Carbohydrate mouth rinsing does not affect 6-min walk test performance and blood glucose responses in older adults.

PURPOSE: Carbohydrate (CHO) mouth rinsing (MR) prior to exercise has been shown to elicit enhanced performance and energy availability in some studies. Previous literature has concentrated on examining CHO MR strategies for improving aerobic endurance performance in younger athletic adults. Knowledge of the impact of CHO MR on functional performance in older adults is scarce. The purpose of this investigation was to determine if CHO MR would improve 6-min walk test (6MWT) performance, perceived exertion, and blood glucose responses in older adults. METHOD: Thirty-three individuals (16 males, 17 females), age ≥ 70 years performed two 6MWT trials, one of which utilized a 6.4% maltodextrin CHO MR and one of which utilized a placebo MR. Participants held the MR in their mouth for 20 s prior to the 6MWT, and trials occurred in a counterbalanced fashion. Total distance walked and rating of perceived exertion (RPE) were recorded upon completion of each 6MWT. Heart rate (HR), peripheral blood oxygen saturation (SpO2), systolic and diastolic blood pressures (BP), blood glucose, and blood lactate were measured before and after each 6MWT. RESULT: CHO MR did not alter the response of any study parameter compared to the placebo MR (p = 0.13-0.94). HR, systolic BP, and blood lactate increased and SpO2 decreased across time (p < 0.01). CONCLUSION: A 6.4% maltodextrin CHO MR did not alter total distance walked, perceived exertion, or other physiological responses elicited by the 6MWT in older adults.

Aurone derivatives as Vps34 inhibitors that modulate autophagy.

We report in this study the identification of a natural product-like antagonist (1a) of Vps34 as a potent autophagy modulator via structure-based virtual screening. Aurone derivative 1a strongly inhibited Vps34 activity in cell-free and cell-based assays. Significantly, 1a prevents autophagy in human cells induced either by starvation or by an mTOR inhibitor. In silico modeling and kinetic data revealed that 1a could function as an ATP-competitive inhibitor of Vps34. Moreover, it suppressed autophagy in vivo and without inducing heart or liver damage in mice. 1a could be utilized as a new motif for more selective and efficacious antagonists of Vps34 for the potential treatment of autophagy-related human diseases.

Silver-Catalyzed 1,3-Acyloxy Migration/Diels-Alder Reaction of 1,9-Dien-4-yne Esters to Partially Hydrogenated Isoquinolines.

A synthetic method to prepare partially hydrogenated isoquinolines efficiently from silver-mediated [3,3]-sigmatropic rearrangement/Diels-Alder reaction of 1,9-dien-4-yne esters is described. The reactions were shown to be robust with a wide variety of substitution patterns tolerated to provide the corresponding nitrogen-containing heterocyclic products in good to excellent yields. This includes examples containing a bridgehead sp3 quaternary carbon center as well as the cycloisomerization of one substrate to give the corresponding bicyclic adduct in excellent yield at the gram scale.

Structure-based screening and optimization of cytisine derivatives as inhibitors of the menin-MLL interaction.

The natural product-like compound 1 was identified as a direct inhibitor of the menin-MLL interaction by in silico screening. Structure-based optimization furnished analogue 1a, which showed significantly higher potency than both the lead structure 1 and the reference compound MI-2.

Gold-Catalyzed Sequential Cyclization of 1-En-3,9-Diyne Esters to Partially Hydrogenated 3H-Dicyclopenta[a,b]naphthalenes.

A synthetic method that relies on a gold(I)-catalyzed cycloisomerization of 1-en-3,9-diyne esters to spiro[4.4]non-2-ene-substituted 1,2-dihydronaphthalenes is described. Robust with a wide variety of substitution patterns tolerated, the reaction provides the first example of a one-step strategy to construct such novel and architecturally challenging members of the carbocycle family in good to excellent yields. A mechanism is proposed in which the sequential cycloisomerization pathway was thought to involve a gold-catalyzed 1,3-acyloxy migration/Nazarov cyclization followed by a formal [4+2] cycloaddition to give the tetracarbocyclic product.

Copper-Mediated Cross-Dehydrogenative Coupling of 2-Methylpyridine and 8-Methylquinoline with Methyl Ketones and Benzamides.

A synthetic method to prepare (E)-(pyridin-2-yl)enones and (E)-(quinolin-8-yl)enones that relies on the respective copper(I)-catalyzed formal cross-dehydrogenative coupling (CDC) reaction of 2-methylpyridine and 8-methylquinoline with methyl ketones has been discovered. The mechanism was delineated to follow a pathway involving oxidation of the N-heterocycle to its corresponding aldehyde adduct prior to reaction with the methyl ketone. The versatility and substrate dependent divergence in the reactivity of the copper-mediated CDC strategy was exemplified by its application to the synthesis of N-(quinolin-8-ylmethyl)amide and N-(quinolin-8-ylmethyl)aniline adducts on switching the cross-coupling partner to benzamides or an aniline derivative.