The potential role of febrile condition in reversing the hepatoprotective effects of quercetin in the livers of LPS-presensitized mice.

AIMS: Consumption of nutraceuticals without enough data regarding their interactions has raised safety concerns. Importantly, consumption of some natural-products in health-compromised conditions has caused liver injury due to the evolved pro-oxidant load. This study evaluates the safety of quercetin (QUR), as an extensively-used flavonoid owing to its antioxidant and hepatoprotective activities, in normal- and lipopolysaccharides (LPS)-primed livers, and to investigate the influence of the LPS-induced mild inflammatory/febrile condition on QUR effects. MAIN METHODS: For liver priming, a non-injurious LPS dose that mediates limited inflammation/mild fever was chosen. Selection of QUR dose/duration of treatment, for a coherent combination-regimen, was also adopted. Single LPS i.p injection (1.5 mg/kg)/oral QUR (20 mg/kg/day, IG) for 5-days was the optimal regimen for the combination group. On day-6, serum ALT/AST/ALP levels were measured, as liver-damage biomarkers. Hepatic; MDA/GSH were determined, as oxidative-stress measures, Bcl-2/cleaved-caspase-3 were assessed as apoptosis biomarkers, IL-6 expression/NF-κB/Nrf-2 immunoreactivities were evaluated as regulators for inflammation. KEY FINDINGS: Exaggerated hepatic injury was seen upon QUR treatment in LPS-presensitized mice; as evidenced by liver histopathological degeneration, which was confirmed by biochemical elevations of serum AST/ALT/ALP, along with oxidant-burden increase (↑MDA/↓GSH) and molecular augmentation of inflammation (NF-κB/IL-6 activation) that led to enhancement of proapoptotic signaling (caspase-3 activation/Bcl-2 inhibition). Such events were accompanied by potentiation of endogenous anti-inflammatory/antioxidant response (↑ hepatic Nrf-2). SIGNIFICANCE: The study highlights caution when QUR is consumed in health-compromised conditions, by revealing the role of fever/mild inflammation in enhancing liver toxicity upon QUR utilization, which was not apparent with moderate consumption of QUR-alone.

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.

Modulation of brain ACE and ACE2 may be a promising protective strategy against cerebral ischemia/reperfusion injury: an experimental trial in rats.

The brain renin-angiotensin system (RAS) is considered a crucial regulator for physiological homeostasis and disease progression. We evaluated the protective effects of the angiotensin receptor blocker (ARB) telmisartan and the angiotensin-converting enzyme 2 (ACE2) activator xanthenone on experimental cerebral ischemia/reperfusion (I/R) injury. Rats were divided into a sham control, a cerebral I/R control, a standard treatment (nimodipine, 10 mg/kg/day, 15 days, p.o.), three telmisartan treatments (1, 3, and 10 mg/kg/day, 15 days, p.o.), and three xanthenone treatments (0.5, 1, and 2 mg/kg/day, 15 days, s.c.) groups. One hour after the last dose, all rats except the sham control group were exposed to 30-min cerebral ischemia followed by 24-h reperfusion. Brain ACE and ACE2 activities and the apoptotic marker caspase-3 levels were assessed. Glutathione (GSH), malondialdehyde (MDA), and nitric oxide end products (NOx) as oxidative markers and tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-10 as immunological markers were assessed. Histopathological examination and immunohistochemical evaluation of glial fibrillary acidic protein (GFAP) were performed in cerebral cortex and hippocampus sections. Telmisartan and xanthenone in the higher doses restored MDA, NOx, TNF-α, IL-6, caspase-3, ACE, and GFAP back to normal levels and significantly increased GSH, IL-10, and ACE2 compared to I/R control values. Histopathologically, both agents showed mild degenerative changes and necrosis of neurons in cerebral cortex and hippocampus compared with I/R control group. Modulation of brain RAS, either through suppression of the classic ACE pathway or stimulation of its antagonist pathway ACE2, may be a promising strategy against cerebral I/R damage.

Zinc oxide nanoparticles as a novel anticancer approach; in vitro and in vivo evidence.

Currently, the outcomes of conventional chemotherapeutic approaches are unsatisfactory. Clinical application of nanoparticles seems promising. We aim to evaluate the possible antitumor activity of zinc oxide nanoparticles (ZnONPs) as a chemotherapeutic approach in in vitro and in vivo experimental models. An in vitro study was performed on three different cell lines, namely human hepatocellular carcinoma (HEPG2), human prostate cancer (PC3), and none-small cell lung cancer (A549) cell lines. An in vivo study using diethylnitrosamine (DENA)-induced HCC in adult male Wistar rats was conducted to investigate the potential antitumor activity of ZnONPs in HCC and the possible underlying mechanisms. Hepatocellular carcinoma (HCC) was induced by oral administration of DENA given in drinking water (100 mg/L) for 8 weeks. Rats were allocated into four groups, namely a control group, an HCC control group receiving DENA alone, a ZnONPs (10 µg/kg per week, intravenous (i.v.) for 1 month) control group, and a ZnONPs treatment group (receiving ZnONPs + DENA). ZnONPs significantly reduced the elevated serum levels of HCC-related tumor markers alphafetoprotein and alpha-l-fucosidase and the apoptotic marker caspase-3 compared with the untreated HCC rats. In addition, treatment with ZnONPs significantly decreased the elevated levels of hepatocyte integrity and oxidative stress markers as compared with the untreated HCC control group. Furthermore, the histopathological study revealed anaplasia and fibrous degenerations which were significantly corrected by ZnONPs treatment. In conclusion, administration of ZnONPs exhibited a promising preclinical anticancer efficacy in HCC and could be considered as a novel strategy for the treatment HCC in clinical practices.