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Nature Communications Jul 2021Glutathione (GSH) is the most abundant cellular antioxidant. As reactive oxygen species (ROS) are widely believed to promote aging and age-related diseases, and...
Glutathione (GSH) is the most abundant cellular antioxidant. As reactive oxygen species (ROS) are widely believed to promote aging and age-related diseases, and antioxidants can neutralize ROS, it follows that GSH and its precursor, N-acetyl cysteine (NAC), are among the most popular dietary supplements. However, the long- term effects of GSH or NAC on healthy animals have not been thoroughly investigated. We employed C. elegans to demonstrate that chronic administration of GSH or NAC to young or aged animals perturbs global gene expression, inhibits skn-1-mediated transcription, and accelerates aging. In contrast, limiting the consumption of dietary thiols, including those naturally derived from the microbiota, extended lifespan. Pharmacological GSH restriction activates the unfolded protein response and increases proteotoxic stress resistance in worms and human cells. It is thus advantageous for healthy individuals to avoid excessive dietary antioxidants and, instead, rely on intrinsic GSH biosynthesis, which is fine-tuned to match the cellular redox status and to promote homeostatic ROS signaling.
Topics: Acetylcysteine; Aging; Animals; Animals, Genetically Modified; Caenorhabditis elegans; Caenorhabditis elegans Proteins; DNA-Binding Proteins; Dietary Supplements; Escherichia coli; Female; Fibroblasts; Gene Expression Regulation; Glutathione; Humans; Male; Paraquat; Reactive Oxygen Species; Sulfhydryl Compounds; Transcription Factors; Unfolded Protein Response
PubMed: 34267196
DOI: 10.1038/s41467-021-24634-3 -
Food Safety (Tokyo, Japan) Dec 2022Food Safety Commission of Japan (FSCJ) conducted a risk assessment of a bipyridinium herbicide, paraquat (CAS No. 1910-42-5), based on results from various studies....
Food Safety Commission of Japan (FSCJ) conducted a risk assessment of a bipyridinium herbicide, paraquat (CAS No. 1910-42-5), based on results from various studies. Major adverse effects of paraquat in experimental animals were observed in body weight (suppressed weight gain), lungs (increased weight, alveolar epithelium hyperplasia, and pneumonia), kidneys (renal tubule dilatation) and eyes (cataract in rats and dogs). The effects on the lung were considered to be the most critical endpoints in the assessment. Neither carcinogenicity, effects on fertility, teratogenicity, genotoxicity, or immunotoxicity was observed. FSCJ reasonably concluded no obvious concern of paraquat-residue in foods to yield neurotoxicity through human dietary exposure, as long as paraquat is applied following the registered standard use of the pesticide. The lowest no-observed-adverse-effect level (NOAEL) obtained from all the studies was 0.45 mg paraquat ion/kg bw per day in one-year chronic toxicity study in dogs. FSCJ specified an acceptable daily intake (ADI) of 0.0045 mg paraquat ion/kg bw per day by applying a safety factor of 100 to the NOAEL. FSCJ judged these effects also as the end-point of the acute reference dose (ARfD). The lowest NOAEL was 0.45 mg paraquat ion/kg bw per day in one-year chronic toxicity study in dogs. For potential adverse effects of a single oral administration of paraquat, FSCJ specified an ARfD to be 0.0045 mg paraquat ion/kg bw by applying a safety factor of 100 to the NOAEL.
PubMed: 36619009
DOI: 10.14252/foodsafetyfscj.D-22-00012 -
Oxidative Medicine and Cellular... 2019Mitochondria supply cellular energy and are key regulators of intrinsic cell death and consequently affect longevity. The nematode is frequently used for lifespan...
INTRODUCTION
Mitochondria supply cellular energy and are key regulators of intrinsic cell death and consequently affect longevity. The nematode is frequently used for lifespan assays. Using paraquat (PQ) as a generator of reactive oxygen species, we here describe its effects on the acceleration of aging and the associated dysfunctions at the level of mitochondria.
METHODS
Nematodes were incubated with various concentrations of paraquat in a heat-stress resistance assay (37°C) using nucleic staining. The most effective concentration was validated under physiological conditions, and chemotaxis was assayed. Mitochondrial membrane potential (m) was measured using rhodamine 123, and activity of respiratory chain complexes determined using a Clark-type electrode in isolated mitochondria. Energetic metabolites in the form of pyruvate, lactate, and ATP were determined using commercial kits. Mitochondrial integrity and structure was investigated using transmission electron microscopy. Live imaging after staining with fluorescent dyes was used to measure mitochondrial and cytosolic ROS. Expression of longevity- and mitogenesis-related genes were evaluated using qRT-PCR.
RESULTS
PQ (5 mM) significantly increased ROS formation in nematodes and reduced the chemotaxis, the physiological lifespan, and the survival in assays for heat-stress resistance. The number of fragmented mitochondria significantly increased. The ∆m, the activities of complexes I-IV of the mitochondrial respiratory chain, and the levels of pyruvate and lactate were significantly reduced, whereas ATP production was not affected. Transcript levels of genetic marker genes, , , , and , were significantly upregulated after PQ incubation, which implicates a close connection between mitochondrial dysfunction and oxidative stress response. Expression levels of and were unchanged.
CONCLUSION
Using paraquat as a stressor, we here describe the association of oxidative stress, restricted energy metabolism, and reduced stress resistance and longevity in the nematode making it a readily accessible model for mitochondrial dysfunction.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Energy Metabolism; Heat-Shock Response; Herbicides; Longevity; Membrane Potential, Mitochondrial; Mitochondria; Oxidative Stress; Paraquat; Pyruvic Acid; Reactive Oxygen Species; Signal Transduction
PubMed: 31827694
DOI: 10.1155/2019/6840540 -
BMJ Case Reports Nov 2021
Topics: Humans; Paraquat; Poisoning
PubMed: 34764128
DOI: 10.1136/bcr-2021-246585 -
Indian Journal of Critical Care... Dec 2019Paraquat is a commonly used herbicide in India that has lethal consequences even on minimal consumption. The case fatality rate for this poisoning is high and there is...
UNLABELLED
Paraquat is a commonly used herbicide in India that has lethal consequences even on minimal consumption. The case fatality rate for this poisoning is high and there is dearth of evidence-based recommendation for the treatment of this poison. This review article explores the diagnosis and management of paraquat poisoning with an emphasis on recent advances in treatment. Though immunosuppressants and antioxidants are conventionally used, there is a gap in evidence to prove survival benefit of these treatment regimens. There are also some data showing the use of hemoperfusion (with toxin-specific cartridges) as an early intervention, i.e., within 4 hours of exposure to the poison. The recent drug, Edaravone, has also shown promise in the prevention of renal and hepatic injury in paraquat poisoning. Though it did not reduce pulmonary fibrosis in patients with paraquat poisoning, it delays the generation and development of pulmonary fibrosis. However, there is a need for more clinical and experimental studies to validate its use in paraquat poisoning.
HOW TO CITE THIS ARTICLE
Sukumar CA, Shanbhag V, Shastry AB. Paraquat: The Poison Potion. Indian J Crit Care Med 2019;23(Suppl 4):S263-S266.
PubMed: 32021001
DOI: 10.5005/jp-journals-10071-23306 -
Biochimica Et Biophysica Acta.... Sep 2022Paraquat is a quaternary nitrogen herbicide evoking mitochondrial damage and heart failure with little therapeutic remedies available. Recent reports depicted a role for...
Paraquat is a quaternary nitrogen herbicide evoking mitochondrial damage and heart failure with little therapeutic remedies available. Recent reports depicted a role for unchecked autophagy in paraquat-induced cardiotoxicity. This study was designed to examine the role of the mitophagy receptor protein FUNDC1 in paraquat-induced cardiac contractile and mitochondrial injury using a murine model of FUNDC1 knockout (FUNDC1) mice. WT and FUNDC1 mice were challenged with paraquat (45 mg/kg, single injection, i.p.) for 72 h prior to examination of cardiac contractile and intracellular Ca properties, mitochondrial integrity, mitochondrial function, O production, apoptosis, autosis and ferroptosis. Our results found that paraquat challenge compromised echocardiographic, contractile and intracellular Ca properties in conjunction with mitochondrial damage (reduced levels of PGC1α, UCP2, NAD+, and citrate synthase activity along with fragmentation manifested by elevated Drp1 and TEM ultrastructural changes), the effects of which were overtly attenuated or obliterated by FUNDC1 ablation. Paraquat triggered ferroptosis, apoptosis (but not autosis) and unchecked mitophagy as evidenced by downregulation of GPx4, SLC7A11, Bcl2, TOM20 and ferritin as well as upregulated levels of Bax, TNFα, IL6, NCOA4 and FUNDC1, the effects of which were relieved by FUNDC1 ablation. Further study noted dephosphorylation of JNK upon paraquat challenge, the effect of which was obliterated by FUNDC1 knockout. In vitro evaluation of BODIPY ferroptosis and cardiomyocyte function revealed FUNDC1 ablation inhibited paraquat-induced increase in BODIPY lipid peroxidation and cardiomyocyte contractile dysfunction, the effects of which were nullified and mimicked by inhibition of JNK or ferroptosis and activation of JNK, respectively. Taken together, our data suggest an essential role for FUNDC1/JNK-mediated ferroptosis in paraquat exposure-evoked cardiac and mitochondrial injury.
Topics: Animals; Ferroptosis; Membrane Proteins; Mice; Mice, Knockout; Mitochondrial Proteins; Mitophagy; Myocardium; Myocytes, Cardiac; Paraquat
PubMed: 35598771
DOI: 10.1016/j.bbadis.2022.166448 -
Neurotoxicology Sep 2021To examine the extent to which a consensus exists in the scientific community regarding the relationship between exposure to paraquat and Parkinson's disease, a critical... (Review)
Review
To examine the extent to which a consensus exists in the scientific community regarding the relationship between exposure to paraquat and Parkinson's disease, a critical review of reviews was undertaken focusing on reviews published between 2006 and the present that offered opinions on the issue of causation. Systematic searches were undertaken of scientific databases along with searches of published bibliographies to identify English language reviews on the topic of paraquat and Parkinson's disease including those on the broader topic of environmental and occupational risk factors for Parkinson's disease. Of the 269 publications identified in the searches, there were twelve reviews, some with meta-analyses, that met the inclusion criteria. Information on methods used by the reviewers, if any, and source of funding was collected; the quality of the reviews was considered. No author of any published review stated that it has been established that exposure to paraquat causes Parkinson's disease, regardless of methods used and independent of funding source. A consensus exists in the scientific community that the available evidence does not warrant a claim that paraquat causes Parkinson's disease. Future research on this topic should focus on improving the quality of epidemiological studies including better exposure measures and identifying specific mechanisms of action. Future reviews of emerging evidence should be structured as systematic narrative reviews with meta-analysis if appropriate.
Topics: Animals; Herbicides; Humans; Meta-Analysis as Topic; Paraquat; Parkinson Disease; Parkinson Disease, Secondary; Risk Factors; Systematic Reviews as Topic
PubMed: 34400206
DOI: 10.1016/j.neuro.2021.08.006 -
Frontiers in Microbiology 2019Paraquat herbicide has served over five decades to control annual and perennial weeds. Despite agricultural benefits, its toxicity to terrestrial and aquatic... (Review)
Review
Paraquat herbicide has served over five decades to control annual and perennial weeds. Despite agricultural benefits, its toxicity to terrestrial and aquatic environments raises serious concerns. Paraquat cannot rapidly degrade in the environment and is adsorbed in clay lattices that require urgent environmental remediation. Advanced oxidation processes (AOPs) and bioaugmentation techniques have been developed for this purpose. Among various techniques, bioremediation is a cost-effective and eco-friendly approach for pesticide-polluted soils. Though several paraquat-degrading microorganisms have been isolated and characterized, studies about degradation pathways, related functional enzymes and genes are indispensable. This review encircles paraquat removal from contaminated environments through adsorption, photocatalyst degradation, AOPs and microbial degradation. To provide in-depth knowledge, the potential role of paraquat degrading microorganisms in contaminated environments is described as well.
PubMed: 31428067
DOI: 10.3389/fmicb.2019.01754 -
Environment International Nov 2022Paraquat (PQ) is the most widely used herbicide in the world and a well-known potent neurotoxin for humans. PQ exposure has been linked to increase the risk of...
Paraquat (PQ) is the most widely used herbicide in the world and a well-known potent neurotoxin for humans. PQ exposure has been linked to increase the risk of Parkinson's disease (PD). However, the mechanism underlying its neurotoxic effects in PD pathogenesis is unclear. In our present study, C57BL/6J mice treated with PQ manifested severe motor deficits indicated by the significant reductions in suspension score, latency to fall from rotarod, and grip strength at 8 weeks after PQ exposure. Pathological hallmarks of Parkinsonism in the midbrain such as dopaminergic neuron loss, increased α-synuclein protein, and dysregulated PD-related genes were observed. Non-targeted lipidome analysis demonstrated that PQ exposure alters lipid profile and abundance, increases pro-inflammatory lipids.27 significantly altered subclasses of lipids belonged to 6 different lipid categories. Glycerophospholipids, sphingolipids, and glycerides were the most abundant lipids. Abundance of pro-inflammatory lipids such as Cer, LPC, LPS, and LPI was significantly increased in the midbrain. mRNA expressions of genes regulating ceramide biosynthesis in the midbrain were markedly up-regulated. Moreover, PQ exposure increased serum pro-inflammatory cytokines and provoked neuroinflammation in the midbrain. Pro-inflammatory lipids and cytokines in the midbrain were positively correlated with motor deficits. PQ poisoning in humans significantly also elevated serum pro-inflammatory cytokines and induced an intense systemic inflammation. In summary, we presented initial investigations of PQ induced molecular events related to the PD pathogenesis, capturing aspects of disturbed lipid metabolism, neuroinflammation, impairment of dopaminergic neurons in the midbrain, and an intense systemic inflammation. These neurotoxic effects of PQ exposure may mechanistically contribute to the pathogenesis of PQ induced Parkinsonism. Results of this study also strongly support the hypothesis that ever-increasing prevalence of Parkinson's disease is etiologically linked to the health risk of exposure to neurotoxic environmental pollutants.
Topics: Animals; Ceramides; Cytokines; Environmental Pollutants; Glycerides; Glycerophospholipids; Herbicides; Humans; Lipopolysaccharides; Mesencephalon; Mice; Mice, Inbred C57BL; Neuroinflammatory Diseases; Neurotoxicity Syndromes; Neurotoxins; Paraquat; Parkinson Disease; Parkinsonian Disorders; RNA, Messenger; Sphingolipids; alpha-Synuclein
PubMed: 36108500
DOI: 10.1016/j.envint.2022.107512 -
Heliyon Jul 2022Paraquat (PQ) is a herbicide belonging to the group of bipyridylium salts. The objective of this study was to evaluate oxidative stress, DNA damage, and cytotoxicity...
Paraquat (PQ) is a herbicide belonging to the group of bipyridylium salts. The objective of this study was to evaluate oxidative stress, DNA damage, and cytotoxicity induced by paraquat in peripheral lymphocyte cells in vivo as well as pathological changes in various tissues. For this purpose, 28 male Wistar rats in 6 different groups were poisoned by paraquat gavage and blood samples were taken from the hearts of rats after during the poisoning period. Oxidative stress, DNA damage, cell membrane integrity, serum lactate dehydrogenase, and cytotoxicity, were investigated by Ferric Reducing Antioxidant Potential (FRAP) test, alkaline comet assay, measuring serum lactate dehydrogenase (LDH), Hoechst staining and flow cytometry with propidium iodide (PI) respectively. The lung, kidney, and liver tissues were also examined pathologically. Paraquat caused dose-dependent DNA damage in peripheral lymphocyte cells and significant oxidative cell membrane damage. The most damage was caused by a single dose of 200 mg/kg b.w of paraquat by gavage. The gradual exposure to a dose of 300 mg/kg b.w of paraquat showed less damage, which could be due to the activation of the antioxidant defense mechanism.
PubMed: 35855999
DOI: 10.1016/j.heliyon.2022.e09895