Nucleobindin 2 inhibits senescence in gastric carcinoma.

Here, we focused on the role of Nucleobindin 2 (NUCB2), a multifunctional protein, in gastric carcinoma (GC) progression. NUCB2 expression was investigated in 150 GC cases (20 non-invasive (pT1) and 130 invasive (pT2/pT3/pT4) tumors) by immunohistochemistry (IHC), and in situ hybridization for detection of the mRNA in 21 cases. Using GC cell lines, we determined whether NUCB2 expression was associated with specific cellular phenotypes. In GC clinical samples, NUCB2 was transcriptionally upregulated when compared to normal tissues. High NUCB2 expression was associated with clinicopathological factors including deep tumor invasion, lymphovascular invasion, lymph node metastasis, and advanced clinical stages, and was a significant independent predictor of unfavorable progression-free survival in 150 non-invasive and invasive GC patients. Similar findings were also evident in 72 invasive GC cases in which patients received post-operative chemotherapy, but not in 58 invasive tumors from patients who did not receive the chemotherapy. In cell lines, NUCB2 knockout inhibited proliferation, susceptibility to apoptosis, and migration capability by inducting cellular senescence; this was consistent with higher proliferation and apoptotic indices in the NUCB2 IHC-high compared to NUCB2 IHC-low GC cases. NUCB2-dependent inhibition of senescence in GC engenders aggressive tumor behavior by modulating proliferation, apoptosis, and migration.

Nesfatin-1 and nesfatin-1-like peptide attenuate hepatocyte lipid accumulation and nucleobindin-1 disruption modulates lipid metabolic pathways.

Nesfatin-1 (NESF-1) has been shown to modulate lipid metabolism. We have identified a nesfatin-1-like-peptide (NLP) processed from a related precursor nucleobindin 1 (NUCB1). Here we determined if NLP, like NESF-1, regulates lipid accumulation in vitro, and tested if the disruption of nucb1 gene affects hepatic lipid metabolism genes in mice. Hepatocytes (HepG2/C3A cells) express NLP and NESF-1 and both peptides significantly reduced lipogenic enzyme mRNAs and enhanced beta-oxidation enzyme mRNAs. Lipid contents in oleic acid induced HepG2/C3A cells were attenuated by NESF-1 and NLP. The inhibitory effect on cellular lipid content was blocked by compound C, an inhibitor of AMPK. The disruption of nucb1 gene affected lipid metabolism-related enzyme mRNAs, endogenous nucb2 mRNA and AMPK phosphorylation. The lipid-lowering effects identified here highlights the potential of nucleobindins and peptides processed from them to address lipid disorders, and its possible benefits in metabolic disease management.

Nuclear Binding Protein 2/Nesfatin-1 Affects Trophoblast Cell Fusion during Placental Development via the EGFR-PLCG1-CAMK4 Pathway.

Previous studies have shown that nuclear binding protein 2 (NUCB2) is expressed in the human placenta and increases with an increase in the syncytialization of trophoblast cells. This study aimed to investigate the role of NUCB2 in the differentiation and fusion of trophectoderm cells. In this study, the expression levels of NUCB2 and E-cadherin in the placentas of rats at different gestation stages were investigated. The results showed that there was an opposite trend between the expression of placental NUCB2 and E-cadherin in rat placentas in different trimesters. When primary human trophoblast (PHT) and BeWo cells were treated with high concentrations of Nesfatin-1, the trophoblast cell syncytialization was significantly inhibited. The effects of NUCB2 knockdown in BeWo cells and Forskolin-induced syncytialization were investigated. These cells showed a significantly decreased cell fusion rate. The mechanism underlying NUCB2-regulated trophoblast cell syncytialization was explored using RNA-Seq and the results indicated that the epidermal growth factor receptor (EGFR)-phospholipase C gamma 1 (PLCG1)-calmodulin-dependent protein kinase IV (CAMK4) pathway might be involved. The results suggested that the placental expression of NUCB2 plays an important role in the fusion of trophoblasts during differentiation via the EGFR-PLCG1-CAMK4 pathway.

Effects of physical activity and exercise on Nucleobindin-2 gene expression and Nesfatin-1 concentration: A rapid review.

The aim of this rapid review is to examine the research evidence that presents the effects of physical activity and exercise on Nucleobindin-2 (NUCB2) gene expression and Nesfatin-1 concentration. Five databases (PubMed, Science Direct, Springer, Wiley, and Google Scholar) were searched for eligible studies from the earliest available date to August 2023. In human studies, Nesfatin-1 concentration either remains unchanged or increases after exercise training. It appears that higher exercise intensity and longer duration of training accentuate the increase of blood Nesfatin-1 concentration. The few human studies that have examined the acute response of exercise on Nesfatin-1 concentration from blood draws show conflicting results. There is a severe lack of biopsy studies in humans which warrants attention. All published animal studies have used the mouse model. The majority show that regular exercise training increases tissue NUCB2/Nesfatin-1. In some animal studies, where the effects of exercise on tissue Nesfatin-1 concentration has been seen as significant, there has been no significant effect of exercise on plasma Nesfatin-1 concentration. All animal studies evaluated the effect of endurance training except one which used resistance training. No animal studies have investigated the effects of acute exercise, which warrants investigation. In conclusion, human and animal studies have shown that physical training can increase NUCB2/Nesfatin-1, but research evidence examining the effect of acute exercise is in its infancy. In addition, future comparative studies are needed to compare the effects of different training protocols on NUCB2/Nesfatin-1 in humans and animals.

Role of Nucleobindin-2 in the Clinical Pathogenesis and Treatment Resistance of Glioblastoma.

Glioblastoma (GBM) stands as the most prevalent primary malignant brain tumor, typically resulting in a median survival period of approximately thirteen to fifteen months after undergoing surgery, chemotherapy, and radiotherapy. Nucleobindin-2 (NUCB2) is a protein involved in appetite regulation and energy homeostasis. In this study, we assessed the impact of NUCB2 expression on tumor progression and prognosis of GBM. We further evaluated the relationship between NUCB2 expression and the sensitivity to chemotherapy and radiotherapy in GBM cells. Additionally, we compared the survival of mice intracranially implanted with GBM cells. High NUCB2 expression was associated with poor prognosis in patients with GBM. Knockdown of NUCB2 reduced cell viability, migration ability, and invasion ability of GBM cells. Overexpression of NUCB2 resulted in reduced apoptosis following temozolomide treatment and increased levels of DNA damage repair proteins after radiotherapy. Furthermore, mice intracranially implanted with NUCB2 knockdown GBM cells exhibited longer survival compared to the control group. NUCB2 may serve as a prognostic biomarker for poor outcomes in patients with GBM. Additionally, NUCB2 not only contributes to tumor progression but also influences the sensitivity of GBM cells to chemotherapy and radiotherapy. Therefore, targeting NUCB2 protein expression may represent a novel therapeutic approach for the treatment of GBM.

Expression and correlation of COX-2 and NUCB1 in colorectal adenocarcinoma.

Objective: To investigate the expression and correlation of COX-2 and NUCB1 in colorectal adenocarcinoma and adjacent tissues. Methods: The expression of COX-2 and NUCB1 and their effects on prognosis were predicted using bioinformatics. Immunohistochemistry was used to identify the expression of two molecules in 56 cases of colorectal adenocarcinoma and the surrounding tissues. The expression of two molecules and their association with clinicopathological variables were examined using the chi-square test. The association between COX-2 and NUCB1 was investigated using the Spearman correlation test. Results: The STRING database revealed that COX-2 and NUCB1 were strongly linked. According to the UALCAN and HPA database, COX-2 was upregulated while NUCB1 was downregulated in colorectal adenocarcinoma, both at the protein and gene levels. The OS times for COX-2 and NUCB1 high expression, however, exhibited the same patterns. The rate of positive COX-2 immunohistochemical staining in cancer tissues was 69.64% (39/56), which was significantly higher than the rate in healthy tissues 28.57% (16/56). NUCB1 was expressed positively in cancer tissues at a rate of 64.29% (36/56) compared to just 19.64% (11/56) in neighboring tissues. The positive expression levels of COX-2 and NUCB1 were both closely related to clinical stage, differentiation degree, and lymphatic metastases (P < 0.05). In colorectal cancer, COX-2 and NUCB1 expression were significantly correlated (rs = 0.6312, P < 0.001). Conclusion: Both COX-2 and NUCB1 are overexpressed and significantly associated in colorectal adenocarcinoma.

Calnuc-derived nesfatin-1-like peptide is an activator of tumor cell proliferation and migration.

Calnuc (nucleobindin-1, nucb1) is a Ca2+ -binding protein involved in the etiology of many human diseases. To understand the functions of calnuc, we have identified a nesfatin-1-like peptide (NLP) in its N terminus that is proteolyzed by a convertase enzyme in the secretory granules of cells. Mutational studies confirm the presence of a proteolytic cleavage site for proprotein convertase subtilisin/kexin type 1 (PCSK1). We demonstrate that NLP regulates Gαq-mediated intracellular Ca2+ dynamics, likely via a G-protein-coupled receptor. NLP treatment to carcinoma cell lines (SCC131 cells) promotes the expression of regulators of cell cycle, proliferation, and clonogenicity by the AKT/mTOR pathway. NLP is causative of augmented migration and epithelial-mesenchymal transition (EMT), illustrating its metastatic propensity and establishing its tumor promotion ability.

NUCB2/Nesfatin-1 drives breast cancer metastasis through the up-regulation of cholesterol synthesis via the mTORC1 pathway.

BACKGROUND: Reprogramming lipid metabolism for tumor metastasis is essential in breast cancer, and NUCB2/Nesfatin-1 plays a crucial role in regulating energy metabolism. Its high expression is associated with poor prognosis in breast cancer. Here, we studied whether NUCB2/Nesfatin-1 promotes breast cancer metastasis through reprogramming cholesterol metabolism. METHODS: ELISA was employed to measure the concentration of Nesfatin-1 in the serum of breast cancer patients and the control group. Database analysis suggested that NUCB2/Nesfatin-1 might be acetylated in breast cancer, which was confirmed by treating the breast cancer cells with acetyltransferase inhibitors. Transwell migration and Matrigel invasion assays were conducted, and nude mouse lung metastasis models were established to examine the effect of NUCB2/Nesfatin-1 on breast cancer metastasis in vitro and in vivo. The Affymetrix gene expression chip results were analyzed using IPA software to identify the critical pathway induced by NUCB2/Nesfatin-1. We evaluated the effect of NUCB2/Nesfatin-1 on cholesterol biosynthesis through the mTORC1-SREBP2-HMGCR axis by utilizing mTORC1 inhibitor and rescue experiments. RESULTS: NUCB2/Nesfatin-1 was found to be overexpressed in the breast cancer patients, and its overexpression was positively correlated with poor prognosis. NUCB2 was potentially acetylated, leading to high expression in breast cancer. NUCB2/Nesfatin-1 promoted metastasis in vitro and in vivo, while Nesfatin-1 rescued impaired cell metastasis induced by NUCB2 depletion. Mechanistically, NUCB2/Nesfatin-1 upregulated cholesterol synthesis via the mTORC1 signal pathway, contributing to breast cancer migration and metastasis. CONCLUSIONS: Our findings demonstrate that the NUCB2/Nesfatin-1/mTORC1/SREBP2 signal pathway is critical in regulating cholesterol synthesis, essential for breast cancer metastasis. Thus, NUCB2/Nesfatin-1 might be utilized as a diagnostic tool and also used in cancer therapy for breast cancer in the future.

Nesfatin-1 alleviates hyperoxia-induced lung injury in newborn mice by inhibiting oxidative stress through regulating SIRT1/PGC-1α pathway.

Bronchopulmonary dysplasia (BPD) is a pulmonary disease commonly observed in premature infants and it is reported that oxidative stress is a critical induction factor in BPD and is considered as a promising target for treating BPD. Nesfatin-1 is a brain-gut peptide with inhibitory effects on food intake, which is recently evidenced to show suppressive effect on oxidative stress. The present study aims to explore the therapeutic effect and mechanism of Nesfatin-1 in BPD mice. AECIIs were extracted from newborn rats and exposed to hyperoxia for 24 h, followed by treatment with 5 and 10 nM Nesfatin-1. Declined cell viability, increased apoptotic rate, upregulated Bax, downregulated Bcl-2, increased release of ROS and MDA, and suppressed SOD activity were observed in hyperoxia-treated AECIIs, which were extremely reversed by Nesfatin-1. Newborn rats were exposed to hyperoxia, followed by treated with 10 µg/kg Nesfatin-1 and 20 µg/kg Nesfatin-1. Severe pathological changes, elevated MDA level, and declined SOD activity were observed in lung tissues of BPD mice, which were rescued by Nesfatin-1. Furthermore, the protective effect of Nesfatin-1 on hyperoxia-challenged AECIIs was abolished by silencing SIRT1. Collectively, Nesfatin-1 alleviated hyperoxia-induced lung injury in newborn mice by inhibiting oxidative stress through regulating SIRT1/PGC-1α pathway.

Nesfatin-1 regulates steroidogenesis in mouse Leydig cells.

Nesfatin-1 is a polypeptide hormone known to regulate appetite and energy metabolism and is derived from the precursor protein nucleobindin 2 (NUCB2). Recent studies have shown that nesfatin-1 is expressed in many peripheral tissues in mice, including the reproductive organs. However, its function and regulation in the testis remain unknown. In this study, we investigated the expression of Nucb2 mRNA and nesfatin-1 protein in mouse Leydig cells and the Leydig cell line, TM3 cells. We also examined whether Nucb2 mRNA expression is regulated by gonadotropins and whether exogenous nesfatin-1 affects steroidogenesis in primary Leydig cells isolated from the testis and TM3 cells. We found that Nucb2 mRNA and nesfatin-1 protein were present in primary Leydig cells and TM3 cells, and nesfatin-1 binding sites were also found in both cell types. Nucb2 mRNA expression in testis, primary Leydig cells, and TM3 cells was increased after treatment with pregnant mare's serum gonadotropin and human chorionic gonadotropin. After nesfatin-1 treatment, the expression of steroidogenesis-related enzyme genes Cyp17a1 and Hsd3b was upregulated in primary Leydig cells and TM3 cells. Our results suggest that NUCB2/nesfatin-1 expression in mouse Leydig cells may be regulated through the hypothalamic-pituitary-gonadal axis and that nesfatin-1 produced by Leydig cells may locally regulate steroidogenesis in an autocrine manner. This study provides insight into the regulation of NUCB2/nesfatin-1 expression in Leydig cells and the effect of nesfatin-1 on steroidogenesis, which may have implications for male reproductive health.

Nucleobindin-2 Mediates Transforming Growth Factor-ß1-Driven Phenotypes in Zinc Finger E-Box Binding Homeobox 1-High Uterine Carcinosarcoma.

Epithelial-mesenchymal transition is a hallmark of uterine carcinosarcoma (UCS). Here, shotgun proteomics analysis used to identify biomarkers associated with blebbistatin-mediated epithelial-mesenchymal transition in UCS indicated up-regulation of nucleobindin-2 (NUCB2) in endometrial carcinoma (Em Ca) cells. Expression of N-cadherin, Snail, Slug, and ZEB1 was reduced in NUCB2 knockout Em Ca cells, whereas ZEB1, Twist1, and vimentin were up-regulated in NUCB2-overexpressing Em Ca cells. NUCB2 knockout reduced cell proliferation and migration, whereas NUCB2 overexpression had the opposite effect. Treatment of Em Ca cells with transforming growth factor (TGF)-ß1 dramatically altered morphology toward a fibroblastic appearance; concomitantly, expression of NUCB2 and ZEB1 increased. The NUCB2 promoter was also activated by transfection of Smad2. In UCS tissues, NUCB2 expression was significantly higher in sarcomatous compared with carcinomatous components, which was consistent with increased TGF-ß1 mRNA expression in stromal and sarcomatous components compared with carcinomatous components. In addition, NUCB2 score correlated positively with ZEB1 and vimentin scores, whereas ZEB1 score correlated positively with Slug and vimentin scores and inversely with the E-cadherin score. Collectively, these data indicate that TGF-ß-dependent up-regulation of NUCB2 and ZEB1 contributes to the phenotypic characteristics of sarcomatous components in UCS.

Nesfatin-1 suppresses autophagy of chondrocytes in osteoarthritis via remodeling of cytoskeleton and inhibiting RhoA/ROCK signal pathway.

Autophagy and cytoskeleton integrity of chondrocytes are a considered as major factors in the progression of osteoarthritis (OA) involving excessive chondrocyte apoptosis and senescence. Nesfatin-1, an adipokine, has been reported to be closely related to cell autophagy and cytoskeleton malfunction. Our previous study found that nesfatin-1 was highly correlated with OA progress in OA patient, and the expression of nesfatin-1 rises in knee articular tissue, serum and chondrocytes. In current study, we aimed to explore the therapeutic effect of nesfatin-1 on OA and its molecular mechanism related to chondrocyte autophagy and cytoskeleton malfunction. We firstly demonstrated that nesfatin-1 effectively suppressed excessive autophagy of OA chondrocytes at both gene and protein levels. Meanwhile, we also found that nesfatin-1 significantly improved cytoskeleton integrity by showing higher F-actin/G-actin ratio, as well as more organized actin fiber structure. Mechanistically, utility of RhoA activator and inhibitor revealed that regulation of autophagy and cytoskeleton integrity via nesfatin-1 was realized via RhoA/ROCK pathway. We also confirmed that nesfatin-1 significantly ameliorated IL-1ß induced cartilage degeneration via destabilization of the medial meniscus (DMM) model. Overall, our study indicates that nesfatin-1 might be a promising therapeutic molecule for OA intervention.

Circulating Levels of Nesfatin-1 and Spexin in Children with Prader-Willi Syndrome during Growth Hormone Treatment and Dietary Intervention.

BACKGROUND: Despite observable improvement in the treatment outcomes of patients with Prader-Willi syndrome (PWS), adequate weight control is still a clinical problem. Therefore, the aim of this study was to analyze the profiles of neuroendocrine peptides regulating appetite-mainly nesfatin-1 and spexin-in children with PWS undergoing growth hormone treatment and reduced energy intake. METHODS: Twenty-five non-obese children (aged 2-12 years) with PWS and 30 healthy children of the same age following an unrestricted age-appropriate diet were examined. Serum concentrations of nesfatin-1, spexin, leptin, leptin receptor, total adiponectin, high molecular weight adiponectin, proinsulin, insulin-like growth factor-I, and total and functional IGF-binding protein-3 concentrations were determined using immunoenzymatic methods. RESULTS: The daily energy intake in children with PWS was lower by about 30% (p < 0.001) compared with the controls. Daily protein intake was similar in both groups, but carbohydrate and fat intakes were significantly lower in the patient group than the controls (p < 0.001). Similar values for nesfatin-1 in the PWS subgroup with BMI Z-score < -0.5 and the control group, while higher values in the PWS subgroup with BMI Z-score ≥ -0.5 (p < 0.001) were found. Spexin concentrations were significantly lower in both subgroups with PWS than the controls (p < 0.001; p = 0.005). Significant differences in the lipid profile between the PWS subgroups and the controls were also observed. Nesfatin-1 and leptin were positively related with BMI (p = 0.018; p = 0.001, respectively) and BMI Z-score (p = 0.031; p = 0.027, respectively) in the whole group with PWS. Both neuropeptides also correlated positively in these patients (p = 0.042). CONCLUSIONS: Altered profiles of anorexigenic peptides-especially nesfatin-1 and spexin-in non-obese children with Prader-Willi syndrome during growth hormone treatment and reduced energy intake were found. These differences may play a role in the etiology of metabolic disorders in Prader-Willi syndrome despite the applied therapy.

Expression of phoenixin-14 and nesfatin-1 in the hypothalamo-pituitary-gonadal axis in the phases of the estrous cycle.

Phoenixin-14 (PNX-14) and nucleobindin 2 (NUCB2)/nesfatin-1 are regulatory neuropeptides expressed in the hypothalamus. These neuropeptides can be effective in hormonal regulation of the hypothalamo-pituitary-gonadal (HPG) axis and reproductive functions. In the present study, the distribution of PNX-14 and NUCB2/nesfatin-1 in the hypothalamus, pituitary, ovary, and uterus tissues during the phases of the estrous cycle in female rats was investigated. Eighteen Wistar Albino rats determined among animals showing regular estrous cycle by vaginal smear method were divided into three groups: proestrus (Group I), estrus (Group II) and diestrus (Group III). Serum gonadotropin-releasing hormone (GnRH), plasma PNX-14, and NUCB2/nesfatin-1 concentrations were the highest, moderate, and lowest in estrus, diestrus, and proestrus phases, respectively. PNX-14 immunoreactivity in the supraoptic and arcuate nuclei of the hypothalamus and NUCB2/nesfatin-1 immunoreactivity in the paraventricular nuclei were particularly evident in the estrus phase. These neuropeptide immunoreactivities were decreased in different cells of anterior pituitary during proestrus compared with those during estrus and diestrus. PNX-14 immunoreactivity in the ovary, especially during the estrus phase, was diffuse and intense in the granulosa and luteal cells and oocytes, and it was few and weak in theca cells. In addition, NUCB2/nesfatin-1 immunoreactivity was abundant and strong in granulosa and luteal cells, theca and interstitial cells, and oocytes during estrus. In the estrus phase, PNX-14 immunoreactivity was strong in the glandular epithelial cells and stromal cells of the endometrium, also NUCB2/nesfatin-1 immunoreactivity was strong in the epithelial and glandular epithelial cells. As a result, when the estrous cycle was evaluated, it was concluded that the changes in the distribution of PNX-14 and NUCB2/nesfatin-1 at all phases were related to GnRH and that these neuropeptides showed the highest immunoreactivity especially in the HPG axis and uterus tissues of estrus rats.

Blood nesfatin-1 levels in patients with polycystic ovary syndrome: a systematic review and meta-analysis.

Background: Previous studies have investigated the relationship between nesfatin-1 level and polycystic ovary syndrome (PCOS). However, these studies have produced conflicting results. Thus, in this meta-analysis, we aimed to clarify the association between blood nesfatin-1 levels and PCOS, and the ability of nesfatin-1 as a biomarker in PCOS. Methods: Meta-analysis was performed using STATA 12.0 software. We computed standard mean difference (SMD) and 95% confidence interval (CI) regarding the comparison of blood nesfatin-1 in patients with PCOS and controls. Results: The present meta-analysis showed no significant difference in blood nesfatin-1 level between patients with PCOS and controls with a random effects model (SMD = 0.03; 95%CI: -0.71, 0.77; I2 = 97.1%, p value for Q test < 0.001). Subgroup analysis for different ethnicities reported no significant difference in blood nesfatin-1 level between patients with PCOS and controls in both Caucasian and Asian populations. Subgroup analysis for different sample types reported no significant difference in serum nesfatin-1 level between patients with PCOS and controls. Subgroup studies reported no significant difference in blood nesfatin-1 level between PCOS and controls in both obese and non-obese populations. Conclusion: In conclusion, there is no significant relationship between blood nesfatin-1 levels and PCOS.

Does one plus one always equal two? Structural differences between nesfatin-1, -2, and nesfatin-1/2.

Nesfatin-1 and -2 are produced from a reaction in which the N-terminus of human Nucleobindin-2 undergoes proteolytical processing. To date, Nucleobindin-2 and/or nesfatin-1 have only been shown to act as peptide hormones. On the other hand, the purpose of nesfatin-2 remains unknown. Since Nucleobindin-2/nesfatin-1 is thought impact the control of a wide range of physiological processes, including energy homeostasis, neurodegenerative processes and carcinogenesis, its ligands/interactions deserve special studies and attention. However, there are no reports about the molecular properties of the proteolytical products of human Nucleobindin-2 in the literature. Hence, this study aimed to analyze the effect of Zn(II) and Ca(II) on human nesfatin-1, -2, and -1/2 structures. Herein, we report that human nesfatin-1 is a member of the intrinsically disordered protein family, as indicated by circular dichroism and analytical ultracentrifugation experiments. In contrast, we found that the human nesfatin-2 and nesfatin-1/2 structures were globular with intrinsically disordered regions. Under Zn(II) treatment, we observed concentration-dependent structurization and compaction of intrinsically disordered nesfatin-1 and its propensity for oligomerization, as well as destabilization of both nesfatin-2 and nesfatin-1/2. Furthermore, dissociation constants for Zn(II) binding by nesfatin-1, nesfatin-2, and nesfatin-1/2 were also reported. Moreover, structurally distinct nesfatin-1 and -2 seem to be interdependent when linked together, as indicated by the observed molecular properties of nesfatin-1/2, which in turn are not a simple sum of the properties exhibited by the former peptides. Thus, herein, we shed new light on the molecular behavior of human nesfatins, which might help to elucidate the complex function of those peptides. Video abstract.

The protective effects of nesfatin-1 in neurological dysfunction after spinal cord injury by inhibiting neuroinflammation.

AIMS: Spinal cord injury (SCI) is one of the most severe neurological diseases. However, there is still no effective treatment for it. Nesfatin, a precursor neuropeptide derived from nucleobindin 2 (NUCB2), has displayed a wide range of protective effects in different types of cells and tissue. However, the effects of nesfatin-1 in SCI have not been reported before. MATERIALS AND METHODS: A SCI model was established. The behavior of mice was assessed using the Basso, Beattie, and Bresnahan (BBB) assessment. RESULTS: Here, we report that the administration of nesfatin-1 improved neurological recovery in SCI mice by increasing BBB scores, reducing lesion area volume and spinal cord water content. Also, nesfatin-1 ameliorated oxidative stress by reducing reactive oxygen species (ROS) levels and increasing superoxide dismutase (SOD) activity. We also found that nesfatin-1 prevented neuronal apoptosis in SCI mice by reducing caspase 3 activity and the expression of Bax, as well as increasing B-cell lymphoma-2 (Bcl-2). Additionally, nesfatin-1 reduced the levels of interleukin 6 (IL-6), interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α). Nesfatin-1 also promoted microglia towards M2 polarization by increasing the marker CD206 but reducing CD16. Importantly, nesfatin-1 enhanced the phosphorylation of signal transducer and activator of transcription 1 (STAT1) but reduced the expression levels of toll-like receptor 4 (TLR4) and phosphorylated nuclear factor kappa-B p65 (p-NF-κB p65). CONCLUSION: Our findings imply that nesfatin-1 exerts neuroprotective actions in SCI by promoting the activation of M2 microglia, and its underlying mechanisms might be related to the activation of STAT1 and inhibition of the TLR4/NF-κB signaling pathway.

Influence of circulating nesfatin-1, GSH and SOD on insulin secretion in the development of T2DM.

Aims: To evaluate the correlation of nesfatin-1, GSH and SOD levels with ß-cell insulin secretion and their influence on insulin secretion in the development of type 2 diabetes mellitus (T2DM). Materials and methods: 75 patients with T2DM, 67 with prediabetes and 37 heathy participants were recruited in this study. Serum levels of nesfatin-1, GSH and SOD were quantified and statistically analyzed. Results: The levels of nesfatin-1, GSH and SOD in T2DM were significantly decreased (P < 0.001) compared to either in prediabetes or in healthy control, and significant reduction of these biomarkers was also observed in prediabetes when compared to the control (P < 0.001). Circulating nesfatin-1, GSH and SOD were not only strongly correlated with ß-cell insulin secretion, but also exerted remarkable influence on the secretion. Conclusion: Serum nesfatin-1, GSH and SOD are important factors involving insulin secretion in the development of T2DM, which may help provide new ideas for forthcoming investigations on the roles of these factors in pathogenesis of T2DM, as well as for active prediction and prevention of prediabetes before it develops into overt T2DM.

Nucleobindin-2/nesfatin-1 enhances the cell proliferation, migration, invasion and epithelial-mesenchymal transition in gastric carcinoma.

Nesfatin-1, a newly discovered adipokine derived from nucleobindin-2 (NUCB2), has been described as a new prognostic marker in cancers. This study aimed to explore the functional role of NUCB2/nesfatin-1 in the cell proliferation, migration and invasion in gastric carcinoma (GC). The expressions of NUCB2/nesfatin-1 in GC tissues and normal adjacent tissues (NATs) were compared, and the effect of inhibition of NUCB2/nesfatin-1 on the cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) in GC cell line SGC-7901 was investigated. Cell transfection was conducted to inhibit NUCB2/nesfatin-1 by short hairpin RNA. Cell proliferation, migration and invasion abilities were determined using cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), wound healing and transwell assays, respectively. The expressions of EMT markers E-Cadherin and N-Cadherin were determined using western blotting. The expression of NUCB2/nesfatin-1 protein in GC tissues was significantly increased compared with that in NATs. Consistently, the serum concentrations of NUCB2/nesfatin-1 were significantly higher in patients with GC as compared with those in the control group. Moreover, the results of CCK-8 assay and EdU assay indicated that knockdown of NUCB2/nesfatin-1 could markedly decrease SGC-7901 proliferation. Furthermore, the results of wound healing assay and transwell assay demonstrated that knockdown of NUCB2/nesfatin-1 significantly suppressed SGC-7901 migration and invasion abilities. Additionally, knockdown of NUCB2/nesfatin-1 decreased the expressions of N-Cadherin and increased the expressions of E-Cadherin in SGC-7901 cells. These findings suggest that knockdown of NUCB2/nesfatin-1 suppressed the proliferation, migration, invasion and EMT of SGC-7901 cells, suggesting a potentially promising therapeutic target for GC.

Nesfatin-1 alleviated lipopolysaccharide-induced acute lung injury through regulating inflammatory response associated with macrophages modulation.

Acute lung injury (ALI) is a continuum of lung changes associated with uncontrolled excessive lung inflammation. However, the pathogenesis of ALI is still complicated and effective clinical pharmacological management is required. Various signaling pathways are involved in the inflammatory responses of ALI. Here, we aimed to explore the role of nesfatin-1, an amino-acid peptide with anti-inflammatory action, in an LPS-induced ALI mice model, and its role in regulating macrophages in response to LPS stimulation in vitro. This was to clarify the underlying mechanisms of regulating the inflammatory response in the development of ALI. The results show that nesfatin-1 expression was downregulated in the lung tissues of ALI mice compared to control mice. Nesfatin-1 treatment ameliorated the inflammatory response and lung tissue damage in LPS-induced ALI in mice. In vitro studies showed that nesfatin-1 attenuated the generation and release of proinflammatory cytokines interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) in LPS-induced RAW 264.7 cells. Nesfatin-1 also inhibited reactive oxygen species production and improved superoxide dismutase (SOD) activity in LPS-induced RAW 264.7 cells. These findings suggest that nesfatin-1 exerted a crucial role in regulating the LPS-mediated activation of M1 macrophages. Further mechanism investigations indicated that nesfatin-1 inhibited the activation of p38 MAPK/c-Jun and NF-κB pathways in LPS-induced RAW 264.7 cells, as evidenced by decreased expression levels of p-p38, p-c-Fos, and p-p65. Overall, nesfatin-1 alleviated LPS-induced ALI, which might be attributed to regulating inflammatory response through macrophages modulation.