Irisin interaction with adipose tissue secretions by exercise training and flaxseed oil supplement.

BACKGROUND: Previous studies have shown that physical training and natural diet able to change the expression and concentration of peptides and proteins. Myokines and adipokines play an important role in metabolism and metabolic syndrome. Therefore, the purpose of the present study was to investigate the effect of high-intensity interval training (HIIT) and supplementation of flaxseed oil on plasma irisin, nesfatin-1 and resistin in male rats. METHODS: Forty adult male rats were randomly divided into four groups (ten in each group) including Control-Saline (CS), Training-Saline (TS), Control-FlaxOil supplement (CO), and Training-FlaxOil supplement (TO). The training groups performed for 10 weeks and 5 sessions each week, interval training with 90-95% VO2max on rodent treadmill, and supplement groups received flaxseed oil (300 mg / kg). Five days after the last training session, rats were sacrificed. Blood samples were taken from the heart and plasma was evaluated. RESULTS: Exercise Training significantly increased plasma levels of irisin (P = 0.019), nesfatin-1 (P = 0.01), and decreased resistin (P = 0.01). Flaxseed oil significantly reduced plasma resistin levels (P = 0.02). Plasma irisin levels in the supplementation group were higher than all groups (P = 0.041). CONCLUSION: There was a significant positive correlation between plasma levels of irisin with nesfatin-1 and negative correlation with resistin. HIIT program with flaxseed oil as a modality can create a metabolic crosstalk between skeletal muscle and adipose tissues and have health benefits.

Neuronal pentraxin 1: A synaptic-derived plasma biomarker in Alzheimer's disease.

Synaptic neurodegeneration is thought to be an early event initiated by soluble ß-amyloid (Aß) aggregates that closely correlates with cognitive decline in Alzheimer disease (AD). Apolipoprotein ε4 (APOE4) is the most common genetic risk factor for both familial AD (FAD) and sporadic AD; it accelerates Aß aggregation and selectively impairs glutamate receptor function and synaptic plasticity. However, its molecular mechanisms remain elusive and these synaptic deficits are difficult to monitor. AD- and APOE4-dependent plasma biomarkers have been proposed, but synapse-related plasma biomarkers are lacking. We evaluated neuronal pentraxin 1 (NP1), a potential CNS-derived plasma biomarker of excitatory synaptic pathology. NP1 is preferentially expressed in brain and involved in glutamate receptor internalization. NP1 is secreted presynaptically induced by Aß oligomers, and implicated in excitatory synaptic and mitochondrial deficits. Levels of NP1 and its fragments were increased in a correlated fashion in both brain and plasma of 7-8 month-old E4FAD mice relative to E3FAD mice. NP1 was also found in exosome preparations and reduced by dietary DHA supplementation. Plasma NP1 was higher in E4FAD+ (APOE4+/+/FAD+/-) relative to E4FAD- (non-carrier; APOE4+/+/FAD-/-) mice, suggesting NP1 is modulated by Aß expression. Finally, relative to normal elderly, plasma NP1 was also elevated in patients with mild cognitive impairment (MCI) and elevated further in the subset who progressed to early-stage AD. In those patients, there was a trend towards increased NP1 levels in APOE4 carriers relative to non-carriers. These findings indicate that NP1 may represent a potential synapse-derived plasma biomarker relevant to early alterations in excitatory synapses in MCI and early-stage AD.

The potential role of the novel hypothalamic neuropeptides nesfatin-1, phoenixin, spexin and kisspeptin in the pathogenesis of anxiety and anorexia nervosa.

Due to the dynamic development of molecular neurobiology and bioinformatic methods several novel brain neuropeptides have been identified and characterized in recent years. Contemporary techniques of selective molecular detection e.g. in situ Real-Time PCR, microdiffusion and some bioinformatics strategies that base on searching for single structural features common to diverse neuropeptides such as hidden Markov model (HMM) have been successfully introduced. A convincing majority of neuropeptides have unique properties as well as a broad spectrum of physiological activity in numerous neuronal pathways including the hypothalamus and limbic system. The newly discovered but uncharacterized regulatory factors nesfatin-1, phoenixin, spexin and kisspeptin have the potential to be unique modulators of stress responses and eating behaviour. Accumulating basic studies revelaed an intriguing role of these neuropeptides in the brain pathways involved in the pathogenesis of anxiety behaviour. Nesfatin-1, phoenixin, spexin and kisspeptin may also distinctly affect the energy homeostasis and modulate food intake not only at the level of hypothalamic centres. Moreover, in patients suffered from anxiety and anorexia nervosa a significant, sex-related changes in the plasma neuropeptide levels occurred. It should be therefore taken into account that the targeted pharmacomodulation of central peptidergic signaling may be potentially helpful in the future treatment of certain neuropsychiatric and metabolic disorders. This article reviews recent evidence dealing with the hypothetical role of these new factors in the anxiety-related circuits and pathophysiology of anorexia nervosa.

Gastrointestinal Peptides During Chronic Gastric Electrical Stimulation in Patients With Intractable Vomiting.

OBJECTIVES: Gastric electrical stimulation (GES) is an alternative therapy to treat patients with intractable vomiting. A preclinical study has demonstrated the modulation of the gastrointestinal (GI) peptide ghrelin by GES but such mechanism has never been investigated in patients. The aim of this work was to assess the effect of GES on GI peptide levels in patients with intractable vomiting. MATERIALS AND METHODS: Twenty-one patients were randomized to receive either ON or OFF GES, 14 completed the study (10 ON, 4 OFF stimulation). Vomiting episodes, gastric emptying, and gastrointestinal quality of life index (GIQLI) were assessed. Gastric and blood samples were collected before and four months after the ON period of gastric stimulation. mRNA and/or peptide levels were assessed in gastric biopsies for ghrelin, leptin, and NUCB2/nesfatin-1 and in duodenal biopsies for glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) using RT-qPCR and multiplex technology. Ghrelin, leptin, GLP-1, PYY, gastric inhibitory peptide (GIP), and NUCB2/nesfatin-1 levels also were quantified in blood samples. RESULTS: Among clinical parameters, vomiting episodes were slightly reduced by GES (p = 0.09). In tissue, mRNA or protein levels were not modified following chronic GES. In blood, a significant reduction of postprandial PYY levels (p < 0.05) was observed at M4 and a reduction of NUCB2/nesfatin-1 levels in fasted patients (p < 0.05). Increased plasma leptin levels after GES were correlated with reduction of vomiting and improvement of GIQLI. CONCLUSIONS: GES reduces NUCB2/nesfatin-1 levels under fasting conditions and postprandial PYY levels in patients suffering from nausea and/or vomiting refractory to pharmacological therapies.

The effect of thyroid dysfunction on nesfatin-1 and adiponectin levels in rats.

Background Changes in thyroid hormone concentrations may affect adiponectin concentrations through various mechanisms. A molecule released primarily from the fat cells adiposities; adiponectin has important effects on the regulation of body weight. Aim The present study aimed to explore the effects of experimental thyroid dysfunction and its treatment on nesfatin-1 and adiponectin levels in rats. Methods The study included 40 adult male Sprague-Dawley rats which were grouped as follows: (1) control; (2) hypothyroidism [hypothyroidism was induced by intraperitoneal injection of 10 mg/kg/day propylthiouracil (PTU) for 3 weeks]; (3) hypothyroidism + thyroxine group [after hypothyroidism was induced by 2-week PTU injection, they were treated with high-dose L-thyroxine (1.5 mg/kg/day) for 1 week]; (4) hyperthyroidism [hyperthyroidism was induced by 3-weeks' thyroxine injection (0.3 mg/kg/day)]; (5) hyperthyroidism + PTU (after hyperthyroidism was induced by 2-weeks' thyroxine injection, the animals were given 10 mg/kg/day PTU for 1 week). Blood samples taken at the end of the study were analyzed to measure nesfatin-1 and adiponectin levels. Results It was found that nesfatin-1 levels increased in hypothyroidism, while adiponectin levels decreased (p < 0.001). In experimental hyperthyroidism, on the other hand, both nesfatin-1 and adiponectin levels were found significantly elevated (p < 0.001). Conclusion The results of the study indicate that nesfatin-1 and adiponectin levels were modified considerably in hypo- and hyperthyroidism, whereas with the restoration of the thyroid function, modified hormone levels went back to normal.

The effects of Nigella sativa on thyroid function, serum Vascular Endothelial Growth Factor (VEGF) - 1, Nesfatin-1 and anthropometric features in patients with Hashimoto's thyroiditis: a randomized controlled trial.

BACKGROUND: Hashimoto's thyroiditis is an autoimmune disorder and the most common cause of hypothyroidism. The use of Nigella sativa, a potent herbal medicine, continues to increase worldwide as an alternative treatment of several chronic diseases including hyperlipidemia, hypertension and type 2 diabetes mellitus (T2DM). The aim of the current study was to evaluate the effects of Nigella sativa on thyroid function, serum Vascular Endothelial Growth Factor (VEGF) - 1, Nesfatin-1 and anthropometric features in patients with Hashimoto's thyroiditis. METHODS: Forty patients with Hashimoto's thyroiditis, aged between 22 and 50 years old, participated in the trial and were randomly allocated into two groups of intervention and control receiving powdered Nigella sativa or placebo daily for 8 weeks. Changes in anthropometric variables, dietary intakes, thyroid status, serum VEGF and Nesfatin-1 concentrations after 8 weeks were measured. RESULTS: Treatment with Nigella sativa significantly reduced body weight and body mass index (BMI). Serum concentrations of thyroid stimulating hormone (TSH) and anti-thyroid peroxidase (anti-TPO) antibodies decreased while serum T3 concentrations increased in Nigella sativa-treated group after 8 weeks. There was a significant reduction in serum VEGF concentrations in intervention group. None of these changes had been observed in placebo treated group. In stepwise multiple regression model, changes in waist to hip ratio (WHR) and thyroid hormones were significant predictors of changes in serum VEGF and Nesgfatin-1 values in Nigella sativa treated group (P < 0.05). CONCLUSIONS: Our data showed a potent beneficial effect of powdered Nigella sativa in improving thyroid status and anthropometric variables in patients with Hashimoto's thyroiditis. Moreover, Nigella sativa significantly reduced serum VEGF concentrations in these patients. Considering observed health- promoting effect of this medicinal plant in ameliorating the disease severity, it can be regarded as a useful therapeutic approach in management of Hashimoto's thyroiditis. TRIAL REGISTRATION: Iranian registry of clinical trials (registration number IRCT2015021719082N4 - Registered March-15-2015).

Neutrophil/Lymphocyte Ratio, Serum Endocan, and Nesfatin-1 Levels in Patients with Psoriasis Vulgaris Undergoing Phototherapy Treatment.

BACKGROUND Psoriasis is an autoimmune, inflammatory, and chronic disease. Recent studies have evaluated serum endocan and nesfatin-1 levels in patients with inflammatory disorders. The neutrophil-to-lymphocyte ratio (NLR) is an inflammatory marker currently used in many diseases. The aim of the present study was to evaluate NLR, serum endocan, and nesfatin-1 levels in psoriasis vulgaris before and after narrow-band ultraviolet B (NB-UVB) phototherapy treatment and compared to healthy controls. MATERIAL AND METHODS This study was conducted on a total of 88 cases, 39 of which had psoriasis vulgaris and 49 were healthy volunteers. Thirty-nine psoriasis vulgaris patients underwent NB-UVB phototherapy treatment for 3 months. NLR, serum endocan, and nesfatin-1 levels were measured in all psoriasis patients before and after NB-UVB phototherapy and in the control group. RESULTS Compared with the control group, neutrophil count and NLR were significantly higher (p<0.001) in psoriasis patients before NB-UVB phototherapy. Serum endocan levels were significantly correlated with disease activity before treatment. There was no significant difference in NLR, serum endocan, and nesfatin-1 levels in psoriasis patients before and after NB-UVB phototherapy (p>0.05). CONCLUSIONS The current study shows that NLR was higher in psoriasis vulgaris patients when compared with the control group, whereas serum endocan and nesfatin-1 levels were not significantly different. In addition, NB-UVB phototherapy did not affect NLR, serum endocan, or nesfatin-1 levels. Further larger-scale studies are required on this subject.

Acute, but not chronic, stress increased the plasma concentration and hypothalamic mRNA expression of NUCB2/nesfatin-1 in rats.

Nesfatin-1, a newly discovered satiety peptide, has recently been reported to be involved in the stress response. Stress-induced expression of nesfatin-1 has been reported and few studies focus on its expression in the hypothalamus, which is the center of the stress response. To test our hypothesis that peripheral and hypothalamic nesfatin-1 overexpression should play an important role in the stress response and the associated hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis, acute stress (AS) was induced using water avoidance stress (WAS), and chronic unpredictable mild stress (CUMS) was also induced using 3 consecutive weeks of 7 different stressors. The behavior of CUMS rats was evaluated by an open field test (OFT), sucrose preference test (SPT), and forced swimming test (FST). The activity of the HPA axis was detected by measurement of the plasma corticosterone concentration and hypothalamic mRNA expression of corticotropin-releasing-hormone (CRH). The plasma concentration and hypothalamic mRNA expression of nesfatin-1 were measured with an enzyme-linked immunosorbent assay (ELISA) and real-time fluorescent quantitative PCR, respectively. The results showed that both AS and CUMS increased the plasma corticosterone concentration and hypothalamic CRH mRNA expression. Depression-like behavior was induced in CUMS rats, as indicated by a decreased movement distance, frequency of rearing and grooming in the OFT, and sucrose preference index and increased immobility in the FST. Moreover, the AS rats showed increased plasma concentration and hypothalamic mRNA expression of nesfatin-1, which were positively correlated with the plasma corticosterone concentration and hypothalamic CRH expression, respectively. These results indicated that acute stress, but not chronic stress, increased the plasma concentration and hypothalamic mRNA expression of NUCB2/nesfatin-1 in rats.

Supplementation of apelin increase plasma levels of nesfatin-1 in normal and DOCA-salt hypertensive rats.

AIMS: We aimed to observe the effects of apelin supplementation on the plasma levels of nesfatin-1 in DOCA-salt hypertensive and normal rats. METHODS: For this purpose, 28 young Wistar albino male rats were divided into four groups; Control (C), Control + Apelin (C+A), Hypertension (HT) and Hypertension + Apelin (HT+A). Hypertension was induced by injection of DOCA-salt (25 mg/kg, s.c.) twice weekly, 4 weeks, whereas intraperitoneal apelin was administered (200 µg.kg-1) for 17 days. Plasma nesfatin-1 and apelin levels were measured with ELISA. Systolic blood pressure was monitored using a tail cuff system. The relationships between plasma nesfatin levels and blood pressure were assessed. RESULTS: Plasma nesfatin-1 levels was found lower in control animals compared to C+A, HT and HT+A groups (p = 0.002, p = 0.026 and p = 0.011, respectively). Systolic blood pressures were similar in the C and C+A groups, but systolic blood pressures of the HT and HT+A groups was found significantly higher than the C and C+A groups. CONCLUSIONS: In conclusion, apelin administration induced an increment of nesfatin-1 in normal rats and plasma levels of nesfatin-1 increase in DOCA-salt hypertension rats. But apelin addition in hypertension did not cause an extra increase in nesfatin-1 levels. This is the first report to investigate the effect of apelin administration on plasma nesfatin levels of normal and hypertensive rats (Fig. 2, Ref. 44).

Plasma nesfatin-1 level in obese patients after acupuncture: a randomised controlled trial.

BACKGROUND: Nesfatin-1 is an anorexigenic hormone suggested to regulate obesity. OBJECTIVE: To investigate the relationship between nesfatin-1 level and anthropometric and metabolic parameters in obese patients, and examine the change in plasma nesfatin-1 level after acupuncture treatment. METHODS: 64 obese adult patients without diabetes and 58 normal weight control subjects were enrolled in this study. The obese patients were randomly divided into an acupuncture plus diet group (n=32) and a diet only group (n=32). Measurements were repeated after 45 days. RESULTS: Body mass index (BMI), waist and hip circumferences, serum insulin, lipoprotein and insulin resistance measures were significantly higher, and plasma nesfatin-1 level was significantly lower, in obese patients than in normal weight controls. In addition, negative correlations were found between plasma nesfatin-1 level and BMI, waist and hip circumferences. Weight reduction in participants after acupuncture and diet restriction was 7.0% and 4.3%, respectively. Plasma nesfatin-1 level increased from 2.75±1.16 to 3.44±1.28 ng/mL and from 2.86±1.07 to 3.23±1.06 ng/mL in acupuncture and diet groups, respectively; the difference was significant, p<0.05. CONCLUSIONS: Plasma nesfatin-1 level is reduced in obese adults, and is increased after acupuncture. The beneficial effect of acupuncture on obesity is associated with increased plasma nesfatin-1 level.

Weight gain in risperidone therapy: investigation of peripheral hypothalamic neurohormone levels in psychotic patients.

The use of antipsychotic drugs has started a new era in the treatment of psychotic disorders. Nevertheless, they cause complications in the long-term treatment, which is mainly weight gain. In this study, we investigated circulating levels of hypothalamic neuropeptides, which are related to appetite regulation, neuropeptide Y (NPY), α-melanocyte-stimulating hormone (α-MSH), cocaine- and amphetamine-regulated transcript (CART), and leptin, in first-attack psychotic patients who were treated with an atypical antipsychotic drug, risperidone, for 4 weeks. We used a case-control association design to compare the neuropeptides in the control group versus before and after treatment of the patient group. Samples were obtained from psychotic patients who were admitted to the Psychiatry Outpatient Clinics, Gulhane School of Medicine, Ankara, Turkey. When compared with the control group, NPY and α-MSH plasma levels of psychotic patients were severely reduced, and the CART levels were substantially increased when they were first diagnosed (before treatment). However, the patients' body mass index and circulating leptin levels were markedly high after the treatment. Circulating levels of those neurohormones were not significantly changed between before and after treatment of the patients. These data demonstrate that peripheral α-MSH and NPY, although reflecting only secretion from peripheral organs, nevertheless, may provide an insight into the patients sympathetic tone and also suggest change of their appetite regulation. α-Melanocyte-stimulating hormone, NPY, and CART plasma levels may be used as a predictor of weight gain in the early treatment of the patients along with the leptin levels.

Nesfatin-1 stimulates fatty-acid oxidation by activating AMP-activated protein kinase in STZ-induced type 2 diabetic mice.

Nesfatin-1 is an anorexigenic peptide involved in energy homeostasis. Recently, nesfatin-1 was reported to decrease blood glucose level and improve insulin sensitivity in high-fat diet-fed rats. However, little information is known about the influence of nesfatin-1 on lipid metabolism either in physiological or diabetic condition. This study undertook whether nesfatin-1 was involved in the pathophysiology in Streptozotocin-induced type 2 diabetic mice (T2DM), which was induced by a combination of high-calorie diet and two low-doses Streptozotocin. We observed that plasma nesfatin-1 was significantly increased while expression of nesfatin-1 neurons were decreased in hypothalamus in diabetes group compared to only high-calorie diet control group; intravenous injection of nesfatin-1 decreased 0-1h, 0-2h, 0-3h cumulative food intake in T2DM, but 0-24h total food intake had no difference between groups. Body weight and plasma FFA were normalized after nesfatin-1(10 µg/Kg) administration for 6 days. These results suggested that nesfatin-1 improved lipid disorder in T2DM. It was found that blood glucose and insulin resistance coefficient decreased with treatment of nesfatin-1 (both in 1 µg/Kg and 10 µg/Kg doses) in diabetes mice. For further understanding the role of nesfatin-1 on lipid metabolism, we detected p-AMPK and p-ACC of skeletal muscle in T2DM using western blotting. The expression of p-AMPK and p-ACC increased when nesfatin-1 was given with doses 1 µg/Kg but not in doses 10 µg/Kg. Taken together, nesfatin-1 participated in the development of T2DM and stimulated free fatty acid utilization via AMPK-ACC pathway in skeletal muscle in T2DM.

The investigation of leptin and hypothalamic neuropeptides role in first attack psychotic male patients: olanzapine monotherapy.

The mechanism underlying the weight gain due to treatment with olanzapine and other second generation antipsychotics has not been fully understood. To examine olanzapine's weight gain effects, we accepted first attack psychotic patients with no medication (pre-treatment) (n=22) and the healthy control group (n=26) in this study. After patients diagnosis, they were hospitalized and then treated for four weeks with olanzapine (post-treatment). We used case-control association design to test body mass index (BMI) and biochemical changes in each group. We also investigated peripheral leptin and neuropeptides/hormones namely, pro-opiomelanocortin (POMC), cocaine and amphetaime regulated transcript (CART), and neuropeptide Y (NPY) levels. These neuropeptides which are synthesized/secreted from arcuate nucleus of hypothalamus affect food intake and therefore, body weight. After 4 weeks of olanzapine treatment; BMI (body mass index), waist circumference, blood triglyceride, total cholesterol, and very low density lipoprotein (VLDL) levels were increased significantly in patients compared to their pre-treatment baseline. In pre-treatment, patients' NPY levels were significantly lower while α-MSH, the anorexigenic product of POMC levels were significantly higher vs. control. Both leptin and NPY levels were significantly increased in patients after the treatment but the NPY levels were also significantly lower in post-treatment vs. the control group. The CART levels did not change after the treatment. We may presume that the antagonist effect of olanzapine on the serotonin (5HT2CR and 5HT1BR) receptors of the arcuate hypothalamic neurons may be a basis for a deregulation of the neurohormones secretion.

The monoacylglycerol lipase inhibitor JZL184 attenuates LPS-induced increases in cytokine expression in the rat frontal cortex and plasma: differential mechanisms of action.

BACKGROUND AND PURPOSE: JZL184 is a selective inhibitor of monoacylglycerol lipase (MAGL), the enzyme that preferentially catabolizes the endocannabinoid 2-arachidonoyl glycerol (2-AG). Here, we have studied the effects of JZL184 on inflammatory cytokines in the brain and plasma following an acute immune challenge and the underlying receptor and molecular mechanisms involved. EXPERIMENTAL APPROACH: JZL184 and/or the CB1 receptor antagonist, AM251 or the CB2 receptor antagonist, AM630 were administered to rats 30 min before lipopolysaccharide (LPS). 2 h later cytokine expression and levels, MAGL activity, 2-AG, arachidonic acid and prostaglandin levels were measured in the frontal cortex, plasma and spleen. KEY RESULTS: JZL184 attenuated LPS-induced increases in IL-1ß, IL-6, TNF-α and IL-10 but not the expression of the inhibitor of NFkB (IκBα) in rat frontal cortex. AM251 attenuated JZL184-induced decreases in frontal cortical IL-1ß expression. Although arachidonic acid levels in the frontal cortex were reduced in JZL184-treated rats, MAGL activity, 2-AG, PGE2 and PGD2 were unchanged. In comparison, MAGL activity was inhibited and 2-AG levels enhanced in the spleen following JZL184. In plasma, LPS-induced increases in TNF-α and IL-10 levels were attenuated by JZL184, an effect partially blocked by AM251. In addition, AM630 blocked LPS-induced increases in plasma IL-1ß in the presence, but not absence, of JZL184. CONCLUSION AND IMPLICATIONS: Inhibition of peripheral MAGL in rats by JZL184 suppressed LPS-induced circulating cytokines that in turn may modulate central cytokine expression. The data provide further evidence for the endocannabinoid system as a therapeutic target in treatment of central and peripheral inflammatory disorders.

Nesfatin-1, corticotropin-releasing hormone, thyrotropin-releasing hormone, and neuronal histamine interact in the hypothalamus to regulate feeding behavior.

Nesfatin-1, corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), and hypothalamic neuronal histamine act as anorexigenics in the hypothalamus. We examined interactions among nesfatin-1, CRH, TRH, and histamine in the regulation of feeding behavior in rodents. We investigated whether the anorectic effect of nesfatin-1, α-fluoromethyl histidine (FMH; a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine), a CRH antagonist, or anti-TRH antibody affects the anorectic effect of nesfatin-1, whether nesfatin-1 increases CRH and TRH contents and histamine turnover in the hypothalamus, and whether histamine increases nesfatin-1 content in the hypothalamus. We also investigated whether nesfatin-1 decreases food intake in mice with targeted disruption of the histamine H1 receptor (H1KO mice) and if the H1 receptor (H1-R) co-localizes in nesfatin-1 neurons. Nesfatin-1-suppressed feeding was partially attenuated in rats administered with FMH, a CRH antagonist, or anti-TRH antibody, and in H1KO mice. Nesfatin-1 increased CRH and TRH levels and histamine turnover, whereas histamine increased nesfatin-1 in the hypothalamus. Immunohistochemical analysis revealed H1-R expression on nesfatin-1 neurons in the paraventricular nucleus of the hypothalamus. These results indicate that CRH, TRH, and hypothalamic neuronal histamine mediate the suppressive effects of nesfatin-1 on feeding behavior.

VGF peptides upon osmotic stimuli: changes in neuroendocrine regulatory peptides 1 and 2 in the hypothalamic-pituitary-axis and plasma.

VGF or VGF nerve growth factor inducible is a protein that has been found to play a role in regulating energy homeostasis and metabolism. From VGF precursor derive two neuroendocrine regulatory peptides NERP-1 and NERP-2 that, intracerebroventricular (icv) injected, modulate the antidiuretic hormone (ADH) release. Thus, we investigated possible modulations of the NERPs and other VGF peptides (namely VGF C-terminus, TLQP and PGH) in the hypothalamic-pituitary-axis, adrenal gland and plasma upon osmotic stimuli. The latter tissues were studied using water deprived (WD), salt loaded (SL), rehydrated after salt cargo and control rats by immunohistochemistry and immunoenzymatic assays. The high-performance liquid chromatography ensured the endogenous presence of the two NERPs in both plasma and hypothalamus. Upon dehydration, NERP-1 levels increased in the median eminence (M.E.) only, while using SL rats, the values of both NERPs increased in the M.E. and even in the hypothalamus. Conversely, in the blood of WD and SL rats, the levels of NERP-1 and NERP-2 decreased while, using pituitary from both rat groups, levels of NERP-2 increased and those of NERP-1 decreased. Reduction in the VGF C-terminus peptide levels was observed exclusively in the M.E. (using WD rats) and pituitary (using WD and SL rats), while PGH and TLQP peptide levels never changed in all tissues tested. By immunohistochemistry, the VGF peptides studied (apart from the TLQP peptides) were present in the hypothalamic and pituitary ADH containing neurons of the control rats, while using WD and SL rats, an immunostaining increase was selectively revealed for VGF C-terminus peptides in the hypothalamic neurons that produce ADH. All VGF changes found using SL rats disappeared after only 1h of rehydration. In conclusion, we hypothesize that NERPs may be involved in both autocrine and endocrine mechanisms important for the fluid balance.

Ethanol-induced loss-of-righting response during ethanol withdrawal in male and female rats: associations with alterations in Arc labeling.

BACKGROUND: There is increasing evidence for relevant sex differences in responses to ethanol. Several investigations have found differences in expression and recovery from ethanol withdrawal (EW) in people and across various animal models. We have found that female rats recover more quickly than male rats and show differential responses to various behavioral assessments and pharmacological challenges during withdrawal. The purpose of this study was to determine whether sex differences in EW behaviors extend to the hypnotic effects of acute ethanol administration. METHODS: We used a repeated measures design to assess duration and latency for loss-of-righting reflex following an acute injection of ethanol (4.2 g/kg; 20% w/v) to pair-fed control or ethanol-withdrawn animals at 1 and 3 days EW in male, female, and ovariectomized female (OVX) rats. We determined protein levels of the activity-regulated cytoskeletal protein (Arc), used as a marker for synaptic activity in glutamatergic synapses, in the motor cortex and prefrontal cortex across these same treatment conditions. RESULTS: Ethanol-withdrawn animals had a reduced ethanol-induced sleep time compared to controls at 1 day EW. Sleep time remained shortened at 3 days EW for males and OVX, but not females. Arc protein levels in motor cortex and preoptic nuclei significantly increased at 1 day EW across all sex conditions, suggestive of an association with the reduced ethanol-induced sleep times during EW. Arc levels increased further for males and OVX, but not females, at the 3 days EW time point. CONCLUSIONS: These findings add further support to sex differences in effects of and responses to ethanol. They suggest that the more rapid recovery from EW for females than males also includes expression of tolerance to the hypnotic effects of ethanol. These sex differences may involve some differential neuroadaptations in glutamatergic signaling.

Erythropoietin protects against apoptosis and increases expression of non-neuronal cell markers in the hypoxia-injured developing brain.

Erythropoietin (EPO) is a cytokine hormone with cytoprotective effects in many tissues including the brain. Although the benefits of administration of recombinant human EPO (rhEPO) for neonatal hypoxic brain injury have been demonstrated in neuronal tissue, the effect on non-neuronal cell populations is unclear. We tested the hypothesis that rhEPO would not only protect neuronal cells but also glial cells at a stage of brain development where their maturation was particularly sensitive, and also protect the vasculature. This was evaluated in a rat model of hypoxic injury. 1000 IU/kg rhEPO was delivered intraperitoneally at the start of 4 h hypoxia or normoxia. Treatment groups of neonatal rats (day of birth, at least N = 10 per group) were as follows: normoxia; normoxia plus rhEPO; hypoxia (8% FiO(2) delivered in temperature-controlled chambers); and hypoxia plus rhEPO. Day of birth in rats is equivalent to human gestation of 28-32 weeks. The effects of rhEPO administration, especially to non-neuronal cell populations, and the associated molecular pathways, were investigated. Apoptosis was increased with hypoxia and this was significantly reduced with rhEPO (p < 0.05). The neuronal marker, microtubule-associated protein-2, increased in expression (p < 0.05) when apoptosis was significantly reduced by rhEPO. In addition, compared with hypoxia alone, rhEPO-treated hypoxia had the following significant protein expression increases (p < 0.05): the intermediate filament structural protein nestin; myelin basic protein (oligodendrocytes); and glial fibrillary acidic protein (astrocytes). In conclusion, rhEPO protects the developing brain via anti-apoptotic mechanisms and promotes the health of non-neuronal as well as neuronal cell populations at a time when loss of these cells would have long-lasting effects on brain function.

Increasing the number of SNP loci does not necessarily improve prediction power at least in the comparison of MTHFR SNP and haplotypes.

BACKGROUND: Rapid advances in genotyping technology have made it possible to easily utilize a large number of genetic markers. According to information theory, an increase in the number of markers provides more information; however, the clinical usefulness does not increase linearly. This study aimed to assess the effect of folic acid supplementation quantitatively in MTHFR haplotypes, and compare its prediction power with that of the C677T single nucleotide polymorphism (SNP) alone. METHODS: The study was a randomized, double-blind, placebo-controlled trial, designed in accordance with the CONSORT statement. The participants were 202 healthy Japanese males who were administered either folic acid at 1 mg/day or a placebo postoperatively for 3 months. The primary endpoint was the total plasma homocysteine levels (tHcy). Stratified analysis by HapMap-based tag SNPs was performed. RESULTS: Of 52 SNPs on the MTHFR gene, 4 SNP loci covering more than 80% of the information were selected, and the haplotypes were estimated. The haplotypes were classified into 3 groups (Hap0, Hap1, and Hap2), on the basis of the number of times the most frequent haplotype was present. The greatest decrease was observed in Hap2 (6.61 micromol/L), compared with the other haplotypes (Hap0, 2.67; Hap1, 2.60) (trend test, P < 0.01). The haplotype information obtained was not more informative than that obtained with grouping by a single SNP, C677T, which strongly influences enzyme activity. CONCLUSIONS: Grouping by the C677T SNP alone was almost as good a predictor of the homocysteine-lowering effects as was grouping by the 4 best SNPs. This shows that increasing the number of typed SNPs does not necessarily provide more information, at least for this gene. A more efficient, cost-informative method for analyzing genomic data is required.

Combining natriuretic peptides and necrosis markers in the assessment of acute coronary syndromes.

Management of patients with acute coronary syndromes (ACS) is becoming more complex as the array of treatment options available to patients and physicians continues to expand. Cardiac biomarkers play an important role in risk stratification in ACS, and results of cardiac biomarker tests can be used to help guide choices between alternative therapies. In addition to biomarkers of myocyte necrosis, markers of neurohormonal activation, such as B-type natriuretic peptide (BNP), provide important prognostic information in ACS. In the future, multimarker strategies that incorporate panels of cardiac biomarkers are likely to be used for risk stratification and for pathophysiology-guided treatment in patients with ACS.