Influence of progressive fluid restriction on mood and physiological markers of dehydration in women.

The present study evaluated, using a well-controlled dehydration protocol, the effects of 24 h fluid deprivation (FD) on selected mood and physiological parameters. In the present cross-over study, twenty healthy women (age 25 (SE 0.78) years) participated in two randomised sessions: FD-induced dehydration v. a fully hydrated control condition. In the FD period, the last water intake was between 18.00 and 19.00 hours and no beverages were allowed until 18.00 hours on the next day (23-24 h). Water intake was only permitted at fixed periods during the control condition. Physiological parameters in the urine, blood and saliva (osmolality) as well as mood and sensations (headache and thirst) were compared across the experimental conditions. Safety was monitored throughout the study. The FD protocol was effective as indicated by a significant reduction in urine output. No clinical abnormalities of biological parameters or vital signs were observed, although heart rate was increased by FD. Increased urine specific gravity, darker urine colour and increased thirst were early markers of dehydration. Interestingly, dehydration also induced a significant increase in saliva osmolality at the end of the 24 h FD period but plasma osmolality remained unchanged. The significant effects of FD on mood included decreased alertness and increased sleepiness, fatigue and confusion. The most consistent effects of mild dehydration on mood are on sleep/wake parameters. Urine specific gravity appears to be the best physiological measure of hydration status in subjects with a normal level of activity; saliva osmolality is another reliable and non-invasive method for assessing hydration status.

Transcriptional modulations by RXR agonists are only partially subordinated to PPARalpha signaling and attest additional, organ-specific, molecular cross-talks.

Nuclear hormone receptors (NR) are important transcriptional regulators of numerous genes involved in diverse pathophysiological and therapeutic functions. Following ligand activation, class II NR share the ability to heterodimerize with the retinoid X receptor (RXR). It is established that RXR activators, rexinoids, transactivate several peroxisome proliferator-activated receptor alpha (PPARalpha) target genes in a PPARalpha-dependent manner. We hypothesized that, once activated, RXR might signal through quiescent NR other than PPARalpha, in an organ-specific manner. To study this putative phenomenon in vivo, we developed an array of 120 genes relevant to the class II NR field. The genes were selected using both published data and high-density screenings performed on RXR or PPARalpha agonist-treated mice. Wild-type C57BL/6J and PPARalpha-deficient mice were treated with fenofibrate (PPARalpha activator) or LGD1069 (RXR activator). Using our customized array, we studied the hepatic, cardiac, and renal expression of this panel of 120 genes and compared them in both murine genotypes. The results obtained from this study confirmed the ability of an RXR agonist to modulate PPARalpha-restricted target genes in the liver and the kidney. Furthermore, we show that various organ-specific regulations occurring in both genotypes (PPARalpha +/+ or -/-) are highly indicative of the ability of RXR to recruit other class II NR pathways. Further development of this molecular tool may lead to a better understanding of the permissiveness of class II nuclear receptor dimers in vivo.

P-Rex2, a new guanine-nucleotide exchange factor for Rac.

We have identified a new guanine-nucleotide exchange factor, P-Rex2, and cloned it from human skeletal muscle and brain libraries. It has widespread tissue distribution but is not expressed in neutrophils. P-Rex2 is a 183 kDa protein that activates the small GTPase Rac and is regulated by phosphatidylinositol (3,4,5)-trisphosphate and the beta gamma subunits of heterotrimeric G proteins in vitro and in vivo. P-Rex2 has structure, activity and regulatory properties similar to P-Rex1 but has divergent tissue distribution, as P-Rex1 is mainly expressed in neutrophils. Together, they form an enzyme family capable of mediating Rac signalling downstream of G protein-coupled receptors and phosphoinositide 3-kinase.

Effects of changes in water intake on mood of high and low drinkers.

OBJECTIVE: To evaluate the effects of a change in water intake on mood and sensation in 22 habitual high-volume (HIGH; 2-4 L/d) and 30 low-volume (LOW; <1.2 L/d) drinkers who were asked to respectively decrease and increase their daily water intake. METHOD: During baseline HIGH consumed 2.5 L and LOW 1 L of water/day. During 3 controlled intervention days HIGH's water intake was restricted to 1 L/day whereas LOW's was increased to 2.5 L water/day. Several mood scales (Bond & Lader Visual Analog Scale (VAS), Profile of Mood States, Karolinska Sleepiness Scale, Thirst & Emotional VAS) were administered at different time points during the study. ANOVA including intervention, time point and intervention by time point as fixed effects on mean values (i.e.; baseline data vs. mean of 3 intervention days) for each mood scale was performed. RESULTS: At baseline HIGH and LOW were comparable in mood state, except for thirst scores (estimate = 17.16, p<0.001) and POMS depression-dejection scores (estimate = 0.55, p<0.05) which were both higher in the HIGH vs. LOW. In HIGH the restricted water intake resulted in a significant increase in thirst (p<0.001) and a decrease in contentedness (p<0.05), calmness (p<0.01), positive emotions (p<0.05) and vigor/activity (p<0.001). In LOW, increased water consumption resulted in a significant decrease in fatigue/inertia (p<0.001), confusion/bewilderment (p = 0.05) and thirst (p<0.001) and a trend to lower sleepiness (p = 0.07) compared to baseline. CONCLUSION: Increasing water intake has beneficial effects in LOW, especially sleep/wake feelings, whereas decreasing water intake has detrimental effects on HIGH's mood. These deleterious effects in HIGH were observed in some sleep/wake moods as well as calmness, satisfaction and positive emotions.

LRH-1-mediated glucocorticoid synthesis in enterocytes protects against inflammatory bowel disease.

Liver receptor homolog-1 (LRH-1) is a nuclear receptor involved in intestinal lipid homeostasis and cell proliferation. Here we show that haploinsufficiency of LRH-1 predisposes mice to the development of intestinal inflammation. Besides the increased inflammatory response, LRH-1 heterozygous mice exposed to 2,4,6-trinitrobenzene sulfonic acid show lower local corticosterone production as a result of an impaired intestinal expression of the enzymes CYP11A1 and CYP11B1, which control the local synthesis of corticosterone in the intestine. Local glucocorticoid production is strictly enterocyte-dependent because it is robustly reduced in epithelium-specific LRH-1-deficient mice. Consistent with these findings, colon biopsies of patients with Crohn's disease and ulcerative colitis show reduced expression of LRH-1 and genes involved in the production of glucocorticoids. Hence, LRH-1 regulates intestinal immunity in response to immunological stress by triggering local glucocorticoid production. These findings underscore the importance of LRH-1 in the control of intestinal inflammation and the pathogenesis of inflammatory bowel disease.

Distinct roles of endoplasmic reticulum cytochrome b5 and fused cytochrome b5-like domain for rat Delta6-desaturase activity.

The Delta6-desaturase catalyzes key steps in long-chain polyunsaturated fatty acid biosynthesis. Although the gene coding for this enzyme has been isolated in diverse animal species, the protein structure remains poorly characterized. In this work, rat Delta6-desaturase expressed in COS-7 cells was shown to localize in the endoplasmic reticulum. As the enzyme contains an N-terminal cytochrome b5-like domain, we investigated by site-directed mutagenesis the role of this domain in the enzyme activity. The typical HPGG motif of the cytochrome b5-like domain, and particularly histidine in this motif, is required for the activity of the enzyme, whatever the substrate. Neither endogenous COS-7 cytochrome b5 nor coexpressed rat endoplasmic reticulum cytochrome b5 could rescue the activity of mutated forms of Delta6-desaturase. Moreover, when rat endoplasmic reticulum cytochrome b5 was coexpressed with wild-type desaturase, both proteins interacted and Delta6-desaturase activity was significantly increased. The identified interaction between these proteins is not dependent on the desaturase HPGG motif. These data suggest distinct and essential roles for both the desaturase cytochrome b5-like domain and free endoplasmic reticulum cytochrome b5 for Delta6-desaturase activity.