Nesfatin-1 regulates the phenotype transition of cavernous smooth muscle cells by activating PI3K/AKT/mTOR signaling pathway to improve diabetic erectile dysfunction.

OBJECTIVE: This study aims to explore the impact of Nesfatin-1 on type 2 diabetic erectile dysfunction (T2DMED) and its underlying mechanism in regulating the phenotypic switching of corpus cavernosum smooth muscle cells (CCSMCs). METHODS: Twenty-four 4-week-old male C57 wild-type mice were randomly assigned to the control group, model group, and Nesfatin-1 treatment group. Monitoring included body weight, blood glucose levels, and penile cavernous pressure (ICP). Histochemistry and Western blot analyses were conducted to assess the expressions of α-SMA, OPN, and factors related to the PI3K/AKT/mTOR signaling pathway. CCSMCs were categorized into the control group, high glucose and high oleic acid group (GO group), Nesfatin-1 treatment group (GO+N group), sildenafil positive control group (GO+S group), and PI3K inhibitor group (GO+N+E group). Changes in phenotypic markers, cell morphology, and the PI3K/AKT/mTOR signaling pathway were observed in each group. RESULTS: (1) Nesfatin-1 significantly ameliorated the body size, body weight, blood glucose, glucose tolerance, and insulin resistance in T2DMED mice. (2) Following Nesfatin-1 treatment, the ICP/MSBP ratio and the peak of the ICP curve demonstrated a significant increase. (3) Nesfatin-1 significantly enhanced smooth muscle and reduced collagen fibers in the corpus cavernosum. (4) Nesfatin-1 notably increased α-SMA expression and decreased OPN expression in CCSMCs. (5) Nesfatin-1 elevated PI3K, p-AKT/AKT, and p-mTOR/mTOR levels in penile cavernous tissue. CONCLUSIONS: Nesfatin-1 not only effectively improves body weight and blood glucose levels in diabetic mice but also enhances erectile function and regulates the phenotypic switching of corpus cavernosum smooth muscle. The potential mechanism involves Nesfatin-1 activating the PI3K/AKT/mTOR signaling pathway to induce the conversion of CCSMCs to a contractile phenotype.

Research progress on the relationship between Nesfatin-1 and glucose metabolism. / Nesfatin-1ä¸Žç³–ä»£è°¢å ³ç³»çš„ç ”ç©¶è¿›å±•.

Nesfatin-1 is a neuropeptide hormone known for its biological functions, including inhibiting food intake, regulating glucose and lipid metabolism, promoting apoptosis, and providing anti-inflammatory and anti-tumor effects. Glucose metabolism is a crucial pathway for the body's energy supply. Current research has demonstrated that Nesfatin-1 can affect glucose metabolism through various mechanisms, such as inhibiting food intake, regulating enzyme activity, and improving insulin resistance, though the findings are not entirely consistent. Investigating the relationship between Nesfatin-1 and glucose metabolism may offer new insights into the diagnosis and treatment of diseases related to glucose metabolism disorders.

Nesfatin-1 ameliorates pathological abnormalities in Drosophila hTau model of Alzheimer's disease.

In human Alzheimer's disease (AD), the aggregation of tau protein is considered a significant hallmark, along with amyloid-beta. The formation of neurofibrillary tangles due to aberrant phosphorylation of tau disrupts microtubule stability, leading to neuronal toxicity, dysfunction, and subsequent cell death. Nesfatin-1 is a neuropeptide primarily known for regulating appetite and energy homeostasis. However, the function of Nesfatin-1 in a neuroprotective role has not been investigated. In this study, we aimed to elucidate the effect of Nesfatin-1 on tau pathology using the Drosophila model system. Our findings demonstrate that Nesfatin-1 effectively mitigates the pathological phenotypes observed in Drosophila human Tau overexpression models. Nesfatin-1 overexpression rescued the neurodegenerative phenotypes in the adult fly's eye and bristle. Additionally, Nesfatin-1 improved locomotive behavior, neuromuscular junction formation, and lifespan in the hTau AD model. Moreover, Nesfatin-1 controls tauopathy by reducing the protein level of hTau. Overall, this research highlights the potential therapeutic applications of Nesfatin-1 in ameliorating the pathological features associated with Alzheimer's disease.

Nesfatin-1 mitigates calcific aortic valve disease via suppressing ferroptosis mediated by GSH/GPX4 and ZIP8/SOD2 axes.

OBJECTIVE: Calcific aortic valve disease (CAVD) predominantly affects the elderly and currently lacks effective medical treatments. Nesfatin-1, a peptide derived from the cleavage of Nucleobindin 2, has been implicated in various calcification processes, both physiological and pathological. This study explores the impact of Nesfatin-1 on the transformation of aortic valve interstitial cells (AVICs) in CAVD. METHODS AND RESULTS: In vitro experiments showed that Nesfatin-1 treatment mitigated the osteogenic differentiation of AVICs. Corresponding in vivo studies demonstrated a deceleration in the progression of CAVD. RNA-sequencing of AVICs treated with and without Nesfatin-1 highlighted an enrichment of the Ferroptosis pathway among the top pathways identified by the Kyoto Encyclopedia of Genes and Genomes analysis. Further examination confirmed increased ferroptosis in both calcified valves and osteoblast-like AVICs, with a reduction in ferroptosis following Nesfatin-1 treatment. Within the Ferroptosis pathway, ZIP8 showed the most notable modulation by Nesfatin-1. Silencing ZIP8 in AVICs increased ferroptosis and osteogenic differentiation, decreased intracellular Mn2+ concentration, and reduced the expression and activity of superoxide dismutase (SOD2). Furthermore, the silencing of SOD2 exacerbated ferroptosis and osteogenic differentiation. Nesfatin-1 treatment was found to elevate the expression of glutathione peroxidase 4 (GPX4) and levels of glutathione (GSH), as confirmed by Western blotting and GSH concentration assays. CONCLUSION: In summary, Nesfatin-1 effectively inhibits the osteogenic differentiation of AVICs by attenuating ferroptosis, primarily through the GSH/GPX4 and ZIP8/SOD2 pathways.

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.

Deciphering the dual nature of nesfatin-1: a tale of zinc ion's Janus-faced influence.

BACKGROUND: Nucleobindin-2 (Nucb2) and nesfatin-1 (N1) are widely distributed hormones that regulate numerous physiological processes, from energy homeostasis to carcinogenesis. However, the role of nesfatin-2 (N2), the second product of Nucb2 proteolytic processing, remains elusive. To elucidate the relationship between the structure and function of nesfatins, we investigated the properties of chicken and human homologs of N1, as well as a fragment of Nucb2 consisting of N1 and N2 conjoined in a head-to-tail manner (N1/2). RESULTS: Our findings indicate that Zn(II) sensing, in the case of N1, is conserved between chicken and human species. However, the data presented here reveal significant differences in the molecular features of the analyzed peptides, particularly in the presence of Zn(II). We demonstrated that Zn(II) has a Janus effect on the M30 region (a crucial anorexigenic core) of N1 and N1/2. In N1 homologs, Zn(II) binding results in the concealment of the M30 region driven by a disorder-to-order transition and adoption of the amyloid fold. In contrast, in N1/2 molecules, Zn(II) binding causes the exposure of the M30 region and its destabilization, resulting in strong exposure of the region recognized by prohormone convertases within the N1/2 molecule. CONCLUSIONS: In conclusion, we found that Zn(II) binding is conserved between chicken and human N1. However, despite the high homology of chicken and human N1, their interaction modes with Zn(II) appear to differ. Furthermore, Zn(II) binding might be essential for regulating the function of nesfatins by spatiotemporally hindering the N1 anorexigenic M30 core and concomitantly facilitating N1 release from Nucb2.

NUCB2 inhibition antagonizes osteosarcoma progression and promotes anti-tumor immunity through inactivating NUCKS1/CXCL8 axis.

The oncogenic properties of Nucleobindin2 (NUCB2) have been observed in various cancer types. Nevertheless, the precise understanding of the biological functions and regulatory mechanisms of NUCB2 in osteosarcoma remains limited. This investigation reported that NUCB2 was significantly increased upon glucose deprivation-induced metabolic stress. Elevated NUCB2 suppressed glucose deprivation-induced cell death and reactive oxygen species (ROS) increase. Depletion of NUCB2 resulted in a reduction in osteosarcoma cell proliferation as well as metastatic potential in vitro and in vivo. Mechanically, NUCB2 ablation suppressed C-X-C Motif Chemokine Ligand 8 (CXCL8) expression which then reduced programmed cell death 1 ligand 1 (PD-L1) expression and stimulated anti-tumor immunity mediated through cytotoxic T cells. Importantly, a combination of NUCB2 depletion with anti-PD-L1 treatment improved anti-tumor T-cell immunity in vivo. Moreover, we further demonstrated that NUCB2 interacted with NUCKS1 to inhibit its degradation, which is responsible for the transcriptional regulation of CXCL8 expression. Altogether, the outcome emphasizes the function of NUCB2 in osteosarcoma and indicates that NUCB2 elevates osteosarcoma progression and immunosuppressive microenvironment through the NUCKS1/CXCL8 pathway.

Spexin and nesfatin-1-expressing neurons in the male human claustrum.

Neuropeptides are involved in numerous brain activities being responsible for a wide spectrum of higher mental functions. The purpose of this concise, structural and qualitative investigation was to map the possible immunoreactivity of the novel regulatory peptides: spexin (SPX) and nesfatin-1 within the human claustrum. SPX is a newly identified peptide, a natural ligand for the galanin receptors (GALR) 2/3, with no molecular structure similarities to currently known regulatory factors. SPX seems to have multiple physiological functions, with an involvement in reproduction and food-intake regulation recently revealed in animal studies. Nesfatin-1, a second pleiotropic neuropeptide, which is a derivative of the nucleobindin-2 (NUCB-2) protein, is characterized by a wide distribution in the brain. Nesfatin-1 is a substance with a strong anorexigenic effect, playing an important role in the neuronal circuits of the hypothalamus that regulate food intake and energy homeostasis. On the other hand, nesfatin-1 may be involved in several important brain functions such as sleep, reproductive behaviour, cognitive processes, stress responses and anxiety. For the first time we detected and described a population of nesfatin-1 and SPX expressing neurons in the human claustrum using immunohistochemical and fluorescent methods. The study presents the novel identification of SPX and nesfatin-1 immunopositive neurons in the human claustrum and their assemblies show similar patterns of distribution in the whole structure.

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 3.5-GHz radiofrequency radiation on energy-regulatory hormone levels in the blood and adipose tissue.

In recent years exposure of living beings to radiofrequency radiation (RFR) emitted from wireless equipment has increased. In this study, we investigated the effects of 3.5-GHz RFR on hormones that regulate energy metabolism in the body. Twenty-eight rats were divided into four groups: healthy sham (n = 7), healthy RFR (n = 7), diabetic sham (n = 7), and diabetic RFR (n = 7). Over a month, each group spent 2 h/day in a Plexiglas carousel. The rats in the experimental group were exposed to RFR, but the sham groups were not. At the end of the experiment, blood and adipose tissues were collected from euthanized rats. Total antioxidant, total oxidant, hydrogen peroxide, ghrelin, nesfatin-1, and irisin were determined. Insulin expression in pancreatic tissues was examined by immunohistochemical analysis. Whole body specific absorption rate was 37 mW/kg. For the parameters analyzed in blood and fat, the estimated effect size varied within the ranges of 0.215-0.929 and 0.503-0.839, respectively. The blood and adipose nesfatin-1 (p = 0.002), blood and pancreatic insulin are decreased, (p = 0.001), gherelin (p = 0.020), irisin (p = 0.020), and blood glucose (p = 0.040) are increased in healthy and diabetic rats exposed to RFR. While nesfatin-1 are negatively correlated with oxidative stress, hyperglycemia and insulin, ghrelin and irisin are positively correlated with oxidative stress and hyperglycemia. Thus, RFR may have deleterious effects on energy metabolism, particularly in the presence of diabetes.

Central administered xenin induced Fos expression in nesfatin-1 neurons in rats.

Xenin is a 25-amino acid peptide identified in human gastric mucosa, which is widely expressed in peripheral and central tissues. It is known that the central or peripheral administration of xenin decreases food intake in rodents. Nesfatin-1/NUCB2 (nesfatin-1) has been identified as an anorexic neuropeptide, it is often found co-localized with many peptides in the central nervous system. After the intracerebroventricular administration of xenin on nesfain-1-like immunoreactivity (LI) neurons, we examined its effects on food intake and water intake in rats. As a result, Fos-LI neurons were observed in the organum vasculosum of the laminae terminalis (OVLT), the median preoptic nucleus (MnPO), the subfornical organ (SFO), the supraoptic nucleus (SON), the paraventricular nucleus (PVN), the arcuate nucleus (Arc), the lateral hypothalamic area (LHA), the central amygdaloid nucleus (CAN), the dorsal raphe nucleus (DR), the locus coeruleus (LC), the area postrema (AP) and the nucleus of the solitary tract (NTS). After the administration, the number of Fos-LI neurons was significantly increased in the LC and the OVLT, the MnPO, the SFO, the SON, the PVN, the Arc, the LHA, the CAN, the DR, the AP and the NTS, compared with the control group. After the administration of xenin, we conducted double immunohistochemistry for Fos and nesfatin-1, and found that the number of nesfatin-1-LI neurons expressing Fos were significantly increased in the SON, the PVN, the Arc, the LHA, the CAN, the DR, the AP and the NTS, compared with the control group. The pretreatment of nesfatin-1 antisense significantly attenuated this xenin-induced feeding suppression, while that of nesfatin-1 missense showed no improvement. These results indicate that central administered xenin may have anorexia effects associated with activated central nesfatin-1 neurons.

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.

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.

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.

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.

Circ_0000274 contributes to renal cell carcinoma progression by regulating miR-338-3p/NUCB2 axis and JAK1/STAT3 pathway.

BACKGROUND: Kidney transplant recipients (KTRs) are at increased risk of developing renal cell carcinoma (RCC). Accumulating evidence has demonstrated that circular RNAs (circRNAs) are essential players in tumor advancement. However, the functions of circ_0000274 in renal cell carcinoma (RCC) are barely explored. METHODS: The primary RCC cell lines 786-O and A498 were used in this study. Quantitative real-time polymerase chain reaction (qRT-PCR) assay was employed for the RNA levels of circ_0000274, microRNA-338-3p (miR-338-3p) and nucleobindin 2 (NUCB2). RNase R assay was conducted to analyze the feature of circ_0000274.Cell Counting Kit-8 (CCK-8) assay, colony formation assay, transwell assay, tube formation assay and flow cytometry analysis were conducted for cell viability, colony formation, metastasis, angiogenesis and apoptosis, respectively. Western blot assay was utilized for protein levels. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were adopted to analyze the associations of circ_0000274 RNA, miR-338-3p RNA and NUCB2 protein. Murine xenograft model was established to explore the function of circ_0000274 RNA in vivo. Immunohistochemistry (IHC) assay was used to analyze NUCB2 protein level in xenograft tumors. RESULTS: Compared to normal tissues and cells, circ_0000274 RNA level was elevated in RCC tissues and cells. Knockdown of circ_0000274 RNA suppressed cell viability, colony formation, metastasis and tube formation and promoted apoptosis in RCC cells in vitro. Circ_0000274 RNA sponged miR-338-3p RNA to positively regulate NUCB2 protein in RCC cells. Inhibition of miR-338-3p reversed the impacts of circ_0000274 knockdown on RCC cell malignant behaviors. MiR-338-3p RNA overexpression repressed the malignant phenotypes of RCC cells, while NUCB2 protein elevation could abrogate the effect. Moreover, circ_0000274 RNA knockdown blocked tumorigenesis in vivo. Besides, circ_0000274 RNA knockdown inactivated the JAK1/STAT3 protein signaling pathway. CONCLUSION: Circ_0000274 RNA functioned as an oncogene in RCC development by regulating miR-338-3p RNA/NUCB2 protein axis and activating the JAK1/STAT3 protein signaling pathway.

The effect of breast milk nesfatin-1 and ghrelin levels on growth in infants with SGA.

BACKGROUND: Current studies claim that peptides such as leptin, adiponectin, ghrelin, and nesfatin-1 found in breast milk may be responsible for the growth of infants. Therefore, we aimed to determine the association between breast milk total ghrelin and nesfatin-1 levels and anthropometric measurements of infants who were small for gestational age (SGA). METHODS: 20 SGA and 20 appropriate for gestational age (AGA) infants were enrolled in the study. Anthropometric measurements of infants were carried out at birth, 1st, and 4th months. In addition, total ghrelin and nesfatin-1 levels in the breast milk were concomitantly measured. RESULTS: Total ghrelin at the 4th month in breast milk waslower-level in the SGA group (p=0.015). In both groups, nesfatin-1 levels at the 4th month were lower than the values at the 1st month. Additionally, nesfatin-1 levels of SGA infants at the 4th month were higher (p=0.035). CONCLUSIONS: Breast milk total ghrelin and nesfatin-1 levels differed in both groups, and it is probably referred to the growth discrepancy of these infants during the first months of life. Furthermore, we consider that higher breast milk nesfatin-1 levels at the 4th month may be a preventive against obesity in SGA infants who have potential risk for obesity in childhood and adulthood.