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MethodsX Jun 2024This paper provides a complete protocol for studying the effects of inhaled paraquat (PQ), a toxic herbicide that has negative effects systemically and on the lungs. The...
This paper provides a complete protocol for studying the effects of inhaled paraquat (PQ), a toxic herbicide that has negative effects systemically and on the lungs. The protocol aims to evaluate the effects of aerosolized PQ exposure on lung and systemic injury in an animal model, which will provide significant information for therapeutic interventions for PQ-induced pulmonary and systemic damage. The protocol involves the following key components: 1. Study groups: By including control, non-treated aerosolized PQ-exposed, and treated PQ-exposed animals with various agent groups in the experiment, lung and systemic injury in each group could be evaluated, and different measured parameters could be compared among groups. 2. PQ exposure: Animals in the PQ-exposed groups are subjected to PQ aerosol inhalation, simulating occupational or accidental exposure in farmers working with this herbicide. 3. Assessment measures: To determine the degree of lung and systemic injury and its physiological effects, several assessments, such as biochemical markers, histopathological analysis, and functional tests, are used. The protocol offers reliable and accurate results by using standardized methods and data collection. The effect of PQ exposure on lung and systemic injury could be evaluated by statistical analysis of the collected data, which also makes it easier to identify possible protective agents or interventions. This comprehensive evaluation protocol provides an essential basis for studying the mechanisms behind PQ-induced lung and systemic injury and assessing the effectiveness of preventative or therapeutic strategies in minimizing its adverse effects.
PubMed: 38883591
DOI: 10.1016/j.mex.2024.102782 -
Iranian Journal of Basic Medical... 2024The effects of , safranal, and pioglitazone on aerosolized paraquat (PQ)-induced systemic changes were examined.
OBJECTIVES
The effects of , safranal, and pioglitazone on aerosolized paraquat (PQ)-induced systemic changes were examined.
MATERIALS AND METHODS
Control (Ctrl) and PQ groups of rats were exposed to saline or PQ (27 and 54 mg/m3, PQ-L and PQ-H) aerosols eight times on alternate days. Nine PQ-H groups were treated with dexamethasone (0.03 mg/kg/day, Dexa), two doses of extract (20 and 80 mg/kg/day, CS-L and CS-H), safranal (0.8 and 3.2 mg/kg/day, Saf-L and Saf-H), pioglitazone (5 and 10 mg/kg/day, Pio-L and Pio-H), and the combination of low dose of the pioglitazone and extract or safranal (Pio + CS and Pio + Saf) after the end of PQ exposure.
RESULTS
Interferon-gamma (INF-γ), interleukin 10 (IL-10), superoxide dismutase (SOD), catalase (CAT), and thiol serum levels were reduced, but tumor necrosis factor (TNF-α), malondialdehyde (MDA), and total and differential WBC were increased in both PQ groups (<0.05 to <0.001). All measured variables were improved in all treated groups (<0.05 to <0.001). The effects of high dose of C. sativus and safranal on measured parameters were higher than dexamethasone (<0.05 to <0.001). The effects of Pio + CS and Pio + Saf treatment on most variables were significantly higher than three agents alone (<0.05 to <0.001).
CONCLUSION
and safranal improved inhaled PQ-induced systemic inflammation and oxidative stress similar to those of dexamethasone and showed synergic effects with pioglitazone suggesting the possible PPARγ receptor-mediated effects of the plant and its constituent.
PubMed: 38629099
DOI: 10.22038/IJBMS.2024.72996.15867 -
Free Radical Biology & Medicine Jun 2024Peroxiredoxin 6 (Prdx6) repairs peroxidized membranes by reducing oxidized phospholipids, and by replacing oxidized sn-2 fatty acyl groups through hydrolysis/reacylation...
Peroxiredoxin 6 (Prdx6) repairs peroxidized membranes by reducing oxidized phospholipids, and by replacing oxidized sn-2 fatty acyl groups through hydrolysis/reacylation by its phospholipase A (aiPLA) and lysophosphatidylcholine acyltransferase activities. Prdx6 is highly expressed in the lung, and intact lungs and cells null for Prdx6 or with single-point mutations that inactivate either Prdx6-peroxidase or aiPLA activity alone exhibit decreased viability, increased lipid peroxidation, and incomplete repair when exposed to paraquat, hyperoxia, or organic peroxides. Ferroptosis is form of cell death driven by the accumulation of phospholipid hydroperoxides. We studied the role of Prdx6 as a ferroptosis suppressor in the lung. We first compared the expression Prdx6 and glutathione peroxidase 4 (GPx4) and visualized Prdx6 and GPx4 within the lung. Lung Prdx6 mRNA levels were five times higher than GPx4 levels. Both Prdx6 and GPx4 localized to epithelial and endothelial cells. Prdx6 knockout or knockdown sensitized lung endothelial cells to erastin-induced ferroptosis. Cells with genetic inactivation of either aiPLA or Prdx6-peroxidase were more sensitive to ferroptosis than WT cells, but less sensitive than KO cells. We then conducted RNA-seq analyses in Prdx6-depleted cells to further explore how the loss of Prdx6 sensitizes lung endothelial cells to ferroptosis. Prdx6 KD upregulated transcriptional signatures associated with selenoamino acid metabolism and mitochondrial function. Accordingly, Prdx6 deficiency blunted mitochondrial function and increased GPx4 abundance whereas GPx4 KD had the opposite effect on Prdx6. Moreover, we detected Prdx6 and GPx4 interactions in intact cells, suggesting that both enzymes cooperate to suppress lipid peroxidation. Notably, Prdx6-depleted cells remained sensitive to erastin-induced ferroptosis despite the compensatory increase in GPx4. These results show that Prdx6 suppresses ferroptosis in lung endothelial cells and that both aiPLA and Prdx6-peroxidase contribute to this effect. These results also show that Prdx6 supports mitochondrial function and modulates several coordinated cytoprotective pathways in the pulmonary endothelium.
Topics: Ferroptosis; Peroxiredoxin VI; Phospholipid Hydroperoxide Glutathione Peroxidase; Lung; Animals; Endothelial Cells; Mice; Lipid Peroxidation; Humans; Phospholipases A2; Mice, Knockout; Piperazines; Group VI Phospholipases A2
PubMed: 38579937
DOI: 10.1016/j.freeradbiomed.2024.04.208 -
Molecular Biology Reports Nov 2023Paraquat (PQ) is a widely used and highly toxic pesticide that is often actively ingested and causes pulmonary fibrosis in patients. Ferroptosis is a regulated form of...
Paraquat (PQ) is a widely used and highly toxic pesticide that is often actively ingested and causes pulmonary fibrosis in patients. Ferroptosis is a regulated form of non-apoptotic cell death associated with iron-dependent lipid peroxidation. Previous studies have shown that ferroptosis is involved in the occurrence and development of acute lung injury (ALI). In this study, a model rat with inflammatory response, oxidative stress, lipid peroxidation, and pulmonary fibrosis was successfully established by PQ administration. The occurrence of ferroptosis in PQ model rats was confirmed by TUNEL staining, iron ion detection, and Ferroptosis related biomarkers detection. Western blotting (WB) and real-time PCR (RT-PCR) showed that the expression of Keap1 was significantly up-regulated and the expression of Nrf2 was significantly down-regulated in the lung tissue of PQ rats. Further transcriptomics and proteomics confirmed: (1) Enrichment of molecular processes related to iron ion binding; (2) Keap1 may promote Nrf2 ubiquitination and lead to Nrf2 degradation; (3) There is functional enrichment in ferroptosis related pathways. Our results suggest that PQ can regulate Keap1/Nrf2 signaling pathway, leading to increased lipid peroxidation and abnormal iron uptake, thereby inducing iron death and exacerbating the progression of pulmonary fibrosis. Our study provides new insights into PQ-induced pulmonary fibrosis.
Topics: Humans; Rats; Animals; Paraquat; Pulmonary Fibrosis; NF-E2-Related Factor 2; Ferroptosis; Kelch-Like ECH-Associated Protein 1; Signal Transduction; Iron
PubMed: 37812357
DOI: 10.1007/s11033-023-08756-z -
Molecular Neurobiology Aug 2023C-terminal binding proteins (CtBP) are transcriptional co-repressors regulating gene expression. CtBP promote neuronal survival through repression of pro-apoptotic...
C-terminal binding proteins (CtBP) are transcriptional co-repressors regulating gene expression. CtBP promote neuronal survival through repression of pro-apoptotic genes, and may represent relevant targets for neurodegenerative disorders, such as Parkinson's disease (PD). Nevertheless, evidence of the role of CtBP1 and CtBP2 in neurodegeneration are scarce. Herein, we showed that CtBP1 and CtBP2 are expressed in neurons, dopaminergic neurons, astrocytes, and microglia in the substantia nigra (SN) and striatum of adult mice. Old mice showed a lower expression of CtBP1 in the SN and higher expression of CtPB2 in the SN and striatum compared with adult mice. In vivo models for PD (paraquat, MPTP, 6-OHDA) showed increased expression of CtBP1 in the SN and striatum while CtBP2 expression was increased in the striatum of paraquat-treated rats only. Moreover, an increased expression of both CtBP was found in a dopaminergic cell line (N27) exposed to 6-OHDA. In the 6-OHDA PD model, we found a dual effect using an unspecific ligand of CtBP, the 4-methylthio 2-oxobutyric acid (MTOB): higher concentrations (e.g. 2500 µM, 1000 µM) inhibited dopaminergic survival, while at 250 μM it counteracted cell death. In vitro, this latter protective role was absent after the siRNA silencing of CtBP1 or CtBP2. Altogether, this is the first report exploring the cellular and regional expression pattern of CtBP in the nigrostriatal pathway and the neuroprotective role in PD toxin-based models. CtBP could counteract dopaminergic cell death in the 6-OHDA PD model and, therefore, CtBP function and therapeutic potential in PD should be further explored.
Topics: Rats; Mice; Animals; Parkinson Disease; Oxidopamine; Paraquat; Transcription Factors; Dopamine; Dopaminergic Neurons; Substantia Nigra; Disease Models, Animal; Neuroprotective Agents; Mice, Inbred C57BL
PubMed: 37060501
DOI: 10.1007/s12035-023-03331-w -
Iranian Journal of Basic Medical... 2024Paraquat (PQ), a potent environmental herbicide, is recognized for inducing irreparable toxic damage to biological systems. This study aimed to evaluate the...
Evaluation of the influence of N-acetylcysteine and broccoli extract on systemic paraquat poisoning: Implications for biochemical, physiological, and histopathological parameters in rats.
OBJECTIVES
Paraquat (PQ), a potent environmental herbicide, is recognized for inducing irreparable toxic damage to biological systems. This study aimed to evaluate the effectiveness of N-acetylcysteine (NAC) and broccoli extract, individually and in combination, in alleviating PQ poisoning in rats, leveraging the exceptional anti-oxidant, anti-inflammatory, and anti-apoptotic properties of broccoli.
MATERIALS AND METHODS
Seventy Wistar rats were categorized into seven groups: C (control, vehicle), PQ (paraquat at 40 mg/kg), BC (broccoli extract at 300 mg/kg), NC (N-acetylcysteine at the same dose of 300 mg/kg), and combined groups PQ+BC, PQ+NC, and NC+PQ+BC, all administered equivalent doses. After 42 days, blood samples were collected to evaluate liver and kidney parameters, proinflammatory biomarkers, caspase-3, and caspase-9. Lung tissues were excised, with one part preserved for hydroxyproline and oxidative stress parameter measurement and another sectioned and stained for histopathological analysis.
RESULTS
The PQ group exhibited the highest lung-to-body weight (LW/BW) ratio, while the PQ+BC+NC group demonstrated the lowest ratio. Results indicated an elevated lung hydroxyproline concentration and a significant reduction in anti-oxidant enzymes (catalase, glutathione peroxidase, superoxide dismutase, and total anti-oxidant capacity) (<0.001). The PQ+BC group showed modified malondialdehyde levels, reaching a peak in the PQ group. Additionally, a significant decrease in tumor necrosis factor, interleukin-1, caspase-3, and caspase-9 was observed in the PQ+BC+NC group (<0.01). Pulmonary edema, hyperemia, and severe hemorrhage observed in the PQ group were notably reduced in the PQ+BC+NC group.
CONCLUSION
The combination of active compounds from broccoli and NAC demonstrated significant systemic and pulmonary effects in mitigating PQ-induced toxicity.
PubMed: 38800031
DOI: 10.22038/IJBMS.2024.75258.16311 -
PloS One 2023The effect of paraquat, oxadiazon and oxyfluorfen herbicides was tested on two populations of hairy fleabane (Erigeron bonariensis L.), collected from a date palm...
The effect of paraquat, oxadiazon and oxyfluorfen herbicides was tested on two populations of hairy fleabane (Erigeron bonariensis L.), collected from a date palm orchard at Tal al-Ramil (Central Jordan Valley) and al-Twal (Northern Jordan Valley) sites using the recommended rates (0.5, 1.25 and 0.792kg a.i ha-1 for each herbicide, respectively) and 10-fold (5, 12.50 and 7.92 kg a.i. ha-1, respectively) under glasshouse conditions. Results showed that the date palm weed population was resistant to the three herbicides at both application rates and al-Twal site population was highly susceptible. Two field experiments were conducted to evaluate the effectiveness of 12 herbicides in controlling the weed in the date palm orchard during the spring of 2017, revealed that E. bonariensis resists paraquat (0.5, 1.0 and 1.5 kg a.i. ha-1), oxadiazon (1.25 kg a.i. ha-1) and oxyfluorfen (0.792 kg a.i. ha-1) herbicides. None of the three herbicides was effective against the weed and treated plants continued to grow normally similar to those of untreated control. Ten-fold higher rates of these herbicides failed to control the weed. The effect of other tested herbicides was variable with bromoxynil plus MCPA (buctril®M), 2,4-D- iso-octyl ester, glyphosate, glyphosate trimesium and triclopyr being the most effective and completely controlling the weed at recommended rates of application. It is concluded that the tested populations of E. bonariensis developed resistance to paraquat, oxadiazon and oxyfluorfen but control of the weed was possible using other herbicides with different mechanisms of action. Herbicide rotation or other nonchemical weed control methods have been suggested to prevent or reduce the buildup and spread of resistant populations of this weed. These results represent the first report of herbicide resistance of E. bonariensis in Jordan.
Topics: Paraquat; Erigeron; Herbicide Resistance; Jordan; Herbicides; Weed Control; Conyza
PubMed: 37824594
DOI: 10.1371/journal.pone.0263154 -
Neurobiology of Disease Jun 2024Idiopathic Parkinson's disease (PD) is epidemiologically linked with exposure to toxicants such as pesticides and solvents, which comprise a wide array of chemicals that...
Idiopathic Parkinson's disease (PD) is epidemiologically linked with exposure to toxicants such as pesticides and solvents, which comprise a wide array of chemicals that pollute our environment. While most are structurally distinct, a common cellular target for their toxicity is mitochondrial dysfunction, a key pathological trigger involved in the selective vulnerability of dopaminergic neurons. We and others have shown that environmental mitochondrial toxicants such as the pesticides rotenone and paraquat, and the organic solvent trichloroethylene (TCE) appear to be influenced by the protein LRRK2, a genetic risk factor for PD. As LRRK2 mediates vesicular trafficking and influences endolysosomal function, we postulated that LRRK2 kinase activity may inhibit the autophagic removal of toxicant damaged mitochondria, resulting in elevated oxidative stress. Conversely, we suspected that inhibition of LRRK2, which has been shown to be protective against dopaminergic neurodegeneration caused by mitochondrial toxicants, would reduce the intracellular production of reactive oxygen species (ROS) and prevent mitochondrial toxicity from inducing cell death. To do this, we tested in vitro if genetic or pharmacologic inhibition of LRRK2 (MLi2) protected against ROS caused by four toxicants associated with PD risk - rotenone, paraquat, TCE, and tetrachloroethylene (PERC). In parallel, we assessed if LRRK2 inhibition with MLi2 could protect against TCE-induced toxicity in vivo, in a follow up study from our observation that TCE elevated LRRK2 kinase activity in the nigrostriatal tract of rats prior to dopaminergic neurodegeneration. We found that LRRK2 inhibition blocked toxicant-induced ROS and promoted mitophagy in vitro, and protected against dopaminergic neurodegeneration, neuroinflammation, and mitochondrial damage caused by TCE in vivo. We also found that cells with the LRRK2 G2019S mutation displayed exacerbated levels of toxicant induced ROS, but this was ameliorated by LRRK2 inhibition with MLi2. Collectively, these data support a role for LRRK2 in toxicant-induced mitochondrial dysfunction linked to PD risk through oxidative stress and the autophagic removal of damaged mitochondria.
Topics: Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Animals; Reactive Oxygen Species; Rats; Trichloroethylene; Mitochondria; Rotenone; Parkinson Disease; Paraquat; Dopaminergic Neurons; Oxidative Stress; Humans; Environmental Pollutants; Rats, Sprague-Dawley
PubMed: 38705492
DOI: 10.1016/j.nbd.2024.106522 -
Brain Sciences Dec 2023Paraquat (PQ), rotenone (RO), and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are neurotoxicants that can damage human health. Exposure to these neurotoxicants...
Paraquat (PQ), rotenone (RO), and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are neurotoxicants that can damage human health. Exposure to these neurotoxicants has been linked to neurodegeneration, particularly Parkinson's disease. However, their mechanisms of action have not been fully elucidated, nor has the relative vulnerability of neuronal subtypes to their exposures. To address this, the current study investigated the cytotoxic effects of PQ, RO, and MPTP and their relative effects on cellular bioenergetics and oxidative stress on undifferentiated human neuroblastoma (SH-SY5Y) cells and those differentiated to dopaminergic (DA) or cholinergic (CH) phenotypes. The tested neurotoxicants were all cytotoxic to the three cell phenotypes that correlated with both concentration and exposure duration. At half-maximal effective concentrations (ECs), there were significant reductions in cellular ATP levels and reduced activity of the mitochondrial complexes I and III, with a parallel increase in lactate production. PQ at 10 µM significantly decreased ATP production and mitochondrial complex III activity only in DA cells. RO was the most potent inhibitor of mitochondrial complex 1 and did not inhibit mitochondrial complex III even at concentrations that induced a 50% loss of cell viability. MPTP was the most potent toxicant in undifferentiated cells. All neurotoxicants significantly increased reactive oxygen species, lipid peroxidation, and nuclear expression of Nrf2, with a corresponding inhibition of the antioxidant enzymes catalase and superoxide dismutase. At a 10 µM exposure to PQ or RO, oxidative stress biomarkers were significant in DA cells. Collectively, this study underscores the importance of mitochondrial dysfunction and oxidative stress in PQ, RO, and MPTP-induced cytotoxicity and that neuronal phenotypes display differential vulnerability to these neurotoxicants.
PubMed: 38137165
DOI: 10.3390/brainsci13121717 -
Toxics Jul 2023The biodegradation of paraquat was investigated using immobilized microbial cells on nanoceramics fabricated from nanoscale kaolinite. and , which degrade paraquat,...
The biodegradation of paraquat was investigated using immobilized microbial cells on nanoceramics fabricated from nanoscale kaolinite. and , which degrade paraquat, were immobilized separately on nanoceramics (respectively called IC-P and IC-B). The attachment of bacteria to nanoceramics resulted from electrostatic force interactions, hydrogen bonding, and covalent bonding (between the cells and the support materials). The initial 10 mg L concentration of paraquat in water was removed by the adsorption process using nanoceramics at 68% and ceramics at 52%, respectively. The immobilized cells on the nanoceramics were able to remove approximately 92% of the paraquat within 10 h, whereas the free cells could only remove 4%. When the paraquat was removed, the cell-immobilized nanoceramics exhibited a significant decrease in dissolved organic nitrogen (DON). IC-B was responsible for 34% of DON biodegradation, while IC-P was responsible for 22%. Ammonia was identified as the end product of ammonification resulting from paraquat mineralization.
PubMed: 37505603
DOI: 10.3390/toxics11070638