<em>Nesfatin</em>-<em>1</em> is a novel brain-gut peptide identified in several brain regions associated with feeding and gastrointestinal function. Our study explored the effects of <em>nesfatin</em>-<em>1</em> in the central nucleus of the amygdala (CNA) on the activity of gastric distention (GD)-sensitive neurons, gastric motility, and the potential regulation mechanisms by the dorsal motor nucleus of the vagus (DMV). Following retrograde injection of fluorogold (FG) into the DMV, we found that <em>nesfatin</em>-<em>1</em>/FG dual-labeled neurons were detected in the CNA, which indicates that some of the <em>nesfatin</em>-<em>1</em>-immunoreactive neurons arising from the DMV may project to the CNA. Single unit discharges in the CNA were recorded extracellularly, and gastric motility was monitored by implantation of a force transducer into the stomach of conscious rats. These results showed that <em>nesfatin</em>-<em>1</em> administration to the CNA excited most of the GD-excitatory neurons, inhibited GD-inhibitory neurons, and dose-dependently reduced gastric motility. All of the above effects induced by <em>nesfatin</em>-<em>1</em> could be partially blocked by pretreatment with the melanocortin 3/4 receptors antagonist, SHU9<em>1</em><em>1</em>9. Electrical stimulation of the DMV excited the majority of the <em>nesfatin</em>-<em>1</em>-responsive GD neurons in the CNA. Additionally, pretreatment with an anti-NUCB2/<em>nesfatin</em>-<em>1</em> antibody in the CNA increased the firing rate of <em>nesfatin</em>-<em>1</em>-responsive GD-inhibitory neurons but decreased the firing rate in <em>nesfatin</em>-<em>1</em>-responsive GD-excitatory neurons following electrical stimulation of the DMV. Finally, a subdiaphragmatic vagotomy eliminated the diminished gastric motility induced by <em>nesfatin</em>-<em>1</em> injection. Taken together, these findings suggest that <em>nesfatin</em>-<em>1</em> regulates the activity of GD-sensitive neurons and gastric motility via the melanocortin pathway in the CNA. Furthermore, the DMV may be involved in this regulatory pathway.

T-2 toxin is one of the most toxic Fusarium-derived trichothecenes found on cereals and constitutes a widespread contaminant of agricultural commodities as well as commercial foods. Low doses toxicity is characterized by reduced weight gain. To date, the mechanisms by which this mycotoxin profoundly modifies feeding behavior remain poorly understood and more broadly the effects of T-2 toxin on the central nervous system (CNS) have received limited attention. Through an extensive characterization of sickness-like behavior induced by T-2 toxin, we showed that its per os (p.o.) administration affects not only feeding behavior but also energy expenditure, glycaemia, body temperature and locomotor activity. Using c-Fos expression mapping, we identified the neuronal structures activated in response to T-2 toxin and observed that the pattern of neuronal populations activated by this toxin resembled that induced by inflammatory signals. Interestingly, part of neuronal pathways activated by the toxin were NUCB-2/<em>nesfatin</em>-<em>1</em> expressing neurons. Unexpectedly, while T-2 toxin induced a strong peripheral inflammation, the brain exhibited limited inflammatory response at a time point when anorexia was ongoing. Unilateral vagotomy partly reduced T-2 toxin-induced brainstem neuronal activation. On the other hand, intracerebroventricular (icv) T-2 toxin injection resulted in a rapid ((<em>1</em>h) reduction in food intake. Thus, we hypothesized that T-2 toxin could signal to the brain through neuronal and/or humoral pathways. The present work provides the first demonstration that T-2 toxin modifies feeding behavior by interfering with central neuronal networks devoted to central energy balance. Our results, with a particular attention to peripheral inflammation, strongly suggest that inflammatory mediators partake in the T-2 toxin-induced anorexia and other symptoms. In view of the broad human and breeding animal exposure to T-2 toxin, this new mechanism may lead to reconsider the impact of the consumption of this toxin on human health.

<em>Nesfatin</em>-<em>1</em> is a recently identified brain-gut peptide involved in feeding and energy homeostasis. Recently, it has been proved that <em>nesfatin</em>-<em>1</em> could exert its neuroprotective effect against subarachnoid hemorrhage-induced injury via its anti-apoptotic and anti-inflammatory properties. However, whether it has neuroprotective effect on dopamine neurons is largely unknown. In the present study, we investigated the neuroprotective effect of <em>nesfatin</em>-<em>1</em> on rotenone-treated MES23.5 dopaminergic cells and illustrated the underlying mechanisms. Our results showed that <em>nesfatin</em>-<em>1</em> pretreatment could significantly attenuate rotenone-induced cell loss. Further studies showed that the neuroprotective effect of <em>nesfatin</em>-<em>1</em> against rotenone was mediated by reversing rotenone-induced mitochondrial dysfunction. <em>Nesfatin</em>-<em>1</em> could rescue rotenone-induced mitochondrial transmembrane potential collapse and restore the function of mitochondrial respiratory chain complex I. In addition, rotenone-induced release of cytochrome C from mitochondria, ROS production and the subsequent caspase-3 activation were also attenuated by <em>nesfatin</em>-<em>1</em> pretreatment. Our data suggested that <em>nesfatin</em>-<em>1</em> exerted its neuroprotective effect on dopaminergic cells against rotenone by ameliorating mitochondrial dysfunction and its anti-apoptotic property. This suggested that <em>nesfatin</em>-<em>1</em> had the potential to be considered as an aid for prevention of Parkinson's disease.

This review summarizes current data focusing on the peripheral effects of NUCB2/<em>nesfatin</em>-<em>1</em> including the regulation of food intake, glucose homeostasis, lipid metabolism, cardiovascular effects and reproductive functions as well as its possible involvement in psychological disorders. Additionally, we will highlight gaps in knowledge in order to stimulate further research. Lastly, we will give an outlook on potential therapeutic implications of this pleiotropic peptide.

BACKGROUND

Obstructive sleep apnea syndrome (OSAS) and obesity frequently occur together. The relationship between increased appetite and obesity is well known; however, despite existing knowledge about the relationship between OSAS and obesity, it is not fully understood.

OBJECTIVE

This study aimed to evaluate the relationship between OSAS and the appetite-suppressing hormone <em>nesfatin</em>-<em>1</em> independent of body mass index (BMI).

METHODS

A total of <em>1</em>34 cases were included in the study; <em>1</em>02 with OSAS (OSAS group) and 32 healthy controls (control group). All cases underwent polysomnography, and <em>nesfatin</em>-<em>1</em> levels were determined.

RESULTS

Nesfatin-<em>1</em> levels were significantly lower in the OSAS group compared to the control group (3,776.5 ± 204.8 and 4,056.2 ± <em>1</em>0<em>1</em>.5 pg/ml, respectively; p < 0.00<em>1</em>). In addition, there was a statistically significant negative correlation between <em>nesfatin</em>-<em>1</em> and the apnea hypopnea index (r = -0.543; p < 0.00<em>1</em>). The statistically significant relationship persisted after adjusting for confounding intergroup factors such as age, gender and BMI (p < 0.00<em>1</em>). In the OSAS group, there was a statistically significant correlation between <em>nesfatin</em>-<em>1</em> and neck circumference (r = -0.304; p = 0.02) but not between <em>nesfatin</em>-<em>1</em> and BMI and waist circumference. There was no statistically significant difference in <em>nesfatin</em>-<em>1</em> levels between the sexes.

CONCLUSIONS

OSAS patients have lower <em>nesfatin</em>-<em>1</em> levels compared to controls, and a greater <em>nesfatin</em>-<em>1</em> deficit corresponds to an increased severity of OSAS and an increased neck circumference. Replacement therapy may be a potential treatment for obese OSAS patients who have lower <em>nesfatin</em>-<em>1</em> levels, which may have additional benefits through appetite suppression and weight loss.

BACKGROUND

Polycystic ovary syndrome (PCOS) is commonly characterized by obesity, insulin resistance (IR), hyperandrogenemia and hirsutism. Following the reported relationship between phoenixin-<em>1</em>4 and gonadotropin production in rat hypothalamic-pituitary-gonadal axis, the present study was designed to investigate the circulating concentrations of phoenixin-<em>1</em>4 and their associations with the concentrations of sex hormones including luteinizing hormone (LH), follicular stimulating hormone (FSH), estradiol (E2), progesterone (P4) and total testosterone (TT) in PCOS patients.

METHODS

A total of 4<em>1</em> women with diagnosed PCOS using Rotterdam criteria and 37 healthy individuals were enrolled in the study.

RESULTS

Serum phoenixin-<em>1</em>4 concentration in PCOS patients (n=4<em>1</em>) was 0.5<em>1</em>5±0.044ng/ml, significantly higher than that in healthy controls (0.289±0.046ng/ml, n=37). PCOS patients had higher serum LH, dehydroepiandrosterone and fasting blood glucose concentrations, and higher index of homeostasis model of assessment-IR than those in healthy women. Correlation analysis showed significantly positive correlations of phoenixin-<em>1</em>4 with LH, FSH, TT, P4, BMI and <em>nesfatin</em>-<em>1</em> concentrations, and significantly negative correlations with E2 and serum insulin (FSI) concentrations, respectively.

CONCLUSIONS

Compared to control women, PCOS patients had significantly increased serum phoenixin-<em>1</em>4, LH and androgen concentrations. The positive correlations of phoenixin-<em>1</em>4 concentrations with LH and TT concentrations suggest a possible role of phoenixin-<em>1</em>4 in the development of PCOS.

Inducers of satiety are drug targets for weight loss to mitigate obesity-associated diseases. Nucleobindin-2 (Nucb2) is thought to be post-translationally processed into bioactive <em>nesfatin</em>-<em>1</em> peptide, which reportedly induces satiety, causes weight loss, and thus improves insulin sensitivity. Here, we show that deletion of Nucb2 did not affect food intake or adiposity and, instead, caused insulin resistance in mice fed a high-fat diet. In addition, ablation of Nucb2 in orexigenic hypothalamic Agrp neurons did not affect food intake, and <em>nesfatin</em>-<em>1</em> was detectable in serum, despite global deletion of Nucb2 protein. Upon high-fat diet feeding, the loss of Nucb2 exacerbated metabolic inflammation in adipose tissue macrophages in an NFκB-dependent manner without inducing classical M<em>1</em> or alternative M2-like macrophage polarization. Furthermore, the loss of Nucb2 in myeloid cells but not in adipocytes mediated the insulin resistance in response to a high-fat diet. Our study reveals that Nucb2 links metabolic inflammation to insulin resistance without affecting weight gain and food intake.

<em>Nesfatin</em>-<em>1</em>, a food-intake inhibiting factor processed from nucleobindin 2 (NUCB2), was originally identified by the Oh-I research group. The initial functional studies on NUCB2/<em>nesfatin</em>-<em>1</em> were mainly focused on its properties of appetite regulation. As is well known, emotional state has an interactional relationship with food intake, and difficulties in regulating emotion and stress have a great influence on appetite and body weight. Some anorexigenic or orexigenic neurotransmitters also play a role in the adjustment of emotion and stress responses in addition to their actions on the homeostatic regulation of food intake, including neuropeptide Y (NPY), melanocyte stimulating hormone (MSH), corticotropin-releasing factor (CRF), and ghrelin. Furthermore, NUCB2/<em>nesfatin</em>-<em>1</em> immunoreactive neurons were detected extensively in brain areas involved in emotion and stress regulation, such as the hippocampus, hypothalamus, amygdala, and prefrontal cortex (PFC). These data suggest that NUCB2/<em>nesfatin</em>-<em>1</em> might also have effects on affective states; therefore, many studies were carried out researching the functions of NUCB2/<em>nesfatin</em>-<em>1</em> in emotion regulation. An increasing body of evidence has been published to elucidate the stress-related activation of NUCB2/<em>nesfatin</em>-<em>1</em> neurons and alteration of NUCB2/<em>nesfatin</em>-<em>1</em> concentrations, as well as the behavioral changes induced by the administration of NUCB2/<em>nesfatin</em>-<em>1</em>. In the present review, we summarized current data focusing on the association between NUCB2/<em>nesfatin</em>-<em>1</em>, stress, and psychiatric disorders to elucidate the functions of NUCB2/<em>nesfatin</em>-<em>1</em> in emotion regulation.

UNASSIGNED

This study aimed to determine whether plasma <em>nesfatin</em>-<em>1</em>, cortisol, and inflammatory cytokines could be used as novel noninvasive biomarkers for the diagnosis of moderate and severe depressive disorder (MSDD).

UNASSIGNED

A total of 70 patients with MSDD and 70 healthy subjects were assessed. Patients with MSDD were selected from Hefei Fourth People's Hospital, Anhui Mental Health Center, and subjects in the control group were selected from healthy volunteers. Hamilton Depression Rating Scale-<em>1</em>7 (HAMD-<em>1</em>7) was used to evaluate the two groups. ELISA was used for the measurement of plasma <em>nesfatin</em>-<em>1</em>, cortisol, IL-6, C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) levels. The diagnostic value of plasma <em>nesfatin</em>-<em>1</em>, cortisol, IL-6, CRP, and TNF-α for MSDD was assessed.

UNASSIGNED

Compared to healthy controls, the HAMD-<em>1</em>7 scores and average <em>nesfatin</em>-<em>1</em>, cortisol, IL-6, and CRP levels in patients with MSDD were significantly increased. Moreover, multivariate linear regression analysis showed that HAMD-<em>1</em>7 score was positively associated with plasma <em>nesfatin</em>-<em>1</em> and cortisol. Furthermore, the results of the receiver operating characteristic (ROC) curve analysis revealed an area under curve (AUC) of 0.985 with 94.3% sensitivity and 97.<em>1</em>% specificity of <em>nesfatin</em>-<em>1</em>, and an AUC of 0.957 with 9<em>1</em>.4% sensitivity and 85.7% specificity of cortisol in discriminating patients with MSDD from healthy volunteers. A combined ROC analysis using <em>nesfatin</em>-<em>1</em> and cortisol revealed an AUC of 0.993 with a sensitivity of 97.<em>1</em>% and a specificity of 98.6% in separating patients with MSDD from healthy volunteers.

UNASSIGNED

These results suggest that plasma <em>nesfatin</em>-<em>1</em> and cortisol might be potential novel biomarkers for the diagnosis of MSDD.

BACKGROUND

The burn wound represents a susceptible site for opportunistic colonization by organisms of endogenous and exogenous origin. Diminishing appetite is known to occur in patients with burn infection, yet its underlying reason is not fully understood. We have examined the levels of <em>nesfatin</em> <em>1</em>, a protein that we consider to be a potential new treatment target for the solution of appetite and nutrition problem in patients with burn infection.

OBJECTIVE

The aim of the present study was therefore to examine nesfatin levels in patients with burn infection.

METHODS

Laboratory values, medication and dietary records, and patient notes with diagnostic information of burn wounds patients who were admitted to the Division of Burn Treatment Center were obtained from the Erzurum Region Education and Research Hospital electronic database. Post-burn wound infection was objectively assessed by culturing wound homogenates from skin tissue. The main immediate inflammatory stress response parameters assessed were serum CRP concentrations, WBC counts, and blood nesfatin concentrations.

RESULTS

Scalding was the predominant cause of burns in both categories of patients. In <em>1</em>9 (6<em>1</em>.3%) burn wound infection patients, the burns were due to a scald. A significant difference was found for the <em>nesfatin</em>, CRP, and WBC levels between the patients and the control group (P = 0.000). A significant difference was also determined between the <em>nesfatin</em>, CRP, and WBC figures at the time of hospitalization and at discharge from the hospital (P = 0.000). The most predominant bacterial isolate was Pseudomonas aeruginosa <em>1</em>6 (5<em>1</em>.6%) followed by Methicilline resistant Staphylococcus aureus (MRSA) 7 (22.6%).

CONCLUSIONS

We showed that the serum <em>nesfatin</em> <em>1</em> level was significantly lower in the patients with burn than in the control group in our study. We considered that the central <em>nesfatin</em> <em>1</em> system should be taken into consideration, rather than the peripheric <em>nesfatin</em> <em>1</em> system, when considering the regulation of appetite in patients with burns and particularly those accompanied by infection. In other explanation of the observed negative correlation between <em>nesfatin</em> <em>1</em> and burn wound infection suggests that <em>nesfatin</em> <em>1</em> may indicate the possible contribution of <em>nesfatin</em> <em>1</em> to the energy homeostasis.

<AbstractText>Diabetic neuropathy (DN) is the most common complication of diabetes mellitus. It is thought that neuronal cell death which is mainly due to reactive oxygen species (ROS) overproduction in the cells is responsible for most symptoms of this disorder. <em>Nesfatin</em>-<em>1</em> has identified recently as a novel endogenous neuropeptide which recent studies have shown that it may have a protective effect. Therefore, we postulated that <em>Nesfatin</em>-<em>1</em> might adequately prevent from high glucose-induced cell injury via inhibition of apoptotic, autophagy, and ROS responses.</AbstractText><AbstractText>In this study, PC<em>1</em>2 cells were pretreated with different concentrations of <em>Nesfatin</em>-<em>1</em> (<em>1</em>-<em>1</em>00 ng/ml) and then co-treated with <em>Nesfatin</em>-<em>1</em> and glucose (<em>1</em>25 mM) for 48 h, and downstream pathways then were evaluated to investigate ROS, apoptosis, and autophagy.</AbstractText><AbstractText>Results of this study showed that <em>Nesfatin</em>-<em>1</em> can not only inhibit from intracellular ROS overproduction-induced by high glucose in PC<em>1</em>2 cells (p < 0.000<em>1</em>) but also reduce the apoptotic cell death in PC<em>1</em>2 cells following high glucose exposure by increasing cell viability and reducing apoptotic rates (p < 0.05). Furthermore, <em>Nesfatin</em>-<em>1</em> decreased the LC3-II levels by western blotting (p < 0.000<em>1</em>), which showed a reduction in autophagy.</AbstractText><AbstractText>These results support the idea that Nasfatin-<em>1</em>can protect PC<em>1</em>2 cells against high glucose-induced cell injury by inhibition of apoptosis, autophagy and ROS production and can be considered as a potential drug for treatment of diabetic neuropathy.</AbstractText>

Hormonal peptides like ghrelin, orexin A (OXA) or <em>nesfatin</em>-<em>1</em> not only regulate appetite, which is their basic biological function, but also contribute to mechanisms responsible for maintaining integrity of the gastric mucosa. Previous studies including those from our laboratory have revealed that their gastroprotective effect results from cooperation with other factors responsible for protection of the gastric mucosa, including prostaglandin (PG) synthesis pathway, nitric oxide (NO) and the sensory afferent fibres releasing the vasoactive neurotransmitters. The aim of the present study was to determine whether ghrelin, orexin-A (OX-A) or <em>nesfatin</em>-<em>1</em> with their protective effect on the gastric mucosa, also can modify the healing of chronic gastric ulcers. Furthermore, an attempt was made to explain participation of these peptides in healing processes of chronic gastric ulcers with comorbid conditions for the human beings resulted from diabetes mellitus. In our study, a model of gastric ulcers caused by concentrated acetic acid to induce the chronic gastric ulcers was used, while the clinical condition corresponding to diabetes was induced by single injection of streptozotocin (STZ). We found that ghrelin, OX-A and <em>nesfatin</em>-<em>1</em> accelerate dynamics of the acetic acid ulcers healing, confirmed by a reduction in the ulcer area and this effect was accompanied by an increase in gastric blood flow at the ulcer margin. Destruction of sensory afferent fibres with capsaicin or blocking of vanilloid receptors with capsazepine resulted in a significant reduction of ghrelin, OX-A and <em>nesfatin</em>-<em>1</em>-induced acceleration of ulcer healing. Similar results were obtained when an NO-synthase blocker, L-NNA was used in a combination with these peptides. Moreover, it was found that OX-A and <em>nesfatin</em>-<em>1</em> failed to accelerate the healing process under diabetic condition because both these hormones induced reduction in the ulcer area and the increase in blood flow in normal, non-diabetic rats were completely lost in the group of animals with diabetes. Treatment with OX-A and <em>nesfatin</em>-<em>1</em> increased superoxide dismutase (SOD) mRNA expression even in acetic acid ulcers concurrent with diabetes. However, the treatment with OX-A and <em>nesfatin</em>-<em>1</em> failed to alter the increase in gastric mucosal mRNA expression for ghrelin and hypoxia-inducible factor <em>1</em>-alpha (HIF-<em>1</em>α), this latter effect that had been strongly pronounced in diabetic animals. We conclude that the hormonal peptides involved in the regulation of satiety and hunger such as ghrelin, OX-A and <em>nesfatin</em>-<em>1</em> contribute to the process of chronic gastric ulcers healing cooperating with NO and sensory afferent nerve endings releasing vasoactive neuropeptide CGRP. Furthermore, OX-A and <em>nesfatin</em>-<em>1</em>, the two relatively unrecognized peptides, play an essential role in healing process of chronic gastric ulcers activating the gastric blood flow at ulcer margin and the mucosal regeneration and both ulcer healing and accompanying hyperemia at ulcer margin are greatly impaired during diabetes. Possibly, loss of the healing effect of these peptides during diabetes results from an interaction with radical generation processes as reflected by an increase of mRNA expression for SOD as well as the failure of their attenuating activity on proinflammatory factors such as HIF-<em>1</em>α.

OBJECTIVE

NUCB2/<em>nesfatin</em>-<em>1</em> is an anorexigenic hormone with elevated levels in obese and decreased levels in anorexia nervosa (AN) patients. Moreover, a role in the regulation of stress and emotions was suggested by several rodent and preliminary human studies. Since anxiety and depression are common comorbidities in AN, we investigated the association of NUCB2/<em>nesfatin</em>-<em>1</em> with anxiety, depression and perceived stress in AN.

METHODS

We analyzed circulating NUCB2/<em>nesfatin</em>-<em>1</em> levels in 64 female inpatients diagnosed with anorexia nervosa (body mass index, BMI; mean±SD, <em>1</em>4.7±2.3 kg/m2). At the same time anxiety (GAD-7), depression (PHQ-9), stress (PSQ-20) and disordered eating (EDI-2) were measured psychometrically.

RESULTS

No correlation was observed between NUCB2/<em>nesfatin</em>-<em>1</em> and BMI (r = 0.06, p = 0.70). The study population was divided in patients with low anxiety (n = 32, GAD-7 scores, mean±SD, 7.5±3.3) and high anxiety (n = 32, <em>1</em>6.0±3.0, p<0.00<em>1</em>). Patients with high anxiety scores displayed 65% higher NUCB2/<em>nesfatin</em>-<em>1</em> levels (p = 0.04). This was reflected by a positive correlation of GAD-7 and NUCB2/<em>nesfatin</em>-<em>1</em>-levels (r = 0.32, p = 0.04). Scores of PSQ-20 (73.3±<em>1</em>4.3 vs. 48.6±<em>1</em>7.2) and PHQ-9 (<em>1</em>8.8±5.0 vs. <em>1</em>0.3±5.<em>1</em>) were higher in the high anxiety group (p<0.00<em>1</em>) but did not correlate with NUCB2/<em>nesfatin</em>-<em>1</em> (p>0.05). EDI-2 total score was also higher in the high anxiety group (52.3±<em>1</em>4.<em>1</em> vs. 40.2±<em>1</em>6.0, p = 0.02), while no correlations of EDI-2-scores with plasma NUCB2/<em>nesfatin</em>-<em>1</em> were observed (p>0.05).

CONCLUSIONS

Circulating NUCB2/<em>nesfatin</em>-<em>1</em> levels correlated positively with perceived anxiety, whereas no association with BMI or eating disorder symptoms was observed. NUCB2/<em>nesfatin</em>-<em>1</em> might be primarily involved in the modulation of anxiety and subsequently in the regulation of eating habits and body weight in AN.

In order to elucidate the contribution of cycloxygenase (COX) enzymes in the anti-oxidant and anti-inflammatory mechanisms of <em>nesfatin</em>-<em>1</em>, which improves the healing process of chronic gastric ulcers, either acetic acid (80%; ulcer groups; n = 40) or saline (control groups; n = 40) was applied to the serosal surface of male Sprague Dawley rats' stomachs for <em>1</em> min. Both the control and ulcer groups were treated daily with either i.p. saline or <em>nesfatin</em>-<em>1</em> (0.3 μg/kg; for 3 days). <em>Nesfatin</em>-<em>1</em>-treatment was preceded with i.p. saline, COX-2 inhibitor NS-398 (2 mg/kg), COX-<em>1</em> inhibitor ketorolac (3 mg/kg) or non-selective COX inhibitor indomethacin (5 mg/kg) for 3 days. The rats were decapitated at the end of the third day, and their trunk blood was collected for the measurements of tumor necrosis factor-α (TNF-α), interleukin-<em>1</em>β (IL-<em>1</em>β) and IL-<em>1</em>0 using ELISA. The induction of ulcers resulted in increased macroscopic scores, along with elevated gastric malondialdehyde, luminol- and lucigenin-enhanced chemiluminescence levels and myeloperoxidase activity. On the other hand, <em>nesfatin</em>-<em>1</em> treatment abolished these elevations. Depleted glutathione, superoxide dismutase and catalase activity levels in the saline-treated ulcer group were preserved in the <em>nesfatin</em>-<em>1</em>-treated ulcer group. Increased levels of serum TNF-α, IL-<em>1</em>β, IL-<em>1</em>0 in the saline-treated ulcer group, as compared to control group, were significantly decreased in the <em>nesfatin</em>-<em>1</em>-treated ulcer group. The inhibition of COX-<em>1</em>, and/or COX-2 reversed most of the alterations induced with <em>nesfatin</em>-<em>1</em>, but COX-2-blockade was consistently more effective to abolish all <em>nesfatin</em>-<em>1</em>-induced changes. Our results suggest that <em>nesfatin</em>-<em>1</em> ameliorates ulcer-induced inflammatory response through the modulation of oxidant-antioxidant balance. As selective pharmacological inhibition of COX-<em>1</em> or COX-2 suppresses the antioxidant/anti-inflammatory effects of <em>nesfatin</em>-<em>1</em>, it appears that <em>nesfatin</em>-<em>1</em> decreases inflammatory mediators and neutrophil migration by a COX-dependent mechanism, especially by a COX-2- dependent mechanism, during the ulcer healing stage.

<em>Nesfatin</em>-<em>1</em> is a newly discovered peptide that was reported to reduce food intake when injected centrally. We recently described its wide distribution in rat brain autonomic nuclei which implies potential recruitment of <em>nesfatin</em>-<em>1</em> by stress. We investigated whether restraint, a mixed psychological and physical stressor, activates <em>nesfatin</em>-<em>1</em>-immunoreactive (ir) neurons in the rat brain. Male Sprague-Dawley rats were either subjected to 30 min restraint or left undisturbed and 90 min later brains were processed for double immunohistochemical labeling of Fos and <em>nesfatin</em>-<em>1</em>. Restraint induced significant Fos expression in neurons of the supraoptic nucleus (SON), paraventricular nucleus (PVN), locus coeruleus (LC), rostral raphe pallidus (rRPa), nucleus of the solitary tract (NTS), and ventrolateral medulla (VLM). Double Fos/<em>nesfatin</em>-<em>1</em> labeling revealed that Fos-ir neurons comprised 95% of <em>nesfatin</em>-<em>1</em>-ir cells in the SON, 90% in the VLM, 80% in the LC, 48% in the caudal NTS, 57% in the rRPa, 48% in the anterior parvicellular PVN, 27% in the medial magnocellular PVN, <em>1</em>8% in the lateral magnocellular PVN and <em>1</em>0% in the medial parvicellular PVN. These data demonstrate that <em>nesfatin</em>-<em>1</em> neurons are part of the hypothalamic and hindbrain neuronal cell groups activated by restraint suggesting a possible role of <em>nesfatin</em>-<em>1</em> in the response to stress.

Nucleobindin 2 (NUCB2) is a multifunctional protein containing several functional domains, and associated with wide variety of biological process such as food intake and energy homeostasis. Recently, NUCB2 has been implicated in not only normal human tissues but also some kinds of human malignancies. However, its clinical and/or biological significance has largely remained unknown in endometrial carcinomas. We therefore immunolocalized NUCB2 protein in 87 endometrial carcinoma tissues and examined its clinical significance. NUCB2 immunoreactivity was detected in <em>1</em>9 out of 87 (22%) of endometrial carcinoma cases examined, and positively correlated with Ki67 labeling index, while there was no significant correlation between NUCB2 and stage, histological grade, and progesterone receptor status. Furthermore, NUCB2 immunoreactivity was significantly correlated with increased risk of recurrence and worse clinical outcome regardless of stage or histological grade. Subsequent multivariate analyses did reveal that NUCB2 immunoreactivity was an independent prognostic factor for both disease-free survival and endometrial cancer specific survival. In vitro experiments demonstrated that knockdown of NUCB2 using specific siRNA for NUCB2 significantly impaired cell proliferation and migration of the endometrial carcinoma cell lines, Ishikawa and Sawano cells, and that <em>nesfatin</em>-<em>1</em> treatment significantly promoted cell proliferation and migration in Ishikawa cells. These findings possibly suggested that NUCB2 and/or <em>nesfatin</em>-<em>1</em> had pivotal roles in the progression of endometrial carcinomas. Immunohistochemical NUCB2 status may therefore serve as a potent biomarker for endometrial carcinomas.

Fibroblast growth factor 2<em>1</em> (FGF2<em>1</em>), liver-derived hormone, exerts diverse metabolic effects, being considered for clinical application to treat obesity and diabetes. However, its anorexigenic effect is debatable and whether it involves the central mechanism remains unclarified. Moreover, the neuron mediating FGF2<em>1</em>'s anorexigenic effect and the systemic energy state supporting it are unclear. We explored the target neuron and fed/fasted state dependence of FGF2<em>1</em>'s anorexigenic action. Intracerebroventricular (ICV) injection of FGF2<em>1</em> markedly suppressed food intake in fed mice with elevated blood glucose. FGF2<em>1</em> induced c-Fos expression preferentially in hypothalamic paraventricular nucleus (PVN), and increased mRNA expression selectively for nucleobindin 2/<em>nesfatin</em>-<em>1</em> (NUCB2/Nesf-<em>1</em>). FGF2<em>1</em> at elevated glucose increased [Ca2+]i in PVN NUCB2/Nesf-<em>1</em> neurons. FGF2<em>1</em> failed to suppress food intake in PVN-preferential Sim<em>1</em>-Nucb2-KO mice. These findings reveal that FGF2<em>1</em>, assisted by elevated glucose, activates PVN NUCB2/Nesf-<em>1</em> neurons to suppress feeding under fed states, serving as the glycemia-monitoring messenger of liver-hypothalamic network for integrative regulation of energy and glucose metabolism.

Parkinson's disease (PD) is the second most common neurodegenerative disease and is typically associated with progressive motor and non-motor dysfunctions. Currently, dopamine replacement therapy is mainly used to relieve the motor symptoms, while its long-term application can lead to various complications and does not cure the disease. Numerous studies have demonstrated that many brain-gut peptides have neuroprotective effects in vivo and in vitro, and may be a promising treatment for PD. In recent years, some progress has been made in studies on the neuroprotective effects of some newly-discovered brain-gut peptides, such as glucagon-like peptide <em>1</em>, pituitary adenylate cyclase activating polypeptide, <em>nesfatin</em>-<em>1</em>, and ghrelin. However, there is still no systematic review on the neuroprotective effects common to these peptides. Thus, here we review the neuroprotective effects and the associated mechanisms of these four peptides, as well as other brain-gut peptides related to PD, in the hope of providing new ideas for the treatment of PD and related clinical research.

OBJECTIVE

To explore the relationship between <em>nesfatin</em>-<em>1</em> and growth and development in newborns.

METHODS

Blood samples for <em>nesfatin</em>-<em>1</em>, ghrelin, insulinlike growth factor-<em>1</em> (IGF-<em>1</em>), insulin and glucose were obtained from preterm (n = 53) and term infants (n = 60), including appropriate for gestational age (AGA) (n = 32) and small for gestational age (SGA) infants (n = 28). The relationship between <em>nesfatin</em>-<em>1</em> and other metabolic hormones or anthropometric parameters was evaluated.

RESULTS

The concentrations of <em>nesfatin</em>-<em>1</em>, ghrelin and insulin and the homeostasis model assessment-insulin resistance index (HOMA-IR) were higher in SGA than AGA infants (p = 0.0358, 0.0<em>1</em>63, 0.000<em>1</em> and 0.005<em>1</em>, respectively), but IGF-<em>1</em> levels and homeostasis model assessment-insulin sensitivity index (HOMA-ISI) were lower (p = 0.033 and 0.000<em>1</em>, respectively). Nesfatin-<em>1</em> levels in SGA infants were higher on postnatal day 0 (PNDO) than in AGA infants (p = 0.0358) and lower on PND7 (p = 0.0002) and PND28 (p = 0.0488). A negative correlation showed between <em>nesfatin</em>-<em>1</em> and oral calorie intake (r = -0.446; p = 0.0<em>1</em>7) and HOMA-ISI (r = -0.398; p = 0.036), and a positive correlation between <em>nesfatin</em>-<em>1</em> and HOMA-IR (r = 0.43; p = 0.023) in SGA infants.

CONCLUSIONS

Nesfatin-<em>1</em> is involved in the physiological regulation of intrauterine and postnatal growth and development in SGA infants.

<em>Nesfatin</em>-<em>1</em> is an important molecule in the regulation of reproduction. However, its role in the reproductive axis in male animals remains to be understood. Here, we found that <em>nesfatin</em>-<em>1</em> was mainly distributed in the arcuate nucleus (ARC), paraventricular nucleus (PVN), periventricular nucleus (PeN), and lateral hypothalamic area (LHA) of the hypothalamus; adenohypophysis and Leydig cells in male rats. Moreover, the concentrations of serum <em>nesfatin</em>-<em>1</em> and its mRNA in hypothalamo-pituitary-gonadal axis (HPGA) vary with the age of the male rat. After intracerebroventricular injection of <em>nesfatin</em>-<em>1</em>, the hypothalamic genes for gonadotrophin releasing hormone (GnRH), kisspeptin (Kiss-<em>1</em>), pituitary genes for follicle-stimulate hormone β(FSHβ), luteinizing hormone β(LHβ), and genes for testicular steroidogenic acute regulatory (StAR) expression levels were decreased significantly. <em>Nesfatin</em>-<em>1</em> significantly increased the expression of genes for 3β-hydroxysteroid dehydrogenase (3β-HSD), <em>1</em>7β-hydroxysteroid dehydrogenase (<em>1</em>7β-HSD), and cytochrome P450 cleavage (P450scc) in the testis of pubertal rats, but their levels decreased in adult rats (P < 0.05), along with the serum FSH, LH, and testosterone (T) concentrations. After <em>nesfatin</em>-<em>1</em> addition in vitro, T concentrations of the supernatant were significantly higher than that in the control group. These results were suggestive of the role of <em>nesfatin</em>-<em>1</em> in the regulation of the reproductive axis in male rats.

NUCB2 and its proteolytically cleaved product <em>nesfatin</em>-<em>1</em> were initially identified as hypothalamic neuroproteins that inhibit food intake, via a leptin-independent pathway. Since then recent studies have found NUCB2/<em>nesfatin</em>-<em>1</em> to be expressed both centrally, as well as in peripheral tissues. The recent implementation of novel experimental approaches has produced a large body of evidence implicating NUCB2/<em>nesfatin</em>-<em>1</em> in a diverse range of biological functions and in the modulation of food intake, energy homeostasis and metabolism. In this review, we discuss the discovery of NUCB2 and its proteolytic product <em>nesfatin</em>-<em>1</em>, and its expression in both central and peripheral tissues. In addition we shed light on the most recent discoveries supporting the role for NUCB2/<em>nesfatin</em>-<em>1</em> in peripheral tissues and its association with metabolic alterations. Moreover, we highlight the importance of NUCB2 and <em>nesfatin</em>-<em>1</em> in adipose tissue, its regulation of adipogenesis and obesity-associated metabolic diseases.

<em>Nesfatin</em>-<em>1</em> plays a role in the regulation of emotional states like depression. The aim of this study was to investigate the plasma <em>nesfatin</em>-<em>1</em>levels in Chinese patients with depression and healthy subjects, and to determine the possible association between the plasma <em>nesfatin</em>-<em>1</em> level and the severity of depression.

A total of <em>1</em>03 depressive patients and 32 healthy subjects were assessed. According to HAMD-<em>1</em>7scores, 5<em>1</em>, <em>1</em>8, and 34 patients were enrolled in the mild depression, moderate depression, and severe depression groups, respectively. Plasma <em>nesfatin</em>-<em>1</em> levels were determined by the ELISA method. Differences between groups were compared and associations between plasma <em>nesfatin</em>-<em>1</em> and other variables were analyzed.

The plasma <em>nesfatin</em>-<em>1</em> was significantly positively correlated with HAMD-<em>1</em>7 score (r = 0.65<em>1</em>). Compared with healthy controls (8.<em>1</em><em>1</em> ± 3.3<em>1</em> ng/mL), the plasma <em>nesfatin</em>-<em>1</em> level significantly increased in patients with mild depression (<em>1</em><em>1</em>.<em>1</em>7 ± 3.58 ng/mL), with moderate depression (<em>1</em>6.33 ± 8.78 ng/mL), and with severe depression (27.65 ± 8.26 ng/mL) respectively. Plasma <em>nesfatin</em>-<em>1</em> level (Odds ratio [OR] = <em>1</em>.269) was an independent indicator for severe depression by multivariate logistic regression analysis.

The plasma <em>nesfatin</em>-<em>1</em> level is positively correlated with the severity of depression. Plasma <em>nesfatin</em>-<em>1</em> level may be a potential indicator for depression severity.

Introduction Severe psoriasis is a chronic systemic immune‑mediated disease associated with increased cardiovascular (CV) risk and several comorbidities. Objectives Our aim was to assess vascular indices and selected serum biomarkers of increased CV risk in patients with nonsevere psoriasis. Patients and methods The study group included 80 patients with mild or moderate psoriasis (mean [SD] psoriasis area severity index, <em>1</em>8.6 [<em>1</em>0.5]), and the control group included 39 individuals matched forage and body mass index. All patients underwent a comprehensive clinical assessment with aplanation tonometry (pulse wave velocity [PWV]), and the following ultrasound indices were measured: flowmediated dilation (FMD) and carotid intima‑media thickness (IMT). Moreover, the following biomarkers were assessed in all individuals: osteoprotegerin, advanced oxidation protein products (AOPPs), visfatin, and <em>nesfatin</em>. Results Patients with nonsevere psoriasis had increased carotid IMT (mean [SD], <em>1</em>027 [35] μm vs 587 [<em>1</em>2] μm; P <0.05), impaired FMD (mean [SD], <em>1</em>6.3% [<em>1</em>0.7%] vs 32.<em>1</em>% [<em>1</em>3.7%]; P <0.00<em>1</em>), and increased serum levels of AOPPs (mean [SD], 2<em>1</em>8.9 [44.6] μmol vs <em>1</em>62.<em>1</em> [9.9] μmol; P <0.00<em>1</em>) and visfatin (mean [SD], <em>1</em>3.<em>1</em> [<em>1</em>6.7] ng/ml vs 3.43 [<em>1</em>] ng/ml; P <0.00<em>1</em>) compared with the control group. There were no significant differences in the serum levels of osteoprotegerin, <em>nesfatin</em>, and PWV. Oxidative stress (AOPP) was significantly associated with IMT (r = 0.3), FMD (r = -0.25), and visfatin (r = 0.6). Conclusions Our study suggests increased CV risk in patients with mild to m oderate psoriasis.

<em>Nesfatin</em>-<em>1</em>, derived from the nucleobindin-2 gene product, is expressed in neurons located in brain centers known to be important in the central regulation of both cardiovascular function and fluid and electrolyte homeostasis. In fact the peptide colocalizes in those neurons with an impressive list of neuropeptides and neurotransmitters known to be important in the regulation of thirst, appetite and central autonomic control. We and others have demonstrated potent sympatho-stimulatory actions of <em>nesfatin</em>-<em>1</em> in brain and the potential physiologic relevance of those effects. In addition, although <em>nesfatin</em>-<em>1</em> was originally described as a peptide with potent anorexigenic actions in brain, effects corroborated by several groups, it is possible that the anorexigenic actions of <em>nesfatin</em>-<em>1</em> are secondary to a primary action to reduce thirst. Progress in unraveling the importance of endogenous <em>nesfatin</em>-<em>1</em> in cardiovascular function, or fluid and electrolyte homeostasis, has been limited due to the to date unavailability of <em>nesfatin</em>-<em>1</em> antagonists and the fact that the receptor for <em>nesfatin</em>-<em>1</em> remains unidentified.