A Dual Inhibitor of DYRK1A and GSK3β for β-Cell Proliferation: Aminopyrazine Derivative GNF4877

Loss of β-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase β-cell mass are less developed. Promoting β-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring β-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3β (GSK3β) was previously reported to induce primary human β-cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring β-cell proliferation.     

Acidified sodium chlorite solution as an antimicrobial treatment for rainbow trout (Oncorhynchus mykiss) fillets

Minimizing microbial growth and maintaining overall quality are priorities for intervention strategies that extend the shelf life of fresh, aquatic foods. Four treatments included a control (fresh fillets), water, 50 ppm of acidified sodium chlorite (ASC), and 1,000 ppm of ASC. Fillets were stored at 1 to 2 degrees C for 0, 8, and 15 days. A significant (P < 0.05) interaction between treatment and storage time was observed for psychrotrophic counts. The increase in psychrotrophic counts with storage time was less for fillets treated with ASC, regardless of ASC concentration. Aerobic plate counts were not affected (P > 0.05) by intervention; however, a significant increase in counts was observed during storage (P < 0.05). Fillet pH, moisture, fat, thiobarbituric acid-reactive substances, fatty acid composition, color, cook yield, and shear force were not affected (P > 0.05) by intervention. Thiobarbituric acid-reactive substances decreased (P < 0.05) during storage. Percentages of individual fatty acids were constant, with the exception of C15 and C20:2; they decreased with storage to 15 days. Percent fat, L* (lightness) and b* (yellowness) values, and cook yield increased (P < 0.05) during storage. Fillet pH, moisture, a* (redness) value, and shear force did not change (P > 0.05) with storage to 15 days. Based on these data, 50 ppm of ASC performed equally as well as 1,000 ppm of ASC. The value of ASC is as a decontaminant; however, fillets in this study had low psychrotrophic counts pretreatment (2.3 log CFU/cm2) and posttreatment (2.03 log CFU/cm2), which did not demonstrate ASC's effectiveness as a decontaminant.     

High Dietary Vitamin E Affects Storage Stability of Frozen-refrigerated Trout Fillets

Fillets were processed from trout fed a diet containing either 200 (low vitamin E [LVE] diet) or 5000 (high vitamin E [HVE] diet) mg a‐tocopheryl acetate/kg for 0, 4, and 9 wk. These fillets were evaluated fresh and after 6 mo of frozen storage. Frozen fillets were thawed and stored 3 d at 1 °C before analyses. Muscle α‐tocopherol of fish fed the HVE diet continuously increased through 9 wk of feeding. Reduced muscle α‐tocopherol and moisture, and increased muscle redness and fat were observed in frozen‐refrigerated fillets compared with fresh fillets. Thiobarbituric acid‐reactive substances were lower in frozen‐refrigerated fillets produced from fish fed the HVE diet. Proportion of unsaturated fatty acids and omega‐3 fatty acids increased as feeding duration increased from 0 to 9 wk.     

Effect of dietary vitamin E supplementation and refrigerated storage on quality of rainbow trout fillets

Rainbow trout were fed a low vitamin E (200 mg/kg; LVE) or a high vitamin E (5000 mg/kg; HVE) diet for 9 wk to characterize the effect of vitamin E supplementation at 5000 mg/kg on fillet quality. Fish were sampled at 2, 3, 4, 5, 7, and 9 wk of the trial. Fillets were stored at 2 °C for 0, 7, and 14 d, and analyzed for pH, psychrotrophic counts, color, cook yield, shear force, crude fat and moisture content, α-tocopherol, fatty acid composition, and lipid oxidation. There was a significant feeding duration by fillet storage time interaction for psychrotrophic counts, crude fat content, cook yield, and shear force. Fillet L* value was not affected by diet, feeding duration or storage time. Fillet a* was lowest at 14-d storage, and b* values increased with fillet storage time. High vitamin E diet increased fillet α-tocopherol from 33 to 155 mg/kg. High vitamin E decreased palmitic acid and increased linoleic acid and omega-6 fatty acids. Feeding through 9 wk increased the relative proportions of unsaturated, polyunsaturated, and omega-3 fatty acids, and decreased saturated and omega-6 fatty acids. At 0-d storage, HVE diet did not affect thiobarbituric acid-reactive substances (TBARS) at any sampling week, and fasted fish generated fewer TBARS compared to non-fasted fish.