Nesfatin-1: A Novel Diagnostic and Prognostic Biomarker in Digestive Diseases
Abstract
:1. Introduction
2. Implication of Nesfatin-1 in Multiple Disorders
3. Implication of Nesfatin-1 in Digestive Disorders
3.1. Gastric Ulcer
3.2. Gastric Cancer
3.3. Necrotizing Enterocolitis
3.4. Mesenteric Ischemia
3.5. Colitis
3.6. Pancreatitis
3.7. Cholecystitis
3.8. Obstructive Jaundice
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Pathway | Study Type | Description of the Pathway/Effect | Conclusion | Citation |
---|---|---|---|---|
AMPK | Animal models: C57BL/6J mice with induced hepatic steatosis Hepatocyte cultures | Decreased lipogenesis transcription factors PPARγ and SREBP1 In cultured hepatocytes, it stimulates AMPK phosphorylation | Reduces the accumulation of lipids in the liver | Yin et al., 2015 [23] |
Animal model: Male Kunming SPF mice with high-calorie diet + 2 Streptozotocin doses to induce type 2 Diabetes Mellitus | Lowered food intake, insulin resistance coefficient, and blood glucose Nesfatin-1 in low doses stimulates the AMPK-ACC pathway and activates free fatty acid utilization | Inhibits free fatty acid production and stimulates their oxidation | Dong et al., 2013 [24] | |
Human colon cancer samples SW480 and SW620 cancer cell lines | In colon cancer tissue samples and SW480 and SW620 cancer cell lines: increased nesfatin-1 expression Nesfatin-1 activated LKB1/AMPK/TORC1/ZEB1 pathway in vivo and in vitro | Nesfatin-1/NUCB2 promotes migration and invasion in colon cancer | Kan et al., 2016 [25] | |
Animal model: male Sprague-Dawley rats on normal or a high-fat diet | Activation of AKT/AMPK/TORC2, insulin receptor, and insulin substrate 1 phosphorylation Inhibition of hepatic gluconeogenesis and increased glucose uptake in the muscle | Nesfatin-1 increases insulin peripheral uptake and decreases production of glucose in the liver | Yang et al., 2012 [26] | |
ERK/MAPK | Human gastrointestinal smooth muscle cells (HGSMC) | Up-regulates eNOS activity by involving the ERK/MAPK/mTOR cascade Increases some pro-apoptosis factors (p53 and Fas) | Nesfatin-1 accelerates the apoptosis rate in HGSMC | Tan et al., 2016 [27] |
Rats | Decreases the expression of brain-derived neurotrophic factor (BDNF) and of phosphorylated ERK in the prefrontal cortex and the hippocampus | Nesfatin-1 induces anxiety-like behavior in rats | Ge et al., 2015 [28] | |
Male Wistar rats and Zucker fatty rats | Increase in p-ERK1/2 positive neurons in the paraventricular hypothalamic nucleus Increased co-expression in the corticotropin-releasing hormone cells Activation of sympathetic activity in the kidney, liver, and white adipose tissue Hypertensive effects | Nesfatin-1 regulates the autonomic nervous system | Tanida et al., 2015 [29] | |
Human SH-SY5Y neuroblastoma cells | Stimulates the protein expression of synapsin-1, p-ERK1/2, and CRH | Nesfatin-1 could be involved in the hypothalamic–pituitary–adrenal axis and in synaptic plasticity | Chen et al., 2018 [30] | |
Melanocortin pathway | Adult male Wistar rats | Enhances the excitability of glucose-sensitive neurons in the lateral parabrachial nucleus Weight loss and increased the expression of uncoupling protein 1 (UCP1) in brown adipose tissue in chronic administration | Nesfatin-1 inhibits food intake and regulates body weight | Yuan et al., 2017 [31] |
Adult male Harlan Sprague-Dawley rats | Nesfatin-1 increases mean arterial pressure | Nesfatin-1 stimulates sympathetic activity | Yosten et al., 2009 [32] | |
Ventricular myocytes from adult male Wistar rats | Treatment with nesfatin-1 inhibited L-type Ca2+ channels in cardiomyocytes | Nesfatin-1 modulates cardiac performance | Ying et al., 2015 [33] | |
AKT | Wistar rats with isoproterenol-induced myocardial infarction | Nesfatin-1 increases p-GSK-3β/GSK-3β and p-Akt/Akt expression in the myocardium Nesfatin-1 decreases the levels of troponin-T and proinflammatory cytokines Reduces the apoptotic and necrotic cells | Nesfatin-1 has cardioprotective activity against myocardial infarction | Tasatargil et al., 2017 [34] |
Wistar–Kyoto rats Human aortic vascular smooth muscle cells (VSMCs) | Nesfatin-1 activates PI3K/Akt/mTOR and JAK2/STAT pathways induces VSMCs proliferation and phenotypic transformation Down-regulation of the nesfatin-1 gene inhibited cardiovascular remodeling | Nesfatin-1 is involved in vascular remodeling and hypertension by regulating VSMC proliferation | Lu et al., 2018 [35] | |
Sprague-Dawley rats, C57BL/6J mice, and high-fat-diet-induced obese mice Myocytes, hepatocytes, and adipose cells isolated from C57BL/6J mice | Nesfatin-1 increased insulin secretion in vivo and in min6 cells via AKT phosphorylation Nesfatin-1 up-regulated the phosphorylation of AKT in adipose tissue, skeletal muscle, and liver in the mice that received a high-fat diet Nesfatin-1 promotes GLUT4 translocation in the adipose tissue and in the skeletal muscle irrespective of the diet (high-fat or normal diet) | Nesfatin-1 increases the secretion of insulin and the sensitivity to insulin in peripheral tissues | Li et al., 2013 [36] | |
CRF pathway | Adult male Wistar rats | Nesfatin-1 inhibits excitatory neurons involved in gastric distention Nesfatin-1 stimulates the inhibitory gastric distention neurons in the ventromedial hypothalamic nucleus | Nesfatin-1 has implications for digestive disorders and obesity | Feng et al., 2017 [37] |
Adult male Sprague-Dawley rats | Nesfatin-1 decreased dark-phase food intake in case of intracerebral administration, with no effect after ip administration | Nesfatin-1 is involved in the central regulation of food intake | Stengel et al., 2009 [38] | |
Ion currents | Hypothalamic neuronal cultures from Sprague-Dawley rats | Nesfatin-1 increased intracellular Ca2+ concentrations in hypothalamic neurons | Nesfatin-1 increases calcium influx in hypothalamic neurons via a G protein-coupled receptor | Brailoiu et al., 2007 [22] |
Beta cells from ICR mice | Nesfatin-1 increases the Ca2+ influx in pancreatic beta cells through the L-type Ca2+ channels after treatment with glucose | Nesfatin-1 stimulates the release of insulin from beta islet cells in a glucose-dependent manner | Nakata et al., 2011 [39] | |
Islet cells from male C57BL/6J mice | Nesfatin-1 inhibits the activity of the Kv channels that stimulate insulin secretion | Nesfatin-1 increases the release of insulin from beta islet cells via the inhibition of Kv channels | Maejima et al., 2017 [40] | |
Heart samples from Wistar albino rats | The expression level of the α1c subunit protein of the L-type Ca2+ channels in cardiac extracts was elevated in the rats subjected to chronic restraint stress | Nesfatin-1 may be involved in cardiac failure | Ayada et al., 2015 [41] | |
NO-cGMP system | Mesenteric artery isolated from Wistar rats | Nesfatin-1 impairs the production of SNP-induced cGMP, which leads to reduced smooth muscle relaxation | Nesfatin-1 regulates blood pressure by modulating peripheral arterial resistance | Yamawaki et al., 2012 [42] |
Heart samples from Wistar rats | Nesfatin-1 recruits specific GC-receptors (NPR-A—natriuretic peptide receptor A) activating the ERK1/2 and protein kinase G pathways Pretreatment decreases the size of the infarct and lactate dehydrogenase levels | Nesfatin-1 has negative inotropic and lusitropic effects and modulates heart activity Nesfatin-1 protects against ischemia/reperfusion injury | Angelone et al., 2013 [43] |
Group of Disorder | Disease/Process | Type of Study | Observations | Conclusion | First Author and Year |
---|---|---|---|---|---|
Neurological disorders | Alzheimer’s disease (AD) | Animal model: Drosophila melanogaster | Nesfatin-1 reduces the neurodegenerative process in the eye and bristle of AD-induced models Nesfatin-1 regulates neuromuscular activity Nesfatin-1 reduces the levels of human Tau protein, particularly phospho-tau | Nesfatin-1 impedes neurodegeneration | Yang et al., 2024 [61] |
Parkinson’s disease | C57BL/6 mice | Anti-nesfatin-1 antibody in the lateral ventricle led to: Reduction in the nesfatin-1 level of the cerebrospinal fluid ROS production and depletion of intraneuronal mitochondria Increased membrane permeability, cytochrome c leakage, caspase-3 induced apoptosis | Dopaminergic neuronal depletion is closely correlated with a reduced level of nesfatin-1 in the cerebrospinal fluid | Chen et al., 2021 [62] | |
Subarachnoid hemorrhage | Case-control study | Nesfatin-1 levels were increased in the subarachnoid hemorrhage group compared to healthy controls Nesfatin-1 levels positively correlate with the presence, number, and size of the aneurysm | Potential role of nesfatin-1 as a predictive biomarker for acute subarachnoid hemorrhage and the existence of aneurysms | Acik et al., 2020 [63] | |
Endocrine and metabolic disorders | Ischemic stroke | Case-control study | Nesfatin-1 levels were lower in the ischemic stroke group in comparison to controls No significant association between nesfatin-1 levels and the severity of ischemic stroke | Nesfatin-1 may play a role in the pathogenesis of ischemic stroke | Kazimierczak-Kabzińska et al., 2020 [64] |
Feeding Behavior/Obesity | Male Sprague-Dawley rats | Nesfatin-1 decreases food ingestion by reducing the meal size not frequency or the intervals between meals Increase in satiation (size of a meal) under normal weight conditions Increase in satiety (frequency of meals) under diet-induced obesity conditions | Nesfatin-1 has anorexigenic effects | Carr et al., 2015 [65] | |
Case-control study | High nesfatin-1 levels in the patients under hemodialysis vs. healthy subjects Significant positive correlation between nesfatin-1 levels and malnutrition inflammation score and the increased interleukin-6 levels Significant negative correlation with body mass index (BMI) | Nesfatin-1 is associated with the nutritional status in end-stage renal disease | Elthakaby et al., 2022 [66] | ||
Case-control study | Higher serum nesfatin-1 levels in the obese group Nesfatin-1 positively correlates with copeptin, serum insulin level, and homeostasis model assessment of insulin resistance | Nesfatin-1 might be involved in the appearance of insulin resistance Nesfatin-1 regulates food intake | Yin et al., 2020 [67] | ||
Case-control study | Lower nesfatin-1 level in the metabolic-associated fatty liver disease (MAFLD) group Nesfatin-1 correlated negatively with high-sensitivity-C reactive protein (hs-CRP), alanine aminotransferase, and fasting glucose | Nesfatin-1 could be a new diagnostic biomarker for MAFLD | Afifi et al., 2024 [68] | ||
Diabetes Mellitus | Case-control study | Nesfatin-1 levels are significantly lower in the healthy obese and diabetic group in comparison to healthy individuals, being the highest in the underweight group | Nesfatin-1 may be part of the common pathogenetic pathway between diabetes and obesity | Samani et al., 2019 [69] | |
3T3-L1 mouse adipocytes Human adipocytes (omental visceral adipose tissue) | Nesfatin-1 expression was increased in hypoxic murine adipocytes Nesfatin-1 was highly detectable in the visceral adipose tissue of obese subjects vs. controls Nesfatin-1 levels correlated with binge eating, sweets craving, and hyperphagic behavior | Nesfatin-1 may be an indicator of eating disorders in obese patients | Caroleo et al., 2023 [70] | ||
Case-control study | Serum nesfatin-1 level was the highest in the patients with diabetes mellitus type 2 (DMT2) Higher nesfatin-1 level DMT2 and pre-diabetic patients vs. controls Nesfatin-1 positively correlated with glucose, insulin resistance, and lipid profile parameters | Nesfatin-1 could be a predictor biomarker for pre-diabetes and DMT2 | Matta et al., 2022 [58] | ||
Case-control study | Higher serum nesfatin-1 levels in gestational diabetes mellitus patients Nesfatin-1 is associated with blood glucose, HOMA-IR. and high-density lipoprotein cholesterol (HDL-C) | Nesfatin-1 has diagnostic value for gestational diabetes | Jiang et al., 2020 [71] | ||
Case-control study | Lower nesfatin-1 levels in the gestational diabetes mellitus group | Nesfatin-1 is an alternative screening method to the conventional oral glucose tolerance test (OGTT) | Çaltekin et al., 2021 [72] | ||
Polycystic ovary syndrome (PCOS) | Case-control study | Higher nesfatin-1 levels in PCOS patients Normal nesfatin-1 levels after treatment with Metformin | Nesfatin-1 can be a diagnostic biomarker for PCOS Nesfatin-1 levels can indicate the response to treatment | Mahmood et al., 2023 [73] | |
Case-control study | Lower nesfatin-1 levels in PCOS patients Negative correlations between nesfatin-1 levels, visceral adiposity index, BMI, HOMA-IR, and triglyceride levels | Low nesfatin-1 levels may play an important role in the pathogenesis of PCOS | Çaltekin et al., 2021 [74] | ||
Cardiovascular disorders | Ischemia/reperfusion injury | C57BL/6 mice H9c2 cardiomyocytes | Ischemia led to down-regulation of NUCB2 transcription with low nesfatin-1 levels Wortmannin (inhibitor of Akt/ERK pathway) abolished the beneficial effects of nesfatin-1 Activation of the Akt/ERK pathway reduces endoplasmic reticulum stress | Nesfatin-1 attenuates ischemia-reperfusion stress | Su et al., 2021 [75] |
Myocardial infarction, angina pectoris | Adult male Wistar rats | Restoration of SOD and the GSH content by nesfatin-1 Nesfatin-1 inhibited autophagy and apoptosis (reduction of caspase 3 and Bax) | Nesfatin-1 could be used to treat myocardial infarction | Naseroleslami et al., 2020 [76] | |
Case-control study | Significantly lower nesfatin-1 levels in stable-angina pectoris and acute-myocardial infarction patients No significant difference between the stable-angina pectoris group and the acute-myocardial infarction group Negative correlation between nesfatin-1 low-density lipoproteins, coronary atherosclerosis status (Gensini score), troponin T, and creatine kinase-MB | Nesfatin-1 is involved in the pathogenesis of atherosclerosis and myocardial infarction | Nejati et al., 2021 [77] | ||
Coronary artery disease (CAD) | Case-control study | Low nesfatin-1 levels in the CAD groups (stable chronic CAD and unstable angina) vs. controls Nesfatin-1 correlated negatively with the Gensini score used to quantify the severity of CAD Nesfatin-1 is closely associated with high-sensitivity-C reactive protein (hsCRP) levels | Nesfatin-1 is negatively associated with the presence and severity of CAD | Kadoglou et al., 2021 [78] | |
Normotension, Hypotension | Male Sprague-Dawley rats | Nesfatin-1 increases catecholamine, vasopressin, and renin concentrations Significant increase in the mean arterial pressure in both normotensive and hypotensive rats | Nesfatin-1 has pressor effects and regulates sympathetic activity | Yilmaz et al., 2015 [79] | |
Rheumatologic disorders | Rheumatoid arthritis (RA) | Case-control study | Positive relationship between nesfatin-1, IL-1β, and TNF-alfa levels in synovium and synovial fluid samples Nesfatin-1 synovial levels correlated positively with rheumatoid factor Nesfatin-1 has a sensibility of 77.5% and a specificity of 60% in differentiating patients with RA from healthy individuals | Synovial nesfatin-1 is involved in the inflammatory process in RA and correlates with the severity of the disease | Zhang et al., 2021 [80] |
Case-control study | Nesfatin-1 serum level was higher in the RA group High nesfatin-1 level correlates with CRP and N-terminal propeptide of type I procollagen (P1NP), a biomarker of the formation of bone matrix | Nesfatin-1 might regulate the function of osteoblasts in RA patients | Seewordova et al., 2022 [81] | ||
Synovial fibroblasts from patients with RA | Higher expression of NUCB2 mRNA in the synovium in the patients with RA The high expression of NUCB2 correlated with other genes controlling DNA replication, intercellular adhesion, and the interaction with the surrounding extracellular matrix | Nesfatin-1 is involved in the pathogenesis and progression of RA | Zhang et al., 2022 [82] | ||
Reproductive disorders | Testicular function | Mice testis | Nesfatin-1 had an increased stimulatory role in testosterone production Nesfatin-1 increased intratesticular glucose transport It accelerated cell proliferation and decreased apoptosis; higher sperm production | Nesfatin-1 regulates testicular function | Ranjan et al., 2019 [83] |
Puberty | Male parks strain mice Testes from pre-pubertal mice | Nesfatin-1 facilitated GnRH-R expression, the production of steroid hormones, spermatogenic biomarkers (Bcl2, PCNA), glucose-metabolism-related proteins (GLUT8, insulin receptor) | Nesfatin-1 facilitates spermatogenesis and steroidogenesis Nesfatin-1 promotes pubertal transition | Ranjan et al., 2019 [84] | |
Testicular torsion | Male Sprague-Dawley rats | Nesfatin-1 induced a lower percentage of spermatozoa with head defects and lower levels of pro-inflammatory cytokines: TNF-α, IL-6, caspase-3 | Nesfatin-1 prevents the degeneration of spermatogenic cells induced by torsion | Arabaci et al., 2018 [85] | |
Pregnancy/Abortion | CBA⁄j female mice, BALB⁄c male mice, and DBA⁄2 male mice | The level of nesfatin-1 was higher in the uteri of the abortion animals The expression in the uterus might be down-regulated by cytokines and chemokines in pregnancy | Nesfatin-1 expression might be involved in the maintenance of pregnancy | Chung et al., 2017 [86] | |
Other diseases | Acute lung injury (ALI) | Mice BEAS-2B human alveolar epithelial cell line | Administration of nesfatin-1 reduced oxidative stress and inflammation both in mouse lung tissue and BEAS-2B cells Nesfatin-1 inhibits inflammatory pathways downstream of HMGB-1 | Nesfatin-1 ameliorates inflammation in ALI | Wang et al., 2020 [87] |
Osteoarthritis (OA) | Sprague-Dawley rats | Nesfatin-1 inhibits MAPK, the IL-1β activation of NF-kB and Bax/Bcl-2 signaling pathways in chondrocytes Nesfatin-1 has anti-inflammatory functions and reduces the levels of MMPs, caspase-3, COX-2, and IL-6 | Nesfatin-1 has a protective role in OA | Jiang et al., 2020 [88] | |
Depression | Case-control study | Nesfatin-1 serum levels significantly higher in adolescents with major depressive disorders Positive correlation between nesfatin-1 levels and Hamilton Depression Rating Scale (HAMD-17) used to assess the severity of the disorder | Nesfatin-1 may be a diagnostic and disease-severity biomarker for depression | Sun et al., 2023 [89] |
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Damian-Buda, A.-C.; Matei, D.M.; Ciobanu, L.; Damian-Buda, D.-Z.; Pop, R.M.; Buzoianu, A.D.; Bocsan, I.C. Nesfatin-1: A Novel Diagnostic and Prognostic Biomarker in Digestive Diseases. Biomedicines 2024, 12, 1913. https://doi.org/10.3390/biomedicines12081913
Damian-Buda A-C, Matei DM, Ciobanu L, Damian-Buda D-Z, Pop RM, Buzoianu AD, Bocsan IC. Nesfatin-1: A Novel Diagnostic and Prognostic Biomarker in Digestive Diseases. Biomedicines. 2024; 12(8):1913. https://doi.org/10.3390/biomedicines12081913
Chicago/Turabian StyleDamian-Buda, Adriana-Cezara, Daniela Maria Matei, Lidia Ciobanu, Dana-Zamfira Damian-Buda, Raluca Maria Pop, Anca Dana Buzoianu, and Ioana Corina Bocsan. 2024. "Nesfatin-1: A Novel Diagnostic and Prognostic Biomarker in Digestive Diseases" Biomedicines 12, no. 8: 1913. https://doi.org/10.3390/biomedicines12081913