The Keap1-Nrf2-ARE pathway regulates the constitutive and inducible transcription of various genes that encode detoxification enzymes, antioxidant proteins and anti-inflammatory proteins and has pivotal roles in the defence against cellular oxidative stress. In this study, we investigated the therapeutic potential of
CPUY192018
, a potent small-molecule inhibitor of the Keap1-Nrf2 protein-protein interaction (PPI), in renal inflammation. In human proximal tubular epithelial HK-2 cells,
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treatment significantly increased Nrf2 protein level and Nrf2 nuclear translocation, which enhanced Nrf2-ARE transcription capacity and the downstream protein content in a Nrf2 dependent manner. In lipopolysaccharide (LPS)-challenged human HK-2 cells,
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exhibited cytoprotective effects by enhancing the Nrf2-ARE regulated antioxidant system and diminished the LPS-induced inflammatory response by hindering the ROS-mediated activation of the NF-κB pathway. In the LPS-induced mouse model of chronic renal inflammation, by activating Nrf2,
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treatment balanced renal oxidative stress and suppressed inflammatory responses. Hence, administration of
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reduced kidney damage and ameliorated pathological alterations of the glomerulus. Taken together, our study suggested that small-molecule Keap1-Nrf2 PPI inhibitors can activate the Nrf2-based cytoprotective system and protect the kidney from inflammatory injury, raising a potential application of Keap1-Nrf2 PPI inhibitors in the treatment of inflammatory kidney disorders.
CLoK Central Lancashire online Knowledge www.clok.uclan.ac.uk 4-Nonylphenol effects on rat testis and Sertoli cells determined by spectrochemical techniques coupled with chemometric analysis
The Keap1 (Kelch-like
ECH-associated
protein 1)-Nrf2 (nuclear factor erythroid 2-related factor 2)-ARE
(antioxidant response element) pathway is the major defending mechanism
against oxidative stresses, and directly disrupting the Keap1-Nrf2
protein–protein interaction (PPI) has been an attractive strategy
to target oxidative stress-related diseases, including cardiovascular
diseases. Here, we describe the design, synthesis, and structure–activity
relationships (SARs) of indoline-based compounds as potent Keap1-Nrf2
PPI inhibitors. Comprehensive SAR analysis and thermodynamics-guided
optimization identified 19a as the most potent inhibitor
in this series, with an IC50 of 22 nM in a competitive
fluorescence polarization assay. Further evaluation indicated the
proper drug-like properties of 19a. Compound 19a dose-dependently upregulated genes and protein level of Nrf2 as
well as its downstream markers and showed protective effects against
lipopolysaccharide-induced injury in both H9c2 cardiac cells and mouse
models. Collectively, we reported here a novel indoline-based Keap1-Nrf2
PPI inhibitor as a potential cardioprotective agent.
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