A renal YY1-KIM1-DR5 axis regulates the progression of acute kidney injury.

Acute kidney injury (AKI) exhibits high morbidity and mortality. Kidney injury molecule-1 (KIM1) is dramatically upregulated in renal tubules upon injury, and acts as a biomarker for various renal diseases. However, the exact role and underlying mechanism of KIM1 in the progression of AKI remain elusive. Herein, we report that renal tubular specific knockout of Kim1 attenuates cisplatin- or ischemia/reperfusion-induced AKI in male mice. Mechanistically, transcription factor Yin Yang 1 (YY1), which is downregulated upon AKI, binds to the promoter of KIM1 and represses its expression. Injury-induced KIM1 binds to the ECD domain of death receptor 5 (DR5), which activates DR5 and the following caspase cascade by promoting its multimerization, thus induces renal cell apoptosis and exacerbates AKI. Blocking the KIM1-DR5 interaction with rationally designed peptides exhibit reno-protective effects against AKI. Here, we reveal a YY1-KIM1-DR5 axis in the progression of AKI, which warrants future exploration as therapeutic targets.

A Systematic Screening of Traditional Chinese Medicine Identifies Two Novel Inhibitors Against the Cytotoxic Aggregation of Amyloid Beta.

The toxic aggregates of amyloid beta (Aß) disrupt the cell membrane, induce oxidative stress and mitochondrial dysfunction, and eventually lead to Alzheimer's disease (AD). Intervening with this cytotoxic aggregation process has been suggested as a potential therapeutic approach for AD and other protein misfolding diseases. Traditional Chinese Medicine (TCM) has been used to treat AD and related cognitive impairment for centuries with obvious efficacy. Extracts or active ingredients of TCMs have been reported to inhibit the aggregation and cytotoxicity of Aß. However, there is a lack of systematic research on the anti-Aß aggregation effects of TCM components. In this study, we performed a systematic screening to identify the active ingredients of TCM against the cytotoxic aggregation of Aß42. Through a literature and database survey, we selected 19 TCM herbals frequently used in the treatment of AD, from which 76 major active chemicals without known anti-amyloid effects were further screened. This took place through two rounds of MTT-based screening detection of the cytotoxicity of these chemicals and their effects on Aß42-induced cytotoxicity, respectively. Tetrahydroxystilbene-2-O-ß-D-glucoside (TSG) and sinapic acid (SA) were found to be less toxic, and they inhibited the cytotoxicity of Aß42. Further studies demonstrated that TSG and SA concentration-dependently attenuated the amyloidosis and membrane disruption ability of Aß42. Thus, we identified two novel chemicals (TSG and SA) against the cytotoxic aggregation of Aß42. Nonetheless, further exploration of their therapeutic potential is warranted.