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Frontiers in Chemistry 2023The green revolution model that is followed in the Brazilian Cerrado is dependent on mechanization, chemical fertilization for soil dressing and correction, and the use...
The green revolution model that is followed in the Brazilian Cerrado is dependent on mechanization, chemical fertilization for soil dressing and correction, and the use of herbicides. Paraquat is a methyl viologen herbicide marketed as bipyridylium dichloride salts and used (in low doses) to combat weeds in their post-emergence stage. It is a non-selective pesticide that causes the peroxidation of the lipids that make up the cell membrane, and when it comes into contact with foliage, it results in the death of the plant. The effect of water molecules co-crystallized in Paraquat salt structures was analyzed in anhydrous, dihydrate, and trihydrate forms to understand those physicochemical properties in its redox activity. The frontier molecular orbitals were also carried out using DFT to obtain the chemical reactivity of the bipyridylium cation. Finally, the supramolecular arrangements were evaluated to analyze the physicochemical stability and acquire insights on superoxide anions. The electronic structure indicated that the BP cation presents an acidic character due to its low ELUMO value, while the salt has a more basic character due to its high EHOMO value. For this reason, the BP ion is more susceptible to reduction during the weeds' photosynthesis process. During the process of plant photosynthesis, PQ is reduced to form a stable radical cation. In the supramolecular arrangement, the presence of water molecules increases the number of strong H-bonds, while the weak/moderate H-bonds are stabilized. PQ's toxic effects are observed in wildlife, domesticated animals, human populations, and ecosystems. The influence of PQ on the terrestrial environment is limited because of the soil adsorption capacity associated with good agricultural practices. The current use of good agricultural practices in the Cerrado seems not to prevent the environmental impacts of herbicides like PQ because it aims for the expansion and profitability of large-scale farming based on input-intensive practices instead of sustainable agriculture processes.
PubMed: 37795387
DOI: 10.3389/fchem.2023.1267634 -
Journal of Translational Medicine Mar 2024Paraquat (PQ) is a widely used and highly toxic herbicide that poses a significant risk to human health. The main consequence of PQ poisoning is pulmonary fibrosis,...
BACKGROUND
Paraquat (PQ) is a widely used and highly toxic herbicide that poses a significant risk to human health. The main consequence of PQ poisoning is pulmonary fibrosis, which can result in respiratory failure and potentially death. Our research aims to uncover a crucial mechanism in which PQ poisoning induces senescence in epithelial cells, ultimately regulating the activation of pulmonary fibroblasts through the exosomal pathway.
METHODS
Cellular senescence was determined by immunohistochemistry and SA-β-Gal staining. The expression of miRNAs was measured by qPCR. Pulmonary fibroblasts treated with specific siRNA of SIRT1 or LV-SIRT1 were used to analysis senescent exosomes-mediated fibroblasts activation. Luciferase reporter assay and western blot were performed to elucidated the underlying molecular mechanisms. The effects of miR-217-5p antagomir on pulmonary fibrosis were assessed in PQ-poisoned mice models.
RESULTS
Impairing the secretion of exosomes effectively mitigates the harmful effects of senescent epithelial cells on pulmonary fibroblasts, offering protection against PQ-induced pulmonary fibrosis in mice. Additionally, we have identified a remarkable elevation of miR-217-5p expression in the exosomes of PQ-treated epithelial cells, which specifically contributes to fibroblasts activation via targeted inhibition of SIRT1, a protein involved in cellular stress response. Remarkably, suppression of miR-217-5p effectively impaired senescent epithelial cells-induced fibroblasts activation. Further investigation has revealed that miR-217-5p attenuated SIRT1 expression and subsequently resulted in enhanced acetylation of β-catenin and Wnt signaling activation.
CONCLUSION
These findings highlight a potential strategy for the treatment of pulmonary fibrosis induced by PQ poisoning. Disrupting the communication between senescent epithelial cells and pulmonary fibroblasts, particularly by targeting the miR-217-5p/SIRT1/β-catenin axis, may be able to alleviate the effects of PQ poisoning on the lungs.
Topics: Humans; Mice; Animals; Pulmonary Fibrosis; Paraquat; beta Catenin; Exosomes; Sirtuin 1; Lung; MicroRNAs; Epithelial Cells; Fibroblasts
PubMed: 38532482
DOI: 10.1186/s12967-024-05094-x -
Current Research in Toxicology 2024Paraquat (PQ), a toxic and nonselective bipyridyl herbicide, is one of the most extensively used pesticides in agricultural countries. In addition to pneumotoxicity, the...
Paraquat (PQ), a toxic and nonselective bipyridyl herbicide, is one of the most extensively used pesticides in agricultural countries. In addition to pneumotoxicity, the liver is an important target organ for PQ poisoning in humans. However, the mechanism of PQ in hepatotoxicity remains unclear. In this study, we found that exposure of rat hepatic H4IIE cells to PQ (0.1-2 mM) induced significant cytotoxicity and apoptosis, which was accompanied by mitochondria-dependent apoptotic signals, including loss of mitochondrial membrane potential (MMP), cytosolic cytochrome release, and changes in the Bcl-2/Bax mRNA ratio. Moreover, PQ (0.5 mM) exposure markedly induced JNK and ERK1/2 activation, but not p38-MAPK. Blockade of JNK and ERK1/2 signaling by pretreatment with the specific pharmacological inhibitors SP600125 and PD98059, respectively, effectively prevented PQ-induced cytotoxicity, mitochondrial dysfunction, and apoptotic events. Additionally, PQ exposure stimulated significant oxidative stress-related signals, including reactive oxygen species (ROS) generation and intracellular glutathione (GSH) depletion, which could be reversed by the antioxidant -Acetylcysteine (NAC). Buffering the oxidative stress response with NAC also effectively abrogated PQ-induced hepatotoxicity, MMP loss, apoptosis, and phosphorylation of JNK and ERK1/2 protein, however, the JNK or ERK inhibitors did not suppress ROS generation in PQ-treated cells. Collectively, these results demonstrate that PQ exposure induces hepatic cell toxicity and death via an oxidative stress-dependent JNK/ERK activation-mediated downstream mitochondria-regulated apoptotic pathway.
PubMed: 38379848
DOI: 10.1016/j.crtox.2024.100155 -
Frontiers in Microbiology 2024Oxidative stress plays a pivotal role in modulating the balance of intestinal flora and the gut-liver axis, while also serving as a key determinant of the growth...
INTRODUCTION
Oxidative stress plays a pivotal role in modulating the balance of intestinal flora and the gut-liver axis, while also serving as a key determinant of the growth potential of weaned piglets. However, few studies have subdivided and compared acute and chronic oxidative stress.
METHODS
In this study, an intestinal model of acute oxidative stress in weaned piglets using paraquat (PQ) and a chronic oxidative stress model using D-galactosa in weaned piglets were conducted. And we further systematically compare their effects.
RESULTS
Both acute and chronic oxidative stress models impaired intestinal barrier function and liver function. Chronic stress caused by D-galactose can result in severe redox dysregulation, while acute stress caused by paraquat can lead to inflammation and liver damage. Additionally, the components involved in the CAR pathway were expressed differently. Chronic or acute oxidative stress can reduce the diversity and composition of intestinal flora. In the PQ group, the richness of Mogibacterium and Denitratisoma improved, but in the D-gal group, the richness of Catenisphaera and Syntrophococcus increased.
DISCUSSION
Not only does this research deepen our understanding of the effects of acute and chronic oxidative stress on intestinal functions, but it also characterizes characteristic changes in the gut flora, potentially identifying novel therapeutic targets and opening new avenues for future research.
PubMed: 38952442
DOI: 10.3389/fmicb.2024.1414486 -
Case report: Lung transplantation for treatment of paraquat intoxication: timing of transplantation.Frontiers in Pharmacology 2023To analyze the optimal timing of lung transplantation and summarize postoperative complications and their management after paraquat poisoning. Here, we present the...
To analyze the optimal timing of lung transplantation and summarize postoperative complications and their management after paraquat poisoning. Here, we present the clinical course of a 17-year-old boy with paraquat poisoning, in whom bilateral lung transplantation (LT) was performed. We reviewed the eight previously published articles relevant to LT after paraquat poisoning to summarize the therapeutic strategy. A 17-year-old boy was admitted to the hospital after ingestion of 30-50 mL 25% paraquat. Mechanical ventilation was initiated on the 25th day after intoxication. Venovenous extracorporeal membrane oxygenation was initiated on the 26th day. Sequential bilateral LT was performed on the 27th day. Several complex postoperative complications occurred and the patient was discharged on the 50th day postoperatively. Eight case reports were included in the literature review, including 11 patients with paraquat poisoning undergoing LT. Three patients died due to paraquat poisoning leading to fibrosis in the transplanted lungs or postoperative complications. Eight patients survived during follow-up. LT after herbicide poisoning should be planned when hepatorenal function starts to recover, and waiting for complete recovery is unnecessary. Prevention of infection before surgery is important to reduce the incidence of postoperative infection. Complex perioperative complications caused by the herbicide itself or the late timing of transplantation can be successfully managed by a multidisciplinary team.
PubMed: 37529697
DOI: 10.3389/fphar.2023.1205689 -
Ecotoxicology and Environmental Safety Jun 2024Paraquat (PQ) is a widely used herbicide that poisons human by accident or intentional ingestion. PQ poisoning causes systemic inflammatory response syndrome (SIRS)...
BACKGROUND
Paraquat (PQ) is a widely used herbicide that poisons human by accident or intentional ingestion. PQ poisoning causes systemic inflammatory response syndrome (SIRS) resulting in acute lung injury (ALI) with an extremely high mortality rate. Blood trematode Schistosoma japonicum-produced cystatin (Sj-Cys) is a strong immunomodulatory protein that has been experimentally used to treat inflammation related diseases. In this study, Sj-Cys recombinant protein (rSj-Cys) was used to treat PQ-induced lung injury and the immunological mechanism underlying the therapeutic effect was investigated.
METHODS
PQ-induced acute lung injury mouse model was established by intraperitoneally injection of 20 mg/kg of paraquat. The poisoned mice were treated with rSj-Cys and the survival rate was observed up to 7 days compared with the group without treatment. The pathological changes of PQ-induced lung injury were observed by examining the histochemical sections of affected lung tissue and the wet to dry ratio of lung as a parameter for inflammation and edema. The levels of the inflammation related cytokines IL-6 and TNF-α and regulatory cytokines IL-10 and TGF-β were measured in sera and in affected lung tissue using ELISA and their mRNA levels in lung tissue using RT-PCR. The macrophages expressing iNOS were determined as M1 and those expressing Arg-1 as M2 macrophages. The effect of rSj-Cys on the transformation of inflammatory M1 to regulatory M2 macrophages was measured in affected lung tissue in vivo (EKISA and RT-PCR) and in MH-S cell line in vitro (flow cytometry). The expression levels of TLR2 and MyD88 in affected lung tissue were also measured to determine their role in the therapy of rSj-Cys on PQ-induced lung injury.
RESULT
We identified that treatment with rSj-Cys significantly improved the survival rate of mice with PQ-induced lung injury from 30 % (untreated) to 80 %, reduced the pathological damage of poisoning lung tissue, associated with significantly reduced levels of proinflammatory cytokines (IL-6 from 1490 to 590 pg/ml, TNF-α from 260 to 150 pg/ml) and increased regulatory cytokines (IL-10 from360 to 550 pg/ml, and TGF-β from 220 to 410 pg/ml) in both sera (proteins) and affected lung tissue (proteins and mRNAs). The polarization of macrophages from M1to M2 type was found to be involved in the therapeutic effect of rSj-Cys on the PQ-induced acute lung injury, possibly through inhibiting TLR2/MyD88 signaling pathway.
CONCLUSIONS
Our study demonstrated the therapeutic effect of rSj-Cys on PQ poisoning caused acute lung injury by inducing M2 macrophage polarization through inhibiting TLR2/MyD88 signaling pathway. The finding in this study provides an alternative approach for the treatment of PQ poisoning and other inflammatory diseases.
PubMed: 38905933
DOI: 10.1016/j.ecoenv.2024.116615 -
Microbiology Spectrum Feb 2024Drug repurposing efforts led to the discovery of bactericidal activity in auranofin, a gold-containing drug used to treat rheumatoid arthritis. Auranofin kills...
Drug repurposing efforts led to the discovery of bactericidal activity in auranofin, a gold-containing drug used to treat rheumatoid arthritis. Auranofin kills Gram-positive bacteria by inhibiting thioredoxin reductase, an enzyme that scavenges reactive oxygen species (ROS). Despite the presence of thioredoxin reductase in Gram-negative bacteria, auranofin is not always active against them. It is not clear whether the lack of activity in several Gram-negative bacteria is due to the cell envelope barrier or the presence of other ROS protective enzymes such as glutathione reductase (GOR). We previously demonstrated that chemical analogs of auranofin (MS-40 and MS-40S), but not auranofin, are bactericidal against the Gram-negative complex. Here, we explore the targets of auranofin, MS-40, and MS-40S in and elucidate the mechanism of action of the auranofin analogs by a genome-wide, randomly barcoded transposon screen (BarSeq). Auranofin and its analogs inhibited the thioredoxin reductase and induced ROS but did not inhibit the bacterial GOR. Genome-wide, BarSeq analysis of cells exposed to MS-40 and MS-40S compared to the ROS inducers arsenic trioxide, diamide, hydrogen peroxide, and paraquat revealed common and unique mediators of drug susceptibility. Furthermore, deletions of and that encode enzymes in the glutathione biosynthetic pathway led to increased susceptibility to MS-40 and MS-40S. Overall, our data suggest that the auranofin analogs kill by inducing ROS through inhibition of thioredoxin reductase and that the glutathione system has a role in protecting against these ROS-inducing compounds.IMPORTANCEThe Burkholderia cepacia complex is a group of multidrug-resistant bacteria that can cause infections in the lungs of people with the autosomal recessive disease, cystic fibrosis. Specifically, the bacterium Burkholderia cenocepacia can cause severe infections, reducing lung function and leading to a devastating type of sepsis, cepacia syndrome. This bacterium currently does not have an accepted antibiotic treatment plan because of the wide range of antibiotic resistance. Here, we further the research on auranofin analogs as antimicrobials by finding the mechanism of action of these potent bactericidal compounds, using a powerful technique called BarSeq, to find the global response of the cell when exposed to an antimicrobial.
Topics: Humans; Auranofin; Reactive Oxygen Species; Thioredoxin-Disulfide Reductase; Anti-Bacterial Agents; Burkholderia cepacia complex; Burkholderia cenocepacia; Glutathione
PubMed: 38206016
DOI: 10.1128/spectrum.03201-23 -
SAGE Open Medical Case Reports 2024Paraquat, a highly toxic herbicide, accounts for a substantial number of poisoning-related fatalities, primarily prevalent in agricultural regions. The ingestion gives...
Paraquat, a highly toxic herbicide, accounts for a substantial number of poisoning-related fatalities, primarily prevalent in agricultural regions. The ingestion gives rise to severe complications affecting various organs, including the lungs, gastrointestinal tract, kidneys and liver. This report details the case of an 18-year-old male who had been using cannabis for a year and inadvertently ingested paraquat. He presented at the emergency room exhibiting symptoms of vomiting characterized by hematemesis and regurgitated food particles, along with heartburn, dysphagia and reduced urine output. Given the absence of a specific antidote, the prognosis for paraquat poisoning remains generally unfavourable. Diagnosis relies on circumstantial evidence and clinical manifestations, necessitating a focus on supportive care. Presently, no specific antidote for paraquat poisoning is available. Efforts should concentrate on preventive measures, efficient decontamination strategies and vigilant stabilization protocols in instances of exposure.
PubMed: 38559410
DOI: 10.1177/2050313X241240098 -
ACS Omega Aug 2023The role of Semen saponins in sedative and hypnosis has attracted much attention. The study aimed to investigate its possible UV damage protection and anti-aging...
The role of Semen saponins in sedative and hypnosis has attracted much attention. The study aimed to investigate its possible UV damage protection and anti-aging effects. Total saponins (SZR I) and purified saponins (SZR II) were analyzed and compared by infrared spectroscopy and high-performance liquid chromatography (HPLC). The protective effects of SZR I, SZR II, and their three monomers on HaCaT cells damaged by UV were studied, and their anti-aging activities were observed by with paraquat-induced oxidative stress. The results showed that SZR I and SZR II differ in chemical composition but both have the same three monomers. The cell survival rate treated with SZR I and SZR II at a concentration of 400 μg/mL increased by 34.45 and 88.98%, respectively, indicating that they could promote the proliferation of UVB-damaged HaCaT cells. Jujuboside A, Jujuboside B, and spinosin from the saponins exhibited similar effects on UVB-damaged HaCaT cells. SZR I and SZR II had little effect on reproductive performance but could delay the senescence caused by heat and oxidative stress of the model. These results provide useful data that Semen saponin is a potential natural product with UV damage protection and anti-aging characteristics.
PubMed: 37576697
DOI: 10.1021/acsomega.3c00433 -
Respiratory Research May 2024Paraquat (PQ) is a widely used herbicide and a common cause of poisoning that leads to pulmonary fibrosis with a high mortality rate. However, the underlying mechanisms...
Paraquat (PQ) is a widely used herbicide and a common cause of poisoning that leads to pulmonary fibrosis with a high mortality rate. However, the underlying mechanisms of PQ-induced pulmonary fibrosis and whether pulmonary epithelial cell senescence is involved in the process remain elusive. In this study, PQ-induced pulmonary epithelial cell senescence and Hippo-YAP/TAZ activation were observed in both C57BL/6 mice and human epithelial cells. PQ-induced senescent pulmonary epithelial cells promoted lung fibroblast transformation through secreting senescence-associated secretory phenotype (SASP) factors. Yap/Taz knockdown in mice lungs significantly decreased the expression of downstream profibrotic protein Ctgf and senescent markers p16 and p21, and alleviated PQ-induced pulmonary fibrosis. Interfering YAP/TAZ in senescent human pulmonary epithelial cells resulted in decreased expression of the anti-apoptosis protein survivin and elevated level of apoptosis. In conclusion, our findings reveal a novel mechanism by which the involvement of Hippo-YAP/TAZ activation in pulmonary epithelial cell senescence mediates the pathogenesis of PQ-induced pulmonary fibrosis, thereby offering novel insights and potential targets for the clinical management of PQ poisoning as well as providing the mechanistic insight of the involvement of Yap/Taz activation in cell senescence in pulmonary fibrosis and its related pulmonary disorders. The YIN YANG balance between cell senescence and apoptosis is important to maintain the homeostasis of the lung, the disruption of which will lead to disease.
Topics: Animals; Cellular Senescence; YAP-Signaling Proteins; Humans; Mice, Inbred C57BL; Mice; Pulmonary Fibrosis; Adaptor Proteins, Signal Transducing; Transcription Factors; Paraquat; Male; Transcriptional Coactivator with PDZ-Binding Motif Proteins; Epithelial Cells; Trans-Activators
PubMed: 38762455
DOI: 10.1186/s12931-024-02832-z