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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 -
Autophagy 2018Chaperone-mediated autophagy (CMA) is a selective degradative process for cytosolic proteins that contributes to the maintenance of proteostasis. The signaling...
UNLABELLED
Chaperone-mediated autophagy (CMA) is a selective degradative process for cytosolic proteins that contributes to the maintenance of proteostasis. The signaling mechanisms that control CMA are not fully understood but might involve response to stress conditions including oxidative stress. Considering the role of CMA in redoxtasis and proteostasis, we sought to determine if the transcription factor NFE2L2/NRF2 (nuclear factor, erythroid derived 2, like 2) has an impact on CMA modulation. In this work, we identified and validated 2 NFE2L2 binding sequences in the LAMP2 gene and demonstrated in several human and mouse cell types that NFE2L2 deficiency and overexpression was linked to reduced and increased LAMP2A levels, respectively. Accordingly, lysosomal LAMP2A levels were drastically reduced in nfe2l2-knockout hepatocytes, which also displayed a marked decrease in CMA activity. Oxidant challenge with paraquat or hydrogen peroxide, or pharmacological activation of NFE2L2 with sulforaphane or dimethyl fumarate also increased LAMP2A levels and CMA activity. Overall, our study identifies for the first time basal and inducible regulation of LAMP2A, and consequently CMA activity, by NFE2L2.
ABBREVIATIONS
ACTB: actin, beta, ARE: antioxidant response element; ATG5: autophagy related 5; BACH1: BTB domain and CNC homolog 1; ChIP: chromatin immunoprecipitation; CMA: chaperone-mediated autophagy; DHE: dihydroethidium; DMF: dimethyl fumarate; ENCODE: Encyclopedia of DNA elements at the University of California, Santa Cruz; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GBA: glucosylceramidase beta; GFP: green fluorescent protein; HMOX1: heme oxygenase 1; HO: hydrogen peroxide; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; KEAP1: kelch like ECH associated protein 1; LAMP2A: lysosomal associated membrane protein 2A; LAMP2B: lysosomal associated membrane protein 2B; LAMP2C: lysosomal associated membrane protein 2C; LAMP1: lysosomal associated membrane protein 1; MAFF: MAF bZIP transcription factor F; MAFK: MAF bZIP transcription factor K; NFE2L2/NRF2: nuclear factor, erythroid derived 2, like 2; NQO1: NAD(P)H quinone dehydrogenase 1; PQ: paraquat; PI: protease inhibitors; qRT-PCR: quantitative real-time polymerase chain reaction; RNASE: ribonuclease A family member; SFN: sulforaphane; SQSTM1/p62: sequestosome 1; TBP: TATA-box binding protein.
Topics: A549 Cells; Animals; Antioxidant Response Elements; Autophagy; HEK293 Cells; Humans; Lysosomal-Associated Membrane Protein 2; Mice, Knockout; Molecular Chaperones; NF-E2-Related Factor 2; Oxidants; Paraquat; Protein Binding
PubMed: 29950142
DOI: 10.1080/15548627.2018.1474992 -
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 -
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 -
BMJ Case Reports Oct 2014
Topics: Adult; Anesthetics, Local; Anti-Infective Agents; Benzocaine; Gels; Herbicides; Humans; Male; Metronidazole; Paraquat; Suicide, Attempted; Tongue Diseases; Ulcer; Young Adult
PubMed: 25336555
DOI: 10.1136/bcr-2014-206581 -
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 -
Journal of Neuroinflammation Feb 2023The mechanisms of cognitive impairments in Parkinson's disease (PD) remain unknown. Accumulating evidence revealed that brain neuroinflammatory response mediated by...
INTRODUCTION
The mechanisms of cognitive impairments in Parkinson's disease (PD) remain unknown. Accumulating evidence revealed that brain neuroinflammatory response mediated by microglial cells contributes to cognitive deficits in neuropathological conditions and macrophage antigen complex-1 (Mac1) is a key factor in controlling microglial activation.
OBJECTIVES
To explore whether Mac1-mediated microglial activation participates in cognitive dysfunction in PD using paraquat and maneb-generated mouse PD model.
METHODS
Cognitive performance was measured in wild type and Mac1 mice using Morris water maze test. The role and mechanisms of NADPH oxidase (NOX)-NLRP3 inflammasome axis in Mac1-mediated microglial dysfunction, neuronal damage, synaptic degeneration and phosphorylation (Ser129) of α-synuclein were explored by immunohistochemistry, Western blot and RT-PCR.
RESULTS
Genetic deletion of Mac1 significantly ameliorated learning and memory impairments, neuronal damage, synaptic loss and α-synuclein phosphorylation (Ser129) caused by paraquat and maneb in mice. Subsequently, blocking Mac1 activation was found to mitigate paraquat and maneb-elicited microglial NLRP3 inflammasome activation in both in vivo and in vitro. Interestingly, stimulating activation of NOX by phorbol myristate acetate abolished the inhibitory effects of Mac1 blocking peptide RGD on paraquat and maneb-provoked NLRP3 inflammasome activation, indicating a key role of NOX in Mac1-mediated NLRP3 inflammasome activation. Furthermore, NOX1 and NOX2, two members of NOX family, and downstream PAK1 and MAPK pathways were recognized to be essential for NOX to regulate NLRP3 inflammasome activation. Finally, a NLRP3 inflammasome inhibitor glybenclamide abrogated microglial M1 activation, neurodegeneration and phosphorylation (Ser129) of α-synuclein elicited by paraquat and maneb, which were accompanied by improved cognitive capacity in mice.
CONCLUSIONS
Mac1 was involved in cognitive dysfunction in a mouse PD model through NOX-NLRP3 inflammasome axis-dependent microglial activation, providing a novel mechanistic basis of cognitive decline in PD.
Topics: Animals; Mice; alpha-Synuclein; Disease Models, Animal; Dopaminergic Neurons; Inflammasomes; Integrins; Macrophages; Maneb; Memory Disorders; Microglia; NADPH Oxidases; NLR Family, Pyrin Domain-Containing 3 Protein; Paraquat; Parkinson Disease; Macrophage-1 Antigen
PubMed: 36804009
DOI: 10.1186/s12974-023-02732-x -
Clinical Journal of the American... Sep 2022The etiology of chronic kidney disease of unclear etiology, also known as Mesoamerican nephropathy, remains unclear. We investigated potential etiologies for...
BACKGROUND AND OBJECTIVES
The etiology of chronic kidney disease of unclear etiology, also known as Mesoamerican nephropathy, remains unclear. We investigated potential etiologies for Mesoamerican nephropathy in an immigrant dialysis population.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
Migrants with Mesoamerican nephropathy kidney failure (=52) were identified by exclusion of known causes of kidney disease and compared using a cross-sectional survey with demographically similar patients with kidney failure from other causes (=63) and age/sex/place of origin-matched healthy participants (=16). Survey results were extended to the bench; C57BL/6 mice (=73) received 10-15 weekly intraperitoneal injections of paraquat (a reactive oxygen species-generating herbicide) or vehicle. Kidney function, histology, and expression of organic cation transporter-2 (proximal tubule entry for paraquat) and multidrug and toxin extrusion 1 (extrusion pathway) were examined. Kidney biopsies from Nicaraguan patients with acute Mesoamerican nephropathy were stained for the above transporters and compared with patients with tubulointerstitial nephritis and without Mesoamerican nephropathy.
RESULTS
Patients with Mesoamerican nephropathy and kidney failure were young agricultural workers, almost exclusively men; the majority were from Mexico and El Salvador; and they had prior exposures to agrochemicals, including paraquat (27%). After adjustment for age/sex, exposure to any agrochemical or paraquat was associated with Mesoamerican nephropathy kidney failure (odds ratio, 4.86; 95% confidence interval, 1.82 to 12.96; =0.002 and odds ratio, 12.25; 95% confidence interval, 1.51 to 99.36; =0.02, respectively). Adjusted for age/sex and other covariates, 1 year of agrochemical exposure was associated with Mesoamerican nephropathy kidney failure (odds ratio, 1.23; 95% confidence interval, 1.04 to 1.44; =0.02). Compared with 16 matched healthy controls, Mesoamerican nephropathy kidney failure was significantly associated with exposure to paraquat and agrochemicals. Paraquat-treated male mice developed kidney failure and tubulointerstitial nephritis consistent with Mesoamerican nephropathy. Organic cation transporter-2 expression was higher in male kidneys versus female kidneys. Paraquat treatment increased organic cation transporter-2 expression and decreased multidrug and toxin extrusion 1 expression in male kidneys; similar results were observed in the kidneys of Nicaraguan patients with Mesoamerican nephropathy.
CONCLUSIONS
Exposure to agrochemicals is associated with Mesoamerican nephropathy, and chronic exposure of mice to paraquat, a prototypical oxidant, induced kidney failure similar to Mesoamerican nephropathy.
Topics: Male; Female; Animals; Mice; Paraquat; Cross-Sectional Studies; Mice, Inbred C57BL; Renal Insufficiency, Chronic; Nephritis, Interstitial; Renal Insufficiency; Chronic Kidney Diseases of Uncertain Etiology; Agrochemicals; Cations
PubMed: 35944911
DOI: 10.2215/CJN.16831221