Ascorbate uptake enables tubular mitophagy to prevent septic AKI by PINK1-PARK2 axis.

Ascorbate (Vitamin C) has been proposed as a promising therapeutic agent against sepsis in clinical trials, but there is little experimental evidence on its anti-septic efficacy. We report that Toll-like receptor 4 (TLR4) activation by LPS stimuli augments ascorbate uptake in murine and human tubular cells through upregulation of two ascorbate transporters SVCT-1 and -2 mediated by Fn14/SCFFbxw7α cascade. Ascorbate restriction, or knockout of SVCT-1 and -2, the circumstance reminiscent to blockade of ascorbate uptake, endows tubular cells more vulnerable to the LPS-inducible apoptosis, whereas exogenous administration of ascorbate overrides the ruin execution, for which the PINK1-PARK2, rather than BNIP3-NIX axis is required. Ascorbate increases, while SVCT-1 and -2 knockout or ascorbate restriction dampens tubular mitophagy upon LPS stimuli. Treatment of endotoxemic mice with high-dose ascorbate confers mitophagy and substantial protection against mortality and septic acute kidney injury (AKI). Our work provides a rationale for clinical management of septic AKI with high doses of ascorbate.

A novel artificial intelligence protocol to investigate potential leads for diabetes mellitus.

Dipeptidyl peptidase-4 (DPP4) is highly participated in regulating diabetes mellitus (DM), and inhibitors of DPP4 may act as potential DM drugs. Therefore, we performed a novel artificial intelligence (AI) protocol to screen and validate the potential inhibitors from Traditional Chinese Medicine Database. The potent top 10 compounds were selected as candidates by Dock Score. In order to further screen the candidates, we used numbers of machine learning regression models containing support vector machines, bagging, random forest and other regression algorithms, as well as deep neural network models to predict the activity of the candidates. In addition, as a traditional method, 2D QSAR (multiple linear regression) and 3D QSAR methods are also applied. The AI methods got a better performance than the traditional 2D QSAR method. Moreover, we also built a framework composed of deep neural networks and transformer to predict the binding affinity of candidates and DPP4. Artificial intelligence methods and QSAR models illustrated the compound, 2007_4105, was a potent inhibitor. The 2007_4105 compound was finally validated by molecular dynamics simulations. Combining all the models and algorithms constructed and the results, Hypecoum leptocarpum might be a potential and effective medicine herb for the treatment of DM.

A novel artificial intelligence protocol to investigate potential leads for Parkinson's disease.

Previous studies have shown that small molecule inhibitors of NLRP3 may be a potential treatment for Parkinson's disease (PD). NACHT, LRR and PYD domains-containing protein 3 (NLRP3), heat shock protein HSP 90-beta (HSP90AB1), caspase-1 (CASP1) and cellular tumor antigen p53 (TP53) have significant involvement in the pathogenesis pathway of PD. Molecular docking was used to screen the traditional Chinese medicine database TCM Database@Taiwan. Top traditional Chinese medicine (TCM) compounds with high affinities based on Dock Score were selected to form the drug-target interaction network to investigate potential candidates targeting NLRP3, HSP90AB1, CASP1, and TP53 proteins. Artificial intelligence model, 3D-Quantitative Structure-Activity Relationship (3D-QSAR) were constructed respectively utilizing training sets of inhibitors against the four proteins with known inhibitory activities (pIC50). The results showed that 2007_22057 (an indole derivative), 2007_22325 (a valine anhydride) and 2007_15317 (an indole derivative) might be a potential medicine formula for the treatment of PD. Then there are three candidate compounds identified by the result of molecular dynamics.

The Effect of Tartary Buckwheat Flavonoids in Inhibiting the Proliferation of MGC80-3 Cells during Seed Germination.

Tartary buckwheat (Fagopyrum tataricum (L.) Gaertn) is rich in functional compounds such as rutin, quercetin, d-chiro-inositol, dietary fiber, and essential amino acids. Electric field (EF) treatment before sprout germination results in physiological and chemical changes, and some alterations might lead to positive applications in plant seeds. MTT assay showed that the effect of total flavonoids on human gastric cancer cell line MGC80-3 was significantly changed after EF treatment for different germination days (3-7 days). Among them, the total flavonoids of tartary buckwheat (BWTF) on the third day had the most obvious inhibitory effect on MGC80-3 (p < 0.01). In addition, flow cytometry evidenced that different ratios of quercetin and rutin had effects on the proliferation of MGC80-3. The same content of quercetin and rutin had the best effect, reaching 6.18 ± 0.82%. The anti-cancer mechanism was mainly promoted by promoting the expression of apoptotic proteins. The expression of Bax/Bcl-2 and caspase-8 in MGC80-3 cells was mediated by BWTFs. This study has good research value for improving the biological and economic value of tartary buckwheat.