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Biomedicine & Pharmacotherapy =... Feb 2024Pulmonary fibrosis is the result of dysfunctional repair after lung tissue injury, characterized by fibroblast proliferation and massive extracellular matrix...
Pulmonary fibrosis is the result of dysfunctional repair after lung tissue injury, characterized by fibroblast proliferation and massive extracellular matrix aggregation. Once fibrotic lesions develop, effective treatment is difficult, with few drugs currently available. Here, we identified a short cyclic decapeptide RL-RF10 derived from frog skin secretions as a potential novel lead molecule for the amelioration of pulmonary fibrosis. In vivo experiments indicated that RL-RF10 treatment ameliorated lung histopathological damage and fibrogenesis after paraquat (PQ) induction in a concentration-dependent manner. On day 7, bronchoalveolar lavage fluid assays performed on mice showed that RL-RF10 exerted anti-inflammatory effects by decreasing the expression of inflammation-related factors, including transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α, in lung tissue. In addition, RL-RF10 down-regulated the levels of collagen I, collagen III, and vimentin, while increasing the expression of E-cadherin to inhibit epithelial-mesenchymal transition. Further research demonstrated that the SMAD2/3 signaling pathway, which is strongly linked to TGF-β1, played a critical function in enhancing the pulmonary fibrosis relief achieved by RL-RF10. Both in vivo and in vitro assays showed that RL-RF10 treatment led to a significant reduction in the phosphorylation levels of SMAD2 and SMAD3 following PQ induction. Overall, we investigated the protective effects and underlying mechanisms of the RL-RF10 peptide against pulmonary fibrosis and demonstrated its potential as a novel therapeutic drug candidate for the treatment of pulmonary fibrotic diseases.
Topics: Mice; Animals; Pulmonary Fibrosis; Paraquat; Transforming Growth Factor beta1; Collagen; Lung Injury; Amphibians; Epithelial-Mesenchymal Transition
PubMed: 38244328
DOI: 10.1016/j.biopha.2024.116184 -
Scientific Reports Jan 2024This study aimed to develop and validate a predictive model to determine the risk of in-hospital mortality in patients with acute paraquat poisoning. This retrospective... (Observational Study)
Observational Study
This study aimed to develop and validate a predictive model to determine the risk of in-hospital mortality in patients with acute paraquat poisoning. This retrospective observational cohort study included 724 patients with acute paraquat poisoning whose clinical data were collected within 24 h of admission. The primary outcome was in-hospital mortality. Patients were randomly divided into training and validation cohorts (7/3 ratio). In the training cohort, the least absolute shrinkage and selection operator regression models were used for data dimension reduction and feature selection. Multivariate logistic regression was used to generate a predictive nomogram for in-hospital mortality. The prediction model was assessed for both the training and validation cohorts. In the training cohort, decreased level of consciousness (Glasgow Coma Scale score < 15), neutrophil-to-lymphocyte ratio, alanine aminotransferase, creatinine, carbon dioxide combining power, and paraquat plasma concentrations at admission were identified as independent predictors of in-hospital mortality in patients with acute paraquat poisoning. The calibration curves, decision curve analysis, and clinical impact curves indicated that the model had a good predictive performance. It can be used on admission to the emergency department to predict mortality and facilitate early risk stratification and actionable measures in clinical practice after further external validation.
Topics: Humans; Hospital Mortality; Nomograms; Paraquat; Prognosis; Retrospective Studies
PubMed: 38238454
DOI: 10.1038/s41598-023-50722-z -
EMBO Reports Jan 2024The E. coli Paraquat Inducible (Pqi) Pathway is a putative Gram-negative phospholipid transport system. The pathway comprises three components: an integral inner...
The E. coli Paraquat Inducible (Pqi) Pathway is a putative Gram-negative phospholipid transport system. The pathway comprises three components: an integral inner membrane protein (PqiA), a periplasmic spanning MCE family protein (PqiB) and an outer membrane lipoprotein (PqiC). Interactions between all complex components, including stoichiometry, remain uncharacterised; nevertheless, once assembled into their quaternary complex, the trio of Pqi proteins are anticipated to provide a continuous channel between the inner and outer membranes of diderms. Here, we present X-ray structures of both the native and a truncated, soluble construct of the PqiC lipoprotein, providing insight into its biological assembly, and utilise neutron reflectometry to characterise the nature of the PqiB-PqiC-membrane interaction. Finally, we employ phenotypic complementation assays to probe specific PqiC residues, which imply the interaction between PqiB and PqiC is less intimate than previously anticipated.
Topics: Escherichia coli; Escherichia coli Proteins; Membrane Proteins; Biological Transport; Lipoproteins
PubMed: 38228789
DOI: 10.1038/s44319-023-00014-4 -
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 -
Clinical and Experimental Emergency... Mar 2024
PubMed: 38204158
DOI: 10.15441/ceem.23.068 -
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 -
Heliyon Dec 2023This research examined the bioremediation of pesticides (Carbofuran and Paraquat) contaminated farmyard soil using compost and Nitrogen, Phosphorus, and Potassium (NPK)...
This research examined the bioremediation of pesticides (Carbofuran and Paraquat) contaminated farmyard soil using compost and Nitrogen, Phosphorus, and Potassium (NPK) fertilizer. Microcosms representing each treatment were set-up in triplicates. Biostimulation was done using two concentrations (0.5 % and 1.0 % w/w) of NPK fertilizer and compost, following pesticides application at recommended rates [Carbofuran (1 g/kg) and Paraquat (5 ml/kg)] and four times the recommended rates. Two control soils were set-up; Abiotic control (sterile farmyard soil + pesticide) and Control (farmyard soil without treatment). Monitoring of the dynamics in microbial community abundance, and pesticide residues during the biostimulation period was done weekly for 28 days, using standard enumeration method, and High Performance Liquid Chromatography (HPLC), respectively. At the end of the monitoring period, considerable reduction in pesticide residues across the treatment set-ups was recorded. In Carbofuran-treated soils, there were no complete, but considerable losses in residual pesticide, however, in most of the Paraquat-treated soils, there were complete losses within 21 days. Lower pesticide residues were recorded in set-ups amended with compost than NPK, across both Carbofuran and Paraquat-treated soils. After pesticides application, decreases in microbial counts were recorded at Day 7 across all the treatments, followed by increases from Day 14-21, then decreases at Day 28. Microbial counts were lower in Carbofuran than in Paraquat-treated soils irrespective of nutrient (compost and NPK) amendments. Bacterial and fungal counts were in the magnitude of 10 and 10 CFU/g soil, respectively. Also, increased counts were recorded for Actinomycetes, Nitrifiers, Phosphate solubilizers across all treatments, and were in magnitude of 10-10 CFU/g soil. Soil microorganisms could breakdown and eliminate large concentrations of Carbofuran and Paraquat in compost-amended soils than in NPK-amended soils. This study suggests that bioremediation of pesticides contaminated soils can be achieved and enhanced by stimulating the indigenous microbial community with requisite nutrients (compost).
PubMed: 38144266
DOI: 10.1016/j.heliyon.2023.e23133 -
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 -
Antioxidants (Basel, Switzerland) Dec 2023Chronic oxidative stress impairs the normal functioning of the retinal pigment epithelium (RPE), leading to atrophy of this cell layer in cases of advance age-related...
Chronic oxidative stress impairs the normal functioning of the retinal pigment epithelium (RPE), leading to atrophy of this cell layer in cases of advance age-related macular degeneration (AMD). The purpose of our study was to determine if buspirone, a partial serotonin 1A (5-HT1A) receptor agonist, protected against oxidative stress-induced changes in the RPE. We exposed differentiated human ARPE-19 cells to paraquat to induce oxidative damage in culture, and utilized a mouse model with sodium iodate (NaIO)-induced oxidative injury to evaluate the effect of buspirone. To investigate buspirone's effect on protective gene expression, we performed RT-PCR. Cellular toxicities and junctional abnormalities due to paraquat induction in ARPE-19 cells and buspirone's impact were assessed via WST-1 assays and ZO-1 immunostaining. We used spectral-domain optical coherence tomography (SD-OCT) and ZO-1 immunostaining of RPE/choroid for structural analysis. WST-1 assays showed dose-dependent protection of viability in buspirone-treated ARPE-19 cells in culture and preservation of RPE junctional integrity under oxidative stress conditions. In the NaIO model, daily intraperitoneal injection (i.p.) of buspirone (30 mg/kg) for 12 days improved the survival of photoreceptors compared to those of vehicle-treated eyes. ZO-1-stained RPE flat-mounts revealed the structural preservation of RPE from oxidative damage in buspirone-treated mice, as well as in buspirone-induced , , , , and genes in the RPE/choroid compared to untreated eyes. Since oxidative stress is implicated in the pathogenesis AMD, repurposing buspirone, which is currently approved for the treatment of anxiety, might be useful in treating or preventing dry AMD.
PubMed: 38136248
DOI: 10.3390/antiox12122129 -
Animal Nutrition (Zhongguo Xu Mu Shou... Mar 2024This study aimed to determine the regulatory mechanism of dietary zinc lactate (ZL) supplementation on intestinal oxidative stress damage in a paraquat (PQ)-induced...
This study aimed to determine the regulatory mechanism of dietary zinc lactate (ZL) supplementation on intestinal oxidative stress damage in a paraquat (PQ)-induced piglet model. Twenty-eight piglets (mean body weight 9.51 ± 0.23 kg) weaned at 28 d of age were randomly divided into control, ZL, PQ, and ZL + PQ groups ( = 7 in each group). The ZL-supplemented diet had little effect on growth performance under normal physiological conditions. However, under PQ challenge, ZL supplementation significantly improved average daily gain ( < 0.05) and reduced the frequency of diarrhea. ZL improved intestinal morphology and ultrastructure by significantly increasing the expression level of the jejunal tight junction protein, zonula occludens-1 (ZO-1) ( < 0.05), and intestinal zinc transport and absorption in PQ-induced piglets, which reduced intestinal permeability. ZL supplementation also enhanced the expression of antioxidant and anti-inflammatory factor-related genes and decreased inflammatory cytokine expression and secretion in PQ-induced piglets. Furthermore, ZL treatment significantly inhibited the activation of constitutive androstane receptor (CAR) signaling ( < 0.01) in PQ-induced piglets and altered the structure of the gut microbiota, especially by significantly increasing the abundance of beneficial gut microbes, including , , , , , , and ( < 0.05). These data reveal that pre-administration of ZL to piglets can suppress intestinal oxidative stress by improving antioxidant and anti-inflammatory capacity and regulating the crosstalk between CAR signaling and gut microbiota.
PubMed: 38131030
DOI: 10.1016/j.aninu.2023.10.001