Nucleophile-Dependent Regioselective Reaction of (<i>S</i>)‑4-Benzyl-2-Fluoroalkyl-1,3-Oxazolines

Nucleophile-dependent regioselectivities in the nucleophilic reaction of (<i>S</i>)-4-benzyl-2-fluoroalkyl-1,3-oxazoline to different types of fluorinated compounds were investigated experimentally and theoretically. The ring opening of (<i>S</i>)-4-benzyl-2-bromodifluoromethyl-1,3-oxazoline by arenethiolates exclusively occurred at the C5 position of the 1,3-oxazoline ring, whereas completely different regioselectivity was observed for a unimolecular radical nucleophilic substitution (S_RN1) at the terminal bromine atom of the CF₂Br group when arenolates were employed as the nucleophiles. The reaction of (<i>S</i>)-4-benzyl-2-trifluoromethyl-1,3-oxazoline with nucleophiles such as arenethiols, arenols, and TMSCl underwent nucleophilic ring opening in a regiospecific way, while the use of TMSCF₃ was determined to proceed through nucleophilic addition to the CN bond

Endurance performance and energy metabolism during exercise in mice with a muscle-specific defect in the control of branched-chain amino acid catabolism

<div><p>It is known that the catabolism of branched-chain amino acids (BCAAs) in skeletal muscle is suppressed under normal and sedentary conditions but is promoted by exercise. BCAA catabolism in muscle tissues is regulated by the branched-chain α-keto acid (BCKA) dehydrogenase complex, which is inactivated by phosphorylation by BCKA dehydrogenase kinase (BDK). In the present study, we used muscle-specific BDK deficient mice (BDK-mKO mice) to examine the effect of uncontrolled BCAA catabolism on endurance exercise performance and skeletal muscle energy metabolism. Untrained control and BDK-mKO mice showed the same performance; however, the endurance performance enhanced by 2 weeks of running training was somewhat, but significantly less in BDK-mKO mice than in control mice. Skeletal muscle of BDK-mKO mice had low levels of glycogen. Metabolome analysis showed that BCAA catabolism was greatly enhanced in the muscle of BDK-mKO mice and produced branched-chain acyl-carnitine, which induced perturbation of energy metabolism in the muscle. These results suggest that the tight regulation of BCAA catabolism in muscles is important for homeostasis of muscle energy metabolism and, at least in part, for adaptation to exercise training.</p></div

Plasma BCAA concentrations of control and BDK-mKO mice with and without the running exercise bout.

<p># Significant difference between control and BDK-mKO mice. * Significant difference in the same group of mice with and without the exercise bout.</p

Exercise performance of control and BDK-mKO mice.

<p><b>(A)</b> Running distance to exhaustion before and after 2 weeks of training, and (B) swimming time to exhaustion of untrained mice on each of 4 consecutive days. # Significant difference between control and BDK-mKO mice.</p

Citrate synthase and cytochrome c oxidase activities.

<p># Significant difference between control and BDK-mKO mice.</p

Dual Enzyme Cascade-Activated Popcorn-Like Nanoparticles Efficiently Remodeled Stellate Cells to Alleviate Pancreatic Desmoplasia

In pancreatic cancer, excessive desmoplastic stroma severely impedes drug access to tumor cells. By reverting activated pancreatic stellate cells (PSCs) to quiescence, all-trans retinoic acid (ATRA) can attenuate their stromal synthesis and remodel the tumor-promoting microenvironment. However, its modulatory effects have been greatly weakened due to its limited delivery to PSCs. Therefore, we constructed a tripeptide RFC-modified gelatin/oleic acid nanoparticle (RNP@ATRA), which delivered ATRA in an enzyme-triggered popcorn-like manner and effectively resolved the delivery challenges. Specifically, surface RFC was cleaved by aminopeptidase N (APN) on the tumor endothelium to liberate l-arginine, generating nitric oxide (NO) for tumor-specific vasodilation. Then, massive nanoparticles were pushed from the vessels into tumors, showing 5.1- and 4.0-fold higher intratumoral accumulation than free ATRA and APN-inert nanoparticles, respectively. Subsequently, in the interstitium, matrix metalloproteinase-2-induced gelatin degradation caused RNP@ATRA to rapidly release ATRA, promoting its interstitial penetration and PSC delivery. Thus, activated PSCs were efficiently reverted to quiescence, and stroma secretion and vascular compression were reduced, thereby enhancing intratumoral delivery of small-molecule or nanosized chemotherapeutics. Ultimately, RNP@ATRA combined with chemotherapeutics markedly suppressed tumor growth and metastasis without causing additional toxicities. Overall, this work provides a potential nanoplatform for the efficient delivery of PSC-modifying agents in pancreatic cancer and other stroma-rich tumors

Metabolites in the glycolytic pathway.

<p>Changes in metabolite levels in skeletal muscle of BDK-mKO mice and control mice with and without the exercise bout are shown. # Significant difference between control and BDK-mKO mice. G6P, glucose 6-phosphate; F1,6BP, fructose 1,6-bisphosphate; DHAP, dihydroxyacetone phosphate; 2PG, 2-phosphoglycerate; and PEP, phosphoenolpyruvate.</p

Acetyl-CoA and metabolites in the TCA cycle.

<p>Changes in metabolite levels in skeletal muscle of BDK-mKO mice and control mice with and without the exercise bout are shown. # Significant difference between control and BDK-mKO mice. * Significant difference in the same group of mice with and without exercise bout. αKG, α-ketoglutarate.</p

BCAAs and their metabolites.

<p>Changes in the metabolite levels in the skeletal muscle of control and BDK-mKO mice with and without the exercise bout are shown. # Significant difference between control and BDK-mKO mice. * Significant difference in the same group of mice with and without the exercise bout. PMP, pyridoxamine 5'-phosphate; KIC, α-ketoisocaproate; KMV, α-keto-ß-methylvalerate; KIV, α-ketoisovalerate; ßMB-CAR, ß-methylbutyryl-carnitine; αMB-CAR, α-methylbutyryl-carnitine; IB-CAR, isobutyryl-carnitine; and αKG, α-ketoglutarate.</p

NADH, NAD⁺, and high energy compounds.

<p>NADH, NAD⁺, and high energy compounds.</p