Immunonutrition stimulates immune functions and antioxidant defense capacities of leukocytes in radiochemotherapy-treated head & neck and esophageal cancer patients: A double-blind randomized clinical trial.

BACKGROUND: Immunonutrition has been reported to improve the immune status of perioperative cancer patients, thereby reducing complications and length of hospital stay. AIM: This study aimed to assess whether immunonutrition enriched in arginine, EPA & DHA and nucleotides could impact the immune cells responses in head & neck and esophageal cancer patients treated by radiochemotherapy (RCT). METHODS: A double-blind clinical trial was carried out in 28 patients randomized into two groups, receiving either an immunomodulating enteral nutrition formula (IEN, n = 13, Impact(®), Nestlé) or an isoenergetic isonitrogenous standard enteral nutrition formula (SEN, n = 15) throughout RCT (5-7 weeks). After isolation from whole blood, immune cells metabolism and functions were assessed at the beginning (Db) and at the end (De) of RCT. RESULTS: Immunonutrition maintained CD4(+)/CD8(+) T-lymphocyte counts ratio and CD3 membrane expression between Db and De. Polymorphonuclear cells CD62L and CD15 densities and ROS production were increased in IEN patients. Peripheral blood mononuclear cells (PBMC) production of pro-inflammatory prostaglandin-E2 was stable in IEN patients and lower than in SEN patients at De. Genes coding for immune receptors, antioxidant enzymes and NADPH oxidase subunits were overexpressed in the PBMC of IEN vs SEN patients at De. CONCLUSION: Immunonutrition can enhance immune cell responses through the modulation of their phenotypes and functions. By modulating the gene expression of immune cells, immunonutrition could make it easier for the organism to adapt to the systemic inflammation and oxidative stress induced by RCT. CLINICAL TRIAL REGISTRATION: This clinical trial has been registered on ClinicalTrial.gov website: NCT00333099.

Extracorporeal photochemotherapy induces arginase 1 in patients with graft versus host disease.

The benefits of extracorporeal photochemotherapy (ECP; psoralen and UVA exposure of blood mononuclear cells) in graft-versus-host-disease (GVHD) are well-recognized, but the mechanisms of action remain elusive. As the metabolism of l-arginine in immune cells is known to play a role in immune tolerance, we investigated the effect of ECP on arginine metabolism, and the influence of extracellular l-arginine concentration on the response to ECP in cells from patients on therapy by ECP for a GVHD and healthy donors cultured before and after ECP in the presence of different concentrations of arginine (0, 50, 100, 200 and 1000 µmol/l). At baseline arginine was not metabolized through the same pathway in patients and donors. When cells were exposed to ECP, the production of ornithine but not NO° was enhanced, while mRNA of arginase 1 was up-regulated but not INOS. In GVHD patients, increasing arginine concentration resulted in down-regulation of IFNγ and TNFα mRNA expression, whereas IL10 was up-regulated especially at physiological plasma levels (between 0 and 100 µM). Overall, our study shows that ECP orients the metabolism of arginine toward the arginase pathway together with shifting the cytokine profile toward IL-10, providing new insights into the enigmatic mechanism of action of ECP.

Involvement of adiponectin and leptin in breast cancer: clinical and in vitro studies.

Obesity is a risk factor for breast cancer development. A recent hypothesis suggests that the adipokines, adiponectin and leptin, are involved in breast cancer development. This prompted us to investigate the role of adiponectin and leptin in mammary carcinogenesis. Adiponectin receptors (AdipoR1 and AdipoR2) and leptin receptor (Ob-Rt, representing all the isoforms of Ob-R) proteins were detected by immunohistochemistry in in situ ductal carcinoma, invasive ductal malignancy, and healthy adjacent tissue. In addition, mRNA expression of adiponectin, AdipoR1, AdipoR2, leptin, Ob-Rt, and Ob-Rl (the long isoform of Ob-R) was observed in MCF-7 breast cancer cells. Interestingly, leptin mRNA expression was 34.7-fold higher than adiponectin mRNA expression in the MCF-7 cell line. Moreover, adiponectin (10 microg/ml) tended to decrease the mRNA expression of leptin (-36%) and Ob-Rl (-28%) and significantly decreased Ob-Rt mRNA level (-26%). In contrast, leptin treatment (1 microg/ml) significantly decreased AdipoR1 mRNA (-23%). Adiponectin treatment (10 microg/ml) inhibited the proliferation of MCF-7 cells, whereas leptin (1 microg/ml) stimulated the growth of cancer cells. In addition, adiponectin inhibited leptin-induced cell proliferation (both 1 microg/ml). Using microarray analysis, we found that adiponectin reduced the mRNA levels of genes involved in cell cycle regulation (mitogen-activated protein kinase 3 and ATM), apoptosis (BAG1, BAG3, and TP53), and potential diagnosis/prognosis markers (ACADS, CYP19A1, DEGS1, and EVL), whereas leptin induced progesterone receptor mRNA expression. In conclusion, the current study indicates an interaction of leptin- and adiponectin-signaling pathways in MCF-7 cancer cells whose proliferation is stimulated by leptin and suppressed by adiponectin.

Long-term effects of vasopressin on the subcellular localization of ENaC in the renal collecting system.

Previous studies revealed that chronic (days) vasopressin treatment stimulates amiloride-sensitive sodium transport in isolated renal cortical collecting ducts and increases the abundance of beta- and gamma-subunits of the epithelial sodium channel (ENaC) in the kidney. The aim of the present work was to investigate in vivo the cellular basis of these effects. The long-term effect of V2 vasopressin agonist (1-deamino-8-D-arginine vasopressin (dDAVP)) on the abundance and subcellular localization of ENaC along the rat renal collecting system was determined by immunohistochemistry and laser confocal microscopy. Moreover, we studied by real-time reverse transcriptase-polymerase chain reaction the effect of vasopressin on proteins implicated in the regulation of ENaC (Nedd4-2, prostasin, Sgk1). After 5 days of administration, dDAVP markedly increased the intracellular pool of the beta- and gamma-ENaC subunits in the principal cells, with an increasing gradient from connecting tubule to the outer medullary collecting duct, but did not increase any subunit at the cell surface. The apical immunostaining of ENaC increased in response to sodium restriction, as expected, but dDAVP did not further enhance this apical labelling. dDAVP increased the gene expression of prostasin in the cortex but not that of Nedd4-2 and Sgk1. These findings suggest that the previously reported increase in sodium transport induced by sustained stimulation of vasopressin V2 receptor is probably mediated by other mechanism than an increase in the apical density of ENaC.