Ultrasensitive quantitation of Paraquat based on a small molecule-induced dual-cycle amplification strategy.

Paraquat (PQ) is a typical biotoxic small molecule. Knowledge of how to directly introduce it into cyclic amplification rather than transform it into a secondary target is lacking in current analytical methods. Considering the urgent need for trace pesticide residue detection and the inherent defects of small molecule analysis, a CRISPR/Cas12a-driven small molecule-induced dual-cycle strategy was developed based on the immune competition method. The key to signal amplification is the mutual activation and acceleration between Cycle 1 triggered by the small molecule and Cycle 2 driven by CRISPR/Cas12a. Impressively, small molecules have been successfully incorporated into the dual-cycle strategy, which achieves a low detection limit (3.1 pg/mL) and a wide linear range (from 10 pg/mL to 50 µg/mL). Moreover, the designed biosensor was successfully employed to evaluate the PQ residual level in real samples and showed effective implementation for the bioanalysis of small molecule targets and pesticide residue-related food safety.

Upregulation of mitochondrial calcium uniporter contributes to paraquat-induced neuropathology linked to Parkinson's disease via imbalanced OPA1 processing.

Paraquat (PQ) is the most widely used herbicide in agriculture worldwide and has been considered a high-risk environmental factor for Parkinson's disease (PD). Chronic PQ exposure selectively induces dopaminergic neuron loss, the hallmark pathologic feature of PD, resulting in Parkinson-like movement disorders. However, the underlying mechanisms remain unclear. Here, we demonstrated that repetitive PQ exposure caused dopaminergic neuron loss, dopamine deficiency and motor deficits dose-dependently in mice. Accordingly, mitochondrial calcium uniporter (MCU) was highly expressed in PQ-exposed mice and neuronal cells. Importantly, MCU knockout (KO) effectively rescued PQ-induced dopaminergic neuron loss and motor deficits in mice. Genetic and pharmacological inhibition of MCU alleviated PQ-induced mitochondrial dysfunction and neuronal death in vitro. Mechanistically, PQ exposure triggered mitochondrial fragmentation via imbalance of the optic atrophy 1 (OPA1) processing manifested by cleavage of L-OPA1 to S-OPA1, which was reversed by inhibition of MCU. Notably, the upregulation of MCU was mediated by miR-129-1-3p posttranscriptionally, and overexpression of miR-129-1-3p could rebalance OPA1 processing and attenuate mitochondrial dysfunction and neuronal death induced by PQ exposure. Consequently, our work uncovers an essential role of MCU and a novel molecular mechanism, miR-MCU-OPA1, in PQ-induced pathogenesis of PD, providing a potential target and strategy for environmental neurotoxins-induced PD treatment.

A rapid and reliable immunochromatographic strip for detecting paraquat poinsoning in domestic water and real human samples.

Paraquat (PQ) is one of the most commonly used herbicides, but it has polluted the environment and threatened human health through extensive and improper usage. Here, a new naked-eye PQ immunochromatographic strip was developed to recognize PQ in domestic water and real human samples within 10 min based on a novel custom-designed anti-PQ antibody. The PQ test strip could recognize PQ at a concentration as low as 10 ng/ml, reaching the high-efficiency time-of-flight mass spectrometry detection level and identifying trace amounts of PQ in samples treated with a diquat (DQ) and PQ mixture. Notably, both the performance evaluation and clinical trial of the proposed PQ strips were validated in multiple hospitals and public health agencies. Taken together, our study firstly provide the clinical PQ-targeted colloidal gold immunochromatographic test strip designed both for environment water and human sample detection with multiple advantages, which are ready for environmental monitoring and clinical practice.

Paraquat exposure induces Parkinsonism by altering lipid profile and evoking neuroinflammation in the midbrain.

Paraquat (PQ) is the most widely used herbicide in the world and a well-known potent neurotoxin for humans. PQ exposure has been linked to increase the risk of Parkinson's disease (PD). However, the mechanism underlying its neurotoxic effects in PD pathogenesis is unclear. In our present study, C57BL/6J mice treated with PQ manifested severe motor deficits indicated by the significant reductions in suspension score, latency to fall from rotarod, and grip strength at 8 weeks after PQ exposure. Pathological hallmarks of Parkinsonism in the midbrain such as dopaminergic neuron loss, increased α-synuclein protein, and dysregulated PD-related genes were observed. Non-targeted lipidome analysis demonstrated that PQ exposure alters lipid profile and abundance, increases pro-inflammatory lipids.27 significantly altered subclasses of lipids belonged to 6 different lipid categories. Glycerophospholipids, sphingolipids, and glycerides were the most abundant lipids. Abundance of pro-inflammatory lipids such as Cer, LPC, LPS, and LPI was significantly increased in the midbrain. mRNA expressions of genes regulating ceramide biosynthesis in the midbrain were markedly up-regulated. Moreover, PQ exposure increased serum pro-inflammatory cytokines and provoked neuroinflammation in the midbrain. Pro-inflammatory lipids and cytokines in the midbrain were positively correlated with motor deficits. PQ poisoning in humans significantly also elevated serum pro-inflammatory cytokines and induced an intense systemic inflammation. In summary, we presented initial investigations of PQ induced molecular events related to the PD pathogenesis, capturing aspects of disturbed lipid metabolism, neuroinflammation, impairment of dopaminergic neurons in the midbrain, and an intense systemic inflammation. These neurotoxic effects of PQ exposure may mechanistically contribute to the pathogenesis of PQ induced Parkinsonism. Results of this study also strongly support the hypothesis that ever-increasing prevalence of Parkinson's disease is etiologically linked to the health risk of exposure to neurotoxic environmental pollutants.

Thallium exposure at low concentration leads to early damage on multiple organs in children: A case study followed-up for four years.

Thallium (TI) is one of the most toxic heavy metals and priority pollutant metals. The emerging TI environmental pollution worldwide has posed a great threat to human health. However, based on the World Health Organization (WHO), the risk and severity of adverse health effects of TI in the range of 5-500 µg/L are uncertain. Moreover, evidence regarding the adverse impacts of TI on children's health is still insufficient. Herein, we aim to investigate the early adverse effects of TI on children's health and provide references for the WHO to establish stricter safety limits of TI. From 2015 to 2019, urinary TI and many clinical laboratory parameters related to blood routine, hepatic, renal, myocardial, coagulation function and serum electrolyte were measured in six children aged 1-9 years. The urinary TI concentration ranged from 13.4 µg/L to 60.1 µg/L with a mean of 36.1 µg/L and a median of 34.8 µg/L in six children in 2015. Although only four children felt a little poor appetite, several laboratory abnormalities indicated early damage in liver, renal, and myocardial functions in all children in 2015. After treatment and following up for four years, although the children's TI concentration decreased below 5 µg/L, their liver and renal functions did not completely recover, and their myocardial function worsened. Results indicated that impaired liver, renal, and myocardial functions were closely associated with elevated urinary TI concentration in children. Considering the increasing use of TI in high-technology industries and emerging TI environmental-contamination zones worldwide, establishing stricter safety limits of TI and paying more attention to the adverse health effects of TI on children are urgently required. SUMMARY: We found that a relatively low concentration of thallium (13.4 µg/L to 60.1 µg/L) impaired liver, renal, and myocardial function in six children. After treatment and following up these children for four years, although their urinary TI concentration decreased below 5 µg/L, their liver and renal functions did not completely recover, and their myocardial function worsened.