Targeting purine synthesis in ASS1-expressing tumors enhances the response to immune checkpoint inhibitors.

Argininosuccinate synthase (ASS1) downregulation in different tumors has been shown to support cell proliferation and yet, in several common cancer subsets ASS1 expression associates with poor patient prognosis. Here we demonstrate that ASS1 expression under glucose deprivation is induced by c-MYC, providing survival benefit by increasing nitric oxide synthesis and activating the gluconeogenic enzymes pyruvate carboxylase and phosphoenolpyruvate carboxykinase by S-nitrosylation. The resulting increased flux through gluconeogenesis enhances serine, glycine and subsequently purine synthesis.

Deletion of endothelial arginase 1 does not improve vasomotor function in diabetic mice.

Endothelial arginase 1 was ablated to assess whether this prevents hyperglycemia-induced endothelial dysfunction by improving arginine availability for nitric oxide production. Endothelial Arg1-deficient mice (Arg1-KO ) were generated by crossing Arg1 (controls) with Tie2Cre mice and analyzed by immunohistochemistry, measurements of hemodynamics, and wire myography. Ablation was confirmed by immunohistochemistry.

Dietary treatment of fatty liver: High dietary protein content has an antisteatotic and antiobesogenic effect in mice.

Few studies have assessed the effect of changing ratios of dietary macronutrients on fat accumulation in adipose tissue and organs such as the liver in a 3×n(n≥3) factorial design. We investigated the effects of 7 diets from a single manufacturer containing 11-58en% protein (casein), 0-81en% carbohydrates (CHO; sucrose, maltrodextrin-10 and corn starch), and 8-42en% fat (triheptanoin, olive oil or cocoa butter) in C57BL/6J mice, a good model for diet-induced obesity and fatty liver. The diets were fed for 3weeks to wild-type and hyperlipidemic male and female mice.

Pivotal role of glutamine synthetase in ammonia detoxification.

Unlabelled: Glutamine synthetase (GS) catalyzes condensation of ammonia with glutamate to glutamine. Glutamine serves, with alanine, as a major nontoxic interorgan ammonia carrier. Elimination of hepatic GS expression in mice causes only mild hyperammonemia and hypoglutaminemia but a pronounced decrease in the whole-body muscle-to-fat ratio with increased myostatin expression in muscle.

The odd-carbon medium-chain fatty triglyceride triheptanoin does not reduce hepatic steatosis.

Background & Aims: Non-alcoholic fatty-liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Previously, we showed that a high-protein diet minimized diet-induced development of fatty liver and even reversed pre-existing steatosis. A high-protein diet leads to amino-acid catabolism, which in turn causes anaplerosis of the tricarboxylic-acid (TCA) cycle.

The growth pattern of the human intestine and its mesentery.

Background: It remains unclear to what extent midgut rotation determines human intestinal topography and pathology. We reinvestigated the midgut during its looping and herniation phases of development, using novel 3D visualization techniques.

Results: We distinguished 3 generations of midgut loops.

High-protein diets prevent steatosis and induce hepatic accumulation of monomethyl branched-chain fatty acids.

The hallmark of nonalcoholic fatty liver disease is steatosis of unknown etiology. To test how dietary protein decreases steatosis, we fed female C57BL/6 J mice low-fat (8 en%) or high-fat (42 en%) combined with low-protein (11 en%), high-protein (HP; 35 en%) or extra-high-protein (HPX; 58 en%) diets for 3 weeks. The 35 en% protein diets reduced hepatic triglyceride, free fatty acid, cholesterol and phospholipid contents to ~50% of that in 11 en% protein diets.

Endothelium-dependent hyperpolarization-related relaxations diminish with age in murine saphenous arteries of both sexes.

Background And Purpose: We investigated the effects of aging on the contributions of NO and endothelium-dependent hyperpolarization (EDH) to endothelium-dependent relaxation in saphenous arteries of male and female C57BL/6J mice aged 12, 34 and 64 weeks.

Experimental Approach: Vasomotor responses of saphenous arteries were analysed by wire myography in the absence and presence of stimuli of the endothelium, inhibitors of NOS, and inhibitors and stimulants of small (KCa 2.3) and intermediate (KCa 3.

Prevention and reversal of hepatic steatosis with a high-protein diet in mice.

Unlabelled: The hallmark of NAFLD is steatosis of unknown etiology. We tested the effect of a high-protein (HP)(2) diet on diet-induced steatosis in male C57BL/6 mice with and without pre-existing fatty liver. Mice were fed all combinations of semisynthetic low-fat (LF) or high-fat (HF) and low-protein (LP) or HP diets for 3weeks.

Pivotal Advance: Arginase-1-independent polyamine production stimulates the expression of IL-4-induced alternatively activated macrophage markers while inhibiting LPS-induced expression of inflammatory genes.

In macrophages, basal polyamine (putrescine, spermidine, and spermine) levels are relatively low but are increased upon IL-4 stimulation. This Th2 cytokine induces Arg1 activity, which converts arginine into ornithine, and ornithine can be decarboxylated by ODC to produce putrescine, which is further converted into spermidine and spermine. Recently, we proposed polyamines as novel agents in IL-4-dependent E-cadherin regulation in AAMs.