Ubiquinol attenuates γ-radiation induced coronary and aortic changes via PDGF/p38 MAPK/ICAM-1 related pathway.

Endothelial vascular injury is one of the most pivotal disorders emerging during radiotherapy. It is crucial to rely on strong antioxidants to defend against vascular damage. The current study was carried out to investigate the ameliorative effect of ubiquinol (Ubq) against gamma (γ)-radiation induced aortic and coronary changes, with highlighting its role in suppression of p38 mitogen activated protein kinase (MAPK). Exposure to γ-radiation was adopted as a potent detrimental model that induces vascular tissue damage. Concisely, male albino rats were irradiated at a dose level of 7 Gy and treated daily with Ubq (10 mg/kg/day, p.o.) for 7 days pre-and post-irradiation. At the end of the experiment, lipid profile, 8-hydroxydeoxyguanosine (8-OHdG), gene expression of intercellular adhesion molecule (ICAM-1), platelet derived growth factor (PDGF), p38 MAPK and matrix metalloproteinase-9 (MMP-9) were estimated. Exposure to radiation significantly deteriorates aortic and coronary tissues. Conversely, administration of Ubq significantly reduced serum t-cholesterol, LDL and triglycerides (p = 0.001). In addition, Ubq prevented oxidative DNA damage (8-OHdG) (p = 0.1) and reduced serum MMP-9 (p = 0.001) which contributed to the endothelial cells damage. The positive impact of Ubq was more apparent in suppression of both PDGF (p = 0.001) and p38 MAPK (p = 0.1) protein concentrations, leading subsequently in reduction of ICAM-1 (p = 0.001) gene expression. As a conclusion, vascular endothelial damage brought on by γ-radiation is one of the leading causes of coronary and aortic deteriorations which could be successfully mitigated by Ubq.

Novel VEGFR2 inhibitors with thiazoloquinoxaline scaffold targeting hepatocellular carcinoma with lower cardiotoxic impact.

Hepatocellular carcinoma (HCC) is a fatal tumor which is usually diagnosed at advanced stage. Molecular targeted drugs were used recently to treat HCC, however, due to serious side effects, mainly cardiotoxicity and emergence of resistance, there is demanding to explore new chemotherapeutics. 10 novel thiazoloquinoxaline derivatives coupled with different sulfonamide moieties 4(a-j) were designed and synthesized fulfilling pharmacophoric features of VEGFR-2 inhibition. Structures of all new compounds were verified via spectral and microanalytical data. After carrying in-vitro VEGFR-2 assay for compounds 4(a-j); sulfapyridine and sulfamethoxazole derivatives 4d and 4f showed potential inhibitory effect [61.04 and 83.35 nM], respectively, comparable to standard sorafenib [51.41 nM]. Both were then further evaluated for their cytocidal activity against HepG2 cell-line and against myocardium cells using H9C2 cell-line. As a result, only sulfapyridine derivative 4d exhibited a significant inhibition of HepG2 cells viability [IC50 = 4.31 µM]. Furthermore, it showed relatively lower cytotoxic impact against normal H9C2 myocardium cells [IC50, 33.47 µM] compared to that of sorafenib [IC50, 98.07 µM]. In-vivo study was carried out to determine myocardium safety of compound 4d on irradiated mice (8 Gy). In-vivo results of sulfapyridine derivative 4d showed normal cardiac enzyme function (CK) and serum catalase activity with significant reductions in LDH, cardiac TNF-α and caspase-9 levels, alongside with its efficacy in suppressing the expression of hepatic VEGF. In conclusion, sulfapyridine derivative 4d could be considered a promising candidate as VEGFR-2 inhibitor with less myocardium side effect.

Amelioration of adjuvant-induced arthritis by exposure to low dose gamma radiation and resveratrol administration in rats.

Purpose: Low dose radiation has been reported as an effective treatment for rheumatoid arthritis via multiple dose exposures. The present study was designed to increase the therapeutic efficacy of low dose radiation with the minimum exposure level in arthritic rats by concurrent administration of resveratrol (RSV) as an adjunctive therapy with anti-inflammatory properties.Materials and methods: Rats were rendered arthritic by sub-plantar injection of Freund's complete adjuvant (FCA) and exposed to low dose radiation at a total exposure level of 0.5 Gy (2 × 0.25). During the exposure course, RSV (50 mg/kg) was orally administered once daily for two weeks. Diclofenac (3 mg/kg) was administered as a standard anti-inflammatory drug. Paw volume was measured every 4 days. After 28 days of induction, rats were sacrificed and serum was collected for estimation of tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1ß), thiobarbituric acid reactive substances (TBARS), and total nitrate/nitrite (NOx). Furthermore, paws were dissected for histopathological examinations and immuno-histochemical estimation of nuclear factor-kappa B p65 (NF-κB p65) expression.Results: Administration of RSV during the low dose radiation exposure course produced a significant decrease in the paw swelling and a potentiated inhibition in the serum levels of TNF-α, IL-1ß, TBARs, and NOx. The dual treatment strategy alleviated the histopathological damage to a greater extent than that produced by each treatment. Moreover, a pronounced suppression of NF-κB p65 expression in the synovial tissue was observed in the combination group. The combination treatment showed a nearly similar potency to that observed in the diclofenac treated group.Conclusion: Administration of RSV augmented the modulatory activity of low dose radiation with minimum exposure level on the disease progression.