Imidacloprid (IMI), a neonicotinoid insecticide extensively applied in agriculture, is among the most frequently detected pesticides in food. However, the long-term impact of chronic dietary exposure to environmentally relevant IMI doses on kidney health has not been fully elucidated, particularly regarding its nephrotoxic mechanisms. To address this gap, chronic exposure to IMI was administered to mice through supplementation of their feed with environmentally relevant doses (approximately 100 and 1000 μg/kg/day) for 24 weeks to investigate its nephrotoxicity and underlying mechanisms. Toxicological analysis revealed that chronic IMI exposure led to renal dysfunction, histopathological alterations, and excessive apoptosis in mice. Mechanistic investigations suggested that IMI might inhibit AMP-activated protein kinase (AMPK) activity through both direct and indirect pathways. Direct inhibition occurred through the binding of IMI and its metabolites to AMPK, reducing its phosphorylation activity. Indirect inhibition involved excessive production of reactive oxygen species, which suppressed AMPK phosphorylation, leading to sustained purine metabolism dysregulation in the renal system. Consequently, the kidneys showed an aggravated redox imbalance, heightened inflammatory states, and increased cellular apoptosis. The results of this study are intended to raise awareness of pesticide use and food safety among agricultural workers and consumers.
The potential of combination therapy using nanoparticle delivery systems in improving triple-negative breast cancer treatment efficacy remains to be explored. Here, we report a novel nanoparticle system using a cholesterol biguanide conjugate hydrochloride (CBH) as both a drug and carrier to load magnolol (MAG). Poly(ethylene glycol)-poly(lactic-co-glycolic acid) (mPEG-PLGA) and aminoethyl anisamide-poly(ethylene glycol)-poly(lactic-co-glycolic acid) (AEAA-PEG-PLGA) were added to form nanoparticles. Nanoparticles accumulated most in tumor tissues when the weight ratio of AEAA-PEG-PLGA to mPEG-PLGA was 4:1. MAG and CBH exerted a synergistic inhibitory effect on 4 T1 cells. An in vitro study showed that nanoparticles displayed the highest tumor cell uptake rate, highest apoptosis rate, and strongest inhibitory effect on tumor cell migration and monoclonal formation. CBH might promote nanoparticle uptake by cells and lysosomal escape. After intravenous administration to mice with 4 T1 breast tumors in situ , the nanoparticles inhibited tumor growth without obvious toxicity. Western blot results showed that nanoparticles altered the levels of p53, p-AKT, and p-AMPK in the tumor tissue. Moreover, cell apoptosis was found in the same area of H&E-stained and TUNEL-stained tumors treated with the nanoparticles. Collectively, this nanoparticle system provides a novel combination drug delivery strategy for treating triple-negative breast cancer.
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