Resveratrol alleviates cardiac apoptosis following exposure to fenitrothion by modulating the sirtuin1/c-Jun N-terminal kinases/p53 pathway through pro-oxidant and inflammatory response improvements: In vivo and in silico studies.

Fenitrothion (FNT), a commonly used organophosphate, can cause oxidative damage and apoptosis on various organs. However, the underlying mechanisms for FNT-induced cardiotoxicity did not formally report. Here, we have evaluated the possible ameliorative roles of resveratrol (RSV) against FNT-induced cardiac apoptosis in male rats through the sirtuin1 (SIRT1)/c-Jun N-terminal kinase (c-JNK)/p53 pathway concerning pro-oxidant and inflammatory cytokines. Forty-eight male rats were equally grouped into control, RSV (20 mg/kg), 5-FNT (5 mg/kg), 10-FNT (10 mg/kg), 20-FNT (20 mg/kg), 5-FNT-RSV, 10-FNT-RSV, and 20-FNT-RSV where all doses administrated by gavage for four weeks. The present findings demonstrated that RSV markedly diminished the level of hyperlipidemia and elevation in lactate dehydrogenase (LDH), total creatine kinase (CK-T), and troponin T (TnT) levels following FNT intoxication. Furthermore, RSV significantly reduced FNT-induced cardiac oxidative injury by reducing malondialdehyde (MDA) level and improving the levels of glutathione (GSH), glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), and acetylcholinesterase (AchE). Also, the levels of interleukin-1ß (IL1ß,), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were significantly attenuated in the co-treated groups. Moreover, RSV alleviated the histopathological changes promoted by FNT and repaired the transcript levels of SIRT1, c-JNK, and caspase-9/3 along with p53 immunoreactivity. In silico study revealed that the free binding energies of RSV complexes with protein and DNA sequences of SIRT1 were lower than docked complexes of FNT. Therefore, RSV reserved myocardial injury-induced apoptosis following exposure to FNT by modulating the SIRT1/c-JNK/p53 pathway through cellular redox status and inflammatory response improvements.

Alpha-mangostin attenuates the apoptotic pathway of abamectin in the fetal rats' brain by targeting pro-oxidant stimulus, catecholaminergic neurotransmitters, and transcriptional regulation of reelin and nestin.

Abamectin, an avermectin member, can induce significant neurodegeneration symptoms in non-target organisms. However, its neurodevelopmental influences in mammals are unclear. Here, we focus on the antiapoptotic action of alpha-mangostin against the developmental neurotoxicity of abamectin with the possible involvement of reelin and nestin mRNA gene expression. Thirty-two pregnant rats were allocated to four groups (8 rats/group); control, alpha-mangostin (20 mg/kg/d), abamectin (0.5 mg/kg), and co-treated group (alpha-mangostin + abamectin). The animals have gavaged their doses during the gestation period. The fetotoxicity and many signs of growth retardation were observed in the abamectin-intoxicated rats. In comparison with the control group, abamectin prompted a significant elevation (p < 0.05) in the levels of malondialdehyde and nitric oxide, along with many symptoms of histopathological changes in the fetal cerebral cortex. However, the glutathione, dopamine, and serotonin concentrations together with the activities of glutathione-S-transferase, catalase, and superoxide dismutase were markedly decreased (p < 0.05) in the abamectin group. Moreover, abamectin remarkably upregulated (p < 0.05) the brain mRNA gene expression of reelin, nestin, and caspase-9 as well as the immunoreactivity of Bax and caspase-3 proteins in the cerebral cortex. It should be noted that alpha-mangostin mitigated the developmental neurotoxicity of abamectin to the normal range by recovering the levels of oxidant/antioxidant biomarkers, catecholamines; and apoptosis-related proteins with the involvement of reelin and nestin genes regulation. Those records revealed that the transcription regulation of reelin and nestin could be involved in the neuroprotective efficacy of alpha-mangostin, especially avermectin's developmental neurotoxicity.

Ginger reserves testicular spermatogenesis and steroidogenesis in difenoconazole-intoxicated rats by conducting oxidative stress, apoptosis and proliferation.

Difenoconazole, a triazole fungicide, can induce reproductive toxicity in aquatic species, but the probable mechanisms of this hazard in mammals are not formally reported. Here, we have examined the possible ameliorative efficiency of the ginger aqueous extract against the reproductive toxicity of difenoconazole in male rats. Thirty-six animals were equally divided into six groups: control, ginger aqueous extract (50 mg/kg), difenoconazole (15 mg/kg), difenoconazole (30 mg/kg) and ginger co-treated with two doses of difenoconazole. Difenoconazole markedly decreased sperm count, motility and normality percentage, together with the Johnson score. Difenoconazole also significantly reduced serum testosterone, luteinizing hormone and follicle-stimulating hormone levels, as well as the activities of testicular steroidogenic acute regulatory protein and 17 ß-hydroxysteroid dehydrogenases. Furthermore, difenoconazole brought a significant decrease in the testicular activity of catalase, but it increased the activity of glutathione peroxidase. Moreover, difenoconazole upregulated the testicular transcripts of Bax and caspase-3, increased Ki-67 immunoreactivity and induced histoarchitecture alterations plus DNA damage. Remarkably, ginger co-treatment preserved sperm toxicity, restored hormone profiles, increased steroidogenic activity and prevented oxidative injury-promoted testicular apoptosis. In conclusion, phenolic acids and flavonoids of ginger can reserve spermatogenesis and steroidogenesis in difenoconazole-intoxicated rats by improving testicular redox status, inhibiting apoptosis and refining proliferation capacity.

Quercetin ameliorates the hepatic apoptosis of foetal rats induced by in utero exposure to fenitrothion via the transcriptional regulation of paraoxonase-1 and apoptosis-related genes.

BACKGROUND & PURPOSE: Exposure to organophosphorus during different phases of pregnancy induces many adverse impacts on the developing foetuses due to their immature detoxification system. We have estimated the potential amelioration role of quercetin against hepatic injury-induced apoptosis in rat foetuses following gestational exposure to fenitrothion and probable involvement of paraoxonase-1. METHODS: Forty pregnant rats were allocated into four groups; the first one kept as control, the second intubated with quercetin (100 mg/kg), the third orally administrated fenitrothion (4.62 mg/kg) and the last group received quercetin two hours before fenitrothion intoxication. RESULTS: Fenitrothion significantly elevated the foetal hepatic levels of thiobarbituric acid reactive substances, protein carbonyl, and nitric oxide, but it reduced the enzymatic activities of glutathione-S-transferase, superoxide dismutase, catalase, and acetylcholinesterase. Furthermore, fenitrothion provoked many histopathological changes in the foetal liver and markedly up-regulated the mRNA gene expression of p53, caspase-9 along with elevation in the immunoreactivity of Bax and caspase-3, but it down-regulated the expression level of paraoxonase-1. Remarkably, quercetin co-treatment successfully ameliorated the hepatic oxidative injury and apoptosis prompted by fenitrothion. CONCLUSIONS: Dietary supplements with quercetin can be used to reduce the risk from organophosphorus exposure probably through paraoxonase-1 up-regulation and enhancement of the cellular antioxidant system.

Linseed ameliorates renal apoptosis in rat fetuses induced by single or combined exposure to diesel nanoparticles or fenitrothion by inhibiting transcriptional activation of p21/p53 and caspase-3/9 through pro-oxidant stimulus.

Gestational exposure to environmental pollutants can induce oxidative injury and apoptosis since the fetal organs are sensitively vulnerable to these chemicals. In this work, we have investigated the renal anti-apoptotic efficiency of linseed (LS) against the oxidative stress-mediated upregulation of the fetal apoptosis-related genes following the prenatal intoxication with diesel nanoparticles (DNPs) and/or fenitrothion (FNT). A fifty-six timed-pregnant rats were equally divided to eight groups; control, LS (20% in diet), DNPs (0.5 mg/kg by intratracheal inoculation), FNT (3.76 mg/kg by gavage), DNPs+FNT, LS + DNPs, LS + FNT, and LS + DNPs+FNT. The transmission electron microscope analysis revealed the spherical shape of diesel particles with a homogeneous nanosized range (20-92.3 nm) and the crystallinity was confirmed by electron diffraction microscopy. Administration of DNPs and/or FNT significantly increased fetal renal malondialdehyde, nitric oxide, and glutathione reductase as compared with the control group. However, they declined the level of glutathione together with the activities of glutathione peroxidase, glutathione-S-transferase, superoxide dismutase, and catalase. Furthermore, DNPs and/or FNT elicited many histopathological changes in fetal renal cells, markedly up-regulated apoptosis-related gene expressions (p53, p21 caspase-3, and caspase-9), and evoked DNA breaks as detected by comet assay. Interestingly, LS supplementation significantly ameliorated the disturbances in oxidant/antioxidant biomarkers, downregulated the apoptosis gene expressions, and alleviated DNA damage alongside renal cell architecture. These findings reveal that the antioxidant and anti-apoptotic characteristics of LS are acceptable defender pointers for the renal injury especially during gestational exposure to DNPs and/or FNT.

Modulation of Paraoxonase-1 and Apoptotic Gene Expression Involves in the Cardioprotective Role of Flaxseed Following Gestational Exposure to Diesel Exhaust Particles and/or Fenitrothion Insecticide.

The developmental exposure to a single chemical may elicit apoptosis in the different fetal organs, while the combined effects are restricted. We have examined the protective role of flaxseed (FS) against diesel exhaust particles (DEPs)- and/or fenitrothion (FNT)-induced fetal cardiac oxidative stress and apoptosis. A total of 48 timed pregnant rats were divided into eight groups (n = 6). The first group was saved as the control and the second fed on 20% FS diet. Animals in the third, fourth, and fifth groups were administered with DEPs (2.0 mg/kg), FNT (3.76 mg/kg), and their combination, respectively, while the sixth, seventh, and eighth groups were supplemented with 20% FS through intoxication with DEPs, FNT, and their combination, respectively. Our results revealed that DEPs and/or FNT significantly elevated the level of protein carbonyl and superoxide dismutase activity in the fetal cardiac tissues. However, the catalase activity and total thiol level were decreased; besides the histopathological alterations were remarked. Moreover, DEPs and/or FNT exhibited significant down-regulation in the anti-apoptotic (Bcl-2) and paraoxonase-1 gene expression, and up-regulation in the apoptotic (Bax and caspase-3) gene expression along with DNA fragmentation. Remarkably, FS supplementation significantly ameliorated the fetal cardiac oxidative injury, down-regulated the expression of the apoptotic genes, up-regulated the anti-apoptotic and paraoxonase-1 gene expression, reduced DNA fragmentation, and alleviated the myocardial cell architectures. These findings revealed that FS attenuates DEPs- and/or FNT-induced apoptotic cell death by repairing the disturbance in the anti-apoptotic/pro-apoptotic gene balance toward cell survival in the fetal myocardial cells.

Quercetin Attenuates the Oxidative Injury-Mediated Upregulation of Apoptotic Gene Expression and Catecholaminergic Neurotransmitters of the Fetal Rats' Brain Following Prenatal Exposure to Fenitrothion Insecticide.

The association between gestational exposure to organophosphate and neurodevelopmental deficits is an area of particular interest, since the developing brain is sensitively susceptible to this neurotoxic pesticide. Instead, the neuroprotective role of quercetin has been suggested, but its exact protective mechanism against the developmental neurotoxicity of organophosphate did not previously notify. In this study, we have evaluated the anti-apoptotic role of quercetin against the developmental neurotoxicity of fenitrothion. Forty timed pregnant rats (from the 5th to the 19th day) were divided into four groups: control, quercetin (100 mg/kg/day), fenitrothion (2.31 mg/kg/day), and quercetin-fenitrothion co-treated groups where all animals received the corresponding doses by gavage. The embryotoxicity and many symptoms of the fetal growth retardation were recorded in the fenitrothion-intoxicated group. As compared with the control, fenitrothion brought significant (p < 0.05) elevation in the fetal brain dopamine, serotonin, and malondialdehyde levels as well as the activities of superoxide dismutase and catalase. However, fenitrothion decreased the glutathione concentration together with the activities of acetylcholinesterase, glutathione-S-transferase, and glutathione reductase. Moreover, fenitrothion induced some of the histopathological alterations in fetal brain and remarkably (p < 0.05) upregulated the mRNA gene expression of Bax and caspase-3 plus their protein immunoreactivity. It is worth mentioning that quercetin co-treatment alleviated (p Ë‚ 0.05) the fetal growth shortfalls, neurotransmission disturbances, lipid peroxidation, antioxidant disorders, and apoptosis evoked by fenitrothion with frequent repair to the control range. These results revealed that the downregulation of apoptosis-related genes and catecholamines is an acceptable indicator for the neuroprotective efficiency of quercetin especially during gestational exposure to organophosphate.

Synergistic antioxidant effects of resveratrol and curcumin against fipronil-triggered oxidative damage in male albino rats.

Fipronil (FPN), a phenylpyrazole insecticide, has been receiving increased attention owing to its toxicity, which is largely mediated through its effects on antioxidant systems. The present study was undertaken to assess the effects of resveratrol (RSV) and curcumin (CUR) on oxidative damage induced by FPN. Forty mature male Wistar rats were randomized into five groups (n = 8 per group): the first group was the control; the second was administered FPN (10 mg/kg); and the third, fourth, and fifth were co-treated with RSV (10 mg/kg), CUR (200 mg/kg), and their combination, respectively, 2 h prior to FPN administration. All animals were dosed via oral gavage for 4 weeks. FPN significantly (p < 0.05) elevated the sera of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), γ-glutamyl transferase (GGT), urea, creatinine, and cholesterol levels, whereas serum total protein, albumin, and triglyceride levels were significantly (p < 0.05) decreased, compared to those of the control group. Reduced glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) were decreased (p < 0.05) in the FPN-treated group compared to those in the control group; however, malondialdehyde (MDA) and nitric oxide (NO) levels were markedly increased (p < 0.05) in the hepatic, renal, and brain tissues. Co-treatment with RSV or CUR alleviated (p Ë‚ 0.05) the increased lipid peroxidation and changes in enzymatic/nonenzymatic antioxidants induced by FPN; all these variables mostly returned to normal levels with the combined of RSV and CUR treatment. In conclusion, RSV and/or CUR relieved and synergistically reversed the FPN-induced tissue oxidative injury, probably by improving the antioxidant defenses via their free radical scavenging and antioxidant characteristics.

Pterocarpus santalinus ameliorates streptozotocin-induced diabetes mellitus via anti-inflammatory pathways and enhancement of insulin function.

OBJECTIVES: Morbidity and mortality due to diabetes mellitus (DM) result in exorbitant psycho-economical costs, so there is a strong need to create new strategies and drugs for controlling DM. The aim of the current study was to investigate the anti-diabetic effect of the aqueous extract of Pterocarpus santalinus on streptozotocin (STZ)-induced DM as compared to glustin. MATERIALS AND METHODS: Thirty male rats were divided into five groups of six rats each as follows: control; the second group, received the aqueous plant extract (250 mg/kg) orally and daily for three weeks; the third group, was intraperitoneally injected with a single dose of 65 mg/kg of STZ and sacrificed after four weeks; the fourth and fifth groups, were injected with STZ, then after one week these were treated orally with either plant extract or with 3 mg/kg of glustin for three weeks, then sacrificed. RESULTS: HPLC analysis of the plant aqueous extract showed that it contains many polyphenols and flavonoids. Treatment with STZ resulted in significant reductions in body weight, insulin level, and the expression of Fetuin-A and IRS-1. It also caused significant elevations in glucose, HOMA-IR, glycated hemoglobin, urea, and the expression of JNK and SIRT-1. STZ also caused an extensive ß-cell degranulation and decreased cellular density. The aqueous extract of red sandalwood was able to abrogate the deleterious effects caused by STZ and improved the histological architecture of pancreas. CONCLUSION: The aqueous extract of P. santalinus ameliorates diabetes mellitus via anti-inflammatory pathways and enhancement of insulin function.

Propolis relieves the cardiotoxicity of chlorpyrifos in diabetic rats via alleviations of paraoxonase-1 and xanthine oxidase genes expression.

Pesticides cardiotoxicity in case of diabetic-induced cardiac complications is unidentified. The probable amelioration role of propolis is gauged against the cardiotoxic effects of chlorpyrifos in the diabetic rats through paraoxonase-1 (PON1) and xanthine oxidase (XO) genes dysregulation. Fifty-six male rats were distributed (n = 7) into eight groups. The first one saved as control whereas the 2nd, 3rd, and 4th were kept for propolis aqueous extract (100 mg/kg), diabetes (60 mg/kg streptozotocin) and chlorpyrifos (2.5 mg/kg), respectively. The 5th was diabetes/chlorpyrifos combination, while 6th, 7th, and 8th were intubated with propolis for four weeks after diabetic induction, chlorpyrifos intoxication, and their combination, respectively. The plasma glucose, lipid profiles, cardiac enzymes and interleukin-6 (IL-6) significantly elevated, while insulin decreased in the diabetic and combination groups. Although the cardiac acetylcholinesterase, total thiols, and PON1 significantly reduced after diabetic and/or chlorpyrifos gavage, the protein carbonyl, superoxide dismutase, catalase, and XO significantly elevated. The mRNA genes expression of PON1 and XO have also confirmed the enzymatic activities. Interestingly, propolis significantly restored the hyperglycemia, hypoinsulinemia, hyperlipidemia, IL-6 elevations, and antioxidant defense system disorder. These records revealed that the immunomodulatory, anti-diabetic and antioxidant tasks are fine pointers for the cardiovascular defender of propolis especially during diabetes and/or pesticides exposure.

Garlic and allopurinol attenuate hepatic apoptosis induced by fipronil in male albino rats.

Fipronil (FPN) can induce oxidative tissue damage and may be contemplated as an apoptosis inducer. Our aim is to investigate the possible hepatoprotective roles of garlic or allopurinol (ALP) against fipronil subacute toxicity. Thirty-six mature male albino rats were randomly divided into six groups; the first group was saved as control (C), the 2nd (G) was orally intubated with 500 mg/kg aqueous garlic extract, and the 3rd (A) received 150 mg/L allopurinol in their drinking water. The 4th group (F) was administered 13.277 mg/kg fipronil by gavage, while the 5th (G + F) and 6th (A + F) groups received the same doses of garlic and allopurinol, respectively two hours before fipronil intoxication. Our results revealed that FPN significantly increased the hepatic malondialdehyde, protein carbonyl levels, and the enzymatic activities of superoxide dismutase, catalase, glutathione peroxidase, and xanthine oxidase, but it decreased glutathione-S-transferase compared to the control group. Moreover, FPN exhibited significant up-regulation in the hepatic pro-apoptotic (Bax) and caspase-3 genes expression, down-regulation in the anti-apoptotic (Bcl-2) mRNA gene expression and induced DNA fragmentation. Surprisingly, garlic or allopurinol co-treatment ameliorated the hepatic lipid peroxidation, antioxidants disruption, and apoptosis induced by FPN. In conclusion, garlic and allopurinol relieved the oxidative injury and reduced the fipronil-induced apoptosis probably by improving the tissue antioxidant defense system.