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Redox Biology Oct 2023Long-chain acyl-CoA synthetase (ACSL) 4 converts polyunsaturated fatty acids (PUFAs) into their acyl-CoAs and plays an important role in maintaining PUFA-containing...
Long-chain acyl-CoA synthetase (ACSL) 4 converts polyunsaturated fatty acids (PUFAs) into their acyl-CoAs and plays an important role in maintaining PUFA-containing membrane phospholipids. Here we demonstrated decreases in various kinds of PUFA-containing phospholipid species in ACSL4-deficient murine lung. We then examined the effects of ACSL4 gene deletion on lung injury by treating mice with two pulmonary toxic chemicals: paraquat (PQ) and methotrexate (MTX). The results showed that ACSL4 deficiency attenuated PQ-induced acute lung lesion and decreased mortality. PQ-induced lung inflammation and neutrophil migration were also suppressed in ACSL4-deficient mice. PQ administration increased the levels of phospholipid hydroperoxides in the lung, but ACSL4 gene deletion suppressed their increment. We further found that ACSL4 deficiency attenuated MTX-induced pulmonary fibrosis. These results suggested that ACSL4 gene deletion might confer protection against pulmonary toxic chemical-induced lung injury by reducing PUFA-containing membrane phospholipids, leading to the suppression of lipid peroxidation. Inhibition of ACSL4 may be promising for the prevention and treatment of chemical-induced lung injury.
Topics: Mice; Animals; Lipid Peroxidation; Lung Injury; Xenobiotics; Gene Deletion; Phospholipids; Fatty Acids, Unsaturated; Lung; Ligases
PubMed: 37586249
DOI: 10.1016/j.redox.2023.102850 -
Biomedicines Dec 2023Club cells have a distinct role in the epithelial repair and defense mechanisms of the lung. After exposure to environmental pollutants, during chronic exposure, the... (Review)
Review
Club cells have a distinct role in the epithelial repair and defense mechanisms of the lung. After exposure to environmental pollutants, during chronic exposure, the secretion of club cells secretory protein (CCSP) decreases. Exposure to occupational hazards certainly has a role in a large number of interstitial lung diseases. According to the American Thoracic Society and the European Respiratory Society, around 40% of the all interstitial lung disease is attributed to occupational hazards. Some of them are very well characterized (pneumoconiosis, hypersensitivity pneumonitis), whereas others are consequences of acute exposure (e.g., paraquat) or persistent exposure (e.g., isocyanate). The category of vapors, gases, dusts, and fumes (VGDF) has been proven to produce subclinical modifications. The inflammation and altered repair process resulting from the exposure to occupational respiratory hazards create vicious loops of cooperation between epithelial cells, mesenchymal cells, innate defense mechanisms, and immune cells. The secretions of club cells modulate the communication between macrophages, epithelial cells, and fibroblasts mitigating the inflammation and/or reducing the fibrotic process. In this review, we describe the mechanisms by which club cells contribute to the development of interstitial lung diseases and the potential role for club cells as biomarkers for occupational-related fibrosis.
PubMed: 38255185
DOI: 10.3390/biomedicines12010078 -
Cell Communication and Signaling : CCS Feb 2024Paraquat (PQ) is an irreplaceable insecticide in many countries for the advantage of fast-acting and broad-spectrum. However, PQ was classified as the most prevailing...
Paraquat (PQ) is an irreplaceable insecticide in many countries for the advantage of fast-acting and broad-spectrum. However, PQ was classified as the most prevailing poisoning substance for suicide with no specific antidote. Therefore, it is imperative to develop more effective therapeutic agents for the treatment of PQ poisoning. In the present study, both the RNA-Seq and the application of various cell death inhibitors reflected that ferroptosis exerts a crucial regulatory role in PQ poisoning. Moreover, we found PQ strengthens lipid peroxidation as evidenced by different experimental approaches. Of note, pretreatment of iron chelation agent DFO could ameliorate the ferroptotic cell death and alleviate the ferroptosis-related events. Mechanistically, PQ treatment intensively impaired mitochondrial homeostasis, enhanced phosphorylation of AMPK, accelerated the autophagy flux and triggered the activation of Nuclear receptor coactivator 4-ferritin heavy chain (NCOA4-FTH) axis. Importantly, the activation of autophagy was observed prior to the degradation of ferritin, and inhibition of autophagy could inhibit the accumulation of iron caused by the ferritinophagy process. Genetic and pharmacological inhibition of ferritinophagy could alleviate the lethal oxidative events, and rescue the ferroptotic cell death. Excitingly, in the mouse models of PQ poisoning, both the administration of DFO and adeno-associated virus-mediated FTH overexpression significantly reduced PQ-induced ferroptosis and improved the pathological characteristics of pulmonary fibrosis. In summary, the current work provides an in-depth study on the mechanism of PQ intoxication, describes a framework for the further understanding of ferroptosis in PQ-associated biological processes, and demonstrates modulation of iron metabolism may act as a promising therapeutic agent for the management of PQ toxicity.
Topics: Animals; Humans; Mice; Autophagy; Ferritins; Ferroptosis; Iron; Lung Injury; Nuclear Receptor Coactivators; Paraquat; Transcription Factors
PubMed: 38388414
DOI: 10.1186/s12964-024-01520-1 -
PLoS Pathogens Jul 2023Staphylococcus aureus is an important pathogen that leads to significant disease through multiple routes of infection. We recently published a transposon sequencing...
Staphylococcus aureus is an important pathogen that leads to significant disease through multiple routes of infection. We recently published a transposon sequencing (Tn-seq) screen in a mouse acute pneumonia model and identified a hypothetical gene (SAUSA300_1902, pgl) with similarity to a lactonase of Escherichia coli involved in the pentose phosphate pathway (PPP) that was conditionally essential. Limited studies have investigated the role of the PPP in physiology and pathogenesis of S. aureus. We show here that mutation of pgl significantly impacts ATP levels and respiration. RNA-seq analysis of the pgl mutant and parent strains identified compensatory changes in gene expression for glucose and gluconate as well as reductions in the pyrimidine biosynthesis locus. These differences were also evident through unbiased metabolomics studies and 13C labeling experiments that showed mutation of pgl led to reductions in pyrimidine metabolism including decreases in ribose-5P, UMP and GMP. These nucleotide reductions impacted the amount of extracellular DNA in biofilms and reduced biofilm formation. Mutation also limited the capacity of the strain to resist oxidant damage induced by hydrogen peroxide and paraquat and subsequent intracellular survival inside macrophages. Changes in wall teichoic acid impacted susceptibility to hydrogen peroxide. We demonstrated the importance of these changes on virulence in three different models of infection, covering respiratory, skin and septicemia, demonstrating the need for proper PPP function in all models. This work demonstrates the multifaceted role metabolism can play in multiple aspects of S. aureus pathogenesis.
Topics: Animals; Mice; Staphylococcus aureus; Pentose Phosphate Pathway; Hydrogen Peroxide; Staphylococcal Infections; Virulence; Escherichia coli; Biofilms
PubMed: 37440594
DOI: 10.1371/journal.ppat.1011531 -
BioRxiv : the Preprint Server For... Oct 2023Parkinson's disease (PD) targets some dopamine (DA) neurons more than others. Sex differences offer insights, with females more protected from DA neurodegeneration. The...
Parkinson's disease (PD) targets some dopamine (DA) neurons more than others. Sex differences offer insights, with females more protected from DA neurodegeneration. The mammalian vesicular glutamate transporter VGLUT2 and ortholog dVGLUT have been implicated as modulators of DA neuron resilience. However, the mechanisms by which VGLUT2/dVGLUT protects DA neurons remain unknown. We discovered DA neuron dVGLUT knockdown increased mitochondrial reactive oxygen species in a sexually dimorphic manner in response to depolarization or paraquat-induced stress, males being especially affected. DA neuron dVGLUT also reduced ATP biosynthetic burden during depolarization. RNA sequencing of VGLUT DA neurons in mice and flies identified candidate genes that we functionally screened to further dissect VGLUT-mediated DA neuron resilience across PD models. We discovered transcription factors modulating dVGLUT-dependent DA neuroprotection and identified dj-1β as a regulator of sex-specific DA neuron dVGLUT expression. Overall, VGLUT protects DA neurons from PD-associated degeneration by maintaining mitochondrial health.
PubMed: 37873436
DOI: 10.1101/2023.10.02.560584 -
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 -
Toxicology in Vitro : An International... Dec 2023Paraquat (PQ) can induce pulmonary fibrosis (PF) by modulating epithelial-mesenchymal transition (EMT) of alveolar epithelial cells, but the molecular mechanism is...
BACKGROUND
Paraquat (PQ) can induce pulmonary fibrosis (PF) by modulating epithelial-mesenchymal transition (EMT) of alveolar epithelial cells, but the molecular mechanism is unknown. In this paper, the role of Wnt-inducible signaling protein-1 (WISP1) in PQ-induced EMT was inspected.
METHODS
The morphology, apoptosis, and mortality of A549 cells were observed through a microscope. The mRNA and protein levels of WISP1, E-cadherin, and Vimentin were confirmed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot.
RESULTS
With the increase of PQ concentration, the morphology of A549 cells was apparently changed, cell apoptosis and mortality were enhanced. Besides, the E-cadherin abundance was reduced (p < 0.01), however, WISP1 and Vimentin contents were boosted after PQ treatment (p < 0.01). With the increase of PQ treatment time, the epithelial index of cells first increased and then decreased. The expression of WISP1 gene increased significantly with the increase of PQ treatment time (p < 0.01). Silence of WISP1 abolished the effect of PQ treatment on E-cadherin and Vimentin levels (p < 0.01). Downregulation of WISP1 curbed morphology change and PQ-induced EMT in A549 cells.
CONCLUSION
Knockdown of WISP1 inhibited PQ-induced EMT in A549 cells. This conclusion might provide a new therapeutic target for PQ poisoning treatment.
Topics: Humans; Cadherins; Epithelial-Mesenchymal Transition; Paraquat; Pulmonary Fibrosis; Vimentin; A549 Cells
PubMed: 37689312
DOI: 10.1016/j.tiv.2023.105693 -
Plant Direct Jul 2023The reversible conjugation of small ubiquitin-like modifier (SUMO) to other proteins has pervasive roles in various aspects of plant development and stress defense...
The reversible conjugation of small ubiquitin-like modifier (SUMO) to other proteins has pervasive roles in various aspects of plant development and stress defense through its selective attachment to numerous intracellular substrates. An intriguing aspect of SUMO is that it can be further modified by SUMOylation and ubiquitylation, which isopeptide-link either or both polypeptides to internal lysines within previously bound SUMOs. Although detectable by mass spectrometry, the functions of these secondary modifications remain obscure. Here, we generated transgenic that replaced the two related and essential SUMO isoforms (SUMO1 and SUMO2) with a lysine-null SUMO1 variant (K0) immune to further SUMOylation/ubiquitylation at these residues. Remarkably, homozygous plants developed normally, were not hypersensitive to heat stress, and have nearly unaltered SUMOylation profiles during heat shock. However, subtle changes in tolerance to salt, paraquat, and the DNA-damaging agents bleomycin and methane methylsulfonate were evident, as were increased sensitivities to ABA and the gibberellic acid biosynthesis inhibitor paclobutrazol, suggesting roles for these secondary modifications in stress defense, DNA repair, and hormone signaling. We also generated viable lines expressing a SUMO1(K0) variant specifically designed to help isolate SUMO conjugates and map SUMOylation sites, thus offering a new tool for investigating SUMO .
PubMed: 37465357
DOI: 10.1002/pld3.506 -
Microglia-derived exosomal circZNRF1 alleviates paraquat-induced neuronal cell damage via miR-17-5p.Ecotoxicology and Environmental Safety Sep 2023Paraquat (PQ) is an environmental poison that causes clinical symptoms similar to those of Parkinson's disease (PD) in vitro and in rodents. It can lead to the...
Paraquat (PQ) is an environmental poison that causes clinical symptoms similar to those of Parkinson's disease (PD) in vitro and in rodents. It can lead to the activation of microglia and apoptosis of dopaminergic neurons. However, the exact role and mechanism of microglial activation in PQ-induced neuronal degeneration remain unknown. Here, we isolated the microglia-derived exosomes exposed with 0 and 40 μM PQ, which were subsequently co-incubated with PQ-exposed neuronal cells to simulate intercellular communication. First, we found that exosomes released from microglia caused a change in neuronal cell vitality and reversed PQ-induced neuronal apoptosis. RNA sequencing data showed that these activated microglia-derived exosomes carried large amounts of circZNRF1. Moreover, a bioinformatics method was used to study the underlying mechanism of circZNRF1 in regulating PD, and miR-17-5p was predicted to be its target. Second, an increased Bcl2/Bax ratio could play an anti-apoptotic role. Bcl2 was predicted to be a downstream target of miR-17-5p. Our results showed that circZNRF1 plays an anti-apoptotic role by absorbing miR-17-5p and regulating the binding of Bcl2 after exosomes are internalized by dopaminergic neurons. In conclusion, we demonstrated a new intercellular communication mechanism between microglia and neurons, in which circZNRF1 plays a key role in protecting against PQ-induced neuronal apoptosis through miR-17-5p to regulate the biological process of PD. These findings may offer a novel approach to preventing and treating PD.
Topics: Microglia; Paraquat; Dopaminergic Neurons; Proto-Oncogene Proteins c-bcl-2; MicroRNAs
PubMed: 37591128
DOI: 10.1016/j.ecoenv.2023.115356 -
Frontiers in Public Health 2023In January 2023, a rare event of collective inhalation paraquat poisoning occurred in Shandong, China. To analyze the clinical characteristics of an event of respiratory...
OBJECTIVE
In January 2023, a rare event of collective inhalation paraquat poisoning occurred in Shandong, China. To analyze the clinical characteristics of an event of respiratory tract paraquat poisoning through inhalation.
METHODS
Clinical data from eight patients with paraquat inhalation poisoning were retrospectively analyzed.
RESULTS
The patients were mainly exposed to paraquat via the respiratory tract. The main clinical manifestations were ocular and respiratory irritation. Lung computed tomography (CT) showed that all eight patients had varying degrees of lung injury, mainly manifesting as exudative lesions. Laboratory tests revealed arterial blood gas hypoxemia, abnormal white blood cell count, and increased neutrophil ratio. Sufficient glucocorticoid impact therapy was effective, and all eight patients survived.
CONCLUSION
Eight patients experienced chest tightness, shortness of breath, and varying degrees of lung injury due to inhalation of paraquat through the respiratory tract. The early use of glucocorticoids and other comprehensive treatment measures, active prevention and treatment of lung infections, and protection of organ function have beneficial effects in such cases.
Topics: Humans; Paraquat; Lung Injury; Retrospective Studies; Lung; Dyspnea
PubMed: 38145083
DOI: 10.3389/fpubh.2023.1309708