9 (CDK9), a potential biomarker of atherosclerosis, was significantly increased in coronary artery disease patient serum and played an important role in inflammatory diseases. This study was to explore the pharmacological role of CDK9 inhibition in attenuating atherosclerosis. Methods: A small-molecule CDK9 inhibitor, LDC000067, was utilized to treat the high fat diet (HFD)-fed ApoE -/mice and human VSMCs. Results: The results showed that inflammation and phenotypic switching of VSMCs were observed in HFDinduced atherosclerosis in ApoE -/mice, which were accompanied with increased CDK9 in the serum and atherosclerotic lesions where it colocalized with VSMCs. LDC000067 treatment significantly suppressed HFDinduced inflammation, proliferation and phenotypic switching of VSMCs, resulting in reduced atherosclerosis in the ApoE -/mice, while had no effect on plasma lipids. Further in vitro studies confirmed that LDC000067 and siRNA-mediated CDK9 knockdown reversed ox-LDL-induced inflammation and phenotypic switching of VSMCs from a contractile phenotype to a synthetic phenotype via inhibiting NF-κB signaling pathway in human VSMCs. Conclusion: These results indicate that inhibition of CDK9 may be a novel therapeutic target for the prevention of atherosclerosis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.