Effects of dietary onion (Allium cepa) extract supplementation on performance, apparent total tract retention of nutrients, blood profile and meat quality of broiler chicks.

OBJECTIVE: This study was conducted to investigate the effect of dietary onion (Allium cepa) extract (OE) supplementation on growth performance, apparent total tract retention (ATTR), blood profile, carcass characteristics and meat quality in broilers. METHODS: Four hundred male broiler chicks (Ross 308, 3-d old) were randomly allocated to four dietary treatments for 28 d feeding trial. Each treatment has five replications with 20 birds each. Four dietary treatments were designated according to the OE supplementation levels (0 as control, 5, 7.5, and 10 g of OE per kg of basal diet respectively). On d 28, a total of 20 birds from each treatment were subjected for ATTR, serum biochemical assay, carcass characteristic and organ weight measurement. RESULTS: Overall weight gain of OE 7.5 g/kg group was higher (p = 0.04) than control group. The ATTRs of dietary energy (p<0.01) and ether extract (p = 0.04) linearly increased with increasing levels of dietary OE. However, no difference in ATTR of dry matter and crude protein was evident. Furthermore, serum IgG concentration increased linearly (p<0.01) and quadratically (p = 0.03) with increasing OE supplementation. No differences in carcass dressing weight and amount of abdominal fat by treatments were observed. Also, the weight of organ including immune organ was not different among the treatments. The TBARS values of 10 d stored breast meat decreased linearly (p<0.01) and quadratically (p<0.01) with increasing dietary OE levels. The meat color was also affected, with lower (p<0.01) redness score in meats from OE supplemented groups. This study showed that dietary OE improved broiler weight gain presumably by increasing feed intake and ATTR of both energy and ether extract. The dietary OE increased serum IgG level and meat anti-oxidation capacity. CONCLUSION: This study implies that the recommended level of dietary OE supplementation could be beneficial for improving broiler performance and meat quality.

Molecular Dynamics Simulation on the Suppression Mechanism of Phosphorylation to Ser222 by Allosteric Inhibitors Targeting MEK1/2 Kinase.

Allosteric inhibitors of mitogen-activated protein kinase 1 (MEK1) reveal distinct interactions with MEK1 activation loop residues. The structural analyses will determine whether, and how, distinct inhibitors suppress the phosphorylation of MEK1 and may guide future therapeutic development. In this study, we explored the suppression mechanism of the phosphorylation process in the presence of MEK allosteric inhibitors, such as selumetinib, trametinib, cobimetinib, and CH5126766, by employing molecular dynamics simulations accompanied by principal component analysis. The simulations of wildtype MEK1 show that Ser222 can come close to γ-phosphate but not Ser218. We have found the conformation where Ser222 is within 5 Šof distance, which makes Ser222 accessible for γ-phosphate. The conformation analysis from the simulations of MEK1 in the presence of allosteric inhibitors reveals that the inhibitor restricts the flexibility of Ser222 through strong interactions with the activation loop, Lys97, and water mediates interactions with amino acids in the vicinity. The results reveal that all the inhibitors act as screeners between the activation loop and Mg-ATP and restricting the flexibility of the activation loop through strong interaction causes the suppression of the phosphorylation process of MEK1. The results conclude that a strong interaction of allosteric inhibitors with the activation loop restricts the movement of Ser222 toward Mg-ATP, which could be the dominant factor for the suppression of phosphorylation in MEK1. This research will provide novel insights to design effective anticancer therapeutics for targeting MEK1 in the future.

PCW-A1001, AI-assisted de novo design approach to design a selective inhibitor for FLT-3(D835Y) in acute myeloid leukemia.

Treating acute myeloid leukemia (AML) by targeting FMS-like tyrosine kinase 3 (FLT-3) is considered an effective treatment strategy. By using AI-assisted hit optimization, we discovered a novel and highly selective compound with desired drug-like properties with which to target the FLT-3 (D835Y) mutant. In the current study, we applied an AI-assisted de novo design approach to identify a novel inhibitor of FLT-3 (D835Y). A recurrent neural network containing long short-term memory cells (LSTM) was implemented to generate potential candidates related to our in-house hit compound (PCW-1001). Approximately 10,416 hits were generated from 20 epochs, and the generated hits were further filtered using various toxicity and synthetic feasibility filters. Based on the docking and free energy ranking, the top compound was selected for synthesis and screening. Of these three compounds, PCW-A1001 proved to be highly selective for the FLT-3 (D835Y) mutant, with an IC50 of 764 nM, whereas the IC50 of FLT-3 WT was 2.54 µM.