-
Current Research in Toxicology 2024Full treatment of the second most common neurodegenerative disorder, Parkinson's disease (PD), is still considered an unmet need. As the psychostimulants, amphetamine...
Full treatment of the second most common neurodegenerative disorder, Parkinson's disease (PD), is still considered an unmet need. As the psychostimulants, amphetamine (AMPH) and methylphenidate (MPH), were shown to be neuroprotective against stroke and other neuronal injury diseases, this study aimed to evaluate their neuroprotective potential against two dopaminergic neurotoxicants, 6-hydroxydopamine (6-OHDA) and paraquat (PQ), in differentiated human dopaminergic SH-SY5Y cells. Neither cytotoxicity nor mitochondrial membrane potential changes were seen following a 24-hour exposure to either therapeutic concentration of AMPH or MPH (0.001-10 μM). On the other hand, a 24-hour exposure to 6-OHDA (31.25-500 μM) or PQ (100-5000 μM) induced concentration-dependent mitochondrial dysfunction, assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, and lysosomal damage, evaluated by the neutral red uptake assay. The lethal concentrations 25 and 50 retrieved from the concentration-toxicity curves in the MTT assay were 99.9 µM and 133.6 µM for 6-OHDA, or 422 µM and 585.8 µM for PQ. Both toxicants caused mitochondrial membrane potential depolarization, but only 6-OHDA increased reactive oxygen species (ROS). Most importantly, PQ-induced toxicity was partially prevented by 1 μM of AMPH or MPH. Nonetheless, neither AMPH nor MPH could prevent 6-OHDA toxicity in this experimental model. According to these findings, AMPH and MPH may provide some neuroprotection against PQ-induced neurotoxicity, but further investigation is required to determine the exact mechanism underlying this protection.
PubMed: 38562456
DOI: 10.1016/j.crtox.2024.100165 -
Analytical Methods : Advancing Methods... Apr 2024The presence of paraquat in the environment poses a danger to human health, leading to a growing demand for an uncomplicated and highly responsive method to detect...
The presence of paraquat in the environment poses a danger to human health, leading to a growing demand for an uncomplicated and highly responsive method to detect paraquat. This work reports a new, simple, and sensitive colorimetric aptasensor based on the designed aptamers containing 1-5 paraquat binding sites (R1-R5) in combination with gold nanoparticles (AuNPs). Although the aptamers with more binding sites exhibited greater paraquat interaction capability, the aptasensor based on the R3 aptamer showed the highest detection sensitivity for paraquat in a linear range of 5-50 nM with a limit of detection of 1.29 nM, meaning that it is 2.14 fold more sensitive than the R1-aptasensor. This R3-aptasensor selectively detected paraquat but not the other tested herbicides, including difenzoquat, 2,4-D, ametryn, atrazine, and glufosinate. Also, it efficiently detected paraquat spiked in water samples within the precision acceptance criterion of recovery rates (96.8-105.0%) and the relative standard deviations (1.50-3.81%). These results demonstrated the development of a new aptasensor for paraquat detection, in which the multiple paraquat binding sites of the aptamers could enhance detection sensitivity.
Topics: Humans; Gold; Paraquat; Metal Nanoparticles; Aptamers, Nucleotide; Colorimetry
PubMed: 38562104
DOI: 10.1039/d4ay00053f -
SAGE Open Medical Case Reports 2024Paraquat, a highly toxic herbicide, accounts for a substantial number of poisoning-related fatalities, primarily prevalent in agricultural regions. The ingestion gives...
Paraquat, a highly toxic herbicide, accounts for a substantial number of poisoning-related fatalities, primarily prevalent in agricultural regions. The ingestion gives rise to severe complications affecting various organs, including the lungs, gastrointestinal tract, kidneys and liver. This report details the case of an 18-year-old male who had been using cannabis for a year and inadvertently ingested paraquat. He presented at the emergency room exhibiting symptoms of vomiting characterized by hematemesis and regurgitated food particles, along with heartburn, dysphagia and reduced urine output. Given the absence of a specific antidote, the prognosis for paraquat poisoning remains generally unfavourable. Diagnosis relies on circumstantial evidence and clinical manifestations, necessitating a focus on supportive care. Presently, no specific antidote for paraquat poisoning is available. Efforts should concentrate on preventive measures, efficient decontamination strategies and vigilant stabilization protocols in instances of exposure.
PubMed: 38559410
DOI: 10.1177/2050313X241240098 -
Plant Cell Reports Apr 2024The CcGRXS12 gene protects plants from cellular oxidative damage that are caused by both biotic and abiotic stresses. The protein possesses GSH-disulphide oxidoreductase...
The CcGRXS12 gene protects plants from cellular oxidative damage that are caused by both biotic and abiotic stresses. The protein possesses GSH-disulphide oxidoreductase property but lacks Fe-S cluster assembly mechanism. Glutaredoxins (Grxs) are small, ubiquitous and multi-functional proteins. They are present in different compartments of plant cells. A chloroplast targeted Class I GRX (CcGRXS12) gene was isolated from Capsicum chinense during the pepper mild mottle virus (PMMoV) infection. Functional characterization of the gene was performed in Nicotiana benthamiana transgenic plants transformed with native C. chinense GRX (Nb:GRX), GRX-fused with GFP (Nb:GRX-GFP) and GRX-truncated for chloroplast sequences fused with GFP (Nb:Δ2MGRX-GFP). Overexpression of CcGRXS12 inhibited the PMMoV-I accumulation at the later stage of infection, accompanied with the activation of salicylic acid (SA) pathway pathogenesis-related (PR) transcripts and suppression of JA/ET pathway transcripts. Further, the reduced accumulation of auxin-induced Glutathione-S-Transferase (pCNT103) in CcGRXS12 overexpressing lines indicated that the protein could protect the plants from the oxidative stress caused by the virus. PMMoV-I infection increased the accumulation of pyridine nucleotides (PNs) mainly due to the reduced form of PNs (NAD(P)H), and it was high in Nb:GRX-GFP lines compared to other transgenic lines. Apart from biotic stress, CcGRXS12 protects the plants from abiotic stress conditions caused by HO and herbicide paraquat. CcGRXS12 exhibited GSH-disulphide oxidoreductase activity in vitro; however, it was devoid of complementary Fe-S cluster assembly mechanism found in yeast. Overall, this study proves that CcGRXS12 plays a crucial role during biotic and abiotic stress in plants.
Topics: Capsicum; Glutaredoxins; Hydrogen Peroxide; Oxidation-Reduction; Disulfides; Tobamovirus
PubMed: 38557872
DOI: 10.1007/s00299-024-03174-2 -
PloS One 2024Syzygium heyneanum is a valuable source of flavonoids and phenols, known for their antioxidant and neuroprotective properties. This research aimed to explore the...
Syzygium heyneanum is a valuable source of flavonoids and phenols, known for their antioxidant and neuroprotective properties. This research aimed to explore the potential of Syzygium heyneanum ethanol extract (SHE) in countering Parkinson's disease. The presence of phenols and flavonoids results in SHE displaying an IC50 value of 42.13 when assessed in the DPPH scavenging assay. Rats' vital organs (lungs, heart, spleen, liver, and kidney) histopathology reveals little or almost no harmful effect. The study hypothesized that SHE possesses antioxidants that could mitigate Parkinson's symptoms by influencing α-synuclein, acetylcholinesterase (AChE), TNF-α, and IL-1β. Both in silico and in vivo investigations were conducted. The Parkinson's rat model was established using paraquat (1 mg/kg, i.p.), with rats divided into control, disease control, standard, and SHE-treated groups (150, 300, and 600 mg/kg) for 21 days. According to the ELISA statistics, the SHE treated group had lowers levels of IL-6 and TNF-α than the disease control group, which is a sign of neuroprotection. Behavioral and biochemical assessments were performed, alongside mRNA expression analyses using RT-PCR to assess SHE's impact on α-synuclein, AChE, TNF-α, and interleukins in brain homogenates. Behavioral observations demonstrated dose-dependent improvements in rats treated with SHE (600 > 300 > 150 mg/kg). Antioxidant enzyme levels (catalase, superoxide dismutase, glutathione) were significantly restored, particularly at a high dose, with notable reduction in malondialdehyde. The high dose of SHE notably lowered acetylcholinesterase levels. qRT-PCR results indicated reduced mRNA expression of IL-1β, α-synuclein, TNF-α, and AChE in SHE-treated groups compared to disease controls, suggesting neuroprotection. In conclusion, this study highlights Syzygium heyneanum potential to alleviate Parkinson's disease symptoms through its antioxidant and modulatory effects on relevant biomarkers.
Topics: Humans; Rats; Animals; Antioxidants; Paraquat; Parkinson Disease; alpha-Synuclein; Syzygium; Acetylcholinesterase; China; Tumor Necrosis Factor-alpha; Rodentia; Ethnicity; Plant Extracts; Phenols; Flavonoids; RNA, Messenger; Oxidative Stress
PubMed: 38551975
DOI: 10.1371/journal.pone.0298986 -
Environmental Pollution (Barking, Essex... May 2024With the evidence emerging that abnormal expression of long noncoding RNAs (lncRNAs) are involved in onset of Parkinson's disease (PD), the role of NR_030777...
With the evidence emerging that abnormal expression of long noncoding RNAs (lncRNAs) are involved in onset of Parkinson's disease (PD), the role of NR_030777 contributing to this disease is of great interest. We recently found that a novel lncRNA "NR_030777" demonstrates protective effects on PQ-induced neurodegeneration. However, the underlying molecular mechanisms of NR_030777 in the regulation of mitochondrial fission and mitophagy involved in PQ-induced neuronal damage remain to be explored. NR_030777 brain conditional overexpressing mice as well as in vitro primary neuronal cells from cerebral cortex and Neuro2a cells were adopted. Immunofluorescence, Immunohistochemistry, qRT-PCR and Western blotting were used to evaluate the expression levels of RNA and proteins. RNA immunoprecipitation and RNA pulldown experiment were used to evaluate the interaction of NR_030777 with its target proteins. NR_030777 and mitophagy were increased, and tyrosine hydroxylase (TH) levels recovered after NR_030777 overexpression upon PQ treatment. The overexpression and knockdown of NR_030777 unveiled that NR_030777 positively regulated mitophagy such as the upregulation of LC3B-II:I, ATG12-ATG5, p62 and NBR1. Moreover, the application of mdivi-1, a DRP-1 inhibitor, in combination with NR_030777 genetic modified cells unveiled that NR_030777 promoted DRP1-mediated mitochondrial fission and mitophagy. Furthermore, NR_030777 were directly bound to CDK1 to increase p-DRP1 levels at the Ser616 site, leading to mitochondrial fission and mitophagy. On the other hand, NR_030777 acted directly on ATG12 within the ATG12-ATG5 complex in the 800-1400 nt region to modulate the membrane formation. Accordingly, NR_030777 deficiency in neuron cells compromised cell mitophagy. Finally, the above findings were confirmed using NR_030777-overexpressing mice. NR_030777 exerted a protective effect on PQ-exposed mice by enhancing mitophagy. Our data provide the first scientific evidence for the precise invention of PQ-induced PD. Our findings further propose a breakthrough for understanding the regulatory relationship between NR_030777, CDK1, ATG12 and mitophagy in PQ-induced PD.
Topics: Animals; Mice; CDC2 Protein Kinase; Mitochondria; Mitochondrial Dynamics; Mitophagy; Neurons; Paraquat; Parkinson Disease; RNA, Long Noncoding
PubMed: 38548152
DOI: 10.1016/j.envpol.2024.123875 -
Genes Feb 2024Heterozygous carriers of the glucocerebrosidase 1 (GBA) L444P Gaucher mutation have an increased risk of developing Parkinson's disease (PD). The GBA mutations result in...
Heterozygous carriers of the glucocerebrosidase 1 (GBA) L444P Gaucher mutation have an increased risk of developing Parkinson's disease (PD). The GBA mutations result in elevated alpha synuclein (aSyn) levels. Heterozygous mice carrying one allele with the L444P mutation knocked-into the mouse gene show increased aSyn levels and are more sensitive to motor deficits following exposure to the neurotoxin (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) MPTP than wild-type mice. Paraquat (PQ), a herbicide, increases PD risk in most studies. Its effects on the brain involve alterations in the gut microbiome. Exposure to dextran sulfate sodium (DSS), a mouse model of colitis, can be used to determine whether gut microbiome alterations are sufficient to induce PD-relevant phenotypes. We rederived the A53T-L444P and A53T mouse lines to assess whether PQ, PQ in combination with radiation exposure (IR), and DSS have differential effects in A53T and A53T-L444P mice and whether these effects are associated with alterations in the gut microbiome. PQ and PQ + IR have differential effects in A53T and A53T-L444P mice. In contrast, effects of DSS are only seen in A53T-L444P mice. Exposure and genotype modulate the relationship between the gut microbiome and behavioral performance. The gut microbiome may be an important mediator of how environmental exposures or genetic mutations yield behavioral and cognitive impacts.
Topics: Mice; Animals; Paraquat; Dextran Sulfate; Gastrointestinal Microbiome; Parkinson Disease; Glucosylceramidase; Cognition
PubMed: 38540341
DOI: 10.3390/genes15030282 -
Antioxidants (Basel, Switzerland) Mar 2024Silybin (Si) is the main element of silymarin isolated from the seeds of L. Gaernt., which has superior antioxidant properties. However, the protective role of Si in...
Silybin Alleviated Hepatic Injury by Regulating Redox Balance, Inflammatory Response, and Mitochondrial Function in Weaned Piglets under Paraquat-Induced Oxidative Stress.
Silybin (Si) is the main element of silymarin isolated from the seeds of L. Gaernt., which has superior antioxidant properties. However, the protective role of Si in maintaining liver health under oxidative stress remains ambiguous. This study aimed to investigate the underlying mechanism of the beneficial effect of dietary Si against hepatic oxidative injury induced by paraquat (PQ) in weaned piglets. A total of 24 piglets were randomly allocated to four treatments with six replicates per treatment and 1 piglet per replicate: the control group; Si group; PQ group; and Si + PQ group. Piglets in the control group and PQ group were given a basal diet, while piglets in the Si and Si + PQ groups were given a Si-supplemented diet. On the 18th day, the pigs in the PQ treatment group received an intraperitoneal injection of PQ, and the others were intraperitoneally injected with the same volume of saline. All piglets were sacrificed on day 21 for plasma and liver sample collection. The results showed that dietary Si supplementation mitigated PQ-induced liver damage, as proven by the reduction in liver pathological changes and plasma activity of alanine transaminase and aspartate transaminase. Si also improved superoxide dismutase and glutathione peroxidase activities and total antioxidant capacity, as well as decreased malondialdehyde and hydrogen peroxide concentration in the liver, which were closely related to the activation of the nuclear factor-erythroid 2-related factor 2 signaling pathway. Meanwhile, Si reduced tumor necrosis factor-α and interleukin-8 production and their transcript levels as well as abrogated the overactivation of nuclear factor-κB induced by PQ. Importantly, Si improved mitochondrial function by maintaining mitochondrial energetics and mitochondrial dynamics, which was indicated by the elevated activity of mitochondrial complexes I and V and adenosine triphosphate content, decreased expression of dynamin 1 protein, and increased expression of mitofusin 2 protein. Moreover, Si inhibited excessive hepatic apoptosis by regulating the B-cell lymphoma-2 (Bcl-2)/Bcl-2-associated-X-protein signaling pathway. Taken together, these results indicated that Si potentially mitigated PQ-induced hepatic oxidative insults by improving antioxidant capacity and mitochondrial function and inhibiting inflammation and cell apoptosis in weaned piglets.
PubMed: 38539857
DOI: 10.3390/antiox13030324 -
Toxics Mar 2024Acute poisonings (AP) are a significant public health problem, accounting for a high number of emergency department visits and thousands of deaths worldwide. This study...
BACKGROUND
Acute poisonings (AP) are a significant public health problem, accounting for a high number of emergency department visits and thousands of deaths worldwide. This study aimed to assess the epidemiology of AP in an adult population admitted to Cayenne Hospital (French Guiana) and to investigate the clinical and sociodemographic characteristics.
METHODS
We conducted a monocentric retrospective study from January 2010 to December 2022, including patients over eighteen years of age who had been admitted to the emergency department of Cayenne Hospital for acute poisoning.
RESULTS
We included 425 patients. The median age was 34 years (IQR: 25-47). The sex ratio (M/F) was 0.52. A psychiatric disorder was found in 41.9% of patients. The Poisoning Severity Score (PSS) on admission was 1 or 2 for 84% of patients, and the mortality rate was 3.9%. The main involved toxicants were psychotropic drugs (43.1%), benzodiazepines (34.8%), and paracetamol (25.6%). The most lethal toxic was paraquat (5.2%). Intoxication was due to intentional self-poisoning in 84.2% of cases. Independent factors associated with severe poisoning (PSS 3 or 4) were chloroquine, neuroleptics, or paraquat poisoning; metabolic acidosis; and hyperglycemia (>5.5 mmol/L). The mortality rate was 3.9%, and the most involved toxic in death was paraquat.
CONCLUSION
This study shows the frequent and deadly use of paraquat in APs in French Guiana. Urgent attention should be given to establishing a toxicovigilance monitoring framework and an antipoison center in the region.
PubMed: 38535933
DOI: 10.3390/toxics12030200 -
Journal of Translational Medicine Mar 2024Paraquat (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,...
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.
Topics: Humans; Mice; Animals; Pulmonary Fibrosis; Paraquat; beta Catenin; Exosomes; Sirtuin 1; Lung; MicroRNAs; Epithelial Cells; Fibroblasts
PubMed: 38532482
DOI: 10.1186/s12967-024-05094-x