Hydroxychloroquine induces endothelium-dependent and endothelium-independent relaxation of rat aorta.

BACKGROUND: Hydroxychloroquine (HCQ) is an antimalarial that is widely used in the management of rheumatoid arthritis and other autoimmune diseases. In this study, we aimed to examine the vascular effects of HCQ on rat aorta (RA). METHODS: The RA rings were suspended in isolated organ baths and tension was recorded isometrically. HCQ-induced relaxations were tested in the presence of the nitric oxide synthase inhibitor, nitro-L-arginine methyl ester (L-NAME, 100 mM); the cyclooxygenase enzyme inhibitor, indomethacin (10 mM); the calcium (Ca2+) ion channel blocker, nilvadipine (10 µM); and the K+ ion channel inhibitors, tetraethylammonium (1 mM), glibenclamide (10 mM), 4-aminopyridine (1 mM), and barium chloride (30 mM). The effect of HCQ on Ca2+ channels was examined using Ca2+-free Krebs solution, and adding calcium chloride (CaCl2 , 10-5- 10-2 M) cumulatively to baths incubated with HCQ. RESULTS: Removing the endothelium resulted in less relaxation of RA rings compared to endothelium-intact rings (p < 0.05). The effect of endothelium was supported by using L-NAME where HCQ produced-vasorelaxation was decreased (p < 0.05). The contraction of vascular rings was inhibited to a significant degree following the addition of CaCl2 , PE, or KCl on HCQ-incubated RA rings (p < 0.05). The incubation of the RA rings with the Ca2+ channel blocker, the K+ channel blockers, and the COX inhibitor, indomethacin did not significantly affect vascular relaxation induced by HCQ. DISCUSSION: HCQ produced relaxation of RA rings. The relaxation mechanism differs according to the concentration of HCQ. At con-centrations of 10-6 and 10-5 M, the relaxation is endothelium-dependent and mediated by NO. We strongly suggest that Ca2+ channel inhibition is involved at concentrations of 10-5 and 10-4 M, as well as NO.

Novel molecular signatures and potential therapeutics in renal cell carcinomas: Insights from a comparative analysis of subtypes.

Renal cell carcinomas (RCCs) are among the highest causes of cancer mortality. Although transcriptome profiling studies in the last decade have made significant molecular findings on RCCs, effective diagnosis and treatment strategies have yet to be achieved due to lack of adequate screening and comparative profiling of RCC subtypes. In this study, a comparative analysis was performed on RNA-seq based transcriptome data from each RCC subtype, namely clear cell RCC (KIRC), papillary RCC (KIRP) and kidney chromophobe (KICH), and mutual or subtype-specific reporter biomolecules were identified at RNA, protein, and metabolite levels by the integration of expression profiles with genome-scale biomolecular networks. This approach revealed already-known biomarkers in RCCs as well as novel biomarker candidates and potential therapeutic targets. Our findings also pointed out the incorporation of the molecular mechanisms of KIRC and KIRP, whereas KICH was shown to have distinct molecular signatures. Furthermore, considering the Dipeptidyl Peptidase 4 (DPP4) receptor as a potential therapeutic target specific to KICH, several drug candidates such as ZINC6745464 were identified through virtual screening of ZINC molecules. In this study, we reported valuable data for further experimental and clinical efforts, since the proposed molecules have significant potential for screening and therapeutic purposes in RCCs.

Protective role of caffeic acid phenethyl ester on serum cholinesterase inhibition by acute exposure to diazinon in rats.

AIM: To evaluate whether caffeic acid phenethyl ester (CAPE), a flavonoid-like natural compound plentifully found in beeswax, has a protective effect on diazinon-induced serum cholinesterase (ChE) inhibition in rats. MATERIALS AND METHODS: Animals were divided into 4 groups. The first animal group was not treated with any substance. The second animal group was orally given a 200 mg/kg body weight (bw) sublethal dose of diazinon. The third animal group was injected intraperitoneally with 2.84 mg (10 micromol)/kg bw of CAPE 1 day prior to administration of 200 mg/kg bw of diazinon orally. The fourth animal group was intraperitoneally injected with 2.84 mg (10 tmol)/kg bw of CAPE 30 min after 200 mg/kg bw of diazinon was orally administered. RESULTS: Analysis of the animal blood samples obtained 48 h after diazinon administration revealed that diazinon decreased serum ChE activity by 75%, while CAPE administration 24 h prior to and 30 min following diazinon application improved serum ChE activity by 25%-32% as compared to levels with diazinon administration only. In silico studies suggest that CAPE prevents diazinon from binding to butyryl ChE due to a higher binding affinity than that of diazinon. CONCLUSION: Our laboratory findings suggest that CAPE plays a protective role against butyryl ChE inhibition by diazinon.