Anti-Ractopamine polyclonal antibody

Background: alpha-Tocopherol (alpha T) in its natural form [2 ' R, 4 ' R, 8 ' R alpha T (RRR-alpha T)] is more bioactive than synthetic alpha-tocopherol (all rac-alpha T). All rac-alpha T is widely used in infant formulas, but its accretion in formula-fed infant brain is unknown. Objective: We sought to compare alpha T and stereoisomer status in infant rhesus macaques (Macaca mulatta) fed infant formula (RRR-alpha T or all rac-alpha T) with a reference group fed a mixed diet of breast milk and maternal diet. Methods: From 1 d after birth until 6 mo of age, infants (n = 23) were either nursery reared and exclusively fed 1 of 2 formulas by staff personnel or were community housed with their mothers and consumed a mixed reference diet of breast milk (69 mL/d at 6 mo) transitioning to monkey diet at similar to 2 mo (MF; n = 8). Formulas contained either 21 mu mol RRR-alpha T/L (NAT-F; n = 8) or 30 mu mol all rac-alpha T/L (SYN-F; n = 7). Total alpha T and alpha T stereoisomers were analyzed in breast milk at 2, 4, and 6 mo and in monkey plasma and liver and 6 brain regions at 6 mo of age. alpha-Tocopherol transfer protein (alpha-TTP), lipoprotein alpha T, and urinary alpha-carboxyethyl-hydroxychroman (alpha-CEHC) were measured. One-way ANOVA with Tukey's post-hoc test was used for analysis. Results: At study termination, plasma, liver, lipoprotein, and brain total alpha T did not differ between groups. However, the NAT-F-fed group had higher RRR-alpha T than the SYN-F-fed group (P < 0.01) and the MF group (P < 0.0001) in plasma (1.7- and 2.7-fold) and brain (1.5- and 2.5-fold). Synthetic alpha T 2R stereoisomers (SYNTH-2R) were generally 3- and 7-fold lower in brain regions of the NAT-F group compared with those of the SYN-F and MF groups (P < 0.05). SYNTH-2R stereoisomers were 2-fold higher in MF than SYN-F (P < 0.0001). The plasma percentage of SYNTH-2R was negatively correlated with the brain percentage of RRR-alpha T (r = -0.99, P < 0.0001). Brain alpha T profiles were not explained by alpha-TTP mRNA or protein expression. Urine alpha-CEHC was 3 times higher in the NAT-F than in the MF group (P < 0.01). Conclusions: Consumption of infant formulas with natural (NAT-F) compared with synthetic (SYN-F) alpha T differentially impacted brain alpha T stereoisomer profiles in infant rhesus macaques. Future studies should assess the functional implications of alpha T stereoisomer profiles on brain health.

Acute myeloid leukemia (AML) is an aggressive disease and, despite advances, its treatment remains challenging. Therefore, it remains important to identify new agents for the management of this disease. Withanolides, a group of steroidal lactones found in Solanaceae plants are of potential interest due to their reported anticancer activities in different settings. In this study we investigated the anti-proliferative effects and mode of action of Solanaceae-derived withanolides in AML cell models; these metabolites include withametelin (WTH) and Coagulansin A (CoA) isolated fromDatura innoxiaandWithania coagluanse, respectively. Both withanolides inhibited the proliferation of AML cells and induced cell death, with WTH being more potent than CoA in the AML models tested. Quantitative label-free proteomics and phosphoproteomics were employed to define the mechanism of action of the studied withanolides. We identified and quantified 5269 proteins and 17,482 phosphosites in cells treated with WTH, CoA or vehicle control. Withanolides modulated the expression of proteins involved in regulating key cellular processes including cell cycle, metabolism, signaling, protein degradation and gene expression. Enrichment analysis of the phosphoproteomics data against kinase substrates, kinase-kinase relationships and canonical pathways showed that the withanolides decreased the activity of kinases such as phosphoinositide 3-kinase (PI3K), protein kinase B (PKB; also known as RAC-alpha serine/threonine-protein kinase or AKT), mammalian target of rapamycin (mTOR), extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) and the serine/threonine-protein kinase A-Raf (ARAF), while increasing the activation of DNA repair kinases. These results indicate that withanolide metabolites have pleiotropic effects in the modulation of oncogenic pro-survival and pro-apoptotic signaling pathways that regulate the induction of apoptosis. Withanolide mediated apoptosis was confirmed by immunoblotting showing increased expression of cleaved PARP and Caspases 3, 8 and 9 as a result of treatment. Overall, our results suggest that WTH and CoA have therapeutic potential against AML with WTH exhibiting more potent effects and should be explored further.