Therapeutic Targets for Diabetic Kidney Disease: Proteome-Wide Mendelian Randomization and Colocalization Analyses.

At present, safe and effective treatment drugs are urgently needed for diabetic kidney disease (DKD). Circulating protein biomarkers with causal genetic evidence represent promising drug targets, which provides an opportunity to identify new therapeutic targets. Summary data from two protein quantitative trait loci studies are presented, one involving 4,907 plasma proteins data from 35,559 individuals and the other encompassing 4,657 plasma proteins among 7,213 European Americans. Summary statistics for DKD were obtained from a large genome-wide association study (3,345 cases and 2,372 controls) and the FinnGen study (3,676 cases and 283,456 controls). Mendelian randomization (MR) analysis was conducted to examine the potential targets for DKD. The colocalization analysis was used to detect whether the potential proteins exist in the shared causal variants. To enhance the credibility of the results, external validation was conducted. Additionally, enrichment analysis, assessment of protein druggability, and the protein-protein interaction networks were used to further enrich the research findings. The proteome-wide MR analyses identified 21 blood proteins that may causally be associated with DKD. Colocalization analysis further supported a causal relationship between 12 proteins and DKD, with external validation confirming 4 of these proteins, and TGFBI was affirmed through two separate group data sets. These results indicate that targeting these four proteins could be a promising approach for treating DKD, and warrant further clinical investigations.

Toxic effects of zinc oxide nanoparticles combined with vitamin C and casein phosphopeptides on gastric epithelium cells and the intestinal absorption of mice.

Zinc oxide nanomaterials have become common food additives in recent years. Casein phosphopeptides (CPP) and vitamin C (VC) are used as functional food additives together with ZnO nanoparticles (ZnO NPs) in many commercial foods. Our previous studies showed that VC can increase the cytotoxicity induced by ZnO NPs both in vitro and in vivo, while CPP can have a cytoprotective effect against oxidative stress induced by ZnO NPs. However, the combined toxic effect of the three additives together in food is unknown. Herein, we have investigated the combined toxicity of ZnO NPs, CPP and VC by altering the sequence of their addition to clarify their toxic mechanisms in the composite systems. When the order of addition of the three materials changes, the cytotoxicity induced by the ZnO NPs changes due to the different concentrations of dissolved Zn ions in the different groups. We have also probed the intestinal absorption of Zn ions with an everted gut sac model. The amount of Zn2+ absorbed in the intestine in different composite systems also responds differently to the sequence of addition of the additives. VC is more powerful at controlling the synergistic toxic effect induced by ZnO NPs compared to the protective role of CPP in the combined systems.