Doxorubicin-induced hepatic toxicity in rats: Mechanistic protective role of Omega-3 fatty acids through Nrf2/HO-1 activation and PI3K/Akt/GSK-3ß axis modulation.

Doxorubicin (DOX), a common antibiotic used to treat a variety of tumors, has several substantial adverse effects that limit its clinical use. As a result, finding effective protective agents to combat DOX-induced organ damage is a necessity. The current study was set to delineate the hepatoprotective role of omega-3 fatty acids (ω-3FA) against DOX-mediated acute liver damage in rats and the underlined mechanism of GSK-3ß inhibition. Five groups of rats were orally received either saline (groups 1 & 2) or ω-3FA (25, 50 and 100 mg/kg/day; groups 3, 4 & 5, respectively) for 28 consecutive days. Single DOX intraperitoneal injection (20 mg/kg) was used to induce hepatic toxicity in all groups except group 1 (negative control). Blood samples and liver tissues were collected 48-hr after injection. Our results revealed that pre-administration of ω-3FA (25, 50 and 100 mg/kg) to DOX-induced hepatic injured rats showed a significant reduction in serum hepatic injury biomarkers (ALT, AST, total and direct bilirubin) as well as hepatic contents of MDA, GSH, Nrf2 and HO-1. Additionally, hepatic PI3K, pAkt and GSK-3ß have been restored significantly in a dose-dependent manner. Furthermore, all the hepatic histopathological features have been retained upon ω-3FA treatment together with the immunostaining intensity of tumor necrosis factor-α and caspase-3. These results suggest that ω-3FA have shown a marked activation of the Nrf2/HO-1 signaling pathway and modulation of the PI3K/pAkt/GSK-3ß axis against DOX-induced hepatotoxicity.

Olmesartan attenuates type 2 diabetes-associated liver injury: Cross-talk of AGE/RAGE/JNK, STAT3/SCOS3 and RAS signaling pathways.

Olmesartan (OLM), an angiotensin receptor blocker, was tested against diabetes/insulin resistance (IR) models associated with renal/cardiovascular complications. Methods: we tested its potential role against diabetes-induced hepatic hitches using an IR/type2 diabetic (IR/D) model induced by high fat/high fructose diet for 7 weeks â€‹+ â€‹a single sub-diabetogenic dose of streptozotocin (35mg/kg; i.p). IR/D rats were orally treated with OLM (10 â€‹mg/kg), pioglitazone (PIO; 5 or 10 â€‹mg/kg) or their combinations for 4 consecutive weeks. OLM alone opposed the detrimental effects of IR/D; it significantly improved metabolic parameters, liver function, and abated hepatic oxidative stress, and inflammatory cytokine interleukin-6 (IL-6) and its upstream mediator nuclear factor kappa B. Consequently, OLM turned off the downstream cue p-Jak2/STAT3/SOCS3. Moreover, it suppressed the elevated AGE/RAGE/p-JNK pathway and increased the PPARγ/adiponectin cue to signify its anti-inflammatory and anti-oxidant capacity (GSH, MDA). Nevertheless, co-administration of OLM to PIO showed a synergistic improvement in all the aforementioned parameters in a dose dependent manner. Additionally, OLM with PIO10 provoked a surge in hepatic PPARγ and adiponectin (5 and 6 folds) with a sharp decrease of about 85% in the NF-κB/IL-6/p-STAT3/SCOS3 pathway. These effects were confirmed by the histopathological study. In conclusion, OLM and its combination with PIO enhanced insulin sensitivity and guarded against hepatic complications associated with type 2 diabetes probably via modulating various inter-related pathways; namely, metabolic alteration, renin-angiotensin system, inflammatory trajectories, as well as oxidative stress. This study manifests the potential synergistic effects of OLM as an adjuvant therapy to the conventional antidiabetic therapies.

Metformin and trimetazidine ameliorate diabetes-induced cognitive impediment in status epileptic rats.

Patients with diabetes and epilepsy are more prone to cognitive impairment, dementia, and even Alzheimer's disease. Diabetes-induced inflammatory process is one of the main contributing factors; however, the impact on seizure is not clear. The current study is aimed to examine the role of metformin and trimetazidine in the reduction of neuronal damage caused by inflammatory mediators and apoptotic factors in diabetic epileptic rodent model. Diabetic epileptic rats received orally either metformin (100 mg/kg) or trimetazidine (10 mg/kg) for 3 weeks exhibited reduced cognitive function and ameliorated the disturbed brain neurotransmission. Besides, they improved both the inflammatory status and the histopathologic alterations. Administration of metformin or trimetazidine ameliorated the deterioration in cognitive function in Morris water maze (MWM) and reduced seizure score. Furthermore, brain neurotransmitters glutamate and γ-aminobutyric acid (GABA) were reverted back to their normal values. Both treatments reduced the rise in inflammatory cytokines interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α), apoptotic markers nuclear factor-κB (NF-κB) and caspase-3, and improved the pathological photomicrograph of the hippocampus of diabetic epileptic rats. Such effects were closely correlated to the observed increase in the adenosine triphosphate and adenosine diphosphate (ATP/ADP) ratio and reduction of death-associated protein (DAP) and mammalian target of rapamycin (mTOR). In conclusion, the current study shed light on the potential neuroprotective role of metformin and trimetazidine in the amelioration of cognitive function via hindering inflammatory processes in diabetic epileptic rats.

Red yeast rice and coenzyme Q10 as safe alternatives to surmount atorvastatin-induced myopathy in hyperlipidemic rats.

Statins are the first line treatment for the management of hyperlipidemia. However, the primary adverse effect limiting their use is myopathy. This study examines the efficacy and safety of red yeast rice (RYR), a source of natural statins, as compared with atorvastatin, which is the most widely used synthetic statin. Statin interference with the endogenous synthesis of coenzyme Q10 (CoQ10) prompted the hypothesis that its deficiency may be implicated in the pathogenesis of statin-associated myopathy. Hence, the effects of combination of CoQ10 with either statin have been evaluated. Rats were rendered hyperlipidemic through feeding them a high-fat diet for 90 days, during the last 30 days of the diet they were treated daily with either atorvastatin, RYR, CoQ10, or combined regimens. Lipid profile, liver function tests, and creatine kinase were monitored after 15 and 30 days of drug treatments. Heart contents of CoQ9 and CoQ10 were assessed and histopathological examination of the liver and aortic wall was performed. RYR and CoQ10 had the advantage over atorvastatin in that they lower cholesterol without elevating creatine kinase, a hallmark of myopathy. RYR maintained normal levels of heart ubiquinones, which are essential components for energy production in muscles. In conclusion, RYR and CoQ10 may offer alternatives to overcome atorvastatin-associated myopathy.

Tissue distribution and efficacy of gold nanorods coupled with laser induced photoplasmonic therapy in ehrlich carcinoma solid tumor model.

Gold nanorods (GNR) within tumor microregions are characterized by their ability to absorb near IR light and emit heat in what is called photoplasmonic effect. Yet, the efficacy of nanoparticles is limited due to intratumoral tissue distribution reasons. In addition, distribution of GNRs to normal tissue might result in non specific toxicity. In the current study, we are assessing the intratumoral and tissue distribution of PEGylated GNRs on the top of its antitumor characteristics when given intravenously or intratumoral to solid tumor bearing mice and coupled with laser photoplasmonic sessions. PEGylated GNRs with a longitudinal size of less than 100 nm were prepared with aspect ratio of 4.6 showing strong surface plasmon absorption at wavelength 800 nm. Pharmacokinetics of GNR after single I.V. administration (0.1 mg/kg) showed very short systemic circulating time (less than 3 h). On the other hand, tissue distribution of I.V. GNR (0.1 mg/kg) to normal animals showed preferential deposition in spleen tissue. Repeated administration of I.V. GNR resulted in preferential accumulation in both liver and spleen tissues. In addition, I.V. administration of GNR to Ehrlich carcinoma tumor bearing mice resulted in similar tissue distribution; tumor accumulation and anti-tumor effect compared to intratumoral administration. In conclusion, the concentration of GNR achieved within tumors microregions after I.V. administration was comparable to I.T. administration and sufficient to elicit tumoral growth arrest when coupled with laser-aided photoplasmonic treatment.

Pharmacological study of the effect of licorice alone and in combination with diclofenac sodium on hepatotoxicity-induced experimentally in rats.

The protective effect of licorice and diclofenac sodium in doses of 50 mg/kg bwt. and 5 mg/kg bwt. respectively against liver toxicity induced by CCl4 (1ml/kg bwt.) in olive oil [1:1 (v/v)] every other day for 8 weeks and by hepatic ischemia/reperfusion in adult male albino rats was studied. Different antioxidant and liver function parameters were reported to find the protective effect of both licorice and diclofenac sodium against hepatotoxicity. Results showed that licorice protected against CCl4-induced hepatotoxicity as well as ischemia/reperfusion-induced liver injury. On the other hand, diclofenac sodium caused deleterious effects, especially in presence of CCl4, where a high mortality rate was observed.

Synthesis and pharmacological evaluation of novel quinoxalines as potential nonulcerogenic anti-inflammatory and analgesic agents.

Some new substituted quinoxaline and furo[2,3-b]quinoxaline derivatives have been synthesized and tested for their anti-inflammatory and analgesic activities and for their ulcerogenic potential. The pharmacological evaluation of selected synthesized compounds revealed that 5a was equipotent and compounds 3, 4b, 4e and 5b possessed strong anti-inflammatory activity in chronic inflammatory models compared with indometacin (CAS 53-86-1) as reference drug. In addition, compound 4a was the safest one and the others showed little ulcerogenic activity. All the tested compounds showed moderate analgesic activity compared to the reference drug.