The possible protective effect of l-cysteine in a rat model of sciatic nerve ischemia-reperfusion: A possible role for NRF1 and Caspase 3; Biochemical, Histological, and Immunohistochemical study.

Organ damage brought on by ischemia is exacerbated by the reperfusion process. L-cysteine is a semi-essential amino acid that acts as a substrate for cystathionine-ß-synthase in the central nervous system. The aim of this study was to investigate the possible protective effects of L- cysteine against the structural and biochemical changes that occur in the rat sciatic nerve after ischemia reperfusion (I/R) and to address some of the underlying mechanisms of these effects. Rats were divided into 4 groups: sham, l-cysteine, I/R, and l-cysteine- I/R groups. Specimens of sciatic nerve were processed for biochemical, histological, and immunohistochemical assessment. The results showed in I/R group, a significant increase in malondialdehyde with a significant decrease in both Nuclear respiratory factor-1 (NRF1) and superoxide dismutase levels. Moreover, with histological alteration. There was a significant increase in the mean surface area fraction of anti-caspase immunopositive cells as well as a significantdecrease in mean surface area fraction of anti-CD 34 immunopositive cells. In contrast, the l-cysteine- I/R group showed amelioration of these biochemical, structural, and immunohistochemical changes. To the best of our knowledge, this is the first study showed the protective effects of l-cysteine in sciatic nerve I/R via NRF1and caspase 3 modulation as well as telocyte activation.

Exercise ameliorates hippocampal damage induced by Wi-Fi radiation; a biochemical, histological, and immunohistochemical study.

INTRODUCTION: Nowadays, using electromagnetic devices (EMD) has been increased. However, the control of EMD hazards was poorly evaluated, especially those affected the hippocampus. Regular physical exercises are safe, easily, inexpensive, and acceptable for long-term use. It is reported that exercise protects against many health problems. AIM: is to investigate the hypothesis of the possible prophylactic effect of exercise on the hippocampal damage induced by electromagnetic waves of Wi-Fi. MATERIAL AND METHODS: Adult male albino rats were divided into four groups: group I (control), group II (exercise), group III (Wi-Fi), and group IV (exercise -Wi-Fi). Hippocampi were subjected to biochemical, histological, and immunohistochemical techniques. RESULTS: In group III, a significant increase in the oxidative enzymes as well as decrease in antioxidant enzymes were detected in rat hippocampus. Additionally, the hippocampus showed degenerated pyramidal and granular neurons. An evident decrease in both PCNA and ZO-1 immunoreactivity was also noticed. In group IV, physical exercise alleviates the effect of Wi-Fi on previously mentioned parameters. CONCLUSION: Regular physical exercise performance significantly minimizes the hippocampal damage and protects against the hazarders of chronic Wi-Fi radiation exposure.

Potential protective effect of 3,3'-methylenebis(1-ethyl-4-hydroxyquinolin-2(1H)-one) against bleomycin-induced lung injury in male albino rat via modulation of Nrf2 pathway: biochemical, histological, and immunohistochemical study.

Acute lung injury is a serious condition accounting for the majority of acute respiratory failure. Bleomycin (BLM) is an antibiotic that was first described as a chemotherapeutic agent. 3,3'-methylenebis(1-ethyl-4-hydroxyquinolin-2(1H)-one) was reported to have anti-inflammatory, anti-apoptotic, and anti-oxidative properties. The current work aimed to assess the possible protective effects and the mechanism of protection of 3,3'-methylenebis-(1-ethyl-4-hydroxyquinolin-2(1H)-one) on BLM-induced lung injury in addition to the effect and underlying mechanisms of nuclear factor-erythroid-related factor 2 pathway against this injury. Rats were equally divided into four groups: control group, BLM group, 1-ethyl-4-hydroxyquinolin-2(1H)-one-treated group, and BLM with 1-ethyl-4-hydroxyquinolin-2(1H)-one-treated group. At the end of the work, the blood samples were proceeded for biochemical study. Lung specimens were obtained for biochemical, histological, and immunohistochemical study. The results exhibited a significant increase in both malondialdehyde and tumor necrotic factor-α with a significant decrease in glutathione, superoxide dismutase, IL 10, surfactant protein A, and nuclear factor erythroid 2-related factor 2 in BLM group. The lung histological results showed various morphological changes in the form of disturbed architecture, inflammatory cell infiltration, and intraluminal debris. This group also displayed a significant increase in the mean surface area fraction of anti-cleaved caspase 3, while group IV exhibited amelioration in the previously mentioned parameters and histological alternations that were induced by BLM. It could be concluded that 3,3'-methylenebis(1-ethyl-4-hydroxyquinolin-2(1H)-one) has anti-oxidative, anti-inflammatory, and anti-apoptotic protective effects against BLM-induced lung injury.

Paeonol Protects against Methotrexate Hepatotoxicity by Repressing Oxidative Stress, Inflammation, and Apoptosis-The Role of Drug Efflux Transporters.

Methotrexate (MTX) is an effective chemotherapeutic agent against a wide range of tumors and autoimmune diseases; however, hepatotoxicity limits its clinical use. Oxidative stress and inflammation have been implicated in the pathogenesis of MTX-induced hepatotoxicity. Paeonol is a natural phenolic compound reported for its antioxidant and anti-inflammatory properties. The current study aimed to investigate the protective effect of paeonol against MTX-induced hepatotoxicity in rats and various mechanisms that underlie this postulated effect. Paeonol was administered orally in a dose of 100 mg/kg, alone or along with MTX, for 10 days. Hepatotoxicity was induced via a single intraperitoneal dose of MTX (20 mg/kg) on day 5 of the experiment. Concomitant administration of paeonol with MTX significantly ameliorated distorted hepatic function and histological structure, restored hepatic oxidative stress parameters (MDA, NO, and SOD), and combated inflammatory response (iNOS and TNF-α). Additionally, paeonol enhanced cell proliferation and survival, evidenced by upregulating the proliferating cell nuclear antigen (PCNA) and suppressing apoptosis and the disposition of collagen fibers in rat livers treated with MTX. Importantly, paeonol upregulated the drug efflux transporters, namely P-glycoprotein (P-gp) and the multidrug resistance-associated protein 2 (Mrp-2) in MTX-treated rats. In conclusion, paeonol offered a potent protective effect against MTX-induced hepatotoxicity through suppressing oxidative stress, inflammation, fibrosis, and apoptosis pathways, along with P-gp and Mrp-2 upregulation.

Role of Platelet-activating factor and HO-1 in mediating the protective effect of rupatadine against 5-fluorouracil-induced hepatotoxicity in rats.

5-fluorouracil (5-FU) is a widely used chemotherapeutic drug, but its hepatotoxicity challenges its clinical use. Thus, searching for a hepatoprotective agent is highly required to prevent the accompanied hepatic hazards. The current study aimed to investigate the potential benefit and mechanisms of action of rupatadine (RU), a Platelet-activating factor (PAF) antagonist, in the prevention of 5-FU-related hepatotoxicity in rats. Hepatotoxicity was developed in male albino rats by a single 5-FU (150 mg/kg) intra-peritoneal injection on the 7th day of the experiment. RU (3 mg/kg/day) was orally administrated to the rodents for 10 days. Hepatic toxicity was assessed by measuring both liver and body weights, serum alanine aminotransferase and aspartate aminotransferase (ALT and AST), hepatic oxidative stress parameters (malondialdehyde (MDA), nitric oxide levels (NOx), reduced glutathione (GSH), superoxide dismutase (SOD)), and heme oxygenase-1 (HO-1). Inflammatory markers expressions (inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNFα), interleukins; IL-1B, IL-6), the apoptotic marker (caspase-3), and PAF were measured in the hepatic tissue. 5-FU-induced hepatotoxicity was proved by the biochemical along with histopathological assessments. RU ameliorated 5-FU-induced liver damage as proved by the improved serum ALT, AST, and hepatic oxidative stress parameters, the attenuated expression of hepatic pro-inflammatory cytokines and PAF, and the up-regulation of HO-1. Therefore, it can be concluded that RU pretreatment exerted a hepatoprotective effect against 5-FU-induced liver damage through both its powerful anti-inflammatory, antioxidant, and anti-apoptotic effect.

Dysfunction of aged liver of male albino rats and the effect of intermitted fasting; Biochemical, histological, and immunohistochemical study.

Intermittent fasting exerts beneficial effects on most age-related degenerative changes throughout the body. This study aimed to investigate the possible protective effects and mechanism of intermittent fasting on aged liver in male albino rats. Forty male albino rats were used in this study and were divided into four equal groups; Group I served as control ; rats aged 1 month sacrfied when they reached age of 4 month. Group II; rats aged 1 month with intermittent fasting for 3 months. The rats sacrfied when they reached age of 4 mounth Group III; rats aged 15-month fed an ad-libitum diet. The rats sacrified when they reached age of 18 month. Group IV; 15 month rats with intermittent fasting for 3 months. The rats sacrified when they reached age of 18 month. Liver specimens were excised and processed for biochemical, histological, and immunohistochemical study. Blood samples were collected for biochemical study. The result showed a significant increase in liver injury, oxidative stress, and inflammatory markers with a marked decrease in the autophagy marker in group III if compared with both group I and II. Additionally, group III showed hepatic vacuolations, cellular filtration, and congestion in both central and portal veins. A highly significant increase in the mean color intensity of positive immunochemical reaction for anti caspase 3 and anti-TNFα as well as a highly significant increase in the surface area fraction of collagen fibers were noticed in group III if compared with group I and II. Interestingly, intermittent fasting (group IV) remarkably reduced the previous alternation that that occurred in group III. It could be concluded that various biochemical, histological, and immunohistochemical alterations were observed in liver rat in group III. Beneficial effects of fasting on these changes were recorded in group IV through its anti-inflammatory, anti-apoptotic effect as well as its effect in modulating autophagy in aged liver cells. This might open the gate for further research and provide a new line for therapeutic intervention in aged liver. These data lead to speculate that sporadic fasting might represent a simple, safe, and inexpensive means to fight the changes occurred in the aged liver.

Cardioprotective effects of bosentan in 5-fluorouracil-induced cardiotoxicity.

5-fluorouracil (5-FU) is a widely used chemotherapeutic agent but cardiotoxicity challenges its clinical usefulness. Thus, searching for more cardioprotective drugs is highly required to prevent the accompanied cardiac hazards. Up to date, the different mechanisms involved in 5-FU cardiotoxicity are still unclear and there is no evaluation of bosentan's role in controlling these cardiac complications. This forced us to deeply study and evaluate the possible cardiopreserving properties of bosentan and different mechanisms involved in mediating it. 32 Wistar albino rats were included in our experiment and induction of cardiotoxicity was performed via administration of 5-FU (150 mg/kg) on 5th day of the experiment by intraperitoneal (i.p.) injection with or without co-administration of bosentan (50 mg/kg/day) orally for 7days. Our data revealed that 5-FU could induce cardiotoxicity which was detected as significant increases of troponin I, lactate dehydrogenase (LDH), creatine kinase- MB (CK-MB), endothelin receptors, malondialdehyde (MDA), toll like receptor4 (TLR4), myeloid differentiation primary response 88 (MyD88), nuclear factor kappa B (NFκB), and caspase 3 levels. However, there is marked decrease in endothelial nitric oxide synthase (eNOS), reduced glutathione (GSH) and total antioxidant capacity (TAC). In addition, the histopathological examination showed severe toxic features of cardiac injury. Interestingly, co-administration of bosentan could ameliorate 5-FU-induced cardiotoxicity via improving the detected biochemical and histopathological changes besides modulation of TLR4/MyD88/NFκB signaling pathway, eNOS, and endothelin receptors. Bosentan had a significant cardioprotective effect against 5-FU induced cardiac damage. This effect may be attributed to its ability to inhibit endothelin receptors, stimulates eNOS, anti-oxidant, anti-inflammatory, anti-apoptotic properties with modulation of TLR4/MyD88/NFκB signaling pathway.

Efficacy of vitamin E in protection against methotrexate induced placental injury in albino rats.

Methotrexate (MXT) is a chemotherapeutic drug that has been used in a wide range of clinical practices. Unfortunately, the administration of MXT during pregnancy may induce abortion, fetal deformities, and intrauterine growth retardation. Vitamin E is an antioxidant agent that can ameliorate free radical damage. The current work aimed to shed more light on the possible protective effect of vitamin E against MXT induced placental toxicity and to determine the possible mechanisms; biochemically, histologically, and immunohistochemically. Four groups were used: control pregnant, Vitamin E (VIT E) pregnant, Methotrexate (MXT) pregnant, and Vitamin E Methotrexate (VIT E-MXT) pregnant. The placental tissues were processed for light, immunohistochemical, and electron microscopic study. Other samples were obtained for biochemical study; the placental oxidant/antioxidant status was evaluated. The results showed that MXT caused various placental morphological changes in the form of distorted chorionic projection with an accumulation of hemosiderin granules in the trophoblastic cells. Maternal blood vessels showed a homogenous acidophilic material Edema of the extra-embryonic fetal membranes was noticed. A significant decreased in placental weight as well as increase in the oxidative and inflammatory markers were detected. Increased COX2 and decreased eNOS expressions were observed in the MXT group if compared to the control group. VIT E significantly restored the normal histological and immunohistochemical appearance, placental weight, and oxidant/antioxidant balance. It could be concluded the biochemical, morphological, and morphometric findings suggested that vitamin E coadministration is promising in attenuating the placental toxic effect of methotrexate. In this study, VIT E decreased the inflammatory and oxidative stress effect of methotrexate on the placental tissue by enhancing the level of eNOS.

Resveratrol reduces gentamicin-induced EMT in the kidney via inhibition of reactive oxygen species and involving TGF-ß/Smad pathway.

AIMS: Gentamicin (GEN) is one of the most valuable aminoglycoside antibiotics utilized against life-threatening bacterial infections. Unfortunately, GEN-induced nephrotoxicity limited its clinical utility. The pathologic process of nephrotoxicity caused by GEN may involve epithelial to mesenchymal transition (EMT). Resveratrol (RES) is a natural compound was revealed to inhibit EMT in kidney. The present work was conducted to explore the potential renoprotective role of RES on GEN-induced EMT. Moreover, the underlying signaling pathway of this inhibition was investigated. MAIN METHODS: Mice were treated with GEN by intraperitoneal (i.p.) route daily for 15 days to identify EMT onset with regard to GEN-induced nephrotoxicity. To assess the ameliorative role of RES against GEN-induced EMT, RES was i.p. administrated in high and low doses before and concurrently with GEN treatment. KEY FINDINGS: GEN administration significantly deteriorated kidney functions. In addition, reduced glutathione (GSH) content and catalase (CAT) activity were significantly decreased with a concomitant increase in the content of kidney malondialdehyde (MDA) after GEN treatment. Histological changes and deposition of collagen were extensive in renal corpuscles and tubules. Increased expression of alpha smooth muscle actin (α-SMA), transforming growth factor-ß1 (TGF-ß1) and phosphorylated (p)-Smad2 were observed after GEN administration, while E-cadherin expression was decreased. On the contrary, pretreatment with both doses of RES reversed the modifications caused by GEN administration. SIGNIFICANCE: We concluded that EMT contributes to pathogenesis of GEN-induced nephrotoxicity. RES has a protective effect on GEN-induced EMT via suppressing oxidative stress and a possible involvement of TGF-ß/Smad signaling pathway.