Paraquat Treatment Research Articles

Differential redox sensitivity of tRNA dihydrouridylation.

Various transfer RNA (tRNA) modifications have recently been shown to regulate stress-dependent gene expression by modulating messenger RNA translation. Among these modifications, dihydrouridine stands out for its increase of tRNA structural flexibility. However, whether and how dihydrouridine synthesis reacts to environmental stimuli is largely unknown. In this study, we manipulated the intracellular redox state of Escherichia coli using paraquat, revealing differential sensitivities of the three tRNA-dihydrouridine synthases towards oxidative stress. Using liquid chromatography-mass spectrometryquantification of dihydrouridine in various knockout strains, we validated the use of a specific RNA sequencing method, namely AlkAnilineSeq, for the precise mapping of dihydrouridines throughout E. coli tRNAs. We found DusA showing high activity, followed by DusB and DusC, whose activity was decreased under paraquat treatment. The relative sensitivity is most plausibly explained by a paraquat-dependent drop of NADPH availability. These findings are substantiated by in vitro kinetics, revealing DusA as the most active enzyme, followed by DusB, while DusC showed little activity, likely related to the efficacy of the redox reaction of the flavin coenzyme with NADPH. Overall, our study underscores the intricate interplay between redox dynamics and tRNA modification processes, revealing a new facet of the regulatory mechanisms influencing cellular responses to oxidative stress.

Sudachitin Alleviates Paraquat Instigated Testicular Toxicity in Albino Rats via Regulating Nrf-2/Keap-1, Inflammatory, Steroidogenic, and Histological Profile.

Paraquat (PQ) is a noxious herbicide which adversely affects the vital organs including male reproductive system. Sudachitin (SCN) is a naturally occurring flavonoid that demonstrates a wide range of biological potentials. The current study was designed to investigate the alleviative potential of SCN to avert PQ-induced testicular toxicity in rats. Forty-eight male rats (Rattus norvegicus) were apportioned into four groups including control, PQ (5 mg/kg), PQ + SCN (5 mg/kg + 30 mg/kg), and SCN (30 mg/kg) only treated group. Our findings elucidated that PQ treatment reduced the expression of nuclear factor erythroid 2-related factor 2 (Nrf-2) and its antioxidant genes as well as the activities of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GSR) and glutathione peroxidase (GPx), while elevating the levels of reactive oxygen species (ROS), and malondialdehyde (MDA). Furthermore, PQ intoxication upregulated the expressions of Keap-1 while downregulating the expression of 3-beta hydroxysteroid dehydrogenase (3β-HSD), 17-beta hydroxysteroid dehydrogenase (17β-HSD), and steroidogenic acute regulatory protein (StAR). Moreover, sperm anomalies were increased following the exposure to PQ. Besides, PQ exposure decreased the levels of plasma testosterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH) while increasing the levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), nuclear factor-kappa B (NF-κB), interleukin-1beta (IL-1β), and cyclooxygenase-2 (COX-2). Additionally, PQ treatment escalated the expressions of cysteinyl aspartate-specific proteases-3 (Caspase-3) and Bcl-2-associated X-protein (Bax) while downregulating the expressions of B-cell lymphoma-2 (Bcl-2). Furthermore, PQ exposure disrupted the normal architecture of testicular tissues. However, SCN treatment remarkably protected the testicular tissues via regulating the aforementioned disruptions owing to its antioxidant, anti-inflammatory, and androgenic potential.

Tau phosphorylation suppresses oxidative stress-induced mitophagy via FKBP8 receptor modulation.

Neurodegenerative diseases are often characterized by mitochondrial dysfunction. In Alzheimer's disease, abnormal tau phosphorylation disrupts mitophagy, a quality control process through which damaged organelles are selectively removed from the mitochondrial network. The precise mechanism through which this occurs remains unclear. Previously, we showed that tau which has been mutated at Thr-231 to glutamic acid to mimic an Alzheimer's-relevant phospho-epitope expressed early in disease selectively inhibits oxidative stress-induced mitophagy in C. elegans. Here, we use immortalized mouse hippocampal neuronal cell lines to extend that result into mammalian cells. Specifically, we show that phosphomimetic tau at Ser-396/404 (EC) or Thr-231/Ser-235 (EM) partly inhibits mitophagy induction by paraquat, a potent inducer of mitochondrial oxidative stress. Moreover, a combination of immunologic and biochemical approaches demonstrates that the levels of the mitophagy receptor FKBP8, significantly decrease in response to paraquat in cells expressing EC or EM tau mutants, but not in cells expressing wildtype tau. In contrast, paraquat treatment results in a decrease in the levels of the mitophagy receptors FUNDC1 and BNIP3 in the presence of both wildtype tau and the tau mutants. Interestingly, FKBP8 is normally trafficked to the endoplasmic reticulum during oxidative stress induced mitophagy, and our results support a model where this trafficking is impacted by disease-relevant tau, perhaps through a direct interaction. We provide new insights into the molecular mechanisms underlying tau pathology in Alzheimer's disease and highlight FKBP8 receptor as a potential target for mitigating mitochondrial dysfunction in neurodegenerative diseases.

Unraveling paraquat-induced toxicity on mouse neural stem cells: Dose-response metabolomics insights and identification of sensitive biomarkers for risk assessment

Exposure to pesticide could contribute to neurodevelopmental and neurodegenerative disorders. Notably, research suggests that prenatal or early postnatal exposure to paraquat (PQ), an herbicide, might trigger neurodevelopmental toxicity in neural stem cells (NSCs) via oxidative stress. However, the molecular mechanisms of PQ-induced perturbations in NSCs, particularly at the metabolite level, are not fully understood. Using a dose-response metabolomics approach, we examined metabolic changes in murine NSCs exposed to different PQ doses (0, 10, 20, 40 μM) for 24h. At 20 μM, PQ treatment led to significant metabolic alterations, highlighting unique toxic mechanisms. Metabolic perturbations, mainly affecting amino acid metabolism pathways (e.g., phenylalanine, tyrosine, arginine, tryptophan, and pyrimidine metabolism), were associated with oxidative stress, mitochondrial dysfunction, and cell cycle dysregulation. Dose-response models were used to identify potential biomarkers (e.g., Putrescine, L-arginine, ornithine, L-histidine, N-acetyl-L-phenylalanine, thymidine) reflecting early damage from low-dose PQ exposure. These biomarkers could be used as points of departure (PoD) for characterizing PQ exposure hazard in risk assessment. Our study offers insights into mechanisms and risk assessment related to PQ-induced neurotoxicity in NSCs.

Silybin Alleviated Hepatic Injury by Regulating Redox Balance, Inflammatory Response, and Mitochondrial Function in Weaned Piglets under Paraquat-Induced Oxidative Stress.

Silybin (Si) is the main element of silymarin isolated from the seeds of Silybum marianum L. Gaernt., which has superior antioxidant properties. However, the protective role of Si in maintaining liver health under oxidative stress remains ambiguous. This study aimed to investigate the underlying mechanism of the beneficial effect of dietary Si against hepatic oxidative injury induced by paraquat (PQ) in weaned piglets. A total of 24 piglets were randomly allocated to four treatments with six replicates per treatment and 1 piglet per replicate: the control group; Si group; PQ group; and Si + PQ group. Piglets in the control group and PQ group were given a basal diet, while piglets in the Si and Si + PQ groups were given a Si-supplemented diet. On the 18th day, the pigs in the PQ treatment group received an intraperitoneal injection of PQ, and the others were intraperitoneally injected with the same volume of saline. All piglets were sacrificed on day 21 for plasma and liver sample collection. The results showed that dietary Si supplementation mitigated PQ-induced liver damage, as proven by the reduction in liver pathological changes and plasma activity of alanine transaminase and aspartate transaminase. Si also improved superoxide dismutase and glutathione peroxidase activities and total antioxidant capacity, as well as decreased malondialdehyde and hydrogen peroxide concentration in the liver, which were closely related to the activation of the nuclear factor-erythroid 2-related factor 2 signaling pathway. Meanwhile, Si reduced tumor necrosis factor-α and interleukin-8 production and their transcript levels as well as abrogated the overactivation of nuclear factor-κB induced by PQ. Importantly, Si improved mitochondrial function by maintaining mitochondrial energetics and mitochondrial dynamics, which was indicated by the elevated activity of mitochondrial complexes I and V and adenosine triphosphate content, decreased expression of dynamin 1 protein, and increased expression of mitofusin 2 protein. Moreover, Si inhibited excessive hepatic apoptosis by regulating the B-cell lymphoma-2 (Bcl-2)/Bcl-2-associated-X-protein signaling pathway. Taken together, these results indicated that Si potentially mitigated PQ-induced hepatic oxidative insults by improving antioxidant capacity and mitochondrial function and inhibiting inflammation and cell apoptosis in weaned piglets.

Regulation of NCOA4-mediated iron recycling ameliorates paraquat-induced lung injury by inhibiting ferroptosis

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.Graphical

Enhanced Resistance to Viruses in Nicotiana edwardsonii 'Columbia' Is Dependent on Salicylic Acid, Correlates with High Glutathione Levels, and Extends to Plant-Pathogenic Bacteria and Abiotic Stress.

Our earlier research showed that an interspecific tobacco hybrid (Nicotiana edwardsonii 'Columbia' [NEC]) displays elevated levels of salicylic acid (SA) and enhanced resistance to localized necrotic symptoms (hypersensitive response [HR]) caused by tobacco mosaic virus (TMV) and tobacco necrosis virus (TNV), as compared with another interspecific hybrid (Nicotiana edwardsonii [NE]) derived from the same parents. In the present study, we investigated whether symptomatic resistance in NEC is indeed associated with the inhibition of TMV and TNV and whether SA plays a role in this process. We demonstrated that enhanced viral resistance in NEC is manifested as both milder local necrotic (HR) symptoms and reduced levels of TMV and TNV. The presence of an adequate amount of SA contributes to the enhanced defense response of NEC to TMV and TNV, as the absence of SA resulted in seriously impaired viral resistance. Elevated levels of subcellular tripeptide glutathione (GSH) in NEC plants in response to viral infection suggest that in addition to SA, GSH may also contribute to the elevated viral resistance of NEC. Furthermore, we found that NEC displays an enhanced resistance not only to viral pathogens but also to bacterial infections and abiotic oxidative stress induced by paraquat treatments. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Paraquat disrupts the blood-brain barrier by increasing IL-6 expression and oxidative stress through the activation of PI3K/AKT signaling pathway.

Paraquat (PQ) is a frequently used herbicide with neurotoxic effects after acute or chronic exposure. Although in vitro evidence supports the PQ toxicity to dopamine cells, its in vivo effects (especially the chronic exposure) remain ambiguous. In this study, we investigated the effect of chronic PQ exposure on the blood-brain barrier (BBB) damage and the underlying mechanisms. Adult male Sprague Dawley rats and primary human brain microvascular endothelial (PHBME) cells were exposed to PQ as the animal and cell models. Evans Blue staining and hematoxylin & eosin staining were conducted to examine the BBB and brain tissue damages. The inflammatory cytokines were quantified via enzyme linked immunosorbent assay. The changes of PI3K/AKT signaling pathway were detected by western blot. PQ exposure can cause significant pathological lesions in the brain tissues and the BBB. IL-6 and reactive oxygen species levels were found to be significantly upregulated after PQ exposure in both the animal and cell models. PQ treatment could arrest the cell proliferation and migration in PHBME cells. PQ treatment promoted the phosphorylation of PI3K and AKT, and the application of PI3K inhibitor could attenuate PQ-induced IL-6 production, oxidative stress, BBB disruption, and brain tissue damage. Our study demonstrated that chronic PQ exposure could impair the BBB function and induce brain tissue damage. The overactivation of the PI3K/AKT pathway, consequent upregulation of IL-6 production, and increased oxidative stress appear to mediate the inflammatory damage resulting from PQ exposure.

Ameliorative potential of sinensetin against paraquat induced renal damage by regulating oxidative, inflammatory, apoptotic and histopathological profile in male albino rats

Background: Paraquat (PQ) is an extremely lethal, water-soluble and non-selective herbicide that is used globally due to its low cost and high efficacy. It exerts strong toxic effects on humans as its exposure leads to free radicals’ production. Sinensetin (SNS) is a natural flavonoid with strong anti-cancer, anti-inflammatory and anti-oxidant potentials. Objective: The present study was planned to ascertain the attenuative effect of SNS against PQ induced renal damage in rats. Methods: Forty eight rats were distributed into four groups: control group, PQ-administered group (5 mg/kg), PQ + SNS co-administered group (5 mg/kg and 20 mg/kg) and SNS administered group (20 mg/kg). Results: PQ administration considerably decreased the activities of anti-oxidant enzymes i.e., catalase (CAT), glutathione reductase (GSR), superoxide dismutase (SOD), glutathione peroxide (GPx), glutathione-S-transferase (GST) activities and glutathione (GSH) contents, while reactive oxygen species (ROS) and malondialdehyde (MDA) contents were upsurged. PQ treatment markedly augmented the levels of creatinine, urobilinogen, urea, KIM-1 and NGAL, while significantly decreased albumin protein as well as creatinine clearance. Moreover, the findings of our experiment revealed that PQ notably escalated inflammatory indices i.e., interleukin-1β (IL-1β), nuclear factor kappa-B (NF-κB), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) level and cyclooxygenase-2 (COX-2) activity. Furthermore, PQ intoxication significantly increased Bax, Caspase-3, Caspase-9 level and lowered Bcl-2 level as well as induced histopathological anomalies in kidneys. However, SNS + PQ co-treatment efficiently averted all the PQ-induced renal damages in the rats. Conclusion: The current study indicates that SNS can be used to treat PQ-instigated renal toxicity due to its anti-oxidant, anti-inflammatory and anti-apoptotic properties.

Therapeutic potential of kaempferide against paraquat instigated cardiac toxicity in rats

Paraquat (PQ) is an effective herbicide however, due to its adverse effects on different organs including heart, it is considered as highly toxic to human beings. Kaempferide (KMF) is a plant-based flavonoid with conspicuous pharmacological properties. This experiment was executed to evaluate the palliative actions of KMF on PQ prompted cardiac toxicity in rats. Twenty-four rats were apportioned into 4 equal groups which were designated as control, toxicant (PQ treated), Co-treated (PQ + KMF) and KMF group. After 30 days of treatment, PQ intoxication resulted in a remarkable reduction in antioxidant enzymes activities which include, glutathione reductase (GSH), glutathione S-transferase (GST), catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), and glutathione disulfide reductase (GSR), whereas an elevation was observed in reactive oxygen species (ROS), & malondialdehyde (MDA) as well as hydrogen peroxide (H2O2) level. Furthermore, concentrations of cardiac injury markers, creatinine phosphokinase (CPK), creatine kinase-myoglobin binding (CK-MB), & lactate dehydrogenase (LDH), as well as troponin I were increased in response to PQ treatment. Moreover, inflammatory cytokines such as tumour necrosis factor alpha (TNF-α), nuclear factor-kappa B (NF-κB), and interleukin-6 (IL-6), interleukin-1 beta (lL-1β), and cyclooxygenase-2 (COX-2) levels were augmented in PQ intoxicated group. PQ exposure reduced the gene expression of cardiac anti-apoptotic markers (Bcl-2), but the gene expression of apoptotic marker (caspase-9, caspase-3 and Bax) was increased. Histopathological damages were also observed in toxicant (PQ) exposed group. However, the administration of KMF significantly palliated PQ induced aforementioned disruptions. In the light of these findings, it is concluded that KMF is a promising bioactive compound that may be used as a curative agent against PQ instigated cardiac damage due to its marvelous antioxidant, anti-apoptotic, anti-inflammatory as well as cardioprotective potential.

Research progress of combination therapy of blood purification in the treatment of paraquat poisoning

Paraquat is a kind of herbicide effective in weeding, characterized by low cost and environmentally friendly property, which is widely used in agricultural weeding. However, the high toxicity of paraquat can cause damage to the lungs, liver, kidney, and other organs after oral intake. Worse still the patient will develop pulmonary fibrosis and will die of respiratory failure. At present, there is no specific detoxification drug for patients poisoned by paraquat. Based on the current therapeutic schedule, blood purification is considered to be the most effective method for the removal of paraquat-related toxins. However, there is a lot of controversy over the combined method. This paper expounds on the poisoning mechanism of paraquat and the advantages and disadvantages of different blood purification methods, aiming to find a specific scheme that can be applied to the clinic and improve the organ function and prognosis of patients.

Efficacy of combined use of acetylcysteine and methylprednisolone in the treatment of paraquat poisoning

Purpose: To investigate the clinical impact of combined application of acetylcysteine and methylprednisolone in treating paraquat poisoning (PQP).Methods: The clinical data of 92 PQP patients who received treatment in our hospital for 1 year were analyzed. The patients were equally divided into control group (CG) and study group (SG), based on treatment plans. All patients underwent routine acute-phase treatment, while SG was additionally treated with acetylcysteine in combination with methylprednisolone. After treatment, the renal function, pulmonary fibrosis indices and inflammatory factor levels of both groups were determined.Results: During the 1 - 4 weeks of treatment, there was no statistical difference in the survival rates of patients at various time periods (p > 0.05). After treatment, there were markedly lower levels of blood urea nitrogen (BUN) and serum creatinine (SCr) in SG than in CG. There was lower incidence of pulmonary fibrosis in SG than in CG, although the difference was not significant. Patients in SG had lower HRCT scores and levels of C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) than those in CG (p < 0.05).Conclusion: Acetylcysteine in combination with methylprednisolone significantly reduces the degree of pulmonary fibrosis and improves renal function and inflammatory levels. It has a positive implication for early treatment of patients, especially for the prognosis of patients with mild-to-moderate poisoning. Therefore, the combined therapy has potential for clinical application.

Study on Antidotal Therapy of Vitamins in Paraquat Induced Dyslipidemia in Rats

Paraquat (PQ) is a toxic chemical substance used in farming for weed management. It is an herbicide with harmful effect when exposed to animals. This study aimed at assessing the effect of vitamin E and C on fasting lipid profile in paraquat induced toxicity in rats. The experimental study consisted of 180 rats divided equally into 4 groups (A, B, C and D) with each group having 3 subgroups of 15 rats (0, VE and VEC). A group served as the control group while B, C, D were test groups. B0, C0 and D0 were treated with 0.02g, 0.04g and 0.06g of paraquat respectively twice in two weeks for 3 months. A0 had no treatment. BVE, CVE and DVE were similarly treated in increasing doses of paraquat and in addition were treated with 500mg of vitamin E once every week for 3 months. AVE had only vitamin E treatment. BVEC, CVEC and DVEC were similarly treated in increasing doses of paraquat and in addition were treated with both 500mg of vitamin E and 2000mg/dl of vitamin C once every week for 3 months. AVEC had only vitamin E and vitamin C treatments. All treatments were done orally. B0, C0 and D0 subgroups were sacrificed and sample collected via cardiac puncture for fasting lipid profile (FLP) after 3 months of paraquat treatment. A0 was also sacrificed too alongside. Other subgroups; AVE, AVEC, BVE, BVEC, CVE, CVEC, DVE and DVEC were sacrificed and sample analyzed for FLP on monthly basis for 3 months. The results showed that paraquat caused a significant drop in FLP levels from the second month after paraquat treatment and this was ameliorated by the treatment of vitamin E and C treatment. This study has therefore demonstrated that vitamins could restore lipid disorder initiated by paraquat poisoning in rats.

A neuroprotective dose of trehalose is harmless to metabolic organs: comprehensive histopathological analysis of liver, pancreas, and kidney.

Trehalose is a non-reducing disaccharide synthesized by lower organisms. It has recently received special attention because of its neuroprotective properties by stimulating autophagy in Parkinson's disease (PD) models. Therefore, evaluating whether trehalose affects metabolic organs is vital to determine its neurotherapeutic safety. We validated the trehalose neuroprotective dosage in a PD model induced with intraperitoneal paraquat administration twice weekly for 7weeks. One week before paraquat administration, mice were treated with trehalose in the drinking water and continued along with paraquat treatment. Histological and morphometrical analyses were conducted on the organs involved in trehalose metabolism, including the liver, pancreas, and kidney. Paraquat-induced dopaminergic neuronal loss was significantly decreased by trehalose. After trehalose treatment, the liver morphology, the mononucleated/binucleated hepatocytes percentage, and sinusoidal diameter remained unchanged in each liver lobes. Endocrine and exocrine pancreas's histology was not affected, nor was any fibrotic process observed. The islet of Langerhans's structure was preserved when analyzing the area, the largest and smallest diameter, and circularity. Renal morphology remained undamaged, and no changes were identified within the glomerular basement membrane. The renal corpuscle structure did not suffer alterations in the Bowman's space, area, diameter, circularity, perimeter, and cellularity. Besides, the renal tubular structures's luminal area and internal and external diameter were preserved. Our study demonstrates that systemic trehalose administration preserved the typical histological architecture of the organs involved in its metabolism, supporting its safety as a potential neuroprotective agent.

Paraquat is toxic to the soil-dwelling arthropod, Folsomia candida (Collembola: Isotomidae), and has potential effects on its Wolbachia endosymbiont

The springtail, Folsomia candida, is a soil arthropod commonly used to evaluate environmental toxins. Conflicting data on the toxicity of the herbicide paraquat prompted re-evaluation of its effects on F. candida survival and reproduction. Paraquat has an LC50 of about 80 μM when tested in the absence of charcoal; charcoal, often used in test arenas to facilitate visualization of the white Collembola, has a protective effect. Survivors of paraquat treatment fail to resume molting and oviposition, suggesting an irreversible effect on the Wolbachia symbiont that restores diploidy during parthenogenetic reproduction of this species.

Integrated physiological and metabolomic analysis reveals new insights into toxicity pathways of paraquat to Microcystis aeruginosa

Chemical pollutants, such as herbicides, released into the aquatic environment adversely affect the phytoplankton community structure. While majority of herbicides are specifically designed to target photosynthetic processes, they also can be toxic to phytoplankton; however, despite the photosynthetic toxicity, some herbicides can target multiple physiological processes. Therefore, a full picture of toxicity pathway of herbicide to phytoplankton is necessary. In the present study, the cyanobacterium Microcystis aeruginosa was exposed to two levels (17 μg L−1 (EC10) and 65 μg L−1 (EC50)) of paraquat for 72 h. The physiological and metabolic responses were analyzed to elucidate the toxicity pathway and establish the adverse outcome pathway of paraquat to M. aeruginosa. The results revealed that enhanced glycolysis (upregulation of pyruvic acid level) and tricarboxylic acid cycle (upregulation of the levels of malic acid, isocitric acid and citric acid) exposed to EC10 level of paraquat, which probably acted as a temporary strategy to maintain a healthy energy status in M. aeruginosa cells. Meanwhile, the expressions of glutathione and benzoic acid were enhanced to scavenge the excessive reactive oxygen species (ROS). Additionally, the accumulation of pigments (chlorophyll a and carotenoid) might play a supplementary role in the acclimation to EC10 level paraquat treatment. In cells exposed to paraquat by EC50 level, the levels of SOD, CAT, glutathione and benzoic acid increased significantly; however, the ROS exceeded the tolerance level of antioxidant system in M. aeruginosa. The adverse effects were revealed by inhibition of chlorophyll a fluorescence, the decreases in several carbohydrates (e.g., glucose 1-phosphate, fructose and galactose) and total protein content. Consequently, paraquat-induced oxidative stress caused the growth inhibition of M. aeruginosa. These findings provide new insights into the mode of action of paraquat in M. aeruginosa.

Melatonin ameliorates acute lung injury caused by paraquat poisoning by promoting PINK1 and BNIP3 expression

Paraquat (PQ) poisoning can result in multiple organ dysfunction syndrome, mainly manifesting as acute lung injury and acute respiratory distress syndrome. No specific cure exists for PQ poisoning. However, by scavenging mitochondrial DNA (mtDNA), the damage-associated molecular pattern during PQ poisoning, mitophagy can ameliorate the downstream inflammatory pathways activated by mtDNA. Melatonin (MEL), however, can promote the expression of PINK1 and BNIP3, which are key proteins involved in mitophagy. In this study, we first explored whether MT could reduce PQ-induced acute lung injury by affecting mitophagy in animal models, and then, we studied the specific mechanism associated with this process through in vitro experiments. We also evaluated MEL intervention in the PQ group, while inhibiting the expression of PINK1 and BNIP3, to further determine whether the protective effects of MEL are associated with its effect on mitophagy. We found that when the expression of PINK1 and BNIP3 was inhibited, MEL intervention could not reduce mtDNA leakage and the release of inflammatory factors caused by PQ exposure, suggesting that the protective effect of MEL was blocked. These results suggest that by promoting the expression of PINK1 and BNIP3 and activating mitophagy, MEL can reduce mtDNA/TLR9-mediated acute lung injury during PQ poisoning. The results of this study could provide guidance for the clinical treatment of PQ poisoning to reduce associated mortality.

Spectroelectrochemical testing of a proposed mechanism for a redox-based therapeutic intervention: Ascorbate treatment of severe paraquat poisoning

The toxicity of paraquat is believed to involve a redox-cycling mechanism that can disrupt cellular redox homeostasis and, also, generate damaging free radicals. It has been suggested that for cases of severe paraquat poisoning the administration of ascorbate (i.e., vitamin C) can confer benefit by quenching the paraquat free radical (PQ+·). Here, we used an electrochemical approach that abstracts-away many of the (bio)chemical complexities and isolates the redox-interactions between paraquat and ascorbate. Specifically, we used a series of experiments that coupled electrochemical measurements of electron flow with optical measurements of paraquat's redox-state switching. Our results demonstrate that the reduced absorbate cannot quench the PQ+·-radical because they are both reductants. However, oxidation of ascorbate does allow PQ+·-radical scavenging. More broadly, we believe this study demonstrates the potential for developing electrochemical approaches to complement existing experimental methods in redox biology.

PurA sensitizes cells to toxicity induced by oxidative stress

Abstract Objectives PurA is an evolutionary conserved protein that is known to bind to single stranded DNA or RNA and regulate both transcription and translation. PurA has been implicated in many neurological and neurodevelopmental deficits, but its role in response to cellular stress has not yet been clarified. In this study, we have studied the cells’ stress response in the presence and absence of PurA expression. Methods Oxidative stress was induced in MEF cells obtained from PURA WT and K/O mice by paraquat treatments. The cellular response to stress was determined and compared by viability assays, immunocytochemistry and biochemical analyses. Results Interestingly, paraquat treated PurA expressing MEF cells showed higher sensitivity and less cellular viability than those with no PurA expression. Moreover, western blot analysis revealed increase in the expression of the apoptotic marker cleaved caspase 3 and autophagy marker LC3-II in PurA WT MEF cells compared to the PurA K/O MEF cells under oxidative stress induction. Conclusions Our observations indicate that PurA may play a key role in regulating cellular toxicity induced by oxidative stress and emphasize its importance for cell-fate determination under cytotoxic stress conditions.

Sexual dysfunction precedes motor defects, dopaminergic neuronal degeneration, and impaired dopamine metabolism: Insights from Drosophila model of Parkinson's disease.

Sexual dysfunction (SD) is one of the most common non-motor symptoms of Parkinson's disease (PD) and remains the most neglected, under-reported, and under-recognized aspect of PD. Studies have shown that Dopamine (DA) in the hypothalamus plays a role in regulating sexual behavior. But the detailed mechanism of SD in PD is not known. Drosophila melanogaster shares several genes and signaling pathways with humans which makes it an ideal model for the study of a neurodegenerative disorder such as PD. Courtship behavior of Drosophila is one such behavior that is closely related to human sexual behavior and so plays an important role in understanding sexual behavior in diseased conditions as well. In the present study, a sporadic SD model of PD using Drosophila was developed and SD phenotype was observed based on abnormalities in courtship behavior markers. The Drosophila SD model was developed in such a way that at the window of neurotoxin paraquat (PQ) treatment [PQ is considered a crucial risk factor for PD due to its structural similarity with 1-methyl-4-phenyl pyridinium (MPP+), the active form of PD-inducing agent, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)], it does not exhibit mobility defects but shows SD. The whole brain tyrosine hydroxylase immunostaining showed no observable dopaminergic (DAergic) degeneration (number of DA neurons and fluorescence intensity of fluorescently labeled secondary antibodies that target anti-TH primary antibody) of the SD model. Similarly, there was no significant depletion of brain DA and its metabolite levels (HVA and DOPAC) as determined using HPLC-ECD (High-Performance Liquid Chromatography using Electrochemical Detector). The present study illustrates that the traits associated with courtship and sexual activity provide sensitive markers at the earlier stage of PD onset. This PQ-induced SD fly model throws an opportunity to decipher the molecular basis of SD under PD conditions and to screen nutraceuticals/potential therapeutic molecules to rescue SD phenotype and further to DAergic neuroprotection.