Citrulline production and protein homeostasis.

PURPOSE OF REVIEW: Protein homeostasis is crucial for maintaining cell functions. Citrulline, an endogenous amino acid, is considered as an efficient source of arginine at systemic and cellular level. Accumulating evidence, obtained from citrulline supplementation studies, suggest anabolic properties especially in malnourished rodents and human. Although these studies might suggest a key role for citrulline in protein homeostasis, the supraphysiological concentrations of citrulline do not allow to conclude on a physiological role. This review aimed to assess the role of endogenous citrulline production on protein homeostasis. RECENT FINDINGS: According to recent studies, endogenous citrulline, through its regulating effect on nitric oxide production, seems to play a key role in regulating endothelial and immune functions. We can assume that citrulline-dependent endothelial vasodilation could improve organ perfusion and thus amino acid and insulin supply. Furthermore, citrulline regulates immune cells and thus could regulate inflammation and indirectly protein metabolism. SUMMARY: Although we have currently no direct evidence of a regulating role of endogenous citrulline production on protein homeostasis, we can hypothesize that physiologically through its role in endothelial and immune function, citrulline could indirectly participate to protein homeostasis.

Indications and contraindications for infusing specific amino acids (leucine, glutamine, arginine, citrulline, and taurine) in critical illness.

PURPOSE OF REVIEW: The review assesses the utility of supplementing parenteral or enteral nutrition of ICU patients with each of five specific amino acids that display pharmacological properties. Specifying indications implies also stating contraindications.Combined supplementation of amino acids with ω3-fatty acids and/or trace elements (immune-enhancing diets) will not be considered in this review because these mixtures do not allow the role of amino acids in the effect (positive or negative) of the mixture to be isolated, and so cannot show whether or not supplementation of a given amino acid is indicated. RECENT FINDINGS: After decades of unbridled use of glutamine (GLN) supplementation in critically ill patients, recent large trials have brought a note of caution, indicating for example that GLN should not be used in patients with multiple organ failure. Yet these large trials do not change the conclusions of recent meta-analyses. Arginine (ARG), as a single dietary supplement, is probably not harmful in critical illness, in particular in a situation of ARG deficiency syndrome with low nitric oxide production. Citrulline supplementation strongly improves microcirculation in animal models with gut injury, but clinical studies are lacking. Taurine has a potent protective effect against ischemic reperfusion injury. SUMMARY: Amino acid-based pharmaconutrition has displayed familiar 'big project' stages: enthusiasm (citrulline and taurine), doubt (GLN), hunt for the guilty (ARG), and backpedalling (leucine). Progress in this field is very slow, and sometimes gives way to retreat, as demonstrated by recent large trials on GLN supplementation.

Primary Cutaneous Mucinous Carcinoma Monitoring: A Role for CA15.3 and CEA?

Primary cutaneous mucinous carcinoma (PCMC) is a rare malignant skin adnexal tumor. Recurrences are most often localized, and long-term follow-up after complete surgery consists essentially of self-examination of skin. We report one case of metastatic PCMC with elevated levels of serum CEA and CA15.3. Because of the difficulty to differentiate PCMC and metastasis of mucinous breast cancer, the hypothesis of a metastasized breast cancer was ruled out. These tumor markers contributed to the monitoring of the metastatic disease. Since metastatic disease was diagnosed after several years of seeming complete remission, CEA and CA15.3 would likely have allowed the clinicians to detect the relapse earlier. Although the use of tumor biomarkers in PCMC is not rooted in clinical practice and not mentioned in guidelines, we suggest that CEA and CA15.3 could be of particular interest to monitor and detect early metastatic PCMC.

Serum Leptin Levels, Nutritional Status, and the Risk of Healthcare-Associated Infections in Hospitalized Older Adults.

We aimed to determine whether serum leptin levels are predictive of the occurrence of healthcare-associated infections (HAIs) in hospitalized older patients. In a prospective cohort, 232 patients had available data for leptin and were monitored for HAIs for 3 months. Admission data included comorbidities, invasive procedures, the Mini Nutritional Assessment (MNA), BMI, leptin, albumin and C-reactive protein levels, and CD4 and CD8 T-cell counts. Multivariate logistic regression modelling was used to identify predictors of HAIs. Of the 232 patients (median age: 84.8; females: 72.4%), 89 (38.4%) experienced HAIs. The leptin level was associated with the BMI (p < 0.0001) and MNA (p < 0.0001) categories. Women who experienced HAIs had significantly lower leptin levels than those who did not (5.9 µg/L (2.6-17.7) and 11.8 (4.6-26.3), respectively; p = 0.01; odds ratio (OR) (95% confidence interval): 0.67 (0.49-0.90)); no such association was observed for men. In a multivariate analysis of the women, a lower leptin level was significantly associated with HAIs (OR = 0.70 (0.49-0.97)), independently of comorbidities, invasive medical procedures, and immune status. However, leptin was not significantly associated with HAIs after adjustments for malnutrition (p = 0.26) or albuminemia (p = 0.15)-suggesting that in older women, the association between serum leptin levels and subsequent HAIs is mediated by nutritional status.

Metabolic Strategies for Inhibiting Cancer Development.

The tumor microenvironment is a complex mix of cancerous and noncancerous cells (especially immune cells and fibroblasts) with distinct metabolisms. These cells interact with each other and are influenced by the metabolic disorders of the host. In this review, we discuss how metabolic pathways that sustain biosynthesis in cancer cells could be targeted to increase the effectiveness of cancer therapies by limiting the nutrient uptake of the cell, inactivating metabolic enzymes (key regulatory ones or those linked to cell cycle progression), and inhibiting ATP production to induce cell death. Furthermore, we describe how the microenvironment could be targeted to activate the immune response by redirecting nutrients toward cytotoxic immune cells or inhibiting the release of waste products by cancer cells that stimulate immunosuppressive cells. We also examine metabolic disorders in the host that could be targeted to inhibit cancer development. To create future personalized therapies for targeting each cancer tumor, novel techniques must be developed, such as new tracers for positron emission tomography/computed tomography scan and immunohistochemical markers to characterize the metabolic phenotype of cancer cells and their microenvironment. Pending personalized strategies that specifically target all metabolic components of cancer development in a patient, simple metabolic interventions could be tested in clinical trials in combination with standard cancer therapies, such as short cycles of fasting or the administration of sodium citrate or weakly toxic compounds (such as curcumin, metformin, lipoic acid) that target autophagy and biosynthetic or signaling pathways.

Citrulline prevents age-related LTP decline in old rats.

The prevalence of cognitive decline is increasing as the ageing population is considerably growing. Restricting this age-associated process has become a challenging public health issue. The age-related increase in oxidative stress plays a major role in cognitive decline, because of its harmful effect on functional plasticity of the brain, such as long-term potentiation (LTP). Here, we show that citrulline (Cit) has powerful antioxidant properties that can limit ex vivo oxidative stress-induced LTP impairment in the hippocampus. We also illustrate that a three-month Cit supplementation has a protective effect on LTP in aged rats in vivo. The identification of a Cit oxidation byproduct in vitro suggests that the antioxidant properties of Cit could result from its own oxidation. Cit supplementation may be a promising preventive nutritional approach to limit age-related cognitive decline.

Ornithine Aminotransferase, an Important Glutamate-Metabolizing Enzyme at the Crossroads of Multiple Metabolic Pathways.

Ornithine δ-aminotransferase (OAT, E.C. 2.6.1.13) catalyzes the transfer of the δ-amino group from ornithine (Orn) to α-ketoglutarate (aKG), yielding glutamate-5-semialdehyde and glutamate (Glu), and vice versa. In mammals, OAT is a mitochondrial enzyme, mainly located in the liver, intestine, brain, and kidney. In general, OAT serves to form glutamate from ornithine, with the notable exception of the intestine, where citrulline (Cit) or arginine (Arg) are end products. Its main function is to control the production of signaling molecules and mediators, such as Glu itself, Cit, GABA, and aliphatic polyamines. It is also involved in proline (Pro) synthesis. Deficiency in OAT causes gyrate atrophy, a rare but serious inherited disease, a further measure of the importance of this enzyme.

Altered hippocampal information coding and network synchrony in APP-PS1 mice.

ß-amyloid is hypothesized to harm neural function and cognitive abilities by perturbing synaptic transmission and plasticity in Alzheimer's disease (AD). To assess the impact of this pathology on hippocampal neurons' ability to encode flexibly environmental information across learning, we performed electrophysiological recordings of CA1 hippocampal unit activity in AD transgenic mice as they acquired an action-reward association in a spatially defined environment; the behavioral task enabled the precise timing of discrete and intentional behaviors of the animal. We found that the proportion of behavioral task-sensitive cells in wild-type (WT) mice typically increased, whereas the proportion of place cells decreased with learning. In AD mice, this learning-dependent change of cell-discharge patterns was absent, and cells exhibited similar firings from the beginning to firings attained at the late learning stage in wild-type cells. These inflexible hippocampal representations of task and space throughout learning are accompanied by remarkable alterations of local oscillatory activity in the theta and ultra-fast ripple frequencies as well as learning abilities. The present data offer new insights into the in vivo cellular and network processes by which ß-amyloid and other AD mutations may exert its harmful effects to produce cognitive and behavioral impairments in early stage of AD.