RARE DISEASE
Paraquat poisoning
Paraquat poisoning
Paraquat poisoning
Drug discovery
0
drugs
With orphan designations
Overview
Paraquat poisoning is a life-threatening condition caused by ingestion, inhalation, or dermal exposure to this highly toxic herbicide. It induces rapid oxidative stress, leading to multi-organ failure, with pulmonary fibrosis being the hallmark of delayed toxicity (2–6 weeks post-exposure). Diagnosis relies on urine dithionite testing and plasma paraquat quantification. No antidote exists, and management prioritizes early decontamination (activated charcoal/Fuller's earth), supportive care, and experimental immunosuppressive therapies. Mortality exceeds 50% even with moderate ingestion due to irreversible lung damage [1][2][6][11].
Population
Predominantly affects agricultural workers (occupational exposure) and individuals in LMICs, where paraquat remains accessible despite bans [2][4][19].
Intentional self-poisoning accounts for 84% of cases; accidental ingestion occurs in children due to improper storage in beverage containers [2][4][15].
Adults (median age: 31 years) show higher mortality (65%) compared to children (22%) [2][11].
Burden
Case fatality: 46–90%, with survivors often developing chronic pulmonary fibrosis or renal dysfunction [6][9][19].
High healthcare costs from prolonged ICU stays, repeated blood purification, and long-term respiratory support [8][15].
Restricted in 58+ countries, but persists as a public health crisis in regions with lax regulation and pesticide storage practices [4][12][19].
Therapies
Immediate decontamination: Activated charcoal/Fuller's earth within 2–4 hours [1][6][16].
Hemoperfusion/hemodialysis for toxin removal if initiated ≤4 hours post-ingestion [3][8][10].
Immunosuppression (methylprednisolone + cyclophosphamide) to mitigate lung fibrosis, though evidence remains limited [5][8][11].
Categories: rare disorders due to toxic effects
Research Papers
1,022 drug discovery papers about Paraquat poisoning, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,022 drug discovery papers about Paraquat poisoning, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-14 | Pentoxifylline, as nonselective phosphodiesterase inhibitor, attenuate paraquat-induced hepatic damage: in vivo and molecular docking insights.
Oxidative stress has a key role in paraquat (PQ)-mediated hepatic failure. Considering the known antioxidant and anti-inflammatory properties of nonselective phosphodiesterase inhibitors, this study investigated the potential of pentoxifylline (PTX) to counteract acute PQ-induced liver damage. The molecular interactions of PQ and PTX with key oxidative stress enzymes (NADPH oxidase, xanthine oxidase) were investigated by molecular docking using AutoDock 4.2.6. For in vivo studies, thirty-six mice were randomized into six groups: a normal saline control, a PQ-intoxicated group (20 mg/kg, single dose), a PTX control group (100 mg/kg for 3 days), and three treatment groups that received PTX (25, 50, or 100 mg/kg) for three consecutive days, starting one hour after PQ administration. Blood and liver tissues were collected 24 hours after the final dose for biochemical and histological analysis. The PQ administration resulted in a significant increase in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), hepatic lipid peroxidation (LPO), and nitric oxide (NO) levels, while concurrently decreasing antioxidant capacity (TAC), total thiol molecule (TTM), and superoxide dismutase (SOD) activity in liver tissue. PTX treatment effectively improved serum hepatic enzymes, LPO, TTM, and SOD levels, as corroborated by histological findings. Moreover, molecular docking analysis suggests that PTX may reduce PQ-induced oxidative stress by competitively inhibiting the FAD-binding site of xanthine oxidase, and by engaging a non-active-site region of NADPH oxidase. This study indicates PTX administration may prevent PQ-induced hepatic damage in mice, potentially by inhibiting free radical formation. Further research is needed to validate the proposed enzymes inhibition mechanisms and assess PTX's potential in acute PQ poisoning.
2026-08-07 | RAGE/NF-κB signaling mediates paraquat-induced alveolar-capillary barrier injury in a human alveolar microphysiological system.
Paraquat (PQ), a highly toxic herbicide that causes fatal pulmonary injury, has no specific clinical antidotes, mainly due to incomplete understanding of its pathogenic mechanisms. Inhalational exposure to PQ is the primary route of toxicity among agricultural workers. However, conventional experimental models fail to accurately replicate the physiological characteristics of the alveolar-capillary barrier and the air-liquid interface (ALI). In this study, we developed an Alveolar Microphysiological System (AMS) that co-cultures alveolar epithelial cells (EPCs) and pulmonary microvascular endothelial cells (EDCs) with ALI, effectively mimicking PQ-induced lung injury. This injury is characterized by increased permeability of the alveolar-capillary barrier, compromised intercellular junction integrity, and ultrastructural alterations. Bulk RNA sequencing, public single-cell RNA sequencing (scRNA-seq), and functional validation assays revealed that PQ triggers divergent, cell-type-specific responses: activating the RAGE/NF-κB signaling pathway and pro-inflammatory programs in EPCs, while suppressing these pathways in EDCs. Furthermore, PQ treatment results in the aberrant expression of pro-inflammatory cytokines (e.g., IL-1α/β, TNF-α), chemokines (e.g., CCL3/5, CXCL8/10), and growth factors (e.g., PDGF, TGF-α) in EPCs, a pattern that significantly differs from the expression profile observed in EDCs. Additionally, FPS-ZM1, a specific inhibitor of RAGE, mitigated PQ-induced barrier dysfunction by restoring normalized AMS permeability, enhancing E-cadherin expression in EPCs, and improving adherens junction integrity in EDCs. Collectively, these findings suggest that the AMS serves as a valuable translational platform for developing therapeutic strategies. Moreover, the RAGE/NF-κB signaling pathway exhibits a cell-type-specific function in pulmonary injury induced by PQ exposure under air-liquid interface conditions, indicating that modulation of the RAGE/NF-κB axis may offer a promising therapeutic avenue for managing paraquat poisoning.
2026-07-18 | Redox-sensitive mTOR-eIF4A signaling promotes selective P-glycoprotein translation.
Cells face a temporal gap in oxidative stress adaptation, in which acute insults require rapid protein synthesis before transcriptional responses are fully established. Here, we show that low-dose glucosamine (GlcN) induces a transient intracellular oxidation-sensitive response and activates redox-sensitive PI3K-AKT-mTORC1 signaling, leading to increased P-glycoprotein (P-gp) abundance without a detectable increase in total ABCB1 mRNA. GlcN enhanced 4E-BP1 phosphorylation and produced a modest increase in global polysome loading. Polysome profiling further showed preferential redistribution of ABCB1 mRNA toward actively translating polysome fractions, whereas the distribution and polysome-associated proportion of GAPDH mRNA remained largely unchanged. Pharmacological inhibition of eIF4A with rocaglamide A and genetic depletion of EIF4A1 both attenuated GlcN-induced P-gp upregulation, supporting a functional contribution of eIF4A to this translational response. Analyses of the ABCB1 5'-untranslated region identified an evolutionarily conserved, highly structured G-rich element with G4-like properties in vitro, providing a candidate structural context for the observed eIF4A sensitivity. In paraquat poisoning models, GlcN increased pulmonary P-gp expression, reduced lung paraquat accumulation, and improved survival, whereas these protective effects were markedly weakened in Abcb1a/Abcb1b knockout mice. Together, these findings support a redox-sensitive mTOR-eIF4A signaling pathway that preferentially enhances ABCB1/P-gp translation and contributes to pulmonary detoxification.
2026-07-10 | Complete pulmonary and renal recovery following severe paraquat poisoning: a six‑month radiological follow‑up and dynamic hematological observation.
Paraquat poisoning is one of the most lethal toxicological emergencies, particularly in low- and middle-income countries. Despite several proposed treatment regimens, no single approach has conclusively demonstrated a reduction in mortality. Early clinical manifestations may be nonspecific, and prompt recognition in the emergency department is critical. We report the unexpected survival of a young woman who ingested a potentially fatal dose of paraquat, with emphasis on long‑term radiological follow‑up and dynamic hematological changes. A 22‑year‑old Iranian woman presented to the emergency department approximately 48 h after reportedly ingesting 20 mL of a 20% paraquat solution in a suicide attempt. She had initially been evaluated at another facility shortly after ingestion but had refused admission against medical advice. She developed oropharyngeal mucosal ulcerations, odynophagia, hemoptysis, and acute kidney injury (peak serum creatinine 3.9 mg/dL). Laboratory data revealed a triphasic white blood cell pattern, including profound leukopenia followed by a marked rebound after granulocyte colony‑stimulating factor (G‑CSF) administration. A chest CT obtained at admission showed no pulmonary involvement; however, a follow-up CT performed on Day 14 demonstrated diffuse bilateral ground‑glass opacities and patchy consolidations consistent with acute alveolar injury. The patient received early multidisciplinary management including high‑dose corticosteroids, cyclophosphamide, antioxidant therapy, broad‑spectrum antibiotics, antimicrobial prophylaxis against opportunistic infections, nutritional support, and electrolyte correction. Clinical improvement was observed within 72 h, and she recovered without requiring dialysis or mechanical ventilation. A six‑month follow‑up chest CT showed complete radiological resolution with no evidence of pulmonary fibrosis. This case suggests that complete pulmonary and renal recovery may be achievable in clinically severe paraquat poisoning. The six‑month imaging follow‑up documents the complete resolution of acute lung injury, while the dynamic leukocyte pattern illustrates the severity of bone marrow suppression and subsequent recovery. These findings highlight the potential value of early recognition, intensive multidisciplinary management, and structured follow‑up, particularly in resource‑limited settings.
2026-07-04 | Myricitrin alleviates paraquat-induced acute lung injury via PERK pathway to attenuate endoplasmic reticulum stress and mitochondrial dysfunction.
Paraquat (PQ) poisoning causes high mortality due to acute lung injury (ALI) and respiratory failure, with no specific antidote available. Myricitrin, a natural flavonol showing antioxidative properties, demonstrates potential against PQ toxicity, yet its exact protective mechanisms in PQ-induced ALI remain unclear. In this study, we investigated the therapeutic effects and mechanisms of myricitrin against PQ-induced ALI using BEAS-2B cells and C57BL/6J mice. Myricitrin significantly attenuated oxidative stress, reduced apoptosis, and restored mitochondrial function in PQ-injured BEAS-2B cells, while also improving survival and mitigating pathological damage in the lung tissues of mice. Mechanistically, myricitrin was suggested to interact with PERK and inhibited its autophosphorylation, thereby suppressing the downstream PERK- eIF2α-ATF4-CHOP signaling axis. This inhibition alleviated endoplasmic reticulum (ER) stress and mitochondrial dysfunction, ultimately exerting a protective effect. Furthermore, myricitrin mitigated oxidative stress and associated ER damage through its intrinsic antioxidant capacity, which acted in synergy with its inhibition of the PERK pathway. Collectively, our findings demonstrate that myricitrin protects against PQ-induced ALI primarily through inhibition of the PERK signaling pathway, thereby suppressing the ER stress and mitochondrial-mediated apoptosis, supporting its therapeutic potential for this life-threatening condition.
proteins
2026-07-27 | Targeted Delivery of Bilirubin to Pulmonary Endothelium Mitigates Paraquat-Induced Lung Injury.
Paraquat (PQ) poisoning causes high mortality via acute lung injury (ALI) driven by excessive reactive oxygen species (ROS) in pulmonary microvascular endothelial cells. We developed BR@Lipo-CerTP, a lung-targeted nanotherapeutic using C16-ceramide-binding peptide-modified bilirubin liposomes, to enhance endothelial delivery and treat PQ-induced ALI. BR@Lipo-CerTP was characterized for physicochemical properties and cellular uptake in pulmonary microvascular endothelial cells (PMVECs). In vitro efficacy was assessed via cytotoxicity, apoptosis, ROS, antioxidant capacity, and mitochondrial function assays in PQ-exposed PMVECs. Multi-omics analysis elucidated therapeutic mechanisms. In vivo efficacy and biosafety were evaluated in a PQ-induced ALI mouse model through survival, histopathology, edema, and toxicity assessments. BR@Lipo-CerTP exhibited uniform ~120 nm spherical morphology, narrow size distribution, excellent stability, and enhanced PMVEC uptake versus non-targeted liposomes. In vitro, it significantly attenuated PQ-induced cytotoxicity, apoptosis, and ROS accumulation while restoring antioxidant capacity and mitochondrial function. Multi-omics revealed it disrupts a vicious cycle of glutathione depletion, ferroptosis, and NF-κB/NLRP3-driven inflammation, resetting pathological crosstalk between redox homeostasis, regulated cell death, and immune activation. In vivo, BR@Lipo-CerTP markedly improved survival, alleviated pulmonary damage and edema, suppressed oxidative stress and inflammation, with no systemic toxicity. Pulmonary endothelial-targeted bilirubin delivery effectively mitigates PQ-induced ALI by coordinately regulating redox balance, cell death, and inflammation. This strategy offers a promising nanotherapeutic for PQ poisoning and other ROS-driven pulmonary diseases, highlighting targeted nanomedicine's potential in toxicological emergencies.
2025-01-03 | Proteomic characterization of molecular mechanisms of paraquat-induced lung injury in a mouse model.
We sought to explore the molecular mechanisms underpinning acute lung injury (ALI) caused by poisoning with paraquat (PQ). Selection mice were intraperitoneally injected with PQ at 40 mg/kg, whereas controls were injected with sterile saline. On days 2, 7, and 14 after administration, mice were anesthetized and sacrificed, and lung tissue was removed. Lung pathological changes were observed with conventional staining techniques. Lung tissue components were assessed with tandem mass spectrometry tag technology, and differentially expressed proteins (DEPs) were bioinformatically analyzed and investigated with parallel reaction monitoring. The expression of 91, 160, and 78 proteins was significantly altered at days 2, 7, and 14, respectively. Gene Ontology analyses revealed that the DEPs in the PQ-2d and PQ-7d groups were involved primarily in humoral immunity and coagulation-related reactions, whereas those in the PQ-14d group were implicated primarily in chemotactic and regulatory responses. Kyoto Encyclopedia of Genes and Genomes analyses indicated that complement and coagulation cascades were key pathways in the PQ-2d and PQ-7d groups, whereas xenobiotic metabolism by cytochrome P450 was a key pathway in the PQ-14d group. Nine proteins at PQ-2d and eight proteins at PQ-7d were validated through parallel reaction monitoring (PRM). PQ-induced ALI depends on over-activation of immune responses by damaged alveolar/endothelial cells, and the complement/coagulation cascade pathway plays a key role during this process. The proteins identified herein might provide new therapeutic targets or biomarkers for PQ poisoning.
2024-08-15 | Synaptotagmin-1 antagonizes paraquat intracellular accumulation and nephrocyte toxicity by up-regulating SERBP1/GLUT2 expression.
Acute kidney injury (AKI) is common and an independent risk factor for mortality in patients with paraquat (PQ) poisoning. Currently, no specific antidote is available. Synaptotagmin-1 (SYT1) has been identified as a key protein that facilitates PQ efflux in PQ-resistant A549 cells, thereby preventing PQ-induced lung injury. However, the protective effect of STY1 on PQ-induced AKI remains to be elucidated. This study exposed human kidney 2 (HK-2) cells overexpressing SYT1 to PQ. These cells exhibited significantly lower levels of growth inhibition, reactive oxygen species production, early apoptosis, and PQ accumulation compared to the parent HK-2 cells. Transcriptomic screening and Western blot analysis revealed that SYT1 overexpression significantly promoted the expression of glucose transporter 2 (GLUT2). Inhibition of GLUT2 completely abolished the protective effects of SYT1 overexpression in HK-2 cells and restored intracellular PQ concentrations. Further immunoprecipitation-shotgun and RNA interference experiments revealed that SYT1 binds to and stabilizes the protein SERPINE1 mRNA-binding protein 1 (SERBP1), enhancing the stability of GLUT2 mRNA and its protein levels. In summary, SYT1 antagonizes PQ intracellular accumulation and prevents nephrocyte toxicity by up-regulating SERBP1/GLUT2 expression. This study identifies a potential target for the treatment of PQ-induced AKI.
2024-07-14 | Schistosoma japonicum cystatin alleviates paraquat poisoning caused acute lung injury in mice through activating regulatory macrophages.
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. 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. 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. 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.
2022-01-20 | Combined effect of reduced glutathione and ulinastatin on the expressions of IL-6, sIL-6 and sgp130 in peripheral blood of paraquat-poisoned patients
Purpose: To investigate the effect of reduced glutathione and ulinastatin on the expressions of interleukin-6 (IL-6), soluble interleukin-6 receptor (sIL-6R), and soluble glycoprotein 130 (sgp130) in peripheral blood of paraquat-poisoned patients.
Methods: In this retrospective study, 88 patients with paraquat poisoning admitted to Dongying People's Hospital, Dongying, China from February 2017 to October 2020 were divided into control group (n = 40) and study group (n = 48), based on treatment type. The control group received conventional treatments, while the study group was given reduced glutathione in combination with ulinastatin. Treatment efficacy and peripheral blood expression levels were compared.
Results: Compared to the control group, curative effect was significantly higher in the study group (p < 0.05). The expression levels of IL-6, sIL-6R, and sgp130 in the peripheral blood at the early, middle and late periods in the study group were markedly lower. The number of patients with flake-like or dotted opacity, increased lung texture, pleural effusion and ground glass opacity in the study group during the early period was lower (p < 0.05). Moreover, the number of patients with pulmonary edema, fibrous cord, pleural effusion, ground glass opacity and reticular opacity during the middle period was markedly lower for the study group, while the population of patients with honeycomb lung, fibrous cord, nodules and reticular opacity in the study group was higher t (p < 0.05).
Conclusion: A combination of reduced glutathione and ulinastatin produces significant therapeutic effect on paraquat poisoning by down-regulating the serum expressions of IL-6, sIL-6 and sgp130, inhibiting inflammation, and mitigating pulmonary lesions.
cell therapies
2026-08-12 | Urine Dithionite-guided Hemoperfusion in Acute Paraquat Poisoning: A Retrospective Observational Study from South India.
Paraquat (PQ) poisoning has a mortality rate of 50-90% with no specific antidote. Hemoperfusion (HP) is used for PQ removal, but evidence for its efficacy is limited, and optimal strategies for guiding HP remain poorly defined. The study aims to describe a urine sodium dithionite test (UDT)-guided HP protocol and evaluate clinical outcomes in patients with acute PQ poisoning. A retrospective observational study of 27 consecutive patients with acute PQ poisoning admitted to a tertiary intensive care unit (ICU) in South India was conducted. Serial UDT was used to guide HP initiation, continuation, and cessation. Clinical data, treatment details, and outcomes were analyzed. Survivors and non-survivors were compared. Mean age was 30.5 ± 11.2 years (74.1% male). Fourteen patients (51.9%) survived. Ingestion-to-door (I-to-D) time ≤4 h was present in 71.4% of survivors vs 20% of non-survivors. Urine sodium dithionite test negative conversion within 10 h occurred in 77.8% of survivors vs 16.7% of non-survivors. Survivors received more HP sessions (mean: 3.3 vs 2.6). Acute kidney injury (AKI) occurred in 80% of non-survivors vs 14.3% of survivors. Early presentation combined with a UDT-guided HP protocol was associated with favorable outcomes. Serial UDT provides a practical, low-cost tool for guiding extracorporeal treatment (ECTR) in resource-limited settings. The UDT-guided HP protocol offers intensivists a bedside decision-making tool that replaces costly plasma PQ assays, enabling evidence-based ECTR decisions in Indian ICU settings where quantitative assays are unavailable.
2026-07-28 | Clinical Characteristics and Prognostic Factors of Patients with Acute Poisoning: A Retrospective Observational Cohort Study of Diquat, Single-Drug and Mixed-Drug Exposures.
Acute poisoning remains a major emergency and toxicology problem, but its clinical pattern differs by toxin type and local availability. Diquat poisoning is increasingly reported where paraquat use has been restricted, whereas metamizole exposure remains relevant in regions where dipyrone remains clinically available. This retrospective observational cohort study described clinical characteristics, treatment patterns and prognostic factors in acute poisoning involving diquat, single-drug pharmaceutical exposure and mixed-drug exposure. We analysed 385 adults with confirmed acute poisoning treated at a single tertiary toxicology centre from January to June 2025. Patients were classified as Group A (diquat, n = 125), Group B (single-drug poisoning, predominantly metamizole, n = 143) or Group C (mixed-drug poisoning, n = 117). Baseline features, laboratory findings, interventions and 30-day outcomes were compared. A presentation-based logistic regression model assessed mortality predictors, and early haemoperfusion was analysed separately in the diquat subgroup. Group A had the highest 30-day mortality (28.8%) compared with Group B (5.6%) and Group C (14.5%) (p < 0.001). Liver injury, renal dysfunction, cardiac biomarker elevation, lactate elevation and acidosis were most pronounced after diquat exposure. In the diquat subgroup, haemoperfusion within 6 hours was associated with lower mortality than delayed haemoperfusion (17.1% vs 47.6%, p < 0.001), including after propensity score matching. Diquat poisoning, delayed presentation, low Glasgow Coma Scale score, hypotension, elevated lactate, renal dysfunction, acidosis and early multi-organ dysfunction were associated with mortality. Acute poisoning showed heterogeneous clinical patterns by toxic agent category. Diquat poisoning carried the greatest mortality and multi-organ injury, whereas mixed-drug poisoning showed intermediate severity. Early haemoperfusion was associated with improved outcomes in diquat poisoning, but causal interpretation is limited by the retrospective design; prospective multicentre validation is needed.
2026-05-01 | C62-16 World’s Youngest Successful Lung Transplantation in a 12 Year Old Boy With Paraquat Induced Pulmonary Fibrosis: A Rare Case Report
Abstract Introduction Paraquat, a rapidly active herbicide can cause multiorgan dysfunction with a mortality rate of 40 - 80 %. Current clinical treatments for paraquat poisoning are only supportive and advancement of pulmonary disease is incurable in most cases. Case Report: A 12-year-old boy presented to intensive care unit with multiple episodes of vomiting and progressive breathlessness following accidental ingestion of approximately 50 mL of Paraquat. Initial evaluation showed renal and hepatic dysfunction and baseline respiratory parameters revealed tachycardia with SpO2: 84 % on room air. Immediate gastric lavage was performed, and hemoperfusion was initiated. Liver and renal parameters gradually normalized over a period of 10 days. Respiratory function continued to deteriorate requiring HFNC and HRCT thorax revealed progressive fibrotic lung injury. In view of worsening PaO2/FiO2 ratios, patient eventually required invasive mechanical ventilation, and subsequently, VV-ECMO was initiated on day 52 post-paraquat consumption. After multidisciplinary discussion by a team of pulmonologists, pediatric intensivist and thoracic surgeon, the option of bilateral lung transplantation was considered. Serial urine paraquat levels were negative prior to consideration for transplantation. After 2 months of paraquat ingestion, the patient underwent bilateral sequential lobar lung transplantation via bilateral anterolateral thoracotomy under ECMO support. Immunosuppression was initiated with steroid and mycophenolate mofetil (MMF), followed by maintenance triple immunosuppression (steroids, MMF and tacrolimus) along with prophylaxis for opportunistic infections. Patient was successfully decannulated from ECMO on post operative day 2 and gradually weaned off mechanical ventilation on post operative day 7. Three months post lung transplantation the patient is stable with good graft function and no evidence of rejection. Discussion This case represents the youngest reported survivor of lung transplantation for paraquat-induced pulmonary fibrosis. Lung transplantation remains the only definitive and effective therapeutic option for paraquat induced irreversible respiratory failure. The case underscores the importance of timely referral to a transplant centre, and a multidisciplinary approach. This abstract is funded by: None
2025-09-02 | Lung Transplantation Following Paraquat Poisoning: Time to Think.
Paraquat, a commonly available herbicide, when consumed in high doses, affects organs with high blood flow (lungs, heart, kidney and liver), leading to pulmonary fibrosis, respiratory failure and death. Few reports of rescue lung transplantation exist. Complete depletion of paraquat from the body is necessary prior to transplant; however, timing for and concerns after lung transplantation remain unknown. We report 2 patients (median age 19 years) with severe respiratory failure requiring extracorporeal membrane oxygenation support, acute kidney injury requiring haemodialysis and acute liver injury in the pre-transplant period. Volume of paraquat consumption was more than 30 mL and PF ratio less than 100 before transplant. Once their urine paraquat level was negative (median time 32 days), both underwent bilateral lung transplantation after receiving an induction agent with basiliximab and were continued on triple immunosuppressant following the transplant. With reported mortality rates reaching up to 90%, lung transplantation remains a reasonable option for patients with paraquat poisoning not responding to conventional treatment options. Once paraquat levels are negative and after optimising renal and liver function, these patients could be considered for bilateral lung transplantation and have successful outcomes as reported here.
2025-08-11 | Retrospective Study of Paraquat Poisoning in the Khandesh Region: Clinical Outcomes and Mortality Predictors
Introduction:Paraquat is a widely used non-selective herbicide in India, especially in rural agricultural regions, and is associated with high morbidity and mortality due to the absence of a specific antidote and rapid progression to multi-organ failure [1]. In North Maharashtra, agricultural dependency, easy availability of paraquat, and limited awareness of its toxicity contribute to frequent accidental or intentional exposures. This study was conducted to evaluate the demographic, clinical, laboratory, and treatment profiles of paraquat poisoning patients, along with their outcomes, to generate evidence for improving prevention and management strategies. Methodology:A hospital-based observational study was conducted at a tertiary care center in North Maharashtra, including 34 confirmed cases of paraquat poisoning admitted during the study period. Data were collected from patient medical records and included demographic details, presenting clinical signs, postmortem findings where applicable, laboratory investigations, treatment modalities, and outcomes. Statistical analysis was performed to determine the frequency and percentage distribution of variables. Results:The majority of patients were males (64.7%) and farmers (61.8%), with the highest incidence in the 21–30 years (23.5%) and 31–40 years (20.6%) age groups. Oral ulcers/mucosal burns were observed in 41.7% of cases, lung congestion in 58.3%, and kidney congestion in 52.8%. Laboratory abnormalities included elevated AST/ALT in 38.2%, hyperbilirubinemia (>2 mg/dL) in 41.2%, elevated creatinine in 52.9%, and low hemoglobin in 44.1%. Steroids were administered to 58.8% of patients, cyclophosphamide to 17.6%, and dialysis to 8.8%, while hemoperfusion was rarely used (2.9%). The overall in-hospital mortality was 61.8%, with multiorgan failure (71.4% of deaths) as the leading cause, followed by acute kidney injury (23.8%) and acute lung injury (4.8%). Conclusion:Paraquat poisoning in North Maharashtra predominantly affects young male farmers and carries a high mortality rate despite medical intervention. The study highlights the need for stricter regulation of paraquat sales, farmer education on its hazards, and improved access to advanced therapeutic measures such as hemoperfusion to reduce mortality.
oligonucleotides
2024-03-26 | Exosomes from senescent epithelial cells activate pulmonary fibroblasts via the miR-217-5p/Sirt1 axis in paraquat-induced pulmonary fibrosis
Abstract 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.
2024-03-07 | Integrated analysis of ceRNA-miRNA changes in paraquat-induced pulmonary epithelial-mesenchymal transition via high-throughput sequencing.
Recent studies have shown that epithelial-mesenchymal transition (EMT) plays an important role in paraquat (PQ)-induced tissue fibrosis, which is the main cause of death in patients with PQ poisoning. However, no effective treatment for pulmonary interstitial fibrosis caused by PQ poisoning exists. It is of great significance for us to find new therapeutic targets through bioinformatics in PQ-induced EMT. We conducted transcriptome sequencing to determine the expression profiles of 1210 messenger RNAs (mRNAs), 558 long noncoding RNAs, 28 microRNAs (miRNAs), including 18 known-miRNAs, 10 novel-miRNAs and 154 circular RNAs in the PQ-exposed EMT group mice. Using gene ontology and Kyoto Encyclopaedia of Genes and Genomes analyses, we identified the pathways associated with signal transduction, cancers, endocrine systems and immune systems were involved in PQ-induced EMT. Furthermore, we constructed long noncoding RNA-miRNA-mRNA interrelated networks and found that upregulated genes included Il22ra2, Mdm4, Slc35e2 and Angptl4, and downregulated genes included RGS2, Gabpb2, Acvr1, Prkd3, Sp100, Tlr12, Syt15 and Camk2d. Thirteen new potential competitive endogenous RNA targets were also identified for further treatment of PQ-induced pulmonary tissue fibrosis. Through further study of the pathway and networks, we may identify new molecular targets in PQ-induced pulmonary EMT.
2023-11-06 | Effect of WISP1 on paraquat-induced EMT.
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. 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. 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. Knockdown of WISP1 inhibited PQ-induced EMT in A549 cells. This conclusion might provide a new therapeutic target for PQ poisoning treatment.
2023-10-01 | Analysis of Human microRNA Expression Profiling During Diquat-Induced Renal Proximal Tubular Epithelial Cell Injury
We established a diquat-induced human kidney-2 cells (HK-2 cells) apoptosis model in this study to identify differentially expressed microRNAs (miRNAs) and signaling pathways involved in diquat poisoning via gene sequencing and bioinformatics analysis and explored the related therapeutic benefits.The effects of diquat on the viability and apoptosis of HK-2 cells were explored using the CCK-8 and Annexin V-FITC/PI double staining methods. Total RNAs were extracted using the TRizol method and detected by Illumina HiSeq 2500. Bioinformatics analysis was performed to explore differentially expressed (DE) miRNAs, their enriched biological processes, pathways, and potential target genes. The RT-qPCR method was used to verify the reliability of the results.Diquat led to HK-2 cell injury and apoptosis played an important role, hence an HK-2 cell apoptosis model in diquat poisoning was established. Thirty-six DE miRNAs were screened in diquat-treated HK-2 cells. The enriched biological process terms were mainly cell growth, regulation of apoptotic signaling pathway, extrinsic apoptotic signaling pathway, and Ras protein signal transduction. The enriched cellular components were mainly cell-cell junction, cell-substrate junction, ubiquitin ligase complex, and protein kinase complex. The enriched molecular functions were mainly Ras GTPase binding, ubiquitin-like protein transferase activity, DNA-binding transcription factor binding, ubiquitin-protein transferase activity, nucleoside-triphosphatase regulator activity, transcription coactivator activity, and ubiquitin-like protein ligase binding. Signaling pathways such as MAPK, FoxO, Ras, PIK3-Akt, and Wnt were also enriched.These findings aid in understanding the mechanisms of diquat poisoning and the related pathways, where DE miRNAs serve as targets for gene therapy.
2023-09-20 | Microglia-derived exosomal circZNRF1 alleviates paraquat-induced neuronal cell damage via miR-17-5p.
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.
other
2022-09-20 | Identification of differentially expressed genes and pathways in diquat and paraquat poisoning using bioinformatics analysis.
In this study, differentially expressed genes (DEGs) and signaling pathways involved in diquat (DQ) and paraquat (PQ) poisoning were identified via bioinformatics analysis, in order to inform the development of novel clinical treatments. Raw data from GSE153959 were downloaded from the Gene Expression Omnibus database. DEGs of the DQ vs. control (CON) and PQ vs. CON comparison groups were identified using R, and DEGs shared by the two groups were identified using TBtools. Subsequently, the shared DEGs were searched in the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, using the Database for Annotation, Visualization, and Integrated Discovery. A protein-protein interaction (PPI) network was constructed, and hub genes were identified using the cytoHubba plug-in in Cytoscape software. Finally, circos and contrast plots showing the DEGs shared between mouse and human chromosomes were constructed using TBtools. Thirty-one DEGs shared by the DQ and PQ groups were identified. Enriched biological process terms included positive regulation of cell proliferation and translation. Enriched cellular component terms included extracellular region, intracellular membrane-bounded organelle and mitochondrion. Enriched molecular function terms included transcription factor activity and sequence-specific double-stranded DNA binding. Enriched KEGG pathways included the interleukin-17 signaling pathway, tumor necrosis factor signaling pathway, and human T-cell leukemia virus 1 infection. The top 10 hub genes in the PPI network were prostaglandin-endoperoxide synthase 2 (Ptgs2), chemokine (C-X-C motif) ligand 2 (Cxcl2), colony-stimulating factor 2 (granulocyte-macrophage) (Csf2), matrix metallopeptidase 13 (Mmp13), amphiregulin (Areg), plasminogen activator, urokinase receptor (Plaur), fos-like antigen 1 (Fosl1), epiregulin (Ereg), activating transcription factor 3 (Atf3), and transferrin receptor (Tfrc). Cxcl2, Csf2, and Atf3 played important roles in the mitogen-activated protein kinase (MAPK) signaling pathway. These pathways and DEGs may serve as targets for gene therapy.
2022-03-24 | Tenascin-C Participates Pulmonary Injury Induced by Paraquat Through Regulating TLR4 and TGF-β Signaling Pathways.
This study was conducted to investigate the role of Tenascin-C (TNC) in paraquat (PQ)-induced lung injury in vivo and in vitro and explore its related mechanism during this process. Six- to eight-week-old male C57BL/6 mice were injected with 30 mg/kg PQ by intraperitoneal injection and sacrificed on 2 days, 7 days, 14 days, and 28 days after PQ administration. In vivo, we detected the expression of TNC at all time points of lung tissues in mice by reverse transcription-quantitative-polymerase chain reaction, western blotting, and immunohistochemistry. Expression of TLR4, NF-κB p65, TGF-β1, and α-SMA in lung tissues have also been tested. In vitro, siRNA was used to knock down TNC expression in A549 cells and TLR4, NF-κB p65, and TGF-β1 expressions were examined after PQ exposure. TNC expression increased in both lung tissues of mice model and A549 cells after PQ administration. In vivo, TNC mostly located at the extracellular matrix of thickened alveolar septum, especially at sites of injury, together with the increasing of TLR4, NF-κB p65, TGF-β1, and α-SMA. In vitro, PQ exposure also increased the expressions of TLR4, NF-κB p65, and TGF-β1 in A549 cells, but knocking down TNC gene expression obviously down-regulated the expressions of TLR4, NF-κB p65, NF-κB Pp65, and TGF-β1. The results of this study demonstrate, for the first time, that TNC participates in the development of lung injury induced by PQ poisoning. The role of TNC in this process is closely related to TLR4 and TGF-β signaling pathways.
2021-05-28 | Depletion of NK cells attenuates paraquat-induced acute lung injury by manipulating macrophage polarization.
Acute lung injury is the main causative factor in paraquat dichloride (PQ)-induced mortality. The innate immune system-triggered detrimental inflammatory cascade plays a vital role in PQ-induced acute lung injury. However, the role of natural killer (NK) cells, which are essential for innate response, in PQ-induced acute lung injury remains largely unknown. Here, we found that in an acute PQ poisoning model, depletion of NK cells attenuated PQ-induced lung injury by inhibiting macrophage polarization towards the M1 type. Specifically, the percentages of NK cells were reduced in the lung, spleen, and peripheral blood in a murine model of acute PQ poisoning. NK cells were aberrantly activated, evidenced by upregulation of the activating markers CD69, CD107a, and NKG2D and downregulation of the inhibitive marker KLRG1. Further, NK-specific depletion in mice greatly prolonged the survival time and ameliorated reactive oxygen species-induced damage following PQ treatment compared with the control group. Importantly, NK cell depletion alleviated macrophage and neutrophil infiltration in the lung and reversed PQ induced-macrophage polarization towards the pro-inflammatory M1 type. Our study demonstrates a crucial role of NK cells and NK cell-to-macrophage interaction in PQ-induced acute lung injury.
2018-12-14 | Effects of paraquat on IL‑6 and TNF‑α in macrophages
Effects of paraquat (PQ) on interleukin‑6 (IL‑6) and tumor necrosis factor‑α (TNF‑α) in macrophages were investigated. Different concentrations of PQ were added to mouse macrophage RAW264.7 for culture. According to different concentrations of PQ, mice were divided into micro concentration (0.01 mmol/l), low concentration (0.1 mmol/l), medium concentration (1 mmol/l), high concentration (10 mmol/l), and control groups without PQ. Trypan blue solution was used for detecting cell viability, a microplate reader for detecting the fluorescence intensity of reactive oxygen species (ROS), ELISA for detecting the expression levels of IL‑6 and TNF‑α. The medium concentration and the high concentration groups had significantly lower cell viability than the other three groups (P<0.050). The high concentration group had significantly lower cell viability than the medium concentration group (P<0.050). At 1, 4 and 8 h, respectively, the medium and the high concentration groups had significantly higher ROS fluorescence intensity than the other three groups (P<0.050). The high concentration group had significantly higher ROS fluorescence intensity than the medium concentration group (P<0.050). There were significant differences in the expression levels of IL‑6 and TNF‑α at the 1st, 4th and 8th hour among the five groups (P<0.050). In the micro, the low, the medium and high concentration groups, the expression levels of IL‑6 and TNF‑α were the lowest at 1 h and the highest at 8 h, which were higher at 4 h than those at 1 h (P<0.050). PQ at a concentration of 1 mmol/l can produce toxicity to macrophages, and greatly increase the ROS fluorescence intensity, the expression levels of IL‑6 and TNF‑α. PQ poisoning is expected to be treated though IL‑6 and TNF‑α in the future.
2018-12-04 | Nrf2 overexpression protects against paraquat‑induced A549 cell injury primarily by upregulating P‑glycoprotein and reducing intracellular paraquat accumulation
Paraquat (PQ) intoxication causes thousands of mortalities every year, worldwide. Its pulmonary-targeted accumulation and the acute lung injury it subsequently causes, remain a challenge for detoxification treatment. A previous study has demonstrated that the upregulation of nuclear factor erythroid-2 related factor 2 (Nrf2) prevents PQ toxicity in cell line and murine models. As Nrf2 target genes include a group of membrane transporters, the current study assessed the protective mechanism exerted by Nrf2 against PQ toxicity and intracellular PQ accumulation via its effects on P-glycoprotein (P-gp), a downstream transporter of Nrf2. Adenovirus vectors containing the Nrf2 gene were transfected into A549 cells. Cell proliferation was assessed by Cell Counting Kit-8. The levels of LDH, MDA, SOD, TNF-α, IL-6 levels were detected using their respective ELISA kits. In addition, the levels of Nrf2 and P-gp protein expression were detected by western blot analysis. The concentration of PQ was measured by HPLC. The results revealed that overexpressed Nrf2 significantly increased P-gp protein levels, decreased the intracellular accumulation of PQ and attenuated PQ-induced toxicity. However, the protective effects of Nrf2 overexpression on PQ-challenged A549 cells were abrogated following cyclosporine A treatment, a competitive inhibitor of P-gp, which also increased intracellular PQ levels. These data indicated that Nrf2 gene overexpression prevented PQ toxicity in A549 cells, potentially via the upregulation of P-gp activity and the inhibition of intracellular PQ accumulation. Thus, Nrf2 and P-gp may serve as potential therapeutic targets for the treatment of PQ-induced injury.
small molecules
2026-08-14 | Pentoxifylline, as nonselective phosphodiesterase inhibitor, attenuate paraquat-induced hepatic damage: in vivo and molecular docking insights.
Oxidative stress has a key role in paraquat (PQ)-mediated hepatic failure. Considering the known antioxidant and anti-inflammatory properties of nonselective phosphodiesterase inhibitors, this study investigated the potential of pentoxifylline (PTX) to counteract acute PQ-induced liver damage. The molecular interactions of PQ and PTX with key oxidative stress enzymes (NADPH oxidase, xanthine oxidase) were investigated by molecular docking using AutoDock 4.2.6. For in vivo studies, thirty-six mice were randomized into six groups: a normal saline control, a PQ-intoxicated group (20 mg/kg, single dose), a PTX control group (100 mg/kg for 3 days), and three treatment groups that received PTX (25, 50, or 100 mg/kg) for three consecutive days, starting one hour after PQ administration. Blood and liver tissues were collected 24 hours after the final dose for biochemical and histological analysis. The PQ administration resulted in a significant increase in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), hepatic lipid peroxidation (LPO), and nitric oxide (NO) levels, while concurrently decreasing antioxidant capacity (TAC), total thiol molecule (TTM), and superoxide dismutase (SOD) activity in liver tissue. PTX treatment effectively improved serum hepatic enzymes, LPO, TTM, and SOD levels, as corroborated by histological findings. Moreover, molecular docking analysis suggests that PTX may reduce PQ-induced oxidative stress by competitively inhibiting the FAD-binding site of xanthine oxidase, and by engaging a non-active-site region of NADPH oxidase. This study indicates PTX administration may prevent PQ-induced hepatic damage in mice, potentially by inhibiting free radical formation. Further research is needed to validate the proposed enzymes inhibition mechanisms and assess PTX's potential in acute PQ poisoning.
2026-08-07 | RAGE/NF-κB signaling mediates paraquat-induced alveolar-capillary barrier injury in a human alveolar microphysiological system.
Paraquat (PQ), a highly toxic herbicide that causes fatal pulmonary injury, has no specific clinical antidotes, mainly due to incomplete understanding of its pathogenic mechanisms. Inhalational exposure to PQ is the primary route of toxicity among agricultural workers. However, conventional experimental models fail to accurately replicate the physiological characteristics of the alveolar-capillary barrier and the air-liquid interface (ALI). In this study, we developed an Alveolar Microphysiological System (AMS) that co-cultures alveolar epithelial cells (EPCs) and pulmonary microvascular endothelial cells (EDCs) with ALI, effectively mimicking PQ-induced lung injury. This injury is characterized by increased permeability of the alveolar-capillary barrier, compromised intercellular junction integrity, and ultrastructural alterations. Bulk RNA sequencing, public single-cell RNA sequencing (scRNA-seq), and functional validation assays revealed that PQ triggers divergent, cell-type-specific responses: activating the RAGE/NF-κB signaling pathway and pro-inflammatory programs in EPCs, while suppressing these pathways in EDCs. Furthermore, PQ treatment results in the aberrant expression of pro-inflammatory cytokines (e.g., IL-1α/β, TNF-α), chemokines (e.g., CCL3/5, CXCL8/10), and growth factors (e.g., PDGF, TGF-α) in EPCs, a pattern that significantly differs from the expression profile observed in EDCs. Additionally, FPS-ZM1, a specific inhibitor of RAGE, mitigated PQ-induced barrier dysfunction by restoring normalized AMS permeability, enhancing E-cadherin expression in EPCs, and improving adherens junction integrity in EDCs. Collectively, these findings suggest that the AMS serves as a valuable translational platform for developing therapeutic strategies. Moreover, the RAGE/NF-κB signaling pathway exhibits a cell-type-specific function in pulmonary injury induced by PQ exposure under air-liquid interface conditions, indicating that modulation of the RAGE/NF-κB axis may offer a promising therapeutic avenue for managing paraquat poisoning.
2026-07-18 | Redox-sensitive mTOR-eIF4A signaling promotes selective P-glycoprotein translation.
Cells face a temporal gap in oxidative stress adaptation, in which acute insults require rapid protein synthesis before transcriptional responses are fully established. Here, we show that low-dose glucosamine (GlcN) induces a transient intracellular oxidation-sensitive response and activates redox-sensitive PI3K-AKT-mTORC1 signaling, leading to increased P-glycoprotein (P-gp) abundance without a detectable increase in total ABCB1 mRNA. GlcN enhanced 4E-BP1 phosphorylation and produced a modest increase in global polysome loading. Polysome profiling further showed preferential redistribution of ABCB1 mRNA toward actively translating polysome fractions, whereas the distribution and polysome-associated proportion of GAPDH mRNA remained largely unchanged. Pharmacological inhibition of eIF4A with rocaglamide A and genetic depletion of EIF4A1 both attenuated GlcN-induced P-gp upregulation, supporting a functional contribution of eIF4A to this translational response. Analyses of the ABCB1 5'-untranslated region identified an evolutionarily conserved, highly structured G-rich element with G4-like properties in vitro, providing a candidate structural context for the observed eIF4A sensitivity. In paraquat poisoning models, GlcN increased pulmonary P-gp expression, reduced lung paraquat accumulation, and improved survival, whereas these protective effects were markedly weakened in Abcb1a/Abcb1b knockout mice. Together, these findings support a redox-sensitive mTOR-eIF4A signaling pathway that preferentially enhances ABCB1/P-gp translation and contributes to pulmonary detoxification.
2026-07-10 | Complete pulmonary and renal recovery following severe paraquat poisoning: a six‑month radiological follow‑up and dynamic hematological observation.
Paraquat poisoning is one of the most lethal toxicological emergencies, particularly in low- and middle-income countries. Despite several proposed treatment regimens, no single approach has conclusively demonstrated a reduction in mortality. Early clinical manifestations may be nonspecific, and prompt recognition in the emergency department is critical. We report the unexpected survival of a young woman who ingested a potentially fatal dose of paraquat, with emphasis on long‑term radiological follow‑up and dynamic hematological changes. A 22‑year‑old Iranian woman presented to the emergency department approximately 48 h after reportedly ingesting 20 mL of a 20% paraquat solution in a suicide attempt. She had initially been evaluated at another facility shortly after ingestion but had refused admission against medical advice. She developed oropharyngeal mucosal ulcerations, odynophagia, hemoptysis, and acute kidney injury (peak serum creatinine 3.9 mg/dL). Laboratory data revealed a triphasic white blood cell pattern, including profound leukopenia followed by a marked rebound after granulocyte colony‑stimulating factor (G‑CSF) administration. A chest CT obtained at admission showed no pulmonary involvement; however, a follow-up CT performed on Day 14 demonstrated diffuse bilateral ground‑glass opacities and patchy consolidations consistent with acute alveolar injury. The patient received early multidisciplinary management including high‑dose corticosteroids, cyclophosphamide, antioxidant therapy, broad‑spectrum antibiotics, antimicrobial prophylaxis against opportunistic infections, nutritional support, and electrolyte correction. Clinical improvement was observed within 72 h, and she recovered without requiring dialysis or mechanical ventilation. A six‑month follow‑up chest CT showed complete radiological resolution with no evidence of pulmonary fibrosis. This case suggests that complete pulmonary and renal recovery may be achievable in clinically severe paraquat poisoning. The six‑month imaging follow‑up documents the complete resolution of acute lung injury, while the dynamic leukocyte pattern illustrates the severity of bone marrow suppression and subsequent recovery. These findings highlight the potential value of early recognition, intensive multidisciplinary management, and structured follow‑up, particularly in resource‑limited settings.
2026-07-04 | Myricitrin alleviates paraquat-induced acute lung injury via PERK pathway to attenuate endoplasmic reticulum stress and mitochondrial dysfunction.
Paraquat (PQ) poisoning causes high mortality due to acute lung injury (ALI) and respiratory failure, with no specific antidote available. Myricitrin, a natural flavonol showing antioxidative properties, demonstrates potential against PQ toxicity, yet its exact protective mechanisms in PQ-induced ALI remain unclear. In this study, we investigated the therapeutic effects and mechanisms of myricitrin against PQ-induced ALI using BEAS-2B cells and C57BL/6J mice. Myricitrin significantly attenuated oxidative stress, reduced apoptosis, and restored mitochondrial function in PQ-injured BEAS-2B cells, while also improving survival and mitigating pathological damage in the lung tissues of mice. Mechanistically, myricitrin was suggested to interact with PERK and inhibited its autophosphorylation, thereby suppressing the downstream PERK- eIF2α-ATF4-CHOP signaling axis. This inhibition alleviated endoplasmic reticulum (ER) stress and mitochondrial dysfunction, ultimately exerting a protective effect. Furthermore, myricitrin mitigated oxidative stress and associated ER damage through its intrinsic antioxidant capacity, which acted in synergy with its inhibition of the PERK pathway. Collectively, our findings demonstrate that myricitrin protects against PQ-induced ALI primarily through inhibition of the PERK signaling pathway, thereby suppressing the ER stress and mitochondrial-mediated apoptosis, supporting its therapeutic potential for this life-threatening condition.
proteins
2026-07-27 | Targeted Delivery of Bilirubin to Pulmonary Endothelium Mitigates Paraquat-Induced Lung Injury.
Paraquat (PQ) poisoning causes high mortality via acute lung injury (ALI) driven by excessive reactive oxygen species (ROS) in pulmonary microvascular endothelial cells. We developed BR@Lipo-CerTP, a lung-targeted nanotherapeutic using C16-ceramide-binding peptide-modified bilirubin liposomes, to enhance endothelial delivery and treat PQ-induced ALI. BR@Lipo-CerTP was characterized for physicochemical properties and cellular uptake in pulmonary microvascular endothelial cells (PMVECs). In vitro efficacy was assessed via cytotoxicity, apoptosis, ROS, antioxidant capacity, and mitochondrial function assays in PQ-exposed PMVECs. Multi-omics analysis elucidated therapeutic mechanisms. In vivo efficacy and biosafety were evaluated in a PQ-induced ALI mouse model through survival, histopathology, edema, and toxicity assessments. BR@Lipo-CerTP exhibited uniform ~120 nm spherical morphology, narrow size distribution, excellent stability, and enhanced PMVEC uptake versus non-targeted liposomes. In vitro, it significantly attenuated PQ-induced cytotoxicity, apoptosis, and ROS accumulation while restoring antioxidant capacity and mitochondrial function. Multi-omics revealed it disrupts a vicious cycle of glutathione depletion, ferroptosis, and NF-κB/NLRP3-driven inflammation, resetting pathological crosstalk between redox homeostasis, regulated cell death, and immune activation. In vivo, BR@Lipo-CerTP markedly improved survival, alleviated pulmonary damage and edema, suppressed oxidative stress and inflammation, with no systemic toxicity. Pulmonary endothelial-targeted bilirubin delivery effectively mitigates PQ-induced ALI by coordinately regulating redox balance, cell death, and inflammation. This strategy offers a promising nanotherapeutic for PQ poisoning and other ROS-driven pulmonary diseases, highlighting targeted nanomedicine's potential in toxicological emergencies.
2025-01-03 | Proteomic characterization of molecular mechanisms of paraquat-induced lung injury in a mouse model.
We sought to explore the molecular mechanisms underpinning acute lung injury (ALI) caused by poisoning with paraquat (PQ). Selection mice were intraperitoneally injected with PQ at 40 mg/kg, whereas controls were injected with sterile saline. On days 2, 7, and 14 after administration, mice were anesthetized and sacrificed, and lung tissue was removed. Lung pathological changes were observed with conventional staining techniques. Lung tissue components were assessed with tandem mass spectrometry tag technology, and differentially expressed proteins (DEPs) were bioinformatically analyzed and investigated with parallel reaction monitoring. The expression of 91, 160, and 78 proteins was significantly altered at days 2, 7, and 14, respectively. Gene Ontology analyses revealed that the DEPs in the PQ-2d and PQ-7d groups were involved primarily in humoral immunity and coagulation-related reactions, whereas those in the PQ-14d group were implicated primarily in chemotactic and regulatory responses. Kyoto Encyclopedia of Genes and Genomes analyses indicated that complement and coagulation cascades were key pathways in the PQ-2d and PQ-7d groups, whereas xenobiotic metabolism by cytochrome P450 was a key pathway in the PQ-14d group. Nine proteins at PQ-2d and eight proteins at PQ-7d were validated through parallel reaction monitoring (PRM). PQ-induced ALI depends on over-activation of immune responses by damaged alveolar/endothelial cells, and the complement/coagulation cascade pathway plays a key role during this process. The proteins identified herein might provide new therapeutic targets or biomarkers for PQ poisoning.
2024-08-15 | Synaptotagmin-1 antagonizes paraquat intracellular accumulation and nephrocyte toxicity by up-regulating SERBP1/GLUT2 expression.
Acute kidney injury (AKI) is common and an independent risk factor for mortality in patients with paraquat (PQ) poisoning. Currently, no specific antidote is available. Synaptotagmin-1 (SYT1) has been identified as a key protein that facilitates PQ efflux in PQ-resistant A549 cells, thereby preventing PQ-induced lung injury. However, the protective effect of STY1 on PQ-induced AKI remains to be elucidated. This study exposed human kidney 2 (HK-2) cells overexpressing SYT1 to PQ. These cells exhibited significantly lower levels of growth inhibition, reactive oxygen species production, early apoptosis, and PQ accumulation compared to the parent HK-2 cells. Transcriptomic screening and Western blot analysis revealed that SYT1 overexpression significantly promoted the expression of glucose transporter 2 (GLUT2). Inhibition of GLUT2 completely abolished the protective effects of SYT1 overexpression in HK-2 cells and restored intracellular PQ concentrations. Further immunoprecipitation-shotgun and RNA interference experiments revealed that SYT1 binds to and stabilizes the protein SERPINE1 mRNA-binding protein 1 (SERBP1), enhancing the stability of GLUT2 mRNA and its protein levels. In summary, SYT1 antagonizes PQ intracellular accumulation and prevents nephrocyte toxicity by up-regulating SERBP1/GLUT2 expression. This study identifies a potential target for the treatment of PQ-induced AKI.
2024-07-14 | Schistosoma japonicum cystatin alleviates paraquat poisoning caused acute lung injury in mice through activating regulatory macrophages.
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. 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. 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. 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.
2022-01-20 | Combined effect of reduced glutathione and ulinastatin on the expressions of IL-6, sIL-6 and sgp130 in peripheral blood of paraquat-poisoned patients
Purpose: To investigate the effect of reduced glutathione and ulinastatin on the expressions of interleukin-6 (IL-6), soluble interleukin-6 receptor (sIL-6R), and soluble glycoprotein 130 (sgp130) in peripheral blood of paraquat-poisoned patients.
Methods: In this retrospective study, 88 patients with paraquat poisoning admitted to Dongying People's Hospital, Dongying, China from February 2017 to October 2020 were divided into control group (n = 40) and study group (n = 48), based on treatment type. The control group received conventional treatments, while the study group was given reduced glutathione in combination with ulinastatin. Treatment efficacy and peripheral blood expression levels were compared.
Results: Compared to the control group, curative effect was significantly higher in the study group (p < 0.05). The expression levels of IL-6, sIL-6R, and sgp130 in the peripheral blood at the early, middle and late periods in the study group were markedly lower. The number of patients with flake-like or dotted opacity, increased lung texture, pleural effusion and ground glass opacity in the study group during the early period was lower (p < 0.05). Moreover, the number of patients with pulmonary edema, fibrous cord, pleural effusion, ground glass opacity and reticular opacity during the middle period was markedly lower for the study group, while the population of patients with honeycomb lung, fibrous cord, nodules and reticular opacity in the study group was higher t (p < 0.05).
Conclusion: A combination of reduced glutathione and ulinastatin produces significant therapeutic effect on paraquat poisoning by down-regulating the serum expressions of IL-6, sIL-6 and sgp130, inhibiting inflammation, and mitigating pulmonary lesions.
cell therapies
2026-08-12 | Urine Dithionite-guided Hemoperfusion in Acute Paraquat Poisoning: A Retrospective Observational Study from South India.
Paraquat (PQ) poisoning has a mortality rate of 50-90% with no specific antidote. Hemoperfusion (HP) is used for PQ removal, but evidence for its efficacy is limited, and optimal strategies for guiding HP remain poorly defined. The study aims to describe a urine sodium dithionite test (UDT)-guided HP protocol and evaluate clinical outcomes in patients with acute PQ poisoning. A retrospective observational study of 27 consecutive patients with acute PQ poisoning admitted to a tertiary intensive care unit (ICU) in South India was conducted. Serial UDT was used to guide HP initiation, continuation, and cessation. Clinical data, treatment details, and outcomes were analyzed. Survivors and non-survivors were compared. Mean age was 30.5 ± 11.2 years (74.1% male). Fourteen patients (51.9%) survived. Ingestion-to-door (I-to-D) time ≤4 h was present in 71.4% of survivors vs 20% of non-survivors. Urine sodium dithionite test negative conversion within 10 h occurred in 77.8% of survivors vs 16.7% of non-survivors. Survivors received more HP sessions (mean: 3.3 vs 2.6). Acute kidney injury (AKI) occurred in 80% of non-survivors vs 14.3% of survivors. Early presentation combined with a UDT-guided HP protocol was associated with favorable outcomes. Serial UDT provides a practical, low-cost tool for guiding extracorporeal treatment (ECTR) in resource-limited settings. The UDT-guided HP protocol offers intensivists a bedside decision-making tool that replaces costly plasma PQ assays, enabling evidence-based ECTR decisions in Indian ICU settings where quantitative assays are unavailable.
2026-07-28 | Clinical Characteristics and Prognostic Factors of Patients with Acute Poisoning: A Retrospective Observational Cohort Study of Diquat, Single-Drug and Mixed-Drug Exposures.
Acute poisoning remains a major emergency and toxicology problem, but its clinical pattern differs by toxin type and local availability. Diquat poisoning is increasingly reported where paraquat use has been restricted, whereas metamizole exposure remains relevant in regions where dipyrone remains clinically available. This retrospective observational cohort study described clinical characteristics, treatment patterns and prognostic factors in acute poisoning involving diquat, single-drug pharmaceutical exposure and mixed-drug exposure. We analysed 385 adults with confirmed acute poisoning treated at a single tertiary toxicology centre from January to June 2025. Patients were classified as Group A (diquat, n = 125), Group B (single-drug poisoning, predominantly metamizole, n = 143) or Group C (mixed-drug poisoning, n = 117). Baseline features, laboratory findings, interventions and 30-day outcomes were compared. A presentation-based logistic regression model assessed mortality predictors, and early haemoperfusion was analysed separately in the diquat subgroup. Group A had the highest 30-day mortality (28.8%) compared with Group B (5.6%) and Group C (14.5%) (p < 0.001). Liver injury, renal dysfunction, cardiac biomarker elevation, lactate elevation and acidosis were most pronounced after diquat exposure. In the diquat subgroup, haemoperfusion within 6 hours was associated with lower mortality than delayed haemoperfusion (17.1% vs 47.6%, p < 0.001), including after propensity score matching. Diquat poisoning, delayed presentation, low Glasgow Coma Scale score, hypotension, elevated lactate, renal dysfunction, acidosis and early multi-organ dysfunction were associated with mortality. Acute poisoning showed heterogeneous clinical patterns by toxic agent category. Diquat poisoning carried the greatest mortality and multi-organ injury, whereas mixed-drug poisoning showed intermediate severity. Early haemoperfusion was associated with improved outcomes in diquat poisoning, but causal interpretation is limited by the retrospective design; prospective multicentre validation is needed.
2026-05-01 | C62-16 World’s Youngest Successful Lung Transplantation in a 12 Year Old Boy With Paraquat Induced Pulmonary Fibrosis: A Rare Case Report
Abstract Introduction Paraquat, a rapidly active herbicide can cause multiorgan dysfunction with a mortality rate of 40 - 80 %. Current clinical treatments for paraquat poisoning are only supportive and advancement of pulmonary disease is incurable in most cases. Case Report: A 12-year-old boy presented to intensive care unit with multiple episodes of vomiting and progressive breathlessness following accidental ingestion of approximately 50 mL of Paraquat. Initial evaluation showed renal and hepatic dysfunction and baseline respiratory parameters revealed tachycardia with SpO2: 84 % on room air. Immediate gastric lavage was performed, and hemoperfusion was initiated. Liver and renal parameters gradually normalized over a period of 10 days. Respiratory function continued to deteriorate requiring HFNC and HRCT thorax revealed progressive fibrotic lung injury. In view of worsening PaO2/FiO2 ratios, patient eventually required invasive mechanical ventilation, and subsequently, VV-ECMO was initiated on day 52 post-paraquat consumption. After multidisciplinary discussion by a team of pulmonologists, pediatric intensivist and thoracic surgeon, the option of bilateral lung transplantation was considered. Serial urine paraquat levels were negative prior to consideration for transplantation. After 2 months of paraquat ingestion, the patient underwent bilateral sequential lobar lung transplantation via bilateral anterolateral thoracotomy under ECMO support. Immunosuppression was initiated with steroid and mycophenolate mofetil (MMF), followed by maintenance triple immunosuppression (steroids, MMF and tacrolimus) along with prophylaxis for opportunistic infections. Patient was successfully decannulated from ECMO on post operative day 2 and gradually weaned off mechanical ventilation on post operative day 7. Three months post lung transplantation the patient is stable with good graft function and no evidence of rejection. Discussion This case represents the youngest reported survivor of lung transplantation for paraquat-induced pulmonary fibrosis. Lung transplantation remains the only definitive and effective therapeutic option for paraquat induced irreversible respiratory failure. The case underscores the importance of timely referral to a transplant centre, and a multidisciplinary approach. This abstract is funded by: None
2025-09-02 | Lung Transplantation Following Paraquat Poisoning: Time to Think.
Paraquat, a commonly available herbicide, when consumed in high doses, affects organs with high blood flow (lungs, heart, kidney and liver), leading to pulmonary fibrosis, respiratory failure and death. Few reports of rescue lung transplantation exist. Complete depletion of paraquat from the body is necessary prior to transplant; however, timing for and concerns after lung transplantation remain unknown. We report 2 patients (median age 19 years) with severe respiratory failure requiring extracorporeal membrane oxygenation support, acute kidney injury requiring haemodialysis and acute liver injury in the pre-transplant period. Volume of paraquat consumption was more than 30 mL and PF ratio less than 100 before transplant. Once their urine paraquat level was negative (median time 32 days), both underwent bilateral lung transplantation after receiving an induction agent with basiliximab and were continued on triple immunosuppressant following the transplant. With reported mortality rates reaching up to 90%, lung transplantation remains a reasonable option for patients with paraquat poisoning not responding to conventional treatment options. Once paraquat levels are negative and after optimising renal and liver function, these patients could be considered for bilateral lung transplantation and have successful outcomes as reported here.
2025-08-11 | Retrospective Study of Paraquat Poisoning in the Khandesh Region: Clinical Outcomes and Mortality Predictors
Introduction:Paraquat is a widely used non-selective herbicide in India, especially in rural agricultural regions, and is associated with high morbidity and mortality due to the absence of a specific antidote and rapid progression to multi-organ failure [1]. In North Maharashtra, agricultural dependency, easy availability of paraquat, and limited awareness of its toxicity contribute to frequent accidental or intentional exposures. This study was conducted to evaluate the demographic, clinical, laboratory, and treatment profiles of paraquat poisoning patients, along with their outcomes, to generate evidence for improving prevention and management strategies. Methodology:A hospital-based observational study was conducted at a tertiary care center in North Maharashtra, including 34 confirmed cases of paraquat poisoning admitted during the study period. Data were collected from patient medical records and included demographic details, presenting clinical signs, postmortem findings where applicable, laboratory investigations, treatment modalities, and outcomes. Statistical analysis was performed to determine the frequency and percentage distribution of variables. Results:The majority of patients were males (64.7%) and farmers (61.8%), with the highest incidence in the 21–30 years (23.5%) and 31–40 years (20.6%) age groups. Oral ulcers/mucosal burns were observed in 41.7% of cases, lung congestion in 58.3%, and kidney congestion in 52.8%. Laboratory abnormalities included elevated AST/ALT in 38.2%, hyperbilirubinemia (>2 mg/dL) in 41.2%, elevated creatinine in 52.9%, and low hemoglobin in 44.1%. Steroids were administered to 58.8% of patients, cyclophosphamide to 17.6%, and dialysis to 8.8%, while hemoperfusion was rarely used (2.9%). The overall in-hospital mortality was 61.8%, with multiorgan failure (71.4% of deaths) as the leading cause, followed by acute kidney injury (23.8%) and acute lung injury (4.8%). Conclusion:Paraquat poisoning in North Maharashtra predominantly affects young male farmers and carries a high mortality rate despite medical intervention. The study highlights the need for stricter regulation of paraquat sales, farmer education on its hazards, and improved access to advanced therapeutic measures such as hemoperfusion to reduce mortality.
oligonucleotides
2024-03-26 | Exosomes from senescent epithelial cells activate pulmonary fibroblasts via the miR-217-5p/Sirt1 axis in paraquat-induced pulmonary fibrosis
Abstract 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.
2024-03-07 | Integrated analysis of ceRNA-miRNA changes in paraquat-induced pulmonary epithelial-mesenchymal transition via high-throughput sequencing.
Recent studies have shown that epithelial-mesenchymal transition (EMT) plays an important role in paraquat (PQ)-induced tissue fibrosis, which is the main cause of death in patients with PQ poisoning. However, no effective treatment for pulmonary interstitial fibrosis caused by PQ poisoning exists. It is of great significance for us to find new therapeutic targets through bioinformatics in PQ-induced EMT. We conducted transcriptome sequencing to determine the expression profiles of 1210 messenger RNAs (mRNAs), 558 long noncoding RNAs, 28 microRNAs (miRNAs), including 18 known-miRNAs, 10 novel-miRNAs and 154 circular RNAs in the PQ-exposed EMT group mice. Using gene ontology and Kyoto Encyclopaedia of Genes and Genomes analyses, we identified the pathways associated with signal transduction, cancers, endocrine systems and immune systems were involved in PQ-induced EMT. Furthermore, we constructed long noncoding RNA-miRNA-mRNA interrelated networks and found that upregulated genes included Il22ra2, Mdm4, Slc35e2 and Angptl4, and downregulated genes included RGS2, Gabpb2, Acvr1, Prkd3, Sp100, Tlr12, Syt15 and Camk2d. Thirteen new potential competitive endogenous RNA targets were also identified for further treatment of PQ-induced pulmonary tissue fibrosis. Through further study of the pathway and networks, we may identify new molecular targets in PQ-induced pulmonary EMT.
2023-11-06 | Effect of WISP1 on paraquat-induced EMT.
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. 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. 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. Knockdown of WISP1 inhibited PQ-induced EMT in A549 cells. This conclusion might provide a new therapeutic target for PQ poisoning treatment.
2023-10-01 | Analysis of Human microRNA Expression Profiling During Diquat-Induced Renal Proximal Tubular Epithelial Cell Injury
We established a diquat-induced human kidney-2 cells (HK-2 cells) apoptosis model in this study to identify differentially expressed microRNAs (miRNAs) and signaling pathways involved in diquat poisoning via gene sequencing and bioinformatics analysis and explored the related therapeutic benefits.The effects of diquat on the viability and apoptosis of HK-2 cells were explored using the CCK-8 and Annexin V-FITC/PI double staining methods. Total RNAs were extracted using the TRizol method and detected by Illumina HiSeq 2500. Bioinformatics analysis was performed to explore differentially expressed (DE) miRNAs, their enriched biological processes, pathways, and potential target genes. The RT-qPCR method was used to verify the reliability of the results.Diquat led to HK-2 cell injury and apoptosis played an important role, hence an HK-2 cell apoptosis model in diquat poisoning was established. Thirty-six DE miRNAs were screened in diquat-treated HK-2 cells. The enriched biological process terms were mainly cell growth, regulation of apoptotic signaling pathway, extrinsic apoptotic signaling pathway, and Ras protein signal transduction. The enriched cellular components were mainly cell-cell junction, cell-substrate junction, ubiquitin ligase complex, and protein kinase complex. The enriched molecular functions were mainly Ras GTPase binding, ubiquitin-like protein transferase activity, DNA-binding transcription factor binding, ubiquitin-protein transferase activity, nucleoside-triphosphatase regulator activity, transcription coactivator activity, and ubiquitin-like protein ligase binding. Signaling pathways such as MAPK, FoxO, Ras, PIK3-Akt, and Wnt were also enriched.These findings aid in understanding the mechanisms of diquat poisoning and the related pathways, where DE miRNAs serve as targets for gene therapy.
2023-09-20 | Microglia-derived exosomal circZNRF1 alleviates paraquat-induced neuronal cell damage via miR-17-5p.
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.
other
2022-09-20 | Identification of differentially expressed genes and pathways in diquat and paraquat poisoning using bioinformatics analysis.
In this study, differentially expressed genes (DEGs) and signaling pathways involved in diquat (DQ) and paraquat (PQ) poisoning were identified via bioinformatics analysis, in order to inform the development of novel clinical treatments. Raw data from GSE153959 were downloaded from the Gene Expression Omnibus database. DEGs of the DQ vs. control (CON) and PQ vs. CON comparison groups were identified using R, and DEGs shared by the two groups were identified using TBtools. Subsequently, the shared DEGs were searched in the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, using the Database for Annotation, Visualization, and Integrated Discovery. A protein-protein interaction (PPI) network was constructed, and hub genes were identified using the cytoHubba plug-in in Cytoscape software. Finally, circos and contrast plots showing the DEGs shared between mouse and human chromosomes were constructed using TBtools. Thirty-one DEGs shared by the DQ and PQ groups were identified. Enriched biological process terms included positive regulation of cell proliferation and translation. Enriched cellular component terms included extracellular region, intracellular membrane-bounded organelle and mitochondrion. Enriched molecular function terms included transcription factor activity and sequence-specific double-stranded DNA binding. Enriched KEGG pathways included the interleukin-17 signaling pathway, tumor necrosis factor signaling pathway, and human T-cell leukemia virus 1 infection. The top 10 hub genes in the PPI network were prostaglandin-endoperoxide synthase 2 (Ptgs2), chemokine (C-X-C motif) ligand 2 (Cxcl2), colony-stimulating factor 2 (granulocyte-macrophage) (Csf2), matrix metallopeptidase 13 (Mmp13), amphiregulin (Areg), plasminogen activator, urokinase receptor (Plaur), fos-like antigen 1 (Fosl1), epiregulin (Ereg), activating transcription factor 3 (Atf3), and transferrin receptor (Tfrc). Cxcl2, Csf2, and Atf3 played important roles in the mitogen-activated protein kinase (MAPK) signaling pathway. These pathways and DEGs may serve as targets for gene therapy.
2022-03-24 | Tenascin-C Participates Pulmonary Injury Induced by Paraquat Through Regulating TLR4 and TGF-β Signaling Pathways.
This study was conducted to investigate the role of Tenascin-C (TNC) in paraquat (PQ)-induced lung injury in vivo and in vitro and explore its related mechanism during this process. Six- to eight-week-old male C57BL/6 mice were injected with 30 mg/kg PQ by intraperitoneal injection and sacrificed on 2 days, 7 days, 14 days, and 28 days after PQ administration. In vivo, we detected the expression of TNC at all time points of lung tissues in mice by reverse transcription-quantitative-polymerase chain reaction, western blotting, and immunohistochemistry. Expression of TLR4, NF-κB p65, TGF-β1, and α-SMA in lung tissues have also been tested. In vitro, siRNA was used to knock down TNC expression in A549 cells and TLR4, NF-κB p65, and TGF-β1 expressions were examined after PQ exposure. TNC expression increased in both lung tissues of mice model and A549 cells after PQ administration. In vivo, TNC mostly located at the extracellular matrix of thickened alveolar septum, especially at sites of injury, together with the increasing of TLR4, NF-κB p65, TGF-β1, and α-SMA. In vitro, PQ exposure also increased the expressions of TLR4, NF-κB p65, and TGF-β1 in A549 cells, but knocking down TNC gene expression obviously down-regulated the expressions of TLR4, NF-κB p65, NF-κB Pp65, and TGF-β1. The results of this study demonstrate, for the first time, that TNC participates in the development of lung injury induced by PQ poisoning. The role of TNC in this process is closely related to TLR4 and TGF-β signaling pathways.
2021-05-28 | Depletion of NK cells attenuates paraquat-induced acute lung injury by manipulating macrophage polarization.
Acute lung injury is the main causative factor in paraquat dichloride (PQ)-induced mortality. The innate immune system-triggered detrimental inflammatory cascade plays a vital role in PQ-induced acute lung injury. However, the role of natural killer (NK) cells, which are essential for innate response, in PQ-induced acute lung injury remains largely unknown. Here, we found that in an acute PQ poisoning model, depletion of NK cells attenuated PQ-induced lung injury by inhibiting macrophage polarization towards the M1 type. Specifically, the percentages of NK cells were reduced in the lung, spleen, and peripheral blood in a murine model of acute PQ poisoning. NK cells were aberrantly activated, evidenced by upregulation of the activating markers CD69, CD107a, and NKG2D and downregulation of the inhibitive marker KLRG1. Further, NK-specific depletion in mice greatly prolonged the survival time and ameliorated reactive oxygen species-induced damage following PQ treatment compared with the control group. Importantly, NK cell depletion alleviated macrophage and neutrophil infiltration in the lung and reversed PQ induced-macrophage polarization towards the pro-inflammatory M1 type. Our study demonstrates a crucial role of NK cells and NK cell-to-macrophage interaction in PQ-induced acute lung injury.
2018-12-14 | Effects of paraquat on IL‑6 and TNF‑α in macrophages
Effects of paraquat (PQ) on interleukin‑6 (IL‑6) and tumor necrosis factor‑α (TNF‑α) in macrophages were investigated. Different concentrations of PQ were added to mouse macrophage RAW264.7 for culture. According to different concentrations of PQ, mice were divided into micro concentration (0.01 mmol/l), low concentration (0.1 mmol/l), medium concentration (1 mmol/l), high concentration (10 mmol/l), and control groups without PQ. Trypan blue solution was used for detecting cell viability, a microplate reader for detecting the fluorescence intensity of reactive oxygen species (ROS), ELISA for detecting the expression levels of IL‑6 and TNF‑α. The medium concentration and the high concentration groups had significantly lower cell viability than the other three groups (P<0.050). The high concentration group had significantly lower cell viability than the medium concentration group (P<0.050). At 1, 4 and 8 h, respectively, the medium and the high concentration groups had significantly higher ROS fluorescence intensity than the other three groups (P<0.050). The high concentration group had significantly higher ROS fluorescence intensity than the medium concentration group (P<0.050). There were significant differences in the expression levels of IL‑6 and TNF‑α at the 1st, 4th and 8th hour among the five groups (P<0.050). In the micro, the low, the medium and high concentration groups, the expression levels of IL‑6 and TNF‑α were the lowest at 1 h and the highest at 8 h, which were higher at 4 h than those at 1 h (P<0.050). PQ at a concentration of 1 mmol/l can produce toxicity to macrophages, and greatly increase the ROS fluorescence intensity, the expression levels of IL‑6 and TNF‑α. PQ poisoning is expected to be treated though IL‑6 and TNF‑α in the future.
2018-12-04 | Nrf2 overexpression protects against paraquat‑induced A549 cell injury primarily by upregulating P‑glycoprotein and reducing intracellular paraquat accumulation
Paraquat (PQ) intoxication causes thousands of mortalities every year, worldwide. Its pulmonary-targeted accumulation and the acute lung injury it subsequently causes, remain a challenge for detoxification treatment. A previous study has demonstrated that the upregulation of nuclear factor erythroid-2 related factor 2 (Nrf2) prevents PQ toxicity in cell line and murine models. As Nrf2 target genes include a group of membrane transporters, the current study assessed the protective mechanism exerted by Nrf2 against PQ toxicity and intracellular PQ accumulation via its effects on P-glycoprotein (P-gp), a downstream transporter of Nrf2. Adenovirus vectors containing the Nrf2 gene were transfected into A549 cells. Cell proliferation was assessed by Cell Counting Kit-8. The levels of LDH, MDA, SOD, TNF-α, IL-6 levels were detected using their respective ELISA kits. In addition, the levels of Nrf2 and P-gp protein expression were detected by western blot analysis. The concentration of PQ was measured by HPLC. The results revealed that overexpressed Nrf2 significantly increased P-gp protein levels, decreased the intracellular accumulation of PQ and attenuated PQ-induced toxicity. However, the protective effects of Nrf2 overexpression on PQ-challenged A549 cells were abrogated following cyclosporine A treatment, a competitive inhibitor of P-gp, which also increased intracellular PQ levels. These data indicated that Nrf2 gene overexpression prevented PQ toxicity in A549 cells, potentially via the upregulation of P-gp activity and the inhibition of intracellular PQ accumulation. Thus, Nrf2 and P-gp may serve as potential therapeutic targets for the treatment of PQ-induced injury.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
0 orphan drug designations.
0 orphan drug designations.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.