Oxidative Stress and Metabolism: A Mechanistic Insight for Glyphosate Toxicology.

Glyphosate (GLYP) is a widely used pesticide; it is considered to be a safe herbicide for animals and humans because it targets 5-enolpyruvylshikimate-3-phosphate synthase. However, there has been increasing evidence that GLYP causes varying degrees of toxicity. Moreover, oxidative stress and metabolism are highly correlated with toxicity. This review provides a comprehensive introduction to the toxicity of GLYP and, for the first time, systematically summarizes the toxicity mechanism of GLYP from the perspective of oxidative stress, including GLYP-mediated oxidative damage, changes in antioxidant status, altered signaling pathways, and the regulation of oxidative stress by exogenous substances. In addition, the metabolism of GLYP is discussed, including metabolites,metabolic pathways, metabolic enzymes, and the toxicity of metabolites. This review provides new ideas for the toxicity mechanism of GLYP and proposes effective strategies for reducing its toxicity.

Dopaminergic and serotoninergic systems as preferential targets of the pyrethroid tefluthrin exposure in the rat brain.

The monoaminergic systems dopamine (DA) and serotonin (5-HT) play important roles in neuromodulation, such as motor control, cognitive, affective, and neuroendocrine functions. In the present research study, we addressed the hypothesis that exposure to Type I pyrethroid tefluthrin may specifically target the dopaminergic and serotoninergic systems. Tefluthrin could modify brain monoamine neurotransmitters, DA and 5-HT levels as well as dopaminergic and serotoninergic signaling pathways. Adult male Wistar rats were treated with tefluthrin [2.2, 4.4 and 5.5 mg/kg bw, equivalent to 1/10, 1/5 and 1/4 of the acute oral rat lethal dose 50 (LD50) value] by oral gavage, six days. After last dose of tefluthrin, DA and 5-HT and metabolites levels were determined in brain regions (striatum, hippocampus, prefrontal cortex and hypothalamus). Tefluthrin induced a decrease of DA, 5-HT and metabolites contents, in a brain regional- and dose-related manner. The major decreases in DA and 5-HT contents were observed in prefrontal cortex tissue. Here, we studied that in vivo exposure to tefluthrin may alter DA and 5-HT neurotransmission in prefrontal cortex. Transcripts related to (i) dopaminergic [dopamine transporter 1 (Dat1), tyrosine hydroxylase (TH), dopamine receptors (Drd1, Drd2)], (ii) serotoninergic [serotonin transporter (SERT), tryptophan hydroxylase 2 (TPH2), serotonin receptors (5-HT1A, 5-HT2A)] and (iii) DA and 5-HT degradation [monoamine oxidases (MAOA, MAOB)] signaling pathways were investigated. Results showed that tefluthrin induced down-regulation of transcripts responsible for the synthesis and action of DA (TH, Drd1, Drd2) and 5-HT (SERT, TPH2). In contrast, tefluthrin treatment induced up-regulation of genes involved in DA transporter (Dat1), 5-HT receptors (5-HT1A, 5-HT2A) and monoamine oxidases (MAOA, MAOB). Given the integral roles of mitochondrial dysfunction and dopaminergic and serotoninergic alterations as hallmarks of neurodegenerative diseases, our data suggest that tefluthrin may be a candidate for pesticides contributing to neurodegenerative disorders pathogenesis by causing damage to the DA and 5-HT systems.

MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia.

Alimentary toxic aleukia (ATA) is correlated with consuming grains contaminated by Fusarium species, particularly T-2 toxin, which causes serious hurt to human and animal health, chiefly in disorders of the haematopoietic system. However, the mechanism of haematopoietic dysfunction induced by T-2 toxin and the possible target pathway for the treatment of T-2 toxin-induced haematopoietic disorder of ATA remains unclear. In this study, genomes and proteomics were used for the first time to investigate the key differential genes and proteins that inhibit erythroid differentiation of K562 cells caused by T-2 toxin, and it was found that heat shock protein 27 (HSP27) and membrane-spanning 4-domains, subfamily A, member 3 (MS4A3) may play an important role in erythroid differentiation. Meanwhile, MS4A3 interference can inhibit the occurrence of erythroid differentiation of K562 cells and promote the phosphorylation of HSP27. Moreover, the binding of HSP27 to MS4A3 in natural state can activate the phosphorylation site of HSP27 (Ser-83), while T-2 toxin can abolish the activation of phosphorylation site by inhibiting the expression of MS4A3. These findings for the first time demonstrated that the MS4A3-HSP27 pathway may function an efficient therapeutic target pathway for treating T-2 toxin elicited haematopoietic disorders of ATA.

Bifurcaria bifurcata extract exerts antioxidant effects on human Caco-2 cells.

The present research study investigated the potential protective effect of Bifurcaria bifurcata extract on cell viability and antioxidant defences of cultured human Caco-2 cells submitted to oxidative stress induced by tert-butylhydroperoxide (tert-BOOH). Aqueous extracts were firstly characterized in terms of total phenolic contents. Concentrations of reduced glutathione (GSH) and malondialdehyde (MDA), generation of reactive oxygen species (ROS), nitric oxide (NO) production, antioxidant enzymes activities [NADPH quinone dehydrogenase 1 (NQO1) and glutathione S-transferase (GST)], caspase 3/7 activity and gene expression linked to apoptosis, proinflammation and oxidative stress signaling pathways were used as markers of cellular oxidative status. B. bifurcata extract prevented the cytotoxicity, the decrease of GSH, the increase of MDA levels and the ROS generation induced by tert-BOOH. B. bifurcata extract prevented the significant decrease of NQO1 and GST activities, and the significant increase of caspase 3/7 activity induced by tert-BOOH. B. bifurcata extract also caused an over-expression of GSTM2, Nrf2 and AKT1 transcriptors, as well as reduced ERK1, JNK1, Bax, BNIP3, NFκB1, IL-6 and HO-1 gene expressions induced by tert-BOOH suggesting an increase in cellular resistance against oxidative stress. The results of the biomarkers analyzed show that treatment of Caco-2 cells with B. bifurcata extract enhance antioxidant defences, which imply an improved cell response to an oxidative challenge. B. bifurcata extract possesses strong antioxidant properties and may be a potential effective alternative to oxidant agents in the functional food industry.

A "Janus" face of the RASSF4 signal in cell fate.

RASSF4 (Ras-association domain family 4) is a protein-coding gene, regarded as a tumor suppressor regulated by DNA methylation. However, RASSF4 acts as a "Janus" in cell fate: death and survival. This review article focuses on the regulatory mechanisms of RASSF4 on cell death and cell survival and puts forward a comprehensive analysis of the relevant signaling pathways. The participation of RASSF4 in the regulation of intracellular store-operated Ca2+ entry also affects cell survival. Moreover, the mechanism of inducing abnormal expression of RASSF4 was summarized. We highlight recent advances in our knowledge of RASSF4 function in the development of cancer and other clinical diseases, which may provide insight into the controversial functions of RASSF4 and its potential application in disease therapy.

Tefluthrin: metabolism, food residues, toxicity, and mechanisms of action.

Tefluthrin is a Type I pyrethroid insecticide widely used all over the world. Residues of tefluthrin in various agricultural and animal-derived products may be related to potential human health risks. Tefluthrin metabolism in mammals involves hydrolysis of the ester bond to form cyclopropane acid and 4-methylbenzyl alcohol moieties, followed by oxidation. In this review manuscript, we provide crucial information regarding the toxicity of pyrethroids and propose natural antioxidants for amelioration poisoning in humans and animals. We call for the rational use of tefluthrin as an agrochemical product and for greater attention to the residual toxicity caused by tefluthrin in primary and succeeding crops. This greater attention is required given the global use of tefluthrin.

Mitochondria as an important target of metformin: The mechanism of action, toxic and side effects, and new therapeutic applications.

Metformin is the oldest and most commonly used first-line antidiabetic drug because of its good clinical efficacy, high safety, low cost and easy access. At the same time, in recent years, we have found that its role as a therapeutic drug is gradually expanding. A large number of basic studies have shown that metformin may become a promising attractive candidate for drug repurposing. Therefore, it is extremely beneficial to conduct an in-depth discussion on the main mechanism of metformin. As early as the year 1950, studies showed that metformin played a biological role by regulating mitochondria. Then, ground-breaking studies showed that metformin functions by inhibiting complex I in the mitochondrial respiratory chain. Although there are still many controversies about the key molecular targets of metformin, with the emergence of more and more evidence, it gradually came to be concluded that mitochondria play a central role in the application of metformin. Mitochondria are important fulcrums for cell functions. The exact mechanism of action in mitochondria of this pleiotropic anti-hyperglycaemic molecule is still unclear. This review article explores the core role of mitochondria in the pharmacological and toxicological effects of metformin, and summarises the mechanism of action if metformin in mitochondria. It also provides ideas and supporting evidence for the re-development and reuse of metformin as an old drug, as well as new insight into the treatment of human diseases.

Neonicotinoids: mechanisms of systemic toxicity based on oxidative stress-mitochondrial damage.

Neonicotinoids are the most widely used pesticides in the world. However, research studies have shown that it can affect the cognitive abilities and health of non-target bees and other wild pollinators by inducing DNA damage, apoptosis and mitochondrial damage, injure to its central nervous system, and it is even developmentally neurotoxic to mammals and humans, with mitochondria being an important target of neonicotinoids. Therefore, this article reviews the role of mitochondrial morphology, calcium ions (Ca2+) homeostasis, respiratory function, apoptosis, and DNA damage in neonicotinoids-induced systemic toxicity. Additionally, it evaluates the protective effects of various active substances including vitamin C, N-acetylcysteine (NAC), curcumin (CUR), glutathione reduced (GSH), caffeic acid phenethyl ester (CAPE), resveratrol, and thymoquinone (TQ) on neonicotinoids-induced toxicity. This review manuscript found that mitochondria are important targets to neonicotinoids. Neonicotinoids can cause DNA damage, apoptosis, protein oxidation, and lipid peroxidation in non-target organisms by altering mitochondrial Ca2+ homeostasis, inhibiting mitochondrial respiration, and inducing reactive oxygen species (ROS) production. Several active substances (vitamin C, NAC, CUR, GSH, resveratrol, CAPE, and TQ) play a protective role against neonicotinoid-induced systemic toxicity by inhibiting ROS signaling pathways, apoptosis, and lipid peroxidation. This review manuscript emphasizes the importance and urgency of the development of neonicotinoid antidotes, emphasizes the prospect of the application of targeted mitochondrial antidotes, and prospects the development of neonicotinoid antidotes in order to provide some strategies for the prevention of neonicotinoid toxicity.

The role of long noncoding RNA in lipid, cholesterol, and glucose metabolism and treatment of obesity syndrome.

Obesity syndromes, characterized by abnormal lipid, cholesterol, and glucose metabolism, are detrimental to human health and cause many diseases, including obesity and type II diabetes. Increasing evidence has shown that long noncoding RNA (lncRNA), transcripts longer than 200 nucleotides that are not translated into proteins, play an important role in regulating abnormal metabolism in obesity syndromes. For the first time, we systematically summarize how lncRNA is involved in complex obesity metabolic syndromes, including the regulation of lipid, cholesterol, and glucose metabolism. Moreover, we discuss lncRNA involvement in food intake that mediates obesity syndromes. Furthermore, this review might shed new light on a lncRNA-based strategy for the prevention and treatment of obesity syndromes. Recent investigations support that lncRNA is a novel molecular target of obesity syndromes and should be emphasized. Namely, lncRNA plays a crucial role in the development of obesity syndrome process. Various lncRNAs are involved in the process of lipid, cholesterol, and glucose metabolism by regulating gene transcription, signaling pathway, and epigenetic modification of metabolism-related genes, proteins, and enzymes. Food intake could also induce abnormal expression of lncRNA associated with obesity syndrome, especially high-fat diet. Notably, some nanomolecules and natural extracts may target lncRNAs, associated with obesity syndrome, as a potential treatment for obesity syndromes.

Mechanism of Neonicotinoid Toxicity: Impact on Oxidative Stress and Metabolism.

Thousands of tons of neonicotinoids are widely used around the world as broad-spectrum systemic insecticides and veterinary drugs. Researchers originally thought that neonicotinoids exhibited low mammalian toxicity. However, following their widespread use, it became increasingly evident that neonicotinoids could have various toxic effects on vertebrates and invertebrates. The primary focus of this review is to summarize the research progress associated with oxidative stress as a plausible mechanism for neonicotinoid-induced toxicity as well as neonicotinoid metabolism. This review summarizes the research conducted over the past decade into the production of reactive oxygen species, reactive nitrogen species, and oxidative stress as aresult of neonicotinoid treatments, along with their correlation with the toxicity and metabolism of neonicotinoids. The metabolism of neonicotinoids and protection of various compounds against neonicotinoid-induced toxicity based on their antioxidative effects is also discussed. This review sheds new light on the critical roles of oxidative stress in neonicotinoid-induced toxicity to nontarget species.

Toxicity induced by ciprofloxacin and enrofloxacin: oxidative stress and metabolism.

Ciprofloxacin (CIP) (human use) and enrofloxacin (ENR) (veterinary use) are synthetic anti-infectious medications that belong to the second generation of fluoroquinolones. They have a wide antimicrobial spectrum and strong bactericidal effects at very low concentrations via enzymatic inhibition of DNA gyrase and topoisomerase IV, which are required for DNA replication. They also have high bioavailability, rapid absorption with favorable pharmacokinetics and excellent tissue penetration, including cerebral spinal fluid. These features have made them the most applied antibiotics in both human and veterinary medicine. ENR is marketed exclusively for animal medicine and has been widely used as a therapeutic veterinary antibiotic, resulting in its residue in edible tissues and aquatic environments, as well as the development of resistance and toxicity. Estimation of the risks to humans due to antimicrobial resistance produced by CIP and ENR is important and of great interest. Moreover, in rare cases due to their overdose and/or prolonged administration, the development of CIP and ENR toxicity may occur. The toxicity of these fluoroquinolones antimicrobials is mainly related to reactive oxygen species (ROS) and oxidative stress (OS) generation, besides metabolism-related toxicity. Therefore, CIP is restricted in pregnant and lactating women, pediatrics and elderly similarly ENR do in the veterinary field. This review manuscript aims to identify the toxicity induced by ROS and OS as a common sequel of CIP and ENR. Furthermore, their metabolism and the role of metabolizing enzymes were reported.

A novel strategy for the diagnosis, prognosis, treatment, and chemoresistance of hepatocellular carcinoma: DNA methylation.

The cancer mortality rate of hepatocellular carcinoma (HCC) is the second highest in the world and the therapeutic options are limited. The incidence of this deadly cancer is rising at an alarming rate because of the high degree of resistance to chemo- and radiotherapy, lack of proper, and adequate vaccination to hepatitis B, and lack of consciousness and knowledge about the disease itself and the lifestyle of the people. DNA methylation and DNA methylation-induced epigenetic alterations, due to their potential reversibility, open the access to develop novel biomarkers and therapeutics for HCC. The contribution to these epigenetic changes in HCC development still has not been thoroughly summarized. Thus, it is necessary to better understand the new molecular targets of HCC epigenetics in HCC diagnosis, prevention, and treatment. This review elaborates on recent key findings regarding molecular biomarkers for HCC early diagnosis, prognosis, and treatment. Currently emerging epigenetic drugs for the treatment of HCC are summarized. In addition, combining epigenetic drugs with nonepigenetic drugs for HCC treatment is also mentioned. The molecular mechanisms of DNA methylation-mediated HCC resistance are reviewed, providing some insights into the difficulty of treating liver cancer and anticancer drug development.

Epigenetic upregulation of galanin-like peptide mediates deoxynivalenol induced-growth inhibition in pituitary cells.

Deoxynivalenol (DON) is an unavoidable contaminant in human food, animal feeds, and agricultural products. Growth retardation in children caused by extensive DON pollution has become a global problem that cannot be ignored. Previous studies have shown that DON causes stunting in children through intestinal dysfunction, insulin-like growth factor-1 (IGF-1) axis disorder and peptide YY (PYY). Galanin-like peptide (GALP) is an important growth regulator, but its role in DON-induced growth retardation is unclear. In this study, we report the important role of GALP during DON-induced growth inhibition in the rat pituitary tumour cell line GH3. DON was found to increase the expression of GALP through hypomethylationin the promoter region of the GALP gene and upregulate the expression of proinflammatory factors, while downregulate the expression of growth hormone (GH). Furthermore, GALP overexpression promoted proinflammatory cytokines, including TNF-α, IL-1ß, IL-11 and IL-6, and further reduced cell viability and cell proliferation, while the inhibitory effect of GALP was the opposite. The expression of GALP and insulin like growth factor binding protein acid labile subunit (IGFALS) showed the opposite trend, which was the potential reason for the regulation of cell proliferation by GALP. In addition, GALP has anti-apoptotic effects, which could not eliminate the inflammatory damage of cells, thus aggravating cell growth inhibition. The present findings provide new mechanistic insights into the toxicity of DON-induced growth retardation and suggest a therapeutic potential of GALP in DON-related diseases.

Deltamethrin toxicity: A review of oxidative stress and metabolism.

Deltamethrin is widely used worldwide due to its valuable insecticidal activity against pests and parasites. Increasing evidence has shown that deltamethrin causes varying degrees of toxicity. Moreover, oxidative stress and metabolism are highly correlated with toxicity. For the first time, this review systematically summarizes the deltamethrin toxicity mechanism from the perspective of oxidative stress, including deltamethrin-mediated oxidative damage, antioxidant status, oxidative signaling pathways and modulatory effects of antagonists, synergists and placebos on oxidative stress. Further, deltamethrin metabolism, including metabolites, metabolic enzymes and pathways and deltamethrin metabolite toxicity are discussed. This review will shed new light on deltamethrin toxicity mechanisms and provide effective strategies to ensure pest control and prevention of human and animal poisoning.

Oxidative stress and related gene expression effects of cyfluthrin in human neuroblastoma SH-SY5Y cells: Protective effect of melatonin.

This study was designed to assess oxidative stress induction in human neuroblastoma SH-SY5Y cells in response to cyfluthrin exposure. Cell viability MTT assay was carried out to assess cyfluthrin cytotoxicity; IC30 and IC50 values for cyfluthrin were calculated to be 4.81 ±â€¯0.92 µM and 19.39 ±â€¯3.44 µM, respectively. Cyfluthrin induced a significant increase in ROS generation, lipid peroxides measured as malondialdehyde (MDA) and nitric oxide (NO) production and a significant decrease in NQO1 activity. The antioxidant activity of melatonin (MEL), Trolox, N-acetylcysteine (NAC) and Sylibin against cyfluthrin-induced oxidative stress was examined. Cyfluthrin increased significantly gene expressions of apoptosis, proinflammation and oxidative stress (Bax, Bcl-2, Casp-3, BNIP3, AKT1, p53, APAF1, NFκB1, TNFα and Nrf2) mediators. In the most genes, the mRNA levels induced by cyfluthrin were partially reduced by MEL (1 µM). Cyfluthrin effects on gene expression profiling of oxidative stress pathway by Real-Time PCR array analysis showed that of the 84 genes examined, (fold change > 1.5) changes in mRNA levels were detected in 31 genes: 13 upregulated and 18 down-regulated. A fold change >3.0 fold was observed on upregulated CYBB, DUOX1, DUOX2, AOX1, BNIP3, HSPA1A, NOS2, and NQO1 genes. The greater fold change reversion (2.5 fold) by MEL (1 µM) was observed on cyfluthrin-upregulated CYBB, AOX1, BNIP3 and NOS2 genes. These results demonstrated that oxidative stress is a key element in cyfluthrin induced neurotoxicity as well as MEL may play a role in reducing cyfluthrin-induced oxidative stress.

Neurotransmitter changes in rat brain regions following glyphosate exposure.

The effects of glyphosate oral exposure (35, 75, 150 and 800mg/kg bw, 6 days) on brain region monoamine levels of male Wistar rats were examined. Glyphosate-treated rats (35, 75, 150 and 800mg/kg bw, 6 days), had no visible injury, i.e., no clinical signs of dysfunction were observed. After last dose of glyphosate, serotonin (5-HT), dopamine (DA) and norepinephrine (NE) and its metabolites levels were determined in the brain regions striatum, hippocampus, prefrontal, cortex, hypothalamus and midbrain, by HPLC. Glyphosate caused statistically significant changes in the 5-HT and its metabolite 5-hydroxy-3-indolacetic acid (5-HIAA), DA and its metabolites 3,4-hydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and NE and its metabolite 3-metoxy-4-hydroxyphenylethyleneglycol (MHPG) levels in a brain regional- and dose-related manner. Moreover, glyphosate, dose-dependent, evoked a statistically significant increase in 5-HT turnover in striatum and hypothalamus and in DA turnover in prefrontal cortex and hippocampus, and a statistically significant decrease in NE turnover in prefrontal cortex and hypothalamus. The present findings indicate that glyphosate significantly altered central nervous system (CNS) monoaminergic neurotransmitters in a brain regional- and dose-related manner, effects that may contribute to the overall spectrum of neurotoxicity caused by this herbicide.

Paracetamol: overdose-induced oxidative stress toxicity, metabolism, and protective effects of various compounds in vivo and in vitro.

Paracetamol (APAP) is one of the most widely used and popular over-the-counter analgesic and antipyretic drugs in the world when used at therapeutic doses. APAP overdose can cause severe liver injury, liver necrosis and kidney damage in human beings and animals. Many studies indicate that oxidative stress is involved in the various toxicities associated with APAP, and various antioxidants were evaluated to investigate their protective roles against APAP-induced liver and kidney toxicities. To date, almost no review has addressed the APAP toxicity in relation to oxidative stress. This review updates the research conducted over the past decades into the production of reactive oxygen species (ROS), reactive nitrogen species (RNS), and oxidative stress as a result of APAP treatments, and ultimately their correlation with the toxicity and metabolism of APAP. The metabolism of APAP involves various CYP450 enzymes, through which oxidative stress might occur, and such metabolic factors are reviewed within. The therapeutics of a variety of compounds against APAP-induced organ damage based on their anti-oxidative effects is also discussed, in order to further understand the role of oxidative stress in APAP-induced toxicity. This review will throw new light on the critical roles of oxidative stress in APAP-induced toxicity, as well as on the contradictions and blind spots that still exist in the understanding of APAP toxicity, the cellular effects in terms of organ injury and cell signaling pathways, and finally strategies to help remedy such against oxidative damage.

Oxidative stress and gene expression profiling of cell death pathways in alpha-cypermethrin-treated SH-SY5Y cells.

In this study, we investigated the induction of oxidative stress and apoptosis in human neuroblastoma cell line SH-SY5Y in response to alpha-cypermethrin (α-CYPER) exposure. MTT and LDH assays were carried out to assess the α-CYPER cytotoxicity. The IC50 value for α-CYPER was calculated to be 78.3 ± 2.98 µM for the MTT assay and 71.5 ± 3.94 µM for LDH assay. The pyrethroid α-CYPER (1-100 µM), in a dose-dependent manner, induced a significant increase in lipid peroxides measured as malondialdehyde (MDA) and in the levels of nitric oxide (NO). The neuroprotective role of three antioxidants, melatonin (MEL), Trolox and N-acetylcysteine (NAC) against α-CYPER-induced oxidative stress was examined. Compared to other antioxidants, MEL (1 µM) treatment showed the most effective protection against α-CYPER-induced lipid peroxidation and NO production. The effects of α-CYPER on gene expression profiling of cell death pathway in human neuroblastoma SH-SY5Y cells were also investigated. Of the 84 genes examined (P < 0.001; fold change >1.5), changes in mRNA levels were detected in 39 genes: 36 were up-regulated and 3 were down-regulated. A greater fold change reversion than 3.5-fold was observed on the up-regulated ATP6V1G2, BCL2, CASP9, FAS, GADD45A, SPATA2, SYCP2, ATG7, NFKB1, SNCA, ULK1 and JPH3 genes. The results demonstrated that α-CYPER alters the expression of apoptosis-, autophagy- and necrosis genes as well as induces oxidative stress which may lead to DNA damage. The detailed knowledge of the changes in gene expression obtained will provide a basis for further elucidating the molecular mechanisms of the α-CYPER-induced toxicity.

The critical role of oxidative stress in the toxicity and metabolism of quinoxaline 1,4-di-N-oxides in vitro and in vivo.

Quinoxaline 1,4-dioxide derivatives (QdNOs) have been widely used as growth promoters and antibacterial agents. Carbadox (CBX), olaquindox (OLA), quinocetone (QCT), cyadox (CYA) and mequindox (MEQ) are the classical members of QdNOs. Some members of QdNOs are known to cause a variety of toxic effects. To date, however, almost no review has addressed the toxicity and metabolism of QdNOs in relation to oxidative stress. This review focused on the research progress associated with oxidative stress as a plausible mechanism for QdNO-induced toxicity and metabolism. The present review documented that the studies were performed over the past 10 years to interpret the generation of reactive oxygen species (ROS) and oxidative stress as the results of QdNO treatment and have correlated them with various types of QdNO toxicity, suggesting that oxidative stress plays critical roles in their toxicities. The major metabolic pathways of QdNOs are N→O group reduction and hydroxylation. Xanthine oxidoreductase (XOR), aldehyde oxidase (SsAOX1), carbonyl reductase (CBR1) and cytochrome P450 (CYP) enzymes were involved in the QdNOs metabolism. Further understanding the role of oxidative stress in QdNOs-induced toxicity will throw new light onto the use of antioxidants and scavengers of ROS as well as onto the blind spots of metabolism and the metabolizing enzymes of QdNOs. The present review might contribute to revealing the QdNOs toxicity, protecting against oxidative damage and helping to improve the rational use of concurrent drugs, while developing novel QdNO compounds with more efficient potentials and less toxic effects.

Fipronil insecticide toxicology: oxidative stress and metabolism.

Fipronil (FIP) is widely used across the world as a broad-spectrum phenylpyrazole insecticide and veterinary drug. FIP was the insecticide to act by targeting the γ-aminobutyric acid (GABA) receptor and has favorable selective toxicity towards insects rather than mammals. However, because of accidental exposure, incorrect use of FIP or widespread FIP use leading to the contamination of water and soil, there is increasing evidence that FIP could cause a variety of toxic effects on animals and humans, such as neurotoxic, hepatotoxic, nephrotoxic, reproductive, and cytotoxic effects on vertebrate and invertebrates. In the last decade, oxidative stress has been suggested to be involved in the various toxicities induced by FIP. To date, few reviews have addressed the toxicity of FIP in relation to oxidative stress. The focus of this article is primarily intended to summarize the progress in research associated with oxidative stress as a possible mechanism for FIP-induced toxicity as well as metabolism. The present review reports that studies have been conducted to reveal the generation of reactive oxygen species (ROS) and oxidative stress as a result of FIP treatment and have correlated them with various types of toxicity. Furthermore, the metabolism of FIP was also reviewed, and during this process, various CYP450 enzymes were involved and oxidative stress might occur. The roles of various compounds in protecting against FIP-induced toxicity based on their anti-oxidative effects were also summarized to further understand the role of oxidative stress in FIP-induced toxicity.