Diquat (DQ), a widely used bipyridyl herbicide, is associated with significantly higher rates of kidney injuries compared to other pesticides. However, the underlying molecular mechanisms are largely unknown. In this study, we identified the molecular changes in the early stage of DQ-induced kidney damage in a mouse model through transcriptomic, proteomic and metabolomic analyses. We identified 869 genes, 351 proteins and 96 metabolites that were differentially expressed in the DQ-treated mice relative to the control mice (p < 0.05), and showed significant enrichment in the PPAR signaling pathway and fatty acid metabolism. Hmgcs2, Cyp4a10, Cyp4a14 and Lpl were identified as the major proteins/genes associated with DQ-induced kidney damage. In addition, eicosapentaenoic acid, linoleic acid, palmitic acid and (R)-3-hydroxybutyric acid were the major metabolites related to DQ-induced kidney injury. Overall, the multi-omics analysis showed that DQ-induced kidney damage is associated with dysregulation of the PPAR signaling pathway, and an aberrant increase in Hmgcs2 expression and 3-hydroxybutyric acid levels. Our findings provide new insights into the molecular basis of DQ-induced early kidney damage.

BACKGROUND: In clinical practice, some patients might not be able or unwilling to provide a thorough history of medication and poison exposure. The aim of this study was to use toxicological analysis to examine the clinical characteristics of patients with acute poisoning whose exposure history was uncertain from a toxicological analysis perspective. METHODS: This was a retrospective and descriptive study from an institute of poisoning. Patient registration information and test reports spanning the period from April 1, 2020 to March 31, 2022, were obtained. Patients with uncertain exposure histories and who underwent toxicological analysis were included. Clinical manifestations and categories of toxics were analyzed. RESULTS: Among the 195 patients with positive toxicological analysis results, the main causes of uncertain exposure history was disturbance of consciousness (62.6%), unawareness (23.6%) and unwillingness or lack of cooperation (13.8%). The predominant clinical manifestations were disturbed consciousness (62.6%), followed by vomiting and nausea (14.4%) and liver function abnormalities (8.7%). A comparison of clinical manifestations between patients with positive and negative (n=99) toxicological analyses results revealed significantly different proportions of disturbances in consciousness (63% vs. 21%), dizziness (1.5% vs. 5.1%), multi-organ failure (1.5% vs. 7.1%), and local pain (0 vs 4%). The main categories of substances involved were psychiatric medications (23.1%), sedatives (20.5%), insecticides (13.8%), and herbicides (12.8%). CONCLUSION: The clinical manifestations of acute poisoning in patients with an uncertain exposure history are diverse and nonspecific, and toxicological analysis plays a pivotal role in the diagnosis and differential diagnosis of such patients.

Objective. Paraquat (PQ), a widely used toxic herbicide, induces lung inflammation through mechanisms that remain incompletely understood. In a previous study, we found that the plasma MUC5B mucin level was implicated in PQ poisoning in patients. Here, we hypothesize that MUC5B is a critical mediator in PQ-induced cell inflammation. Methods. A mouse model of PQ-induced lung injury was used to examine the MUC5B expression level. A549 cells (alveolar epithelial cells line) were exposed to PQ in dose-dependent and time-dependent manners. Cell viability was detected by CCK-8 assays. The expression levels of MUC5B were examined by dot blot enzyme-linked immunosorbent assay (ELISA) and RT-qPCR. Western blotting was used to detect the levels of proteins in the MAPK and NF-κB pathways. Inflammatory factors in the cell culture medium were measured by ELISA. NF-κB and MAPK pathway inhibitors and MUC5B siRNA (siMUC5B) were used to determine the function of MUC5B. Finally, N-acetyl-cysteine (NAC) was added and its regulatory effect on the MAPK-NF-κB-MUC5B pathway was examined in PQ-induced cell inflammation. Results. MUC5B was significantly upregulated accompanying the increases in TNF-α and IL-6 secretion following PQ treatment in mouse and also in A549 cells after treatment with 50 μM PQ at 24 hours. Furthermore, MAPK and NF-κB pathway inhibitors could dramatically decrease the expression of MUC5B and the secretion of TNF-α and IL-6. Importantly, siMUC5B could significantly attenuate the secretion of TNF-α and IL-6 induced by PQ. As expected, the addition of NAC efficiently suppresses the TNF-α and IL-6 secretion stimulated from PQ and also downregulated ERK, JNK, and p65 phosphorylation (ERK/JNK MAPK and NF-κB pathways) as well as MUC5B expression. Conclusion. Our findings suggest that MUC5B participates in the process of PQ-induced cell inflammation and is downstream of the NF-κB and MAPK pathways. NAC can attenuate PQ-induced cell inflammation at least in part by suppressing the MAPK-NF-κB-MUC5B pathway. These results nominate MUC5B as a new biomarker and therapeutic target for PQ-induced lung inflammation.