Discovery of Potential Neonicotinoid Insecticides by an Artificial Intelligence Generative Model and Structure-Based Virtual Screening.

The identification of neonicotinoid insecticides bearing novel scaffolds is of great importance for pesticide discovery. Here, artificial intelligence-based tools and virtual screening strategy were integrated to discover potential leads of neonicotinoid insecticides. A deep generative model was successfully constructed using a recurrent neural network combined with transfer learning. The model evaluation showed that the pretrained model could accurately grasp the SMILES grammar of drug-like molecules and generate potential neonicotinoid compounds after transfer learning. The generated molecules were evaluated by hierarchical virtual screening, hits were subjected to a similarity search, and the most similar structures were purchased for the bioassay. Compounds A2 and A5 displayed 52.5 and 50.3% mortality rates against Aphis craccivora at 100 mg/L, respectively. The docking study indicated that these two compounds have similar binding modes to neonicotinoids, which were verified by further molecular dynamics simulations.

Design, Synthesis, and Synergistic Activities of Eight-Membered Carbon Bridged Neonicotinoid Derivatives.

Insecticide synergists are an effective approach to increase the control efficacy and reduce active ingredient usage. In order to explore neonicotinoid-specific synergists with novel scaffolds and higher potency, a series of eight-membered carbon bridged neonicotinoid derivatives were designed and synthesized in accordance with our previous research. The synergistic effects of the target compounds on neonicotinoids in Aphis craccivora were evaluated, and the structure-activity relationships were summarized. The results indicated that most of the target compounds exhibited significant synergistic effects on imidacloprid in A. craccivora at low concentrations. In particular, compound 1 at a concentration of 1 mg/L reduced the LC50 value of imidacloprid from 0.856 mg/L to 0.170 mg/L. Meanwhile, compound 1 also increased the insecticidal activity of most neonicotinoid insecticides belonging to the Insecticide Resistance Action Committee (IRAC) 4 A subgroup against A. craccivora. The present study might be meaningful for directing the design of neonicotinoid-specific synergists.

Mechanism of nuclear protein 1 in the resistance to axitinib in clear cell renal cell carcinoma / 北京大学学报(医学版)

OBJECTIVE@#To explore the potential mechanism of resistance to axitinib in clear cell renal cell carcinoma (ccRCC), with a view to expanding the understanding of axitinib resistance, facilitating the design of more specific treatment options, and improving the treatment effectiveness and survival prognosis of patients.@*METHODS@#By exploring the half maximum inhibitory concentration (IC50) of axitinib on ccRCC cell lines 786-O and Caki-1, cell lines resistant to axitinib were constructed by repeatedly stimulated with axitinib at this concentration for 30 cycles in vitro. Cell lines that were not treated by axitinib were sensitive cell lines. The phenotypic differences of cell proliferation and apoptosis levels between drug resistant and sensitive lines were tested. Genes that might be involved in the drug resistance process were screened from the differentially expressed genes that were co-upregulated in the two drug resistant lines by transcriptome sequencing. The expression level of the target gene in the drug resistant lines was verified by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB). The expression differences of the target gene in ccRCC tumor tissues and adjacent tissues were analyzed in the Gene Expression Profiling Interactive Analysis (GEPIA) public database, and the impact of the target gene on the prognosis of ccRCC patients was analyzed in the Kaplan-Meier Plotter (K-M Plotter) database. After knocking down the target gene in the drug resistant lines using RNA interference by lentivirus vector, the phenotypic differences of the cell lines were tested again. WB was used to detect the levels of apoptosis-related proteins in the different treated cell lines to find molecular pathways that might lead to drug resistance.@*RESULTS@#Cell lines 786-O-R and Caki-1-R resistant to axitinib were successfully constructed in vitro, and their IC50 were significantly higher than those of the sensitive cell lines (10.99 μmol/L, P < 0.01; 11.96 μmol/L, P < 0.01, respectively). Cell counting kit-8 (CCK-8) assay, colony formation, and 5-ethynyl-2 '-deoxyuridine (EdU) assay showed that compared with the sensitive lines, the proliferative ability of the resistant lines decreased, but apoptosis staining showed a significant decrease in the level of cell apoptosis of the resistant lines (P < 0.01). Although resistant to axitinib, the resistant lines had no obvious new replicated cells in the environment of 20 μmol/L axitinib. Nuclear protein 1 (NUPR1) gene was screened by transcriptome sequencing, and its RNA (P < 0.0001) and protein expression levels significantly increased in the resistant lines. Database analysis showed that NUPR1 was significantly overexpressed in ccRCC tumor tissue (P < 0.05); the ccRCC patients with higher expression ofNUPR1had a worse survival prognosis (P < 0.001). Apoptosis staining results showed that knockdown ofNUPR1inhibited the anti-apoptotic ability of the resistant lines to axitinib (786-O, P < 0.01; Caki-1, P < 0.05). WB results showed that knocking downNUPR1decreased the protein level of B-cell lymphoma-2 (BCL2), increased the protein level of BCL2-associated X protein (BAX), decreased the protein level of pro-caspase3, and increased the level of cleaved-caspase3 in the resistant lines after being treated with axitinib.@*CONCLUSION@#ccRCC cell lines reduce apoptosis through theNUPR1 -BAX/ BCL2 -caspase3 pathway, which is involved in the process of resistance to axitinib.

Treatment efficacy of Lianhua Qingwen capsules for eraly-stage COVID-19.

OBJECTIVE: To systematically determine the effect of Lianhua Qingwen Capsules on the early antiviral and anti-inflammatory action against COVID-19 (Coronavirus 2019) and its applicational value in the treatment of COVID-19. METHODS: The clinical data of 66 early-mid-stage COVID-19 patients admitted to hospitals in Guangzhou between January 2020 and April 2020 were retrospectively analyzed. The patients receiving Lianhua Qingwen Capsule treatment were assigned to the observation group (n=33) and those given conventional therapy were included in the control group (n=33). The two groups were compared in terms of clinical effects and main symptom (fever, cough and fatigue) disappearance rate. RESULTS: In comparison with the control group, 1) the total effective rate was significantly higher in the observation group (P<0.05); 2) the disappearance rates of fever, cough and fatigue were statistically higher in the observation group; 3) the treatment time was significantly shorter and patient recovery was significantly better in the observation group; 4) the laboratory index levels [white blood cell (WBC), interleukin-6 (IL-6), serum amyloid A (SAA)] were better in the observation group. CONCLUSION: Lianhua Qingwen Capsules can significantly improve the total effective rate for COVID-19 patients, as well as shorten the hospital stay and treatment time, which is worth of promotion in the clinic.

Melatonin: an antioxidant in edible plants.

Melatonin, a molecule with antioxidant properties that is widely distributed in the animal kingdom, has now been shown to exist in the plant kingdom, including edible plants. Our findings show that melatonin is not only an endogenously produced antioxidant, but that it is also consumed in the diet. Since melatonin concentrations in the blood correlate with the total antioxidant status of this fluid, it is likely that dietary melatonin could be important in protecting against oxidative damage.