P2X7 receptor antagonist A-438079 alleviates oxidative stress of lung in LPS-induced septic rats.

Sepsis is a deadly systemic inflammatory response of the body against infection resulting in immune response, cell differentiation and organ damage. Endotoxemia is one of the causes of sepsis-related acute respiratory distress and respiratory burst is an important generator of oxidants. Inflammation may be aggravated by overexpression of ATP-gated purinergic receptors (i.e., P2X7R) following cell damage. We aimed to evaluate the effects of P2X7R antagonist A-438079 on lung oxidative status and the receptor expression in endotoxemia of sepsis. Rats were subjected to sepsis by E. coli lipopolysaccharide (LPS) and treated with 15 mg/kg A-438079. The increase in circulatory IL-1ß and IL-8 concentrations in LPS group confirmed the systemic inflammatory response to endotoxemia compared with Control groups (p < 0.001). Besides, there was an increase in P2X7R expression in lung tissue after LPS administration. Compared with Control groups, there were significant increases in the values of malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) (p < 0.001), and myeloperoxidase (MPO) (p < 0.05) in lung tissue of LPS group. P2X7R expression in lung and IL-1ß level in blood did not increase in LPS + A-438079 group. A-438079 decreased the lung levels of MDA, GSH, CAT and SOD (p < 0.001), and MPO (p < 0.01) in septic rats. As a result, administration of pathogen-associated LPS led to increased P2X7R expression into lung tissue and elevated lipid peroxidation product MDA with regard to oxidative damage. The P2X7R antagonist A-438079 alleviated the oxidative stress of lung with a balance of tissue oxidant/antioxidant factors in experimental sepsis in rats.

Chemopreventive effects of hesperidin against paclitaxel-induced hepatotoxicity and nephrotoxicity via amendment of Nrf2/HO-1 and caspase-3/Bax/Bcl-2 signaling pathways.

Paclitaxel (PTX) is a widely used chemotherapeutic drug particularly effective against lung, breast, and ovarian cancer, though its usefulness is limited due to its multi-organ toxicity. The mechanisms underlying PTX toxicity are currently not yet known and there are no approved treatments for its control or prevention. This study aimed to investigate whether hesperidin (HSP) had a protective effect on paclitaxel-induced hepatotoxicity and nephrotoxicity from biochemical, and molecular perspectives. The rats were administered PTX 2 mg/kg, b.w. intraperitoneally for the first 5 consecutive days, then 100 or 200 mg/kg b.w. HSP orally for 10 consecutive days. Our results demonstrated that HSP decreased the PTX induced lipid peroxidation, improved the serum hepatic and renal functions (by decreasing the levels of AST, ALT, ALP, urea, and creatinine), and restored the liver and kidney antioxidant armory (SOD, CAT, GPx, and GSH). HSP also significantly reduced mRNA expression levels of NF-κB, TNF-α, IL-1ß, IL-6, MAPK 14, Caspase-3, Bax, LC3A, LC3B, MMP2, and MMP9 whereas caused an increase in levels of Nrf2, HO-1, and Bcl-2 in the kidney and liver of PTX-induced rats. In addition, caspase-3, Bax, and Bcl-2 protein levels were examined by Western blot analysis, and it was determined that HSP decreased caspase-3 and Bax protein levels, but increased Bcl-2 protein levels. The findings of the study suggest that HSP has chemopreventive potential against PTX-induced hepatorenal toxicity plausibly through the attenuation of oxidative stress, inflammation, apoptosis, and autophagy.

Neuroprotective effects of carvacrol against cadmium-induced neurotoxicity in rats: role of oxidative stress, inflammation and apoptosis.

Cadmium (Cd), is a heavy metal reported to be associated with oxidative stress and inflammation. In this paper, we investigated the possible protective effects of carvacrol against Cd-induced neurotoxicity in rats. Adult male Sprague Dawley rats were treated orally with Cd (25 mg/kg body weight) and with carvacrol (25 and 50 mg/kg body weight) for 7 days. Carvacrol decreased the levels of malondialdehyde (MDA), glial fibrillary acidic protein (GFAP) and monoamine oxidase (MAO), and significantly increased the levels of glutathione (GSH) and activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in brain tissue. Additionally, carvacrol alleviated the in levels of inflammation and apoptosis related proteins involving p38 mitogen-activated protein kinase (p38 MAPK), cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB), B-cell lymphoma-3 (Bcl-3), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), myeloperoxidase (MPO), prostaglandin E2 (PGE2), neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS), cysteine aspartate specific protease-3 (caspase-3) and Bcl-2 associated X protein (Bax) in the Cd-induced neurotoxicity. Carvacrol also decreased the mRNA expression of matrix metalloproteinases (MMP9 and MMP13), as well as 8-hydroxy-2'-deoxyguanosine (8 - OHdG) level, a marker of oxidative DNA damage. Collectively, our findings indicated that carvacrol has a beneficial effect in ameliorating the Cd-induced neurotoxicity in the brain of rats.

Evaluation of the protective effects of morin against acrylamide-induced lung toxicity by biomarkers of oxidative stress, inflammation, apoptosis, and autophagy.

Acrylamide (ACR) has genotoxic, neurotoxic, and carcinogenic effects. From past to present, various plants or their products have been used for therapeutic purposes such as morin. It was aimed to detect possible protective effects of morin vs ACR-induced lung toxicity. The rats, treated with ACR alone or with morin for 10 consecutive days, were included in the study. A broad variety of biomarkers related to oxidative stress, apoptosis, autophagy, and inflammatory responses were evaluated. ACR increased malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), cyclooxygenase-2 (COX-2), nuclear factor kappa-B (NF-κB), Beclin-1, IL-1ß, bcl-2 associated X protein (Bax), caspase-3, light chain 3-A (LC3-A), and light chain 3-B (LC3-B) levels but reduced mammalian target of rapamycin (mTOR), b-cell lymphoma-2 (Bcl-2), catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), glutathione (GSH) in lung tissues. The morin had effects on the level of these molecules in a way that is opposite to ACR. While ACR-induced oxidative stress, apoptotic, autophagic, inflammatory responses, and may cause pulmonary dysfunction, the morin reduced ACR-induced lung damage. PRACTICAL APPLICATIONS: ACR is a toxic chemical produced by frying, baking, roasting, or grilling foods with high starch content and has genotoxic, neurotoxic, and carcinogenic effects. As an antioxidant compound, the morin is obtained from plants or their products. It was aimed to detect possible protective effects of morin against ACR-induced lung toxicity. It was detected that ACR-induced oxidative stress, apoptotic, autophagic, inflammatory responses, and may cause pulmonary dysfunction, but the morin reduced ACR-induced lung damage.