Polymyxin B exerts nephrotoxicity effects via inhibition of the Nrf2/NQO1 pathway-mediated antioxidant response.

Polymyxin B (PMB) is a polypeptide antibiotic widely used in treating multidrug-resistant Gram-negative bacteria. However, nephrotoxicity is a serious adverse effect that limits its clinical use. Therefore, clarification of the molecular mechanism of PMB-induced renal injury is essential. Our study aimed to explore possible mechanisms of PMB-induced nephrotoxicity in vivo and in vitro. Mice were treated with PMB to construct the kidney injury model. The antioxidant capacity was assessed by measuring the superoxide dismutase (SOD) and catalase (CAT) activities and the glutathione (GSH) and malondialdehyde (MDA) contents. The pathway of the nuclear factor erythroid 2-related factor 2/NADH quinone oxidoreductase 1 (Nrf2/NQO1) was examined after PMB treatment in NRK-52E cells and mice. Finally, the expressions of genes and proteins (Bax, Bcl-2, Caspase-3, Caspase-9) related to apoptosis were evaluated through quantitative polymerase chain reaction and western blot assay. The study verified PMB-induced nephrotoxicity in mice and NRK-52E cells in a dose- and time-dependent manner. PMB treatment significantly decreased the expression of Nrf2 and its downstream target gene NQO1 and increased the apoptosis-related proteins expression. In summary, our results suggested that PMB-induced oxidative stress damage by inhibiting the Nrf2/NQO1 pathway and promoting apoptosis in kidney tissues.

Piceatannol-3'-O-ß-D-glucopyranoside attenuates colistin-induced neurotoxicity by suppressing oxidative stress via the NRF2/HO-1 pathway.

BACKGROUND: Multidrug-resistant Gram-negative bacteria are the most pressing problem in treating infectious diseases. As one of the primary drugs for multidrug-resistant Gram-negative bacteria, the neurotoxicity of colistin has become a significant challenge in clinical practice. PURPOSE: This study aimed to investigate the potential effect of piceatannol-3'-O-ß-D glucopyranoside (PG) on colistin-induced neurotoxicity and the underlying mechanism. METHODS: In vitro, nerve cell damage models were established by exposing N2a cells to 400 µM colistin for 24 h. The effects of PG on cell viability, apoptosis level, and oxidative stress level were analyzed. A western blot experiment was performed to determine the NRF2 pathway, apoptosis, and autophagy-related proteins. Mitochondrial morphology and mitochondrial membrane potential were detected after staining using laser confocal microscopy. In vivo, nerve injury mouse model was established by intracerebroventricular colistin administration. Morphological changes in brain tissues were observed using HE and Nissl staining. RESULTS: PG significantly reduced colistin-induced neuronal apoptosis levels. The apoptosis-related protein expressions were suppressed after PG intervention. Mechanistically, PG increased the levels of antioxidant factors and decreased the levels of oxidative factors, which might be related to the activation of the NRF2 pathway. In addition, PG treatment reversed the deviations in mitochondrial morphology and membrane potential. PG suppressed autophagy levels in N2a cells, possibly because PG inhibited colistin-induced apoptosis, thus reducing the level of spontaneous protective autophagy in cells. Nrf2 knockdown N2a cell models were applied to confirm that the activation of the NRF2 pathway played a vital role in PG alleviating the nerve damage caused by colistin. CONCLUSION: PG is a potential treatment option for colistin-induced neurotoxicity. It mitigated colistin-induced oxidative stress-associated injury and mitochondrial damage by activating the NRF2/HO-1 pathway, thus reducing nerve cell apoptosis.