(E)‐2‐Benzylidene‐4‐phenyl‐1,3‐diselenole ameliorates signals of renal injury induced by cisplatin in rats

The present study investigated the protective role of antioxidant (E)‐2‐benzylidene‐4‐phenyl‐1,3‐diselenole (BPD), an organoselenium compound, against the renal injury induced by cisplatin in rats. Canola oil or BPD (50 mg kg^?1) was administered orally by gavage once a day for 6 days to rats. The first dose of BPD was given 24 h before a single intraperitoneal injection of saline or cisplatin (7 mg kg^?1). At day 7, animals were killed and parameters related to renal injury were determined. The histological analysis showed that cisplatin caused renal injury in rats, which was accompanied by an increase in urea and creatinine levels in plasma. The increase of plasma creatinine levels negatively correlated with renal antioxidant defenses including ascorbic acid (AA) and reduced glutathione (GSH) content as well as glutathione S‐transferase (GST), glutathione peroxidase (GPx) and catalase (CAT) activities. As revealed by histological analysis, BPD ameliorated tubular injury in rat kidney and reduced plasma markers altered by cisplatin. The administration of BPD to rats attenuated the reduction of renal AA and GSH content in animals exposed to cisplatin. The decrease of GST activity, but not GPx and CAT activities, in rats exposed to cisplatin was totally reversed by BPD administration. BPD was also effective in attenuating the inhibition of a sulfhydryl enzyme sensitive to oxidative stress, δ‐aminolevulinic dehydratase, in kidneys of rats exposed to cisplatin. The present study demonstrated that BPD reduced renal injury induced by cisplatin in rats and this effect seems to be related to antioxidant mechanisms. Copyright © 2012 John Wiley & Sons, Ltd.     

PI3K/AKT/JNK/p38 signalling pathway‐mediated neural apoptosis in the prefrontal cortex of mice is involved in the antidepressant‐like effect of pioglitazone

Numerous studies have reported that inflammation is involved in the pathophysiology of depression. Pioglitazone, a PPAR‐γ agonist, has potential anti‐inflammatory and antidepressive effects. However, the underlying molecular mechanisms of the antidepressant‐like effect of pioglitazone on an inflammation‐related mouse model of depression remain to be fully elucidated. Herein, we aimed to explore the effects of pioglitazone on depressive‐like behaviours of mice exposed to lipopolysaccharides (LPS), and elucidate the underlying mechanisms. We assessed behaviour changes of mice pretreated with pioglitazone exposed to LPS. Additionally, neural apoptosis, and the expression of apoptosis‐related (cleaved caspase‐3, Bax, Bcl‐2, cyt c) and signalling proteins (AKT, JNK, p38) were assessed in the prefrontal cortex (PFC) of these mice. Furthermore, we assessed the influence of anisomycin, a JNK/p38 agonist, and LY294002, a PI3K/AKT inhibitor, on the antidepressant‐like effect of pioglitazone in mice. We show that pioglitazone pretreatment (20 mg/kg, intragastrically) attenuated LPS‐induced (10 ng/μL per site) depressive‐like behaviours. GW9662, a PPAR‐γ antagonist, significantly blocked the antidepressant‐like effect of pioglitazone. Furthermore, at the molecular level, pioglitazone significantly reversed, via PPAR‐γ‐dependent increase in neural apoptosis in the PFC of mice, accompanied by upregulation of the PI3K/AKT pathway and down‐regulation of the JNK/p38 pathway. Moreover, both anisomycin and LY294002 abrogated the antidepressant‐like effect of pioglitazone.; In conclusion, our results showed that PI3K/AKT/JNK/p38 signalling pathway‐mediated neural apoptosis in the PFC of mice may be involved in the antidepressant‐like effect of pioglitazone. This provides novel insights into and therapeutic targets for inflammation‐related depression.     

Synthesis,docking, in vitro and in vivo antidiabetic activity of pyrazole‐based 2,4‐thiazolidinedione derivatives as PPAR‐γ modulators

The design, synthesis, structure–activity relationship, and biological activity of 2,4‐thiazolidinedione derivatives as peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) modulators for antidiabetic activity are reported. Fifteen 2,4‐thiazolidinedione derivatives clubbed with pyrazole moiety were docked into the ligand binding domain of PPAR‐γ by the Glide XP module of Schrodinger. Eight derivatives ( 5a , 5b , 5d , 5f , 5i , 5l , 5n , 5o ) having Glide XP scores > ?8 as compared to the standard drug, rosiglitazone (Glide XP score = ?9.165), showed almost similar interaction with the amino acids such as HIS 449, TYR 473, TYR 327, HIS 323, and SER 289 in the molecular docking studies. These eight derivatives were further screened for PPAR‐γ transactivation and in vivo blood glucose lowering activity in the streptozotocin‐induced diabetic rat model. Compounds 5o , 5n , 5a , 5i , and 5b showed 52.06, 51.30, 48.65, 43.13, and 40.36% PPAR‐γ transactivation as compared to the reference drugs rosiglitazone and pioglitazone with 85.30 and 65.22% transactivation, respectively. The data analysis showed significant blood glucose lowering effects (hypoglycemia) of compounds 5o , 5n , and 5a (140.1 ± 4.36, 141.4 ± 6.15, and 150.7 ± 4.15, respectively), along with reference drugs pioglitazone (135.2 ± 4.91) and rosiglitazone (141.1 ± 5.88) as compared to the diabetic control. Furthermore, the most potent compound 5o also elevated the PPAR‐γ gene expression by 2.35‐fold as compared to rosiglitazone (1.27‐fold) and pioglitazone (1.6‐fold). It also significantly lowered the AST, ALT, and ALP levels and caused no damage to the liver.

     

Genetic overexpressing of GPx‐1 attenuates cocaine‐induced renal toxicity via induction of anti‐apoptotic factors

The present study investigates the role of the glutathione peroxidase (GPx)‐1 gene in cocaine‐induced renal damage in mice. Multiple doses of cocaine increased lipid peroxidation, protein oxidation, and glutathione oxidation in the kidney of the non‐transgenic mice (non‐TG mice). The enzymatic activities of GPx and glutathione reductase were significantly decreased in non‐TG mice, whereas superoxide dismutase was increased in the early phase of cocaine exposure. Treatment with cocaine resulted in significant decreases in expression of Bcl‐2 and Bcl‐xl in the kidney of non‐TG mice, which resulted in significant increases in Bax and cleaved‐caspase 3. Consistently, cocaine‐induced tubular epithelial vacuolization and focal tubular necrosis were mainly observed in the proximal tubules in the kidneys of non‐TG mice. These renal pathologic changes were much less pronounced in GPx‐1 TG than in non‐TG mice. These results suggest that the GPx‐1 gene is a protective factor against nephrotoxicity induced by cocaine via interactive modulations between antioxidant and cell survival signaling processes.     

Stevioside protects against rhabdomyolysis‐induced acute kidney injury through PPAR‐γ agonism in rats

We explored the potential role of peroxisome proliferator activated receptor‐γ (PPAR‐γ) in stevioside‐mediated renoprotection using rhabdomyolysis‐induced acute kidney injury (AKI) model in rats. Rhabdomyolysis refers to intense skeletal muscle damage, which further causes AKI. Glycerol (50% w/v, 8 ml/kg) was injected intramuscularly in rats to induce rhabdomyolysis. After 24 hr, AKI was demonstrated by quantifying serum creatinine, urea, creatinine clearance, microproteinuria, and electrolytes in rats. Further, oxidative stress was measured by assaying thiobarbituric acid reactive substances, generation of superoxide anion, and reduced glutathione levels. Additionally, serum creatine kinase (CK) level was assayed to determine glycerol‐induced muscle damage in rats. Pathological changes in rat kidneys were studied using hematoxylin–eosin and periodic acid Schiff staining. Moreover, the expression of apoptotic markers (Bcl‐2, Bax) in rat kidneys was demonstrated by immunohistochemistry. Stevioside (10, 25, and 50 mg/kg) was administered to rats, prior to the induction of AKI. In a separate group, bisphenol A diglycidyl ether (BADGE, 30 mg/kg), a PPAR‐γ receptor antagonist was given prior to stevioside administration, which was followed by rhabdomyolysis‐induced AKI in rats. The significant alteration in biochemical and histological parameters in rats indicated AKI, which was attenuated by stevioside treatment. Pretreatment with BADGE abrogated stevioside‐mediated renoprotection, which is suggestive of the involvement of PPAR‐γ in its renoprotective effect. In conclusion, stevioside protects against rhabdomyolysis‐induced AKI, which may be attributed to modulation of PPAR‐γ expression.     

Pioglitazone alleviates the mitochondrial apoptotic pathway and mito‐oxidative damage in the d‐galactose‐induced mouse model

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Selenium modulates β‐cyfluthrin‐induced liver oxidative toxicity in rats

This study was designed to investigate the possibility of β‐cyfluthrin to induce oxidative stress and biochemical perturbations in rat liver and the role of selenium in alleviating its toxic effects. Male Wister rats were randomly divided into four groups of seven each, group I served as control, group II treated with selenium (200 µg/kg BW), group III received β‐cyfluthrin (15 mg/kg BW, 1/25 LD₅₀), and group IV treated with β‐cyfluthrin plus selenium. Rats were orally administered their respective doses daily for 30 days. The administration of β‐cyfluthrin caused elevation in lipid peroxidation (LPO) and reduction in the activities of antioxidant enzymes including catalase (CAT), superoxide dismutase (SOD), glutathione S‐transferase (GST), glutathione peroxidase (GPx), and glutathione reductase (GR). A decrease in reduced glutathione (GSH) content was also observed. Liver aminotransferases (AST and ALT) and alkaline phosphatase (ALP) were decreased, whereas lactate dehydrogenase (LDH) was increased. Selenium in β‐cyfluthrin‐induced liver oxidative injury of the rats modulated LPO, CAT, SOD, GSH, GST, GPx, and GR. Also, liver AST, ALT, ALP, and LDH were maintained near normal level due to selenium treatment. It is concluded that selenium scavenges reactive oxygen species and render a protective effect against β‐cyfluthrin toxicity. © 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 1323–1329, 2014.     

p-Methoxyl-diphenyl diselenide protects against cisplatin-induced renal toxicity in mice

The present study was designed to investigate the effects of p-methoxyl-diphenyl diselenide (OMePhSe)₂ on oxidative stress and renal damage parameters of mice exposed to cisplatin. (OMePhSe)₂ (50 and 100 mg/kg/day) was orally administered to mice for six consecutive days. On the third day after the beginning of (OMePhSe)₂ treatment, the renal toxicity was induced by injecting cisplatin (10 mg/kg intraperitoneal) in mice. (OMePhSe)₂ treatment (50 mg/kg) partially reduced plasma urea and creatinine levels increased by cisplatin. Histopathological examination of kidneys showed that (OMePhSe)₂ ameliorated renal injury caused by cisplatin. (OMePhSe)₂ attenuated the decrease in reduced glutathione (GSH) and ascorbic acid (AA) levels, the inhibition of glutathione peroxidase (GPx), glutathione S-transferase (GST), glutathione reductase (GR) and catalase (CAT) activities caused by cisplatin in kidney. (OMePhSe)₂ treatment partially protected against the inhibition of renal δ-aminolevulinic dehydratase (δ-ALA-D) activity caused by cisplatin. No alteration in renal lipid peroxidation levels was found in cisplatin and/or (OMePhSe)₂ groups. (OMePhSe)₂ was effective against the increase in reactive species (RS) levels caused by the cisplatin exposure. Based on the renoprotective and antioxidant actions of (OMePhSe)₂ we suggest that this organoselenium compound could be considered a feasible candidate to protect against toxicity commonly encountered in cisplatin exposure.     

Aqueous-ethanolic extract of morel mushroom mycelium Morchella esculenta, protects cisplatin and gentamicin induced nephrotoxicity in mice

Morchella esculenta (L) Pers. is an excellently edible and delicious morel mushroom found growing in the temperate forests. The mycelium of this mushroom is widely used as a flavouring agent. The current investigation was undertaken to explore the protective effect of the aqueous-ethanol extract of cultured mycelium of M. esculenta against cisplatin and gentamicin induced acute renal toxicity in Swiss albino mice. Cisplatin and gentamicin when administered induced a marked renal failure, characterized by a significant increase in serum urea and creatinine concentrations. Treatment with the extract at 250 and 500mg/kg body weight decreased the cisplatin and gentamicin induced increase in serum creatinine and urea levels. Treatment with the extract also restored the depleted antioxidant defense system. The decreased activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and reduced glutathione (GSH) in the kidneys consequent to cisplatin and gentamicin administration was significantly elevated. The enhanced renal antioxidant defense system also prevented the tissue lipid peroxidation. The experimental results suggest that aqueous-ethanol extract of morel mushroom, M. esculenta mycelium protected cisplatin and gentamicin induced nephrotoxicity possibly by enhancing renal antioxidant system. The findings thus suggest the potential therapeutic use of morel mushroom mycelium as a novel nephroprotective agent.     

Carnosic acid attenuates renal injury in an experimental model of rat cisplatin-induced nephrotoxicity

Nephrotoxicity is one of the serious dose limiting side effects of cisplatin when used in the treatment of various malignant conditions. Accumulating evidence suggests that oxidative stress caused by free radicals and apoptosis of renal cells contributes to the pathogenesis of cisplatin-induced nephrotoxicity. Present study was aimed to explore the effect of carnosic acid, a potent antioxidant, against cisplatin induced oxidative stress and nephrotoxicity in rats. A single dose of cisplatin (7.5 mg/kg) caused marked renal damage, characterized by a significant (P < 0.05) increase in serum creatinine, blood urea nitrogen (BUN) and relative weight of kidney with higher kidney MDA (malondialdehyde), tROS (total reactive oxygen species), caspase 3, GSH (reduced glutathione) levels and lowered tissue nitrite, SOD (superoxide dismutase), CAT (catalase), GSH-Px (glutathione peroxidase), GR (glutathione reductase) and GST (glutathione S-transferase) levels compared to normal control. Carnosic acid treatment significantly (P < 0.05) attenuated the increase in lipid peroxidation, caspase-3 and ROS generation and enhanced the levels of reduced glutathione, tissue nitrite level and activities of SOD, CAT, GSH-Px, GR and GST compared to cisplatin control. The present study demonstrates that carnosic acid has a protective effect on cisplatin induced experimental nephrotoxicity and is attributed to its potent antioxidant and antiapoptotic properties.     

Brain and lungs of rats are differently affected by cigarette smoke exposure: Antioxidant effect of an organoselenium compound

Cigarette smoke exposure has been associated with oxidative stress in several organs. Antioxidant effect of diphenyl diselenide (PhSe)₂, an organoselenium compound, on oxidative damage induced by sub-chronic cigarette smoke exposure in brain and lungs of rats was investigated. Animals were exposed 5 times/week to one, two, three and four cigarettes for exposure periods of 15 min during the first, second, third and fourth weeks. Reactive species (RS) levels, enzymatic antioxidant defenses (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione S-transferase (GST) activities) and non-enzymatic antioxidant defenses (ascorbic acid and non-protein thiol (NPSH) levels) were examined in brain and lungs of rats. An increase in RS levels induced by cigarette smoke in both tissues of rats was demonstrated. Cigarette smoke altered enzymatic antioxidant defenses (GST, CAT and SOD activities) in both tissues, and reduced the non-enzymatic antioxidant defenses in lungs. (PhSe)₂ (0.5 mg/kg/day, 5 times/week) restored RS levels and antioxidant defenses in brain of rats exposed to cigarette smoke. (PhSe)₂ treatment increased NPSH levels, GST and GR activities per se in lungs of rats. In conclusion, sub-chronic exposure to cigarette smoke caused alterations in antioxidant defense system and a tissue-specific oxidative stress in brain and lungs of rats. (PhSe)₂ restored antioxidant defenses in lungs and brain of rats.     

Diphenyl diselenide protects against glycerol‐induced renal damage in rats

In this study we evaluated the effect of diphenyl diselenide (PhSe)₂ on glycerol‐induced acute renal failure in rats. Rats were pre‐treated by gavage every day with (PhSe)₂ (7.14 mg kg^?1) for 7 days. On the eighth day, rats received an intramuscular injection of glycerol (8 mL kg^?1). Twenty‐four hours afterwards, rats were euthanized and the levels of urea and creatinine were measured in plasma. Catalase (CAT), glutathione peroxidase (GPx), glutathione S‐transferase (GST), δ‐aminolevulinate dehydratase (δ‐ALA‐D) and Na⁺, K⁺‐ATPase activities and ascorbic acid levels were evaluated in renal homogenates. Histopathological evaluations were also performed. The results demonstrated that (PhSe)₂ was able to protect against the increase in urea and creatinine levels and histological alterations in kidney induced by glycerol. (PhSe)₂ protected against the inhibition in δ‐ALA‐D, CAT and GPx activities and the reduction in ascorbic acid levels induced by glycerol in kidneys of rats. In conclusion, the present results indicate that (PhSe)₂ was effective in protecting against acute renal failure induced by glycerol. Copyright © 2009 John Wiley & Sons, Ltd.     

The difference of glutathione antioxidant system in newly weaned and young mice liver and its involvement in isoline-induced hepatotoxicity

Cellular glutathione antioxidant system plays important roles in counteracting hepatotoxins-induced oxidative stress injury. The present study was designed to observe the differences of this system in newly weaned and young mice liver and its involvement in the susceptibility to isoline-induced liver injury. Our results showed that liver reduced glutathione (GSH) amounts were higher in newly weaned mice than young mice. Glutamate-cysteine ligase (GCL) activity was higher in newly weaned mice due to the higher expression of catalytic subunit of GCL (GCLC) protein and mRNA. However, the activities of glutathione reductase (GR), glutathione peroxidase (GPx), and glutathione-S-transferase (GST) were higher in young mice liver, which might be due to the higher expression of GR, GPx-1, and GST-Pi proteins. Next, the results of AST analysis and histopathological evaluation showed that newly weaned mice demonstrated more severe liver injury induced by isoline. Furthermore, liver GSH amounts and the activities of GR, GPx, and GST were all lower in newly weaned mice than young mice after treated with isoline. Depletion of cellular GSH by d,l-buthionine-(S, R)-sulfoximine (BSO) aggravated isoline-induced cytotoxicity, while N-acetyl-l cysteine (NAC) ameliorated such cytotoxicity. Furthermore, the inhibitors of GR, GPx, and GST all aggravated isoline-induced cytotoxicity. In conclusion, our results demonstrated the differences of glutathione antioxidant system between newly weaned and young mice liver. Meanwhile, our results also revealed age-dependent liver injury induced by isoline for the first time, which might be due to the different responses of glutathione antioxidant system to isoline between newly weaned and young mice.     

Pioglitazone protects against cisplatin induced nephrotoxicity in rats and potentiates its anticancer activity against human renal adenocarcinoma cell lines

Cisplatin-induced nephrotoxicity is a serious problem that limits its use in cancer treatment. The present study aimed to investigate the renal protective capacity of pioglitazone to reduce the cisplatin- induced nephrotoxicity. The underlying suggested mechanism(s) and whether this nephroprotective effect (if any) interferes with the cytotoxic effect of cisplatin on cancer cells were also investigated.Pioglitazone, Bisphenol A diglycidyl ether, BADGE, IP injected (Peroxisome proliferator- activated receptor gamma (PPAR-γ) antagonist), or their combination were administered to rats one hour before cisplatin injection. Moreover, their effects on the cell viability of human renal adenocarcinoma cell models (ACHN) were studied. The obtained results showed that pioglitazone improved the renal function, structural changes, renal malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), nuclear factor kappa B (NF-κB) genes expression in cisplatin injected rats. It increased both renal reduced glutathione (GSH) content and PPAR-γ gene expression. In contrast to the data obtained by prior administration of BADGE. Pioglitazone also potentiated the cytotoxic effect of cisplatin on human renal adenocarcinoma cells and this effect was abolished by BADGE co administration. In conclusion, these results suggested that pioglitazone protected against cisplatin- induced nephrotoxicity through its interaction with PPAR-γ receptors and antioxidant effects. Furthermore, pioglitazone did not interfere but rather potentiated the cytotoxic effects of cisplatin on human renal adenocarcinoma cells.     

Glutathione peroxidase‐1 gene rescues cocaine‐induced conditioned place preference in mice by inhibiting σ‐1 receptor expression

The aim of this study was to investigate whether the glutathione peroxidase‐1 gene (GPx‐1) affects cocaine‐induced conditioned place preference (CPP) using a mouse model. Cocaine‐induced CPP was accompanied by an increase in the level of σ‐1 receptor in the nucleus accumbens (NAc). This phenomenon was more pronounced in the GPx‐1 gene knockout (GPx‐1 KO) than in wild type (WT) mice. In contrast, the CPP and expression of σ‐1 receptor were much less pronounced in GPx‐1‐overexpressing transgenic (GPx‐1 TG) mice than non‐transgenic (non‐TG) mice. Treatment of the mice with BD1047 , a σ‐1 receptor antagonist, significantly attenuated both cocaine‐induced CPP and c‐Fos‐immunoreactivity (c‐Fos‐IR) in WT and GPx‐1 KO mice, although the effects were more evident in the latter group. Despite the protective effects of BD1047 on cocaine‐induced CPP and c‐Fos in non‐TG mice, there were no additional protective effects in cocaine‐treated GPx‐1 TG mice, indicating that the σ‐1 receptor is a critical target for GPx‐1‐mediated psychoprotective activity. Overall, our results suggest that GPx‐1 attenuates cocaine‐induced CPP via inhibition of σ‐1 receptor expression.     

Protective effects of emodin against cisplatin‐induced oxidative stress in cultured human kidney (HEK 293) cells

Emodin (a rhubarb anthraquinone) has strong antioxidant and anticancer actions, and recent studies indicated that it reduces cellular oxidative stress induced by various insults and drugs. Cisplatin is an anticancer drug that is associated with nephrotoxicity and induces oxidative stress in cultured human kidney (HEK 293) cells. This study aimed to assess the in‐vitro antioxidant properties of the emodin against cisplatin‐induced oxidative stress in HEK 293 cells. Our study revealed that emodin acted as a potent free radical scavenger and provided nephroprotection against cisplatin‐induced oxidative stress. Emodin as low as 0.5 µm did not decrease cell viability and restored the cisplatin‐induced glutathione depletion and total antioxidant capacity in a dose‐dependent manner. Emodin augmented the cisplatin‐induced inhibition of antioxidant enzymes (catalase, glutathione peroxidase, glutathione S‐transferase, glutathione reductase and superoxide dismutase). These results suggest that emodin has the potential to be used as an adjunct therapeutic agent in patients receiving cisplatin treatment. Copyright © 2012 John Wiley & Sons, Ltd.     

Acute exposure to 3‐methylcholanthrene induces hepatic oxidative stress via activation of the Nrf2/ARE signaling pathway in mice

Polycyclic aromatic hydrocarbons (PAHs) are the most common contaminants in the environment. The primary focus on the toxicity of PAHs is their ability to activate the aryl hydrocarbon receptor (AhR)‐mediated pathway and lead to carcinogenesis in different organisms. However, the influence of PAHs on the antioxidant system in mammalian systems has received only limited attention. In the present study, we observed that the intraperitoneal injection of 100 mg/kg 3‐methylcholanthrene (3MC) into mice significantly increased reactive oxygen species (ROS) levels and malondialdehyde (MDA) contents and decreased glutathione (GSH) contents and the activity of total antioxidant capacity (T‐AOC), indicating that serious oxidative stress had been induced in the liver of mice. Then, the oxidative stress signal activated the nuclear factor erythroid 2‐related factor 2/antioxidant response element (Nrf2/ARE) pathway by enhancing the mRNA levels of Nrf2, p38, and Erk2. Moreover, the mRNA levels of Nrf2/ARE target genes, including glutathione peroxidase (Gpx), glutathione reductase (GR), glutathione synthetase (GS), NAD(P)H: quinone oxidoreductase 1 (Nqo1), superoxide dismutase 1 (Sod1), and Sod2, increased significantly after treatment with 3MC for 24 hours. The hepatic levels of NQO1 and the activities of GR and GS were also significantly enhanced at 24 hours after 3MC treatment. Because the expression of NQO1 is co‐regulated by Nrf2/ARE and AhR/XRE in mammalian tissues, NQO1 may play an important role in protecting against the oxidative stress induced by 3MC. Taken together, our findings suggested that acute exposure to 3MC altered the cellular redox balance in hepatocytes to trigger Nrf2‐regulated antioxidant responses, which may represent an adaptive cell defense mechanism against the oxidative stress induced by PAHs. © 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 1399–1408, 2014.     

β‐LAPachone ameliorates doxorubicin‐induced cardiotoxicity via regulating autophagy and Nrf2 signalling pathways in mice

β‐LAPachone (B‐LAP) is a naphthoquinone that possesses antioxidant properties. In the present investigation, the protective effect of B‐LAP against doxorubicin (DOX)‐induced cardiotoxicity was examined in mice. Thirty‐five mice were divided into 5 groups: control group, B‐LAP (5 mg/kg) group, DOX (15 mg/kg) group, DOX+B‐LAP (2.5 mg/kg) group and DOX+B‐LAP (5 mg/kg) group. B‐LAP was administered orally for 14 days of experimental period. A single dose of DOX (15 mg/kg) was injected intraperitoneally on day 3. Cardiac function, histoarchitecture, indices of oxidative stress and circulating markers of cardiac injury were examined. B‐LAP (5 mg/kg) decreased serum levels of lactate dehydrogenase (LDH), creatine kinase MB (CK‐MB) and cardiac troponin I (cTnI), and ameliorated cardiac histopathological alterations. In addition to increasing cellular NAD⁺/NADH ratio, B‐LAP up‐regulated the cardiac levels of SIRT1, beclin‐1, p‐LKB1 and p‐AMPK, and reduced the cardiac levels of p‐mTOR, interleukin (IL)‐1β, TNF (tumour necrosis factor)‐α and caspase‐3. B‐LAP also elevated the nuclear accumulation of Nrf2 and simultaneously up‐regulated the protein levels of haem oxygenase (HO‐1) and glutathione S‐transferase (GST) in the hearts of DOX mice. While B‐LAP reduced malondialdehyde concentrations in heart of DOX‐treated mice, it further promoted the activities of cardiac superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT).In accordance with increased cell survival, B‐LAP significantly improved the cardiac function of DOX mice. Collectively, these findings underline the protective potential of B‐LAP against DOX‐induced cardiotoxicity by regulating autophagy and AMPK/Nrf2 signalling pathway in mice.     

Quercetin attenuates lambda cyhalothrin‐induced reproductive toxicity in male rats

The aim of this study was to evaluate the possible protective effects of Quercetin (Qe) against oxidative stress induced by λ cyhalothrin (LTC) in reproductive system. Thirty‐two male rats were divided into four groups. First group was allocated as the control group. Second group was given a Qe alone while the third group received a LTC alone. Animals in the fourth group were given a Qe with LTC. Caudae epididymis was removed for sperm analysis. Lipid peroxidation (LPO), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione‐S‐transferase (GST), and reduced glutathione (GSH) were determined in the testis. Additionally, the different histopathologic changes were observed in the testis of animals. LTC exposure significantly increased the abnormal morphology and LPO. On the contrary, sperm motility, viability and count, levels of GSH, and activities of SOD, CAT, GPx, and GST were significantly decreased compared to controls. Qe with LTC offset the decrease in functional sperm parameters, antioxidants enzymatic activities, and nonenzymatic antioxidant levels when compared with LTC‐treated rats. Furthermore, LTC showed irregular seminiferous tubules containing only Sertoli cells and Qe with LTC caused regular seminiferous tubules showing spermatogenesis at level of spermatocytes. We conclude that LTC‐induced oxidative stress and functional sperm parameters in male rats, and dietary of Qe attenuates the reproductive toxicity of LTC to restore the antioxidant system and sperm parameters in male rats. © 2011 Wiley Periodicals, Inc. Environ Toxicol 28: 673–680, 2013.