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BMC Public Health Mar 2024
PubMed: 38532392
DOI: 10.1186/s12889-024-18406-z -
BioRxiv : the Preprint Server For... Mar 2024Oxidative stress is a key factor causing mitochondrial dysfunction and retinal ganglion cell (RGC) death in glaucomatous neurodegeneration. The cyclic adenosine...
Oxidative stress is a key factor causing mitochondrial dysfunction and retinal ganglion cell (RGC) death in glaucomatous neurodegeneration. The cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway is involved in mitochondrial protection, promoting RGC survival. Soluble adenylyl cyclase (sAC) is one of the key regulators of the cAMP/PKA signaling pathway. However, the precise molecular mechanisms underlying the sAC-mediated signaling pathway and mitochondrial protection in RGCs that counter oxidative stress are not well characterized. Here, we demonstrate that sAC plays a critical role in protecting RGC mitochondria from oxidative stress. Using mouse models of oxidative stress, we found that activating sAC protected RGCs, blocked AMP-activated protein kinase activation, inhibited glial activation, and improved visual function. Moreover, we found that this is the result of preserving mitochondrial dynamics (fusion and fission), promoting mitochondrial bioenergetics and biogenesis, and preventing metabolic stress and apoptotic cell death in a paraquat oxidative stress model. Notably, sAC activation ameliorated mitochondrial dysfunction in RGCs by enhancing mitochondrial biogenesis, preserving mitochondrial structure, and increasing ATP production in oxidatively stressed RGCs. These findings suggest that activating sAC enhances the mitochondrial structure and function in RGCs to counter oxidative stress, consequently promoting RGC protection. We propose that modulation of the sAC-mediated signaling pathway has therapeutic potential acting on RGC mitochondria for treating glaucoma and other retinal diseases.
PubMed: 38496531
DOI: 10.1101/2024.03.04.583371 -
BMC Public Health Mar 2024The objective of this study was to detect the urinary levels of chlorpyrifos, paraquat, and cyproconazole in residents living in Fuyang City and to analyze the...
BACKGROUND
The objective of this study was to detect the urinary levels of chlorpyrifos, paraquat, and cyproconazole in residents living in Fuyang City and to analyze the correlation between these urinary pesticides levels and the severity of fatty liver disease (FLD).
METHODS
All participants' fat fraction (FF) values were recorded by MRI (Magnetic resonance imaging). First-morning urine samples were collected from 53 participants from Fuyang Peoples'Hospital. The levels of three urinary pesticides were measured using β-glucuronidase hydrolysis followed by a. The results were analyzed by using Pearson correlation analysis and binary logistic regression analysis to reveal the correlation between three urinary pesticides and the severity of fatty liver.
RESULTS
53 individuals were divided into 3 groups based on the results from MRI, with 20 cases in the normal control group, 16 cases in the mild fatty liver group, and 17 cases in the moderate and severe fatty liver group. Urinary chlorpyrifos level was increased along with the increase of the severity of fatty liver. Urinary paraquat level was significantly higher both in the low-grade fatty liver group and moderate & serve grade fatty liver group compared with the control group. No significant differences in urinary cyproconazole levels were observed among the three groups. Furthermore, urinary chlorpyrifos and paraquat levels were positively correlated with FF value. And chlorpyrifos was the risk factor that may be involved in the development of FLD and Receiver Operating Characteristic curve (ROC curve) analysis showed that chlorpyrifos and paraquat may serve as potential predictors of FLD.
CONCLUSION
The present findings indicate urinary chlorpyrifos and paraquat were positively correlated with the severity of fatty liver. Moreover, urinary chlorpyrifos and paraquat have the potential to be considered as the predictors for development of FLD. Thus, this study may provide a new perspective from the environmental factors for the diagnosis, prevention, and treatment of FLD.
Topics: Humans; Chlorpyrifos; Paraquat; Pesticides; Non-alcoholic Fatty Liver Disease; Magnetic Resonance Imaging; Triazoles
PubMed: 38486191
DOI: 10.1186/s12889-024-18129-1 -
Journal of Research in Pharmacy Practice 2023This study aimed to assess the severity of poisoning, various scoring systems, including Sequential Organ Failure Assessment (SOFA) score, acute physiology and chronic...
Comparing Sequential Organ Failure Assessment Score, Acute Physiology and Chronic Health Evaluation II, Modified Acute Physiology and Chronic Health Evaluation II, Simplified Acute Physiology Score II and Poisoning Severity Score for Outcome Prediction of Pesticide Poisoned Patients Admitted to the...
OBJECTIVE
This study aimed to assess the severity of poisoning, various scoring systems, including Sequential Organ Failure Assessment (SOFA) score, acute physiology and chronic health evaluation II (APACHE II), Simplified Acute Physiology Score (SAPS II), Modified APACHE II, and poisoning severity score (PSS) were used. In this study, we compared the predictive value of these scoring systems on the outcome of pesticide-poisoned patients.
METHODS
This is a cross-sectional study of pesticide-poisoned patients (140 patients) who were admitted to the intensive care unit (ICU) of Khorshid Hospital, Isfahan, Iran, between January 2015 and 2019. The area under the receiver operating characteristic (AUC) curve and the predictive value of scoring systems were compared.
FINDINGS
Poisoning was higher in the male population (72.8%). The causes of poisoning were paraquat, (38.6%), aluminum phosphide, (32.1%), and organophosphate, (29.3%). The mean age of the patients was 33.9 years. Most patients (79.3%) attempted suicide. The mortality rate was 46.43%. The mean of "SOFA score," "APACHE II," "SAPS II," "Modified APACHE II," and "PSS" was 5.9; 15.7; 30.02; 15.8; and 1.9, respectively. There was a significant difference in the mean of all scoring systems for outcome prediction. Among all scoring systems, the SAPS II score with the cutoff point (16.5) had the best criteria for outcome prediction (AUC (0.831 ± 0.037), sensitivity (83.1%, 95% confidence interval [CI]: [71.7-91.2]), specificity (75.7%, 95% CI: [64.3-84.9]), positive predictive values (75.0%, 95% CI: [66.4-82.0]), negative predictive values (83.6%, 95% CI: [74.5-89.9]).
CONCLUSION
The SAPS II scoring system may be a suitable indicator for outcome predictions in pesticide-poisoned patients in the ICU.
PubMed: 38463184
DOI: 10.4103/jrpp.jrpp_43_23 -
Neurochemical Research Jul 2024Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and the most common movement disorder. Although PD etiology is not fully understood,...
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and the most common movement disorder. Although PD etiology is not fully understood, alpha (α)-synuclein is a key protein involved in PD pathology. MicroRNAs (miRNA), small gene regulatory RNAs that control gene expression, have been identified as biomarkers and potential therapeutic targets for brain diseases, including PD. In particular, miR-124 is downregulated in the plasma and brain samples of PD patients. Recently we showed that the brain delivery of miR-124 counteracts 6-hydroxydopamine-induced motor deficits. However, its role in α-synuclein pathology has never been addressed. Here we used paraquat (PQ)-induced rat PD model to evaluate the role of miR-124-3p in α-synuclein accumulation and dopaminergic neuroprotection. Our results showed that an intranigral administration of miR-124-3p reduced the expression and aggregation of α-synuclein in the substantia nigra (SN) of rats exposed to PQ. NADPH oxidases (NOX), responsible for reactive oxygen species generation, have been considered major players in the development of α-synuclein pathology. Accordingly, miR-124-3p decreased protein expression levels of NOX1 and its activator, small GTPase Rac1, in the SN of PQ-lesioned rats. Moreover, miR-124-3p was able to counteract the reduced levels of pituitary homeobox 3 (PITX3), a protein required for the dopaminergic phenotype, induced by PQ in the SN. This is the first study showing that miR-124-3p decreases PQ-induced α-synuclein levels and the associated NOX1/Rac1 signaling pathway, and impacts PITX3 protein levels, supporting the potential of miR-124-3p as a disease-modifying agent for PD and related α-synucleinopathies.
Topics: Animals; MicroRNAs; alpha-Synuclein; Paraquat; Male; Rats; Rats, Wistar; Parkinson Disease; Substantia Nigra; Disease Models, Animal; Parkinson Disease, Secondary; Rats, Sprague-Dawley
PubMed: 38451434
DOI: 10.1007/s11064-024-04130-y -
Ecotoxicology and Environmental Safety Mar 2024Parkinson's disease (PD) is among the most prevalent neurodegenerative diseases, and approximately one third of patients with PD are estimated to have depression....
Parkinson's disease (PD) is among the most prevalent neurodegenerative diseases, and approximately one third of patients with PD are estimated to have depression. Paraquat (PQ) exposure is an important environmental risk factor for PD. In this study, we established a mouse model of PQ-induced PD with depression to comprehensively investigate cellular heterogeneity and the mechanisms underlying the progression of depression in the context of PD. We utilized single-cell RNA-seq (scRNA-seq) to acquire the transcriptomic atlas of individual cells from model mice and characterize the gene expression profiles in each differentially expressed cell type. We identified a specific glutamatergic neuron cluster responsible for the development of heterogeneous depression-associated changes and established a comprehensive gene expression atlas. Furthermore, functional enrichment and cell trajectory analyses revealed that the mechanisms underlying the progression of PD with depression were associated with specific glutamatergic neurons. Together, our findings provide a valuable resource for deciphering the cellular heterogeneity of PD with depression. The suggested connection between intrinsic transcriptional states of neurons and the progression of depression can provide insight into potential biomarkers and specific targets for anti-depression treatment in patients with PD. SYNOPSIS: Our results obtained using model mice confirm the core effects of PQ exposure on glutamatergic neurons and their potential role in the development of PD with depression.
Topics: Humans; Animals; Mice; Paraquat; Parkinson Disease; Depression; Gene Expression Profiling; RNA
PubMed: 38447518
DOI: 10.1016/j.ecoenv.2024.116169 -
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 -
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 -
Light, Science & Applications Feb 2024Raman spectroscopy has tremendous potential for material analysis with its molecular fingerprinting capability in many branches of science and technology. It is also an...
Raman spectroscopy has tremendous potential for material analysis with its molecular fingerprinting capability in many branches of science and technology. It is also an emerging omics technique for metabolic profiling to shape precision medicine. However, precisely attributing vibration peaks coupled with specific environmental, instrumental, and specimen noise is problematic. Intelligent Raman spectral preprocessing to remove statistical bias noise and sample-related errors should provide a powerful tool for valuable information extraction. Here, we propose a novel Raman spectral preprocessing scheme based on self-supervised learning (RSPSSL) with high capacity and spectral fidelity. It can preprocess arbitrary Raman spectra without further training at a speed of ~1 900 spectra per second without human interference. The experimental data preprocessing trial demonstrated its excellent capacity and signal fidelity with an 88% reduction in root mean square error and a 60% reduction in infinite norm ([Formula: see text]) compared to established techniques. With this advantage, it remarkably enhanced various biomedical applications with a 400% accuracy elevation (ΔAUC) in cancer diagnosis, an average 38% (few-shot) and 242% accuracy improvement in paraquat concentration prediction, and unsealed the chemical resolution of biomedical hyperspectral images, especially in the spectral fingerprint region. It precisely preprocessed various Raman spectra from different spectroscopy devices, laboratories, and diverse applications. This scheme will enable biomedical mechanism screening with the label-free volumetric molecular imaging tool on organism and disease metabolomics profiling with a scenario of high throughput, cross-device, various analyte complexity, and diverse applications.
PubMed: 38374161
DOI: 10.1038/s41377-024-01394-5 -
Heliyon Feb 2024Paraquat (PQ) is a herbicide that is used globally in the agriculture sector to eradicate unwanted weeds, however it also induces significant damages in various organs...
BACKGROUND
Paraquat (PQ) is a herbicide that is used globally in the agriculture sector to eradicate unwanted weeds, however it also induces significant damages in various organs of the body such as testes. Tectochrysin (TEC) is an important flavonoid that shows versatile therapeutic potentials. Currently, there is no established antidote to cure PQ-induced testicular toxicity.
OBJECTIVE
The present study was conducted to evaluate the ameliorative effects of TEC against PQ prompted testicular damage.
METHODS
Sprague-Dawley rats (n = 48) were used to conduct the trial. Rats were allocated in to 4 groups i.e., Control, PQ administrated group (5 mgkg), PQ + TEC co-administrated group (5 mgkg + 2.5 mgkg) and TEC only administrated group (2.5 mgkg). The trial was conducted for 8 weeks. The activity of anti-oxidants and the levels of MDA and ROS were determined by spectrophotometric method. Steroidogenic enzymes as well as apoptotic markers expressions were evaluated by qRT-PCR. The level of hormones and inflammatory indices was quantified by enzyme-linked immunosorbent assay.
RESULTS
PQ exposure markedly (P < 0.05) disturbed the biochemical, spermatogenic and histological profile in the rats. Nevertheless, TEC treatment considerably (P < 0.05) increased CAT, GPx GSR and SOD activity, besides decreasing MDA and ROS contents. TEC administration also increased sperm viability, count and motility. 17β-HSD, 3β-HSD, StAR and Bcl-2 expressions were also increased following TEC administration. The supplementation of TEC substantially (P < 0.05) decreased Bax, Caspase-3 expression and the levels of inflammatory markers i.e., interleukin-1β (IL-1β), interleukin-6 (IL-6), nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2) activity. Additionally, the levels of plasma testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were increased following TEC supplementation. Furthermore, TEC supplementation considerably decreased sperm structural abnormalities and histomorphological damages of the testes. The mitigative role of TEC might be due to its anti-inflammatory, anti-apoptotic, androgenic and anti-oxidant potentials.
CONCLUSION
Taken together, it is concluded that TEC can be used as a potential candidate to treat testicular toxicity.
PubMed: 38356568
DOI: 10.1016/j.heliyon.2024.e25337