Loss of RAR-α and RXR-α and enhanced caspase-3-dependent apoptosis in N-acetyl-p-aminophenol-induced liver injury in mice is tissue factor dependent.

Tissue factor (TF) activates the coagulation system and has an important role in the pathogenesis of various diseases. Our previous study stated that retinoid receptors (RAR-α and RXR-α) are released as a lipid droplet in monocrotaline/ lipopolysaccharide-induced idiosyncratic liver toxicity in mice. Herein, the interdependence between the release of retinoid receptors RAR-α and RXR-α and TF in Nacetyl-p-aminophenol (APAP)-induced mice liver toxicity, is investigated. Serum alanine transaminase (ALT) level, platelet and white blood cells (WBCs) counts, protein expression of fibrin, TF, cyclin D1 and cleaved caspase-3 in liver tissues are analyzed. In addition, histopathological evaluation and survival study are also performed. The results indicate that using of TF-antisense (TF-AS) deoxyoligonucleotide (ODN) injection (6 mg/kg), to block TF protein synthesis, significantly restores the elevated level of ALT and WBCs and corrects thrombocytopenia in mice injected with APAP. TF-AS prevents the peri-central overexpression of liver TF, fibrin, cyclin D1 and cleaved caspase- 3. The release of RXR-α and RAR-α droplets, in APAP treated sections, is inhibited upon treatment with TF-AS. In conclusion, the above findings designate that the released RXR-α and RAR-α in APAP liver toxicity is TF dependent. Additionally, the enhancement of cyclin D1 to caspase-3-dependent apoptosis can be prevented by blocking of TF protein synthesis.

Olmesartan ameliorates cyclophosphamide-induced hemorrhagic cystitis in rats via Nrf2/HO-1 signaling pathway.

Hemorrhagic cystitis (HC) is considered a fatal complication of cyclophosphamide (CP). Down-regulation of Nrf2 and induction of pro-inflammatory mediators are the main pathological factors. Recently, ameliorative potential of the angiotensin II (AII) type-1 (AT1) receptor blocker olmesartan (OLM) on oxidative stress and inflammatory cytokines was reported. The current study aims to investigate the possible protective effect of OLM on CP-induced HC in Wistar rats. The animals were divided into the control group (0.5% W/V carboxymethylcellulose, p.o.); OLM group (20 mg/kg, p.o., for 21 days); CP group (a single dose of 100 mg/kg, i.p.); and the remaining groups that received CP i.p. with oral OLM 5, 10 and 20 mg/kg for 21 days, respectively. The bladder tissue was collected for histopathology, immunohistochemistry, ELISA, Western blot, and oxidative stress assay. The OLM at doses of 10 and 20 mg/kg attenuated increase in TNF-α, IL-6, NF-kB, iNOS, and COX-2 induced by CP. Additionally, it up-regulated the Nrf2/HO-1 pathway, bladder GSH content, and CAT and SOD activities. The data indicated that OLM inhibited ROS-induced NF-kB, which caused inhibition of pro-inflammatory cytokines and activation of the Nrf2/HO-1 pathway. Hence, OLM holds great promise for preventing CP-induced HC.

The chemopreventive effect of thymol against dimethylhydrazine and/or high fat diet-induced colon cancer in rats: Relevance to NF-κB.

AIM: Evaluating the possible protective effect of thymol as an approach against 1,2 N,N-dimethylhydrazine and/or high-fat diet (HFD)-induced colon cancer. MAIN METHODS: Adult male Wistar rats were divided into 7 groups, namely a normal control group, colon cancer groups received DMH (40 mg/kg i.p., twice weekly), 20% HFD and DMH/HFD, thymol (20 mg/kg/day, p.o.), thymol/DMH and thymol/DMH/HFD (treatment of all groups continued for 16 weeks). KEY FINDINGS: Thymol significantly reduced the elevated serum levels of colon related tumor markers carbohydrate antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA) as well as the apoptotic marker, caspase-3 compared with the colon cancer group. In addition, it mitigated colonic tissue oxidative stress markers and inflammatory mediators. Moreover, the histopathological study revealed reduction of mucous secretion with elongated nuclei, frequent mitotic figures, focal nuclear stratification, mild interstitial edema, and markedly dilated congested blood vessels, aberrant crypt foci (ACF); adenoma with moderate to severe dysplasia of colon corrected by thymol treatment. SIGNIFICANCE: The administration of thymol had a promising preclinical protective efficacy and could be considered as a new strategy for the prophylaxis from colon cancer in clinical practices.