The effect and mechanism of cypermethrin-induced hippocampal neurotoxicity as determined by network pharmacology analysis and experimental validation

Pesticides, despite their intended use against pests, can have detrimental effects on non-target organisms, including humans. Its main route of exposure in urban areas is through dietary intake of fruits and vegetables. Oxidative stress, apoptosis and compromise to GABAergic interneurons’ integrity can be attributed to cypermethrin-induced neurotoxicity. The hippocampus, a vital region for memory and learning is particularly susceptible to the neurological toxicity caused by cypermethrin. Sixty adult male and female rats were grouped into control and cypermethrin-treatment groups. The treatment groups received oral dosages of 6.25mg/kg and 12.5mg/kg respectively for fourteen consecutive days. The daily weight was noted. The study was carried out on the hippocampal CA1 and CA3 regions of the rats using biochemical markers: GnRH, Na+/K + ATPase, COX-2, PG-E2 and immunohistochemical markers: Nrf2, CC3, BCL-2, parvalbumin and H&E. Cypermethrin caused a compensatory increase in body weight of the low cypermethrin group and decrease in body weight due to increased dose. Cypermethrin toxicity caused brain weight decrease which was seen more prominently in female high cypermethrin group. Using the biochemical markers, cypermethrin caused neuroinflammation and disrupted the normal functioning of the reproductive hormones and cell membrane; it was more prominent in females. Using the immunohistochemical markers, cypermethrin induced oxidative stress, apoptosis and compromise to the GABAergic interneuron integrity. The female rats expressed higher neuroprotection which can be attributed to estrogen and its signaling pathways. The findings of the study shows that there are dose and sex-specific mechanisms may be involved in cypermethrin neurotoxicity, highlighting the importance of considering sex differences in toxicity studies.

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Anti-inflammatory effect of Irisin on LPS-stimulated macrophages through inhibition of MAPK pathway

Du¹,

Yang²,

He³

et al. 2023

Physiol Res

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This study aimed to investigate the effect of irisin on LPS-induced inflammation in RAW 264.7 macrophages through inhibition of the mitogen-activated protein kinase (MAPK) pathway. A network pharmacology-based approach, combined with molecular docking and in vitro validation were performed to identify the biological activity, key targets, and potential pharmacological mechanisms of irisin against LPS-induced inflammation. By matching 100 potential genes of irisin with 1893 ulcerative colitis (UC) related genes, 51 common genes were obtained. Using protein-protein interaction networks (PPI) and component-target network analysis,10 core genes of irisin on UC were further identified. The results of gene ontology (GO) enrichment analysis showed that the molecular mechanisms of irisin on UC were mainly related to major enrichment in the categories of response to xenobiotic stimulus, response to the drug, and negative regulation of gene expression. Molecular docking results showed good binding activity for almost all core component targets. More importantly, MTT assay and flow cytometry results showed that LPS-induced cytotoxicity was reversed by irisin, after coincubation with irisin, the level of IL-12 and IL-23 decreased in LPS-stimulated RAW264.7 macrophages. Irisin pretreatment significantly inhibited the phosphorylation of ERK and AKT and increased the expression of PPAR α and PPAR γ. LPS-induced enhancement of phagocytosis and cell clearance were reversed by irisin pretreatment. Irisin ameliorated LPS-induced inflammation by inhibiting cytotoxicity and apoptosis, and this protective effect may be mediated through the MAPK pathway. These findings confirmed our prediction that irisin plays an anti-inflammatory role in LPS-induced inflammation via the MAPK pathway.

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The effect and mechanism of cypermethrin-induced hippocampal neurotoxicity as determined by network pharmacology analysis and experimental validation

Cited by 3 publications

References 38 publications

Network pharmacology and transcriptomics reveal androgen receptor as a potential protein target for 6PPD-quinone

Network pharmacology and transcriptomics reveal androgen receptor as a potential protein target for 6PPD-quinone

Sex-Specific Cypermethrin Induced Hippocampal Neurotoxicity Is Via the Modulation of Signaling Molecules for Antioxidant Defense, Membrane Integrity, Apoptosis and GABAergic Integrity

Anti-inflammatory effect of Irisin on LPS-stimulated macrophages through inhibition of MAPK pathway

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