NUCB2/<em>nesfatin</em>-<em>1</em> is expressed in variety of tissues. Treatment with <em>nesfatin</em>-<em>1</em> reduces inflammation in rat models of subarachnoid hemorrhage-induced oxidative brain damage and traumatic brain injury as well as myocardial injury. There is only one study showing anti-inflammatory actions of <em>nesfatin</em>-<em>1</em> on acute lung inflammation. To more precisely determine the role of NUCB2/<em>nesfatin</em>-<em>1</em> in acute lung inflammation, we conducted a study using NUCB2/<em>nesfatin</em>-<em>1</em> knockout (NKO) mice as well as neutrophils isolated from the bone marrows of WT and NKO mice. Our findings suggest that the absence of NUCB2/<em>nesfatin</em>-<em>1</em> significantly increases the accumulation of adherent neutrophils by approximately 3 times compared with WT within LPS-treated lungs. Integrating this with observations from both BALF and neutrophil cytokine expression, we propose that although neutrophils lacking NUCB2/<em>nesfatin</em>-<em>1</em> individually secrete less pro-inflammatory cytokines compared with stimulated WT cells, the result of knocking out NUCB2/<em>nesfatin</em>-<em>1</em> is net pro-inflammatory. No change was found in NUCB2/<em>nesfatin</em>-<em>1</em> mRNA or protein expression comparing WT LPS and PBS-treated samples. Taken together, our results show that NUCB2/<em>nesfatin</em>-<em>1</em> is constitutively expressed in mouse lungs and neutrophils and demonstrates anti-inflammatory properties in mouse lungs during acute lung injury, by inhibiting adherent neutrophil accumulation and inflammatory cytokine expression.

<strong class="sub-title"> Keywords: </strong> Inflammation; Lungs; Mouse; Nesfatin-<em>1</em>; Nucleobindin-2.

<em>Nesfatin</em>-<em>1</em> as a new energy-regulating peptide has been known to display a pivotal role in modulation of cardiovascular functions and protection against ischemia/reperfusion injury. However, the detailed knowledge about molecular mechanisms underlying this protection has not been completely investigated yet. This study was designed to clarify the molecular mechanisms by which <em>nesfatin</em>-<em>1</em> exert cardioprotection effects against myocardial ischemia-reperfusion (MI/R). Left anterior descending coronary artery (LAD) was ligated for 30 min to create a MI/R model in rats. MI/R rats were treated with three concentrations of <em>nesfatin</em>-<em>1</em> (<em>1</em>0, <em>1</em>5 and 20 µg/kg) then expression of necroptosis and necrosis mediators were measured by western blotting assay. Fibrosis, morphological damages, cardiac function, myocardial injury indictors and oxidative stress factors were evaluated as well. Induction of MI/R model resulted in cardiac dysfunction, oxidative stress, increased activity of RIPK<em>1</em>-RIPK3-MLKL axis and RhoA/ROCK pathway, extension of fibrosis and heart tissue damage. Highest tested concentration of <em>nesfatin</em>-<em>1</em> markedly improved cardiac function. Moreover, it reduced oxidative stress, collagen deposition, and morphological damages, through inhibiting the expression of necroptosis mediators and also, necrosis including RIPK<em>1</em>, RIPK3, MLKL, ROCK<em>1</em>, and ROCK2 proteins. The lowest and middle tested concentrations of <em>nesfatin</em>-<em>1</em> failed to exert protective effects against MI/R. These findings have shown that <em>nesfatin</em>-<em>1</em> can exert cardioprotection against MI/R in a dose dependent manner by suppressing necroptosis via modulation of RIPK<em>1</em>-RIPK3-MLKL axis and RhoA/ROCK/RIP3 signaling pathway.

<strong class="sub-title"> Keywords: </strong> Myocardial infarction; Necroptosis; <em>Nesfatin</em>-<em>1</em>; RIPK<em>1</em>-RIPK3-MLKL axis.

<strong class="sub-title"> Background/aims: </strong> Gastrointestinal motility changes contribute to development and maintenance of obesity. <em>Nesfatin</em>-<em>1</em> (NES-<em>1</em>) is involved in central appetite control. The aim is to elucidate effects of NES-<em>1</em> and high-fat diet (HFD) on gastrointestinal motility and to explore myenteric neuron expressions of tyrosine hydroxylase (TH), vasoactive intestinal peptide (VIP), and neuronal nitric oxide synthase (nNOS) in HFDinduced oxidative injury.

<strong class="sub-title"> Methods: </strong> Sprague-Dawley rats were fed with normal diet (ND) or HFD. Gastric emptying rate was measured following NES-<em>1</em> (5 pmol/rat, intracerebroventricular) preceded by subcutaneous injections of glucagon-like peptide <em>1</em> (GLP-<em>1</em>), cholecystokinin <em>1</em> (CCK-<em>1</em>), and gastrin/CCK-2 receptor antagonists. In carbachol-contracted gastric and ileal strips, contractile changes were recorded by adding NES- <em>1</em> (0.3 nmol/L), GLP-<em>1</em>, CCK-<em>1</em>, and gastrin/CCK-2 antagonists.

<strong class="sub-title"> Results: </strong> Neither HFD nor NES-<em>1</em> changed methylcellulose emptying, but NES-<em>1</em> delayed saline emptying in cannulated ND-rats. Inhibitory effect of NES-<em>1</em> on gastric emptying in ND-rats was reversed by all antagonists, and abolished in HFD-rats. In HFD-rats, carbachol-induced contractility was enhanced in gastric, but inhibited in ileal strips. HFD increased body weight, while serum triglycerides, alanine transaminase, aspartate aminotransferase, glucose, and levels of malondialdehyde, glutathione, myeloperoxidase activity, and luminolchemiluminescence in hepatic, ileal, and adipose tissues were similar in ND- and HFD-rats, but only lucigenin-chemiluminescence was increased in HFD-rats. Vasoactive intestinal peptide (VIP) and TH immunoreactivities were depressed and nNOS immunoreactivity was increased in gastric tissues of HFD-rats, while VIP and TH were enhanced, but nNOS was reduced in their intestines.

<strong class="sub-title"> Conclusions: </strong> HFD caused mild systemic inflammation, disrupted enteric innervation, enhanced gastric contractility, inhibited ileal contractility, and eliminated inhibitory effect of NES-<em>1</em> on gastric motility.

<strong class="sub-title"> Keywords: </strong> Cholecystokinin; Gastric emptying; <em>Nesfatin</em>-<em>1</em>; Nitric oxide synthase type I; Vasoactive intestinal peptide.

<strong class="sub-title"> Objective: </strong> We evaluated the efficacy of curcumin administration on blood glucose levels and its relationship with <em>nesfatin</em>-<em>1</em> levels in blood brain and adipose tissue of streptozotocin-induced diabetic rats.

<strong class="sub-title"> Materials and methods: </strong> A total of 28 male rats were divided into four groups: control group, type 2 diabetes mellitus (DM) group, control plus curcumin group and type 2DM plus curcumin group. After fifteen days, blood samples were collected from sacrificed rats. Nesftain-<em>1</em> levels were analysed from blood, brain, and fat tissues of rats in all groups.

<strong class="sub-title"> Results: </strong> Nesfatin-<em>1</em> level was found to be significantly lower in blood, brain and fat tissues of type 2 DM rats compared to the control group. A significant decrease in fasting blood glucose levels was observed in the curcumin administration group compared to type 2 DM group. Improvement of fasting blood glucose level was accompanied by improvement of <em>nesfatin</em>-<em>1</em> levels in blood, brain, and fat tissues.

<strong class="sub-title"> Conclusions: </strong> As expected, curcumin administration caused significant improvement in fasting blood glucose levels. However, for the first time, we found marked improvements in <em>nesfatin</em>-<em>1</em> levels in blood, brain, and fat tissues of type 2 DM rats. Thus, considering the crucial role of <em>nesfatin</em>-<em>1</em> in regulation of glucose metabolism, it is logical to expect an interactive relationship between curcumin and <em>nesfatin</em>-<em>1</em>.

Cancer is a heterogeneous disease, and even tumors with similar clinicopathological characteristics show different biology, behavior, and treatment responses. As a result, there is an urgent need to define new prognostic and predictive markers to make treatment options more personalized. According to the latest findings, nucleobindin-2/<em>nesfatin</em>-<em>1</em> (NUCB2/NESF-<em>1</em>) is an important factor in cancer development and progression. Nucleobindin-2 is a precursor protein of <em>nesfatin</em>-<em>1</em>. As NUCB2 and <em>nesfatin</em>-<em>1</em> are colocalized in each tissue, their expression is often analyzed together as NUCB2. The metabolic function of NUCB2/NESF-<em>1</em> is related to food intake, glucose metabolism, and the regulation of immune, cardiovascular and endocrine systems. Recently, it has been demonstrated that high expression of NUCB2/NESF-<em>1</em> is associated with poor outcomes and promotes cell proliferation, migration, and invasion in, e.g., breast, colon, prostate, endometrial, thyroid, bladder cancers, or glioblastoma. Interestingly, <em>nesfatin</em>-<em>1</em> is also considered an inhibitor of the proliferation of human adrenocortical carcinoma and ovarian epithelial carcinoma cells. These conflicting results make NUCB2/NESF-<em>1</em> an interesting target of study in the context of cancer progression. The present review is the first to describe NUCB2/NESF-<em>1</em> as a new prognostic and predictive marker in cancers.

<strong class="sub-title"> Keywords: </strong> NESF-<em>1</em>; NUCB2; cancer; <em>nesfatin</em>-<em>1</em>; nucleobindin-2.

<em>Nesfatin</em>-<em>1</em> was discovered as an anorexigenic peptide derived from proteolytic cleavage of the prepropeptide, nucleobindin 2 (NUCB2). It is widely expressed in central as well as peripheral tissues and is known to have pleiotropic effects such as regulation of feeding, reproduction, cardiovascular functions and maintenance of glucose homeostasis. In order to execute its multifaceted role, <em>nesfatin</em>-<em>1</em> employs diverse signaling pathways though its receptor has not been identified till date. Further, <em>nesfatin</em>-<em>1</em> is reported to be under the regulatory effect of feeding state, nutritional status as well as several metabolic and reproductive hormones. This peptide has also been associated with variety of human diseases, especially metabolic, reproductive, cardiovascular and mental disorders. The current review is aimed to present a consolidated picture and highlight lacunae for further investigation in order to develop a deeper comprehensive understanding on physiological significance of <em>nesfatin</em>-<em>1</em> in vertebrates.

<strong class="sub-title"> Keywords: </strong> <em>Nesfatin</em>-<em>1</em>; cardioprotection reproduction; comparative account; feeding behaviour; glucose homeostasis.

Stress in vertebrates is mediated by the hypothalamus-pituitary-adrenal [in mammals]/interrenal [ in fish] (HPA/I) axis, which produces the corticotropin releasing factor (CRF), adrenocorticotropic hormone (ACTH) and corticosteroids, respectively. <em>Nesfatin</em>-<em>1</em>, a novel anorexigenic peptide encoded in the precursor nucleobindin-2 (NUCB2), is increasingly acknowledged as a peptide that influences the stress axis in mammals. The primary aim of this study was to characterize the putative effects of <em>nesfatin</em>-<em>1</em> on the fish HPI axis, using goldfish (Carassius auratus) as an animal model. Our results demonstrated that nucb2/<em>nesfatin</em>-<em>1</em> transcript abundance was detected in the HPI tissues of goldfish, with most abundant expression in the pituitary. NUCB2/<em>nesfatin</em>-<em>1</em>-like immunoreactivity was found in the goldfish hypothalamus, pituitary and interrenal cells of the head kidney. GPCR<em>1</em>2, a putative receptor for <em>nesfatin</em>-<em>1</em> was also detected in the pituitary and interrenal cells. NUCB2/<em>nesfatin</em>-<em>1</em>-like immunoreactivity was observed in ACTH-expressing pituitary corticotrophs. Acute netting and restraint stress upregulated nucb2/<em>nesfatin</em>-<em>1</em> mRNA levels in the forebrain, hypothalamus and pituitary, as well as crf and crf-r<em>1</em> expression in the forebrain and hypothalamus. Intraperitoneal and intracerebroventricular administration of <em>nesfatin</em>-<em>1</em> increased cortisol release and hypothalamic crf mRNA levels, respectively. Finally, we found that <em>nesfatin</em>-<em>1</em> significantly stimulated ACTH secretion from dispersed pituitary cells in vitro. Collectively, our data provide the first evidence showing that <em>nesfatin</em>-<em>1</em> is a stress responsive peptide, which modulates the stress axis hormones in fish.

<strong class="sub-title"> Keywords: </strong> Cortisol; Goldfish; HPI Axis; <em>Nesfatin</em>-<em>1</em>; Stress.

<strong class="sub-title"> Purpose: </strong> <em>Nesfatin</em>-<em>1</em> plays a crucial role in glucose metabolism and cognitive function. This study aimed to investigate the correlation between plasma <em>nesfatin</em>-<em>1</em> levels and clinical indicators and cognitive function in patients with type 2 diabetes mellitus (T2DM).

<strong class="sub-title"> Methods: </strong> Demographic and medical history data, physical examination, and biochemical test results of <em>1</em>32 T2DM patients were collected. The plasma concentrations of <em>nesfatin</em>-<em>1</em>, C-reactive protein (CRP), interleukin-6 (IL-6), soluble triggering receptors expressed on myeloid cells <em>1</em> (sTREM<em>1</em>), and sTREM2 in T2DM patients were measured. Cognitive function was evaluated using the Behavior Rating Inventory of Executive Function-Adult (BRIEF-A). The patients were divided into two groups: a low-<em>nesfatin</em>-<em>1</em> group (n = 75) and a high-<em>nesfatin</em>-<em>1</em> group (n = 57) based on a plasma <em>nesfatin</em>-<em>1</em> concentration less than or above the 50th percentile value of all the samples.

<strong class="sub-title"> Results: </strong> The results showed that plasma HbA<em>1</em>c levels were positively correlated with CRP, IL-6, sTREM<em>1</em>, and sTREM2 levels in patients with T2DM (<i>P</i> < 0.05). Plasma <em>nesfatin</em>-<em>1</em> concentrations were positively associated with diabetes-related biochemical indicators including glycated haemoglobin (HbA<em>1</em>c), insulin, and homeostatic model assessment of insulin resistance (HOMA-IR), and inflammation-related indicators including CRP, IL-6, sTREM<em>1</em>, and sTREM2 among patients with T2DM (<i>P</i> < 0.05). Moreover, T2DM patients with high <em>nesfatin</em>-<em>1</em> levels showed higher HbA<em>1</em>c and fasting plasma glucose (FPG) levels (<i>P</i> < 0.05). Furthermore, T2DM patients with high <em>nesfatin</em>-<em>1</em> levels also showed higher BRIEF-A scores (<i>P</i> = 0.0<em>1</em>). Additionally, T2DM patients with high total scores of BRIEF-A (scores > 50th percentile) could be identified with a sensitivity of 59.<em>1</em>% and a specificity of 72.7% by <em>nesfatin</em>-<em>1</em>.

<strong class="sub-title"> Conclusion: </strong> These findings indicate that plasma <em>nesfatin</em>-<em>1</em> might be involved in the T2DM-associated comorbidities and the development of cognitive dysfunction, and the mechanism underlying this involvement is related to the imbalance in the expression of CRP, IL-6, sTREM<em>1</em>, and sTREM2 levels.

<strong class="sub-title"> Keywords: </strong> cognitive dysfunction; inflammatoryresponse; <em>nesfatin</em>-<em>1</em>; sTREM<em>1</em>/2; type 2 diabetes mellitus.

<strong class="sub-title"> Objective: </strong> Epilepsy is a common disorder that affects the nervous systems of <em>1</em>% of worldwide population. In epilepsy, one-third of patients are unresponsive to current drug therapies and develop drug-resistant epilepsy. Alterations in ghrelin, <em>nesfatin</em>-<em>1</em>, and irisin levels with epilepsy were reported in previous studies. Vasoactive intestinal peptide is among the most common neuropeptides in the hippocampus, which is the focus of the seizures in temporal lobe epilepsy. However, there is also lack of evidence of whether these four neuropeptide levels are altered with drug resistant temporal lobe epilepsy or not. The aim herein was the evaluation of the serum levels of <em>nesfatin</em>-<em>1</em>, ghrelin, irisin, and Vasoactive intestinal peptide in drug-resistant temporal lobe epilepsy patients and temporal lobe epilepsy (TLE) without drug resistance, and to compare them to healthy controls.

<strong class="sub-title"> Methods: </strong> This cross-sectional study group included 58 temporal lobe epilepsy patients (24 with drug resistant temporal lobe epilepsy and 34 with temporal lobe epilepsy who were not drug-resistant) and 28 healthy subjects. Nesfatin-<em>1</em>, ghrelin, irisin, and Vasoactive intestinal peptide serum levels were determined using enzyme-linked immunosorbent assay.

<strong class="sub-title"> Results: </strong> The serum ghrelin levels of patients with drug resistant temporal lobe epilepsy were seen to have significantly decreased when compared to those of the control group (p<0.05). Serum <em>nesfatin</em>-<em>1</em>, vasoactive intestinal peptide, and irisin levels were seen to have decreased in the drug resistant temporal lobe epilepsy group when compared to those of the control and temporal lobe epilepsy groups; however, the difference was non-significant (p>0.05).

Conclusions: The results herein suggested that ghrelin might contribute to the pathophysiology of drug resistant temporal lobe epilepsy. However, further studies are needed to confirm this hypothesis.

Objective: To study the effect of recombinant human growth hormone (rhGH) treatment on the growth velocities and serum index expressions of short stature children.

<strong class="sub-title"> Methods: </strong> 56 short stature children admitted to our hospital from January 20<em>1</em>8 to January 2020 were recruited as the study cohort. All the children were treated with rhGH. After six months of treatment, their serum indicators [ghrelin, <em>Nesfatin</em>-<em>1</em>, bone-specific alkaline phosphate (BAP), insulin-like growth factor <em>1</em> (IGF-<em>1</em>)], their growth velocity indicators [body mass index (BMI), height, growth velocity (GV)], their blood lipid levels [triglycerides (TG), total cholesterol (TC), low density lipoprotein (LDL), high and low density lipoprotein (HDL)], their insulin statuses [fasting insulin (FINS), their homeostasis model assessment of insulin resistance (HOMA-IR)], and their thyroid function index [thyroid stimulating hormone (TSH), 3'-triiodothyronine (T3), 4'-triiodothyronine (T4)] level changes before and after the treatment were compared.

<strong class="sub-title"> Results: </strong> (<em>1</em>) After the treatment, the children's serum ghrelin and IGF-<em>1</em> levels increased in comparison with their pre-treatment levels (P<0.05), and their nesfatin-<em>1</em> levels decreased (P<0.05). (2) After the treatment, the children's BMI, height, and GV increased in comparison with their pre-treatment levels (P<0.05). (3) After the treatment, the children's TG levels were noticeably higher than they were before the treatment (P<0.05), and the TC and LDL levels were remarkably lower than they were before the treatment (P<0.05). (4) After the treatment, the children's T3 and T4 levels were significantly higher compared to their levels before the treatment (P<0.05).

Conclusion: GH can promote the development and growth of short stature children, improve their related serum indicator levels, and does not induce metabolic dysfunction.

Keywords: Short stature; growth hormone deficiency; growth velocity; idiopathic short stature; metabolic function.

<em>Nesfatin</em>-<em>1</em>, an anorexic neuropeptide discovered in 2006, is widely distributed in the central nervous system and peripheral tissues. It has been shown to be involved in the regulation of food intake and lipid metabolism, inhibiting fat accumulation, accelerating lipid decomposition, and in general, inhibiting the development of lipid-related diseases, ie, obesity and metabolic syndrome. Potential mechanisms of <em>Nesfatin</em>-<em>1</em> action in lipid metabolism and lipid-related diseases will be discussed as well as its role as a biomarker in cardiovascular disease. This review expected to provide a new strategy for the diagnosis and prevention of clinically related diseases.

<strong class="sub-title"> Keywords: </strong> <em>Nesfatin</em>-<em>1</em>; cardiovascular diseases; fat accumulation; lipid metabolism; metabolic syndrome; obesity.

Nucleobindin-2 (Nucb2) is a protein that has been suggested to play roles in a variety of biological processes. Nucb2 contains two Ca²⁺/Mg²⁺-binding EF-hand domains separated by an acidic amino acid residue-rich region and a leucine zipper. All of these domains are located within the C-terminal half of the protein. At the N-terminal half, Nucb2 also possesses a putative Zn²⁺-binding motif. In our recent studies, we observed that Nucb2 underwent Ca²⁺-dependent compaction and formed a mosaic-like structure consisting of intertwined disordered and ordered regions at its C-terminal half. The aim of this study was to investigate the impact of two other potential ligands: Mg²⁺, which possesses chemical properties similar to those of Ca²⁺, and Zn²⁺, for which a putative binding motif was identified. In this study, we demonstrated that the binding of Mg²⁺ led to oligomerization state changes with no significant secondary or tertiary structural alterations of Nucb2. In contrast, Zn²⁺ binding had a more pronounced effect on the structure of Nucb2, leading to the local destabilization of its N-terminal half while also inducing changes within its C-terminal half. These structural rearrangements resulted in the oligomerization and/or aggregation of Nucb2 molecules. Taken together, the results of our previous and current research help to elucidate the structure of the Nucb2, which can be divided into two parts: the Zn²⁺-sensitive N-terminal half (consisting of <em>nesfatin</em>-<em>1</em> and -2) and the Ca²⁺-sensitive C-terminal half (consisting of <em>nesfatin</em>-3). These results may also help to open a new discussion regarding the diverse roles that metal cations play in regulating the structure of Nucb2 and the various physiological functions of this protein.

Keywords: Analytical ultracentrifugation; Intrinsically disordered proteins; Isothermal titration calorimetry; Oligomers; Transmission electron microscopy; Zinc ion binding proteins.

We recently demonstrated that peripheral and central administration of <em>nesfatin</em>-<em>1</em> in fasting and satiety states generate hyperventilation activity by increasing tidal volume (TV), respiratory rate (RR), and respiratory minute ventilation (RVM). The present study aimed to investigate the mediation of central cholinergic receptors effective in respiratory control in the hyperventilation activity of <em>nesfatin</em>-<em>1</em>. Besides this, we intended to determine possible changes in blood gases due to hyperventilation activity caused by <em>nesfatin</em>-<em>1</em> and investigate the mediation of central cholinergic receptors in these changes. Intracerebroventricular (ICV) administration of <em>nesfatin</em>-<em>1</em> revealed a hyperventilation response with an increase in TV, RR, RMV, and pO₂ and a decrease in pCO₂ in saturated Sprague Dawley rats. ICV pretreatment with the muscarinic receptor antagonist atropine partially blocked the RR, RMV, pO₂, and pCO₂ responses produced by <em>nesfatin</em>-<em>1</em> while completely blocking the TV response. However, central pretreatment with nicotinic receptor antagonist mecamylamine blocked the respiratory and blood gas responses induced by <em>nesfatin</em>-<em>1</em>. The study's conclusion demonstrated that <em>nesfatin</em>-<em>1</em> had active hyperventilation effects resulting in an increase in pO₂ and a decrease in pCO₂. The critical finding of the study was that activation of central cholinergic receptors was involved in <em>nesfatin</em>-<em>1</em>-evoked hyperventilation and blood gas responses.

<strong class="sub-title"> Keywords: </strong> Cholinergic muscarinic and nicotinic receptors; Intracerebroventricular; Nesfatin-<em>1</em>; Partial oxygen and carbon dioxide pressure; Respiratory parameters.

Objective: In this study we aimed to assess anorexigenic peptide levels in patients with or without polycystic ovary syndrome (PCOS) and their effects on assisted reproductive treatment (ART) outcomes.

Methods: A prospective case-control study was conducted in a tertiary care university-based ART clinic. Eighty-three patients were included in the study. The PCOS group included 41 patients, and the non-PCOS group included 42 controls. The 2003 Rotterdam criteria were used for PCOS patient selection. The ART indications in the non-PCOS group were tubal factor or unexplained infertility. Venous blood samples were taken on the third day of the menstrual cycle to determine the serum anorexigenic peptide levels. The enzyme-linked immunosorbent assay method was used for laboratory analyses.

Results: In the PCOS group, serum obestatin levels were significantly lower than in the control group, but serum anorexigenic peptide levels were similar in PCOS patients with or without clinical pregnancy. Ovarian hyperstimulation syndrome (OHSS) was diagnosed only in PCOS patients, and the obestatin levels of OHSS patients were significantly lower than those of other PCOS patients.

Conclusion: Baseline anorexigenic peptide levels did not affect the clinical pregnancy rate in ART cycles. Obestatin may play a role in the pathophysiology of OHSS. This possibility should be confirmed in further research.

Keywords: Assisted reproductive technique; Leptin; Nesfatin; Obestatin; Polycystic ovary syndrome.

In human milk banks (HMBs), donor milk (DM) is commonly sterilized by Holder pasteurization (HoP). High hydrostatic pressure (HHP) processing is an innovative, alternative method for DM sterilization. We evaluated the impact of HHP processing on the concentration of seven metabolic milk hormones. Eight samples of raw DM were aliquoted. One aliquot was sterilized by HoP (62 °C for 30 min), and another was processed by HHP (350 MPa at 38 °C). Compared with raw DM, HoP milk displayed reduced concentrations of insulin, <em>nesfatin</em>-<em>1</em>, cortisol, leptin, apelin and GLP-<em>1</em>, though adiponectin levels were unchanged. HHP processing maintained the levels of insulin, <em>nesfatin</em>-<em>1</em>, cortisol and leptin at their initial levels in raw DM, reduced apelin and adiponectin levels, but increased GLP-<em>1</em> level. Sterilization of DM by HHP thus preserves the main metabolic hormones in human milk, underlining the interest of this method for use in HMBs.

Keywords: High hydrostatic pressure; Holder pasteurization; Hormones; Human milk.

<strong class="sub-title"> Background: </strong> This study aimed to explore the effect of <em>nesfatin</em>-<em>1</em> on cobalt chloride (CoCl₂)-induced hypoxic injury in cardiomyocyte H9c2 cells.

<strong class="sub-title"> Methods: </strong> H9c2 cardiomyocytes were induced by different concentrations of CoCl₂ to mimic the hypoxia condition. Cell viability was detected by MTT assay. Cell apoptosis was detected by TUNEL staining and flow cytometry. ROS production was detected using the fluorescence probe DCFH-DA. The mitochondrial membrane potential (MMP) was detected using the TMRE method. The levels of released lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT) were detected using the commercial kits. The protein levels of MAPK signaling members (p-JNK<em>1</em>/2, p-ERK<em>1</em>/2, and p-p38) and Notch<em>1</em> signaling members (Notch<em>1</em>, Hes <em>1</em>, and Jagged <em>1</em>) were detected by Western blot.

<strong class="sub-title"> Results: </strong> CoCl₂ significantly promoted cell apoptosis, increased LDH leakage, MDA concentration, and decreased cell viability, SOD activity, GSH production, and CAT activity. CoCl₂-induced hypoxic injury in H9c2 cells was partially restored by <em>nesfatin</em>-<em>1</em> treatment. Moreover, <em>nesfatin</em>-<em>1</em> treatment attenuated CoCl₂-induced increase in ROS production and mitochondrial dysfunction, decreased mitochondrial membrane potential, Bax/Bcl-2 imbalance, as well as c-caspase-9 and c-caspase-3 levels. Moreover, <em>nesfatin</em>-<em>1</em> treatment inhibited the activation of MAPK and Notch<em>1</em> signaling pathways.

<strong class="sub-title"> Conclusions: </strong> Nesfatin-<em>1</em> could effectively protect H9c2 cells against CoCl₂-induced hypoxic injury by blocking MAPK and Notch<em>1</em> signaling pathways, suggesting that <em>nesfatin</em>-<em>1</em> might be a promising therapeutic agent for hypoxic cardiac injury.

<strong class="sub-title"> Keywords: </strong> CoCl2; MAPK; Nesfatin-<em>1</em>; Notch<em>1</em>; ROS.

The novel peptide phoenixin was shown to be involved in several physiological processes ranging from reproduction to food intake. Interest in this protein has steadily increased over the last few years and its known implications have become much broader, playing a role in glucose homeostasis, anxiety, nociception, and pruritus. Phoenixin is expressed in a multitude of organs such as the small intestine, pancreas, and in the hypothalamus, as well as several other brain nuclei influencing numerous physiological functions. Its highly conserved amino-acid sequence amongst species leads to the assumption, that phoenixin might be involved in essential physiological functions. Its co-expression and opposing functionality to the extensively studied peptide <em>nesfatin</em>-<em>1</em> has given rise to the idea of a possible counterbalancing role. Several recent publications focused on phoenixin's role in stress reactions, namely restraint stress and lipopolysaccharide-induced inflammation response, in which also <em>nesfatin</em>-<em>1</em> is known to be altered. This review provides an overview on the phoenixins and <em>nesfatin</em>-<em>1</em> properties and putative effects, and especially highlights the recent developments on their role and interaction in the response to response.

<strong class="sub-title"> Keywords: </strong> GPR<em>1</em>73; anxiety; brain-gut axis; <em>nesfatin</em>-<em>1</em>; phoenixin; stress.

<strong class="sub-title"> Background: </strong> Adipocytokines have been proven to be involved in the progression of autoimmune diseases, including rheumatoid arthritis (RA). <em>Nesfatin</em>-<em>1</em>, a newly discovered adipokine, has recently been reported to possess potent anti-inflammatory, antiapoptotic, and antioxidative properties. However, its role in RA has not yet been reported. Therefore, this study aimed to determine <em>nesfatin</em>-<em>1</em> levels in the synovium and synovial fluid (SF) of patients with RA and examine their correlation with clinical manifestations and proinflammatory cytokine levels.

<strong class="sub-title"> Methods: </strong> Synovium and SF samples were collected from patients with RA and non-RA patients during joint surgery. Immunohistochemistry was used to measure <em>nesfatin</em>-<em>1</em> protein expression in the synovium. Enzyme-linked immunosorbent assay was used to measure <em>nesfatin</em>-<em>1</em>, interleukin-<em>1</em>β (IL-<em>1</em>β), and tumor necrosis factor-α (TNF-α) levels in the synovium and SF. Pearson correlation analysis was used to evaluate the correlations between <em>nesfatin</em>-<em>1</em> levels, RA clinical features, and proinflammatory cytokines. The diagnostic value of synovium <em>nesfatin</em>-<em>1</em> for RA was assessed using receiver operating characteristic (ROC) curve analysis.

<strong class="sub-title"> Results: </strong> The results showed that <em>nesfatin</em>-<em>1</em>, IL-<em>1</em>β, and TNF-α levels in the synovium were significantly higher in patients with RA than in controls, with age and body mass index as covariates. Moreover, the results of Pearson correlation analysis showed that <em>nesfatin</em>-<em>1</em> levels were positively correlated with IL-<em>1</em>β and TNF-α levels in the synovium of patients with RA. Furthermore, there was a positive relationship between synovium <em>nesfatin</em>-<em>1</em> levels and rheumatoid factor in patients with RA. Additionally, the results of the ROC curve analysis revealed an area under the curve of 0.733 with 77.5% sensitivity and 60.0% specificity for synovium <em>nesfatin</em>-<em>1</em> in discriminating patients with RA from controls.

<strong class="sub-title"> Conclusion: </strong> These findings suggest that increased <em>nesfatin</em>-<em>1</em> levels in the synovium may be associated with proinflammatory cytokines and RA severity.

<strong class="sub-title"> Keywords: </strong> adipocytokine; <em>nesfatin</em>-<em>1</em>; pro-inflammatory cytokines; rheumatoid arthritis; synovial fluid; synovium.

Nucb2 is a multifunctional protein associated with a variety of biological processes. Multiple studies have revealed that Nucb2, and its derivative <em>nesfatin</em>-<em>1</em>, are involved in carcinogenesis. Interestingly, the role of Nucb2/<em>nesfatin</em>-<em>1</em> in tumorigenesis seems to be dual-both pro-metastatic and anti-metastatic. The implication of Nucb2/<em>nesfatin</em>-<em>1</em> in carcinogenesis seems to be tissue dependent. Herein, we review the role of Nucb2/<em>nesfatin</em>-<em>1</em> in both carcinogenesis and the apoptosis process, and we also highlight the multifaceted nature of Nucb2/<em>nesfatin</em>-<em>1</em>.

<strong class="sub-title"> Keywords: </strong> Nucb2; apoptosis; biomarker; carcinogenesis; <em>nesfatin</em>-<em>1</em>; tumors.

Objective Delta-like <em>1</em> (DLK<em>1</em>) and <em>nesfatin</em>-<em>1</em> are adipokines that have been shown to affect glucose metabolism. We aimed to search serum DLK<em>1</em> and <em>nesfatin</em>-<em>1</em> concentrations at 24-28 weeks of pregnancy in women newly defined with gestational diabetes mellitus (GDM) and investigate the relationship of these adipokines with various metabolic parameters. Methods Serum levels of DLK<em>1</em> and <em>nesfatin</em>-<em>1</em> were evaluated in 44 women with GDM, and in 40 healthy pregnant women by enzyme-linked immunosorbent assay (ELISA) kits. While performing oral glucose tolerance test (OGTT) for GDM diagnosis at 24-28 weeks of pregnancy, homeostasis model assessment of insulin resistance (HOMA-IR), lipid profiles, glycosylated hemoglobin (HbA<em>1</em>c) were also measured. Results Maternal serum DLK<em>1</em> and <em>nesfatin</em>-<em>1</em> concentrations were found lower in pregnant women with GDM compared with healthy pregnant women (4<em>1</em>8.4±282.6 vs. 586.7±303 ng/L, p=0.002; <em>1</em>2.2±7.6 vs. 26.7±<em>1</em>6.4 ng/ml, p<0.00<em>1</em>, respectively). Maternal serum DLK<em>1</em> levels correlated positively with HOMA-IR and fasting insulin (r=0.395, p=0.008; r=0.374, p=0.0<em>1</em>2, respectively). Conclusion We determined that DLK<em>1</em> and <em>nesfatin</em>-<em>1</em> levels were lower in GDM. Based on this study, it may be considered that DLK<em>1</em> could be culpable for metabolic disorders in GDM.

<strong class="sub-title"> Keywords: </strong> adipokine; delta-like <em>1</em> (dlk<em>1</em>); gestational diabetes mellitus; insulin resistance; <em>nesfatin</em>-<em>1</em>.

The progression of osteoarthritis (OA) is mediated by adipokines, one of which is <em>nesfatin</em>-<em>1</em>, which is responsible for the production of inflammatory cytokines. However, how this molecule may affect the synthesis of the proinflammatory cytokine interleukin <em>1</em> beta (IL-<em>1</em>β) in OA is unclear. Our analyses of records from the Gene Expression Omnibus (GEO) dataset and clinical specimens of synovial tissue revealed higher levels of <em>nesfatin</em>-<em>1</em> and IL-<em>1</em>β in OA samples compared with normal healthy tissue. We found that <em>nesfatin</em>-<em>1</em> facilitates IL-<em>1</em>β synthesis in human OA synovial fibroblasts (OASFs) and suppresses the generation of micro-RNA (miR)-204-5p, as the miR-204-5p levels in OA patients were lower than those in healthy controls. <em>Nesfatin</em>-<em>1</em>-induced stimulation of IL-<em>1</em>β in human OASFs occurred via the suppression of miR-204-5p synthesis by the PI3K, Akt, AP-<em>1</em> and NF-κB pathways. We suggest that <em>nesfatin</em>-<em>1</em> is worth targeting in OA treatment.

<strong class="sub-title"> Keywords: </strong> interleukin-<em>1</em> beta; miR-204-5p; <em>nesfatin</em>-<em>1</em>; osteoarthritis; synovial fibroblasts.

<strong class="sub-title"> Objective: </strong> The pathogenesis of endometriosis has not been clearly explained. Inflammatory factors of ectopic implantation and the growth of ectopic endometrial cells have been subjects of major interest. The number of studies evaluating salusin-α and <em>nesfatin</em>-<em>1</em> markers in patients with endometriosis is limited. No studies have evaluated the levels of anti-inflammatory markers for adropin and netrin-<em>1</em> in patients with endometriosis. This study investigates how some important inflammatory regulatory markers in the inflammatory process affect the pathogenesis of endometriosis and determines whether any relationship exists between serum levels of these parameters and endometriosis and insulin resistance.

<strong class="sub-title"> Materials and methods: </strong> This prospective study included 73 patients with endometriosis diagnosed histopathologically after laparoscopic surgery and 75 healthy controls. Serum adropin, salusin-α, netrin-<em>1</em>, and <em>nesfatin</em>-<em>1</em> levels and homeostatic model assessment of insulin resistance (HOMA-IR) values of the participants were measured.

<strong class="sub-title"> Results: </strong> The endometriosis group had significantly lower <em>nesfatin</em>-<em>1</em> levels than the control group (3.0±0.53 vs 9.5±0.94, p=0.005). Between the patient and control groups, there was no difference regarding serum adropin, salusin-α, and netrin-<em>1</em> levels (p=0.36, p=0.34, p=0.75, respectively). Nesfatin-<em>1</em> had a significant positive correlation with adropin, salusin-α, and netrin-<em>1</em> (r=0.563, p<0.0<em>1</em>; r=0.738, p<0.0<em>1</em>; r=0.700, p<0.0<em>1</em>, respectively), but had a negative correlation with fasting blood glucose (r=-0.343, p<0.05). HOMA-IR values were comparable between both groups.

<strong class="sub-title"> Conclusion: </strong> The lower <em>nesfatin</em>-<em>1</em> levels leading to increased inflammatory pathway activity in patients with endometriosis might play a role in endometriosis pathogenesis. Without causing systemic insulin resistance, decreased <em>nesfatin</em>-<em>1</em> might contribute to endometriosis pathogenesis locally by leading to the reduced insulin susceptibility of endometriosis cells.

<strong class="sub-title"> Keywords: </strong> Endometriosis; adropin; insulin resistance; <em>nesfatin</em>-<em>1</em>; netrin-<em>1</em>; salusin-α.

Heap-up of α-synuclein (α-Syn) and its association with tau protein are esteemed to trigger the onset of Parkinson's disease (PD). The purpose of this study was to develop multi-functional liposomes incorporated with <em>1</em>,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, <em>1</em>,2-dimyristoyl-sn-glycero-3-phosphocholine and phosphatidylserine (PS) to load astragaloside IV (AS-IV) and nestifin-<em>1</em> (NF-<em>1</em>), followed by grafting with wheat germ agglutinin (WGA) and leptin (Lep) (WGA-Lep-AS-IV-NF-<em>1</em>-PS-liposomes) to protect dopaminergic neurons from apoptosis. Experimental results showed that increasing the mole percentage of DSPC and PS enhanced the particle size, particle stability and entrapment efficiency of AS-IV and NF-<em>1</em>, and reduced the drug releasing rate. Strong affinity of NF-<em>1</em> to PS was evidenced by nuclear magnetic resonance spectroscopy. WGA-Lep-AS-IV-NF-<em>1</em>-PS-liposomes diminished transendothelial electrical resistance and improved the capacity of propidium iodide, AS-IV and NF-<em>1</em> to penetrate the blood-brain barrier (BBB). Immunocytochemical staining exhibited the ability of functionalized liposomes to target Lep receptor and α-Syn in MPP⁺-insulted SH-SY5Y cells. Western blots revealed a substantial reduction of α-Syn and phosphorylated tau protein in the anti-oxidative pathway through interaction with PS. During the course of treatment with WGA-Lep-AS-IV-NF-<em>1</em>-PS-liposomes, the combined activity of AS-IV and NF-<em>1</em> and recognition capability simultaneously decreased the expression of Bax, and increased the expressions of Bcl-2, tyrosine hydroxylase and dopamine transporter. The liposomes carrying AS-IV and NF-<em>1</em> can rescue degenerated neurons and are a promising formulation to achieve better PD management.

Keywords: Blood-brain barrier; Liposome; Parkinson's disease; Targeted delivery; Tau protein; α-Synuclein.

<strong class="sub-title"> Background: </strong> <em>Nesfatin</em>-<em>1</em> is an 82-amino acid polypeptide, cleaved from the 396-amino acid precursor protein nucleobindin-2 (NUCB2) and discovered in 2006 in the rat hypothalamus. In contrast to the growing body of evidence for the pleiotropic effects of the peptide, the receptor mediating these effects and the exact signaling cascades remain still unknown.

<strong class="sub-title"> Methods: </strong> This systematic review was conducted using a search in the Embase, PubMed, and Web of Science databases. The keywords "nesfatin-<em>1</em>" combined with "receptor", "signaling", "distribution", "pathway", g- protein coupled receptor", and "binding" were used to identify all relevant articles reporting about potential nesfatin-<em>1</em> signaling and the assumed mediation <i>via</i> a G_i protein-coupled receptor.

<strong class="sub-title"> Results: </strong> Finally, <em>1</em>,<em>1</em>47 articles were found, of which <em>1</em>,077 were excluded in several steps of screening, 70 articles were included in this systematic review. Inclusion criteria were studies investigating nesfatin-<em>1</em>'s putative receptor or signaling cascade, observational preclinical and clinical studies, experimental studies, registry-based studies, cohort studies, population-based studies, and studies in English language. After screening for eligibility, the studies were assigned to the following subtopics and discussed regarding intracellular signaling of nesfatin-<em>1</em> including the potential receptor mediating these effects and downstream signaling of the peptide.

<strong class="sub-title"> Conclusion: </strong> The present review sheds light on the various effects of nesfatin-<em>1</em> by influencing several intracellular signaling pathways and downstream cascades, including the peptide's influence on various hormones and their receptors. These data point towards mediation <i>via</i> a G_i protein-coupled receptor. Nonetheless, the identification of the nesfatin-<em>1</em> receptor will enable us to better investigate the exact mediating mechanisms underlying the different effects of the peptide along with the development of agonists and antagonists.

<strong class="sub-title"> Keywords: </strong> NUCB2; food intake; gut-brain axis; nesfatin-<em>1</em>; nucleobindin-2; stress.