Search Results (157)

Enteroendocrine cells (EECs) are specialized secretory cells in the gut epithelium that differentiate from intestinal stem cells (ISCs). Mature EECs secrete incretin hormones that stimulate pancreatic insulin secretion and regulate appetite. Decreased EEC numbers and impaired secretion of the incretin glucagon-like peptide-1 (GLP1) have been implicated in obesity-associated metabolic complications. Gut microbial metabolites of dietary tryptophan (TRP) were recently shown to modulate ISC proliferation and differentiation. However, their specific effects on EEC differentiation are not known. We hypothesized that the gut microbial metabolites of dietary tryptophan counteract impaired GLP1 production and function in obesity by stimulating EEC differentiation from ISCs. We utilized complementary models of human and rat intestines to determine the effects of obesity or TRP metabolites on EEC differentiation. EEC differentiation was assessed by the EEC marker chromogranin A (CHGA) levels in the intestinal mucosa of normal versus obese rats. The effects of TRP metabolites on EEC differentiation were determined in human intestinal organoids treated with indole, a primary TRP metabolite, or the culture supernatant of Lactobacillus acidophilus grown in TRP media (LA-CS-TRP). Our results showed that the mRNA and protein levels of CHGA, the EEC marker, were significantly decreased (~60%) in the intestinal mucosa of high-fat-diet-induced obese rat intestines. The expression of the transcription factors that direct the ISC differentiation towards the EEC lineage was also decreased in obesity. In human organoids, treatment with indole or LA-CS-TRP significantly increased (more than 2-fold) CHGA levels, which were blocked by the aryl hydrocarbon receptor (AhR) antagonist CH-223191. Thus, the stimulation of EEC differentiation by colonic microbial metabolites highlights a novel therapeutic role of TRP metabolites in obesity and associated metabolic disorders. Full article

Background: Hypothermia, occurring when core temperature drops below 35 °C, can lead to death when the body’s heat loss exceeds its heat production. This study investigates two hypothermia-related deaths, exploring the utility of immunohistochemistry, specifically focusing on chromogranin A (CgA) as a potential diagnostic tool. The aim is to assess whether CgA expression in neuroendocrine tissues can be considered a reliable indicator of premortem stress response in fatal hypothermia cases. Case Presentation: In the first case, a 67-year-old man was found on a snowy road 24 h after his disappearance. The autopsy revealed cold-induced skin lesions, gastric hemorrhages, and cerebral and pulmonary edema. Positive CgA immunostaining was observed in the pancreatic islets and adrenal medulla. In the second case, a 49-year-old man was found dead in a wooded area with indications of suicide. Both cases were examined with attention to macroscopic findings and histological samples from major neuroendocrine organs. As in previous cases, CgA immunostaining was positive in the pancreatic islets and adrenal medulla. Staining intensity was moderate to strong, consistent with heightened neuroendocrine activity, supporting the hypothesis of systemic stress prior to death. Conclusions: Although CgA is a potentially valuable adjunct in hypothermia diagnosis, careful consideration of cadaveric preservation is emphasized, particularly when bodies are preserved before autopsy. Further studies with larger sample sizes are needed to confirm its diagnostic specificity and to distinguish true pathological patterns from postmortem artifacts. Full article

Anxiety and depression are highly prevalent mental health disorders often associated with dysregulation of neuroendocrine and immune systems, particularly the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic–adrenal–medullary (SAM) system. Recent research highlights the potential of salivary biomarkers to serve as non-invasive indicators for psychological distress. This narrative review synthesizes current evidence on key salivary biomarkers, cortisol, alpha-amylase (sAA), secretory immunoglobulin A (sIgA), chromogranin A (CgA), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), brain-derived neurotrophic factor (BDNF), and salivary microRNAs (miRNAs), in relation to anxiety, depression, and stress. A comprehensive literature search (2010–2025) was conducted using multiple databases and relevant MeSH terms. The review reveals consistent associations between these salivary analytes and stress-related disorders, reflecting changes in neuroendocrine activity, immune response, and neuroplasticity. Cortisol and sAA mirror acute stress reactivity, while cytokines and CRP indicate chronic inflammation. BDNF and miRNAs provide insight into neuroplastic dysfunction and gene regulation. Despite promising results, limitations such as variability in sampling methods and biomarker specificity remain. In conclusion, salivary biomarkers offer a promising avenue for early detection, monitoring, and personalization of treatment in mood and anxiety disorders. Conclusions: Cortisol and alpha-amylase serve as the principal markers of acute stress response, whereas cytokines such as IL-6 and TNF-α, together with CRP, indicate chronic inflammation associated with extended emotional distress. Full article

Cancer during pregnancy is a rare but complex clinical scenario that affects approximately 0.1% of pregnant individuals and is associated with increased maternal morbidity. With the trend of delayed childbearing, the incidence of pregnancy-associated cancers is expected to rise. Neuroendocrine neoplasms (NENs), although rare in pregnancy, present unique diagnostic and therapeutic challenges due to their hormonal activity, histological diversity, and limited data on management in the gestational context. Objectives: This manuscript reviews the current evidence on the diagnosis, staging, and management of NENs during pregnancy, focusing on maternal–fetal safety, therapeutic limitations, and multidisciplinary care strategies. Methods: A comprehensive narrative review was conducted using relevant case reports, retrospective studies, clinical guidelines, and expert consensus documents addressing cancer in pregnancy and NEN-specific management. Results: Pregnancy complicates the evaluation and treatment of NENs due to overlapping symptoms, contraindications to standard imaging and systemic therapies, and unreliable biomarkers such as chromogranin A and 5-HIAA. Most systemic therapies for NENs, including somatostatin analogs, tyrosine kinase inhibitors, and peptide receptor radionuclide therapy, are contraindicated or lack safety data in pregnancy. Surgical interventions and supportive care require careful planning. Decisions regarding pregnancy continuation or termination must be individualized and supported by a multidisciplinary team. Conclusions: The management of NENs during pregnancy demands a highly individualized approach, coordinated among oncology, maternal–fetal medicine, and supportive care teams. Given the paucity of robust data, future research is essential to establish evidence-based guidelines and improve outcomes for both mother and fetus. Full article

Background: Pancreatic neuroendocrine tumors (PanNETs) are relatively rare neoplasms with heterogeneous behavior, ranging from indolent to aggressive disease. The evolution of nuclear medicine has allowed the development of an efficient and advanced toolkit for the diagnosis and treatment of PanNETs. Case: A 45-year-old woman was diagnosed with a grade 1 PanNET and multiple liver metastases. She underwent distal pancreatectomy with splenectomy, extended liver resection, and radiofrequency ablation (RFA). Surgical planning was guided by [^99mTc]Tc-EDDA/HYNIC-TOC SPECT/CT (single-photon emission computed tomography/computed tomography) and preoperative [^99mTc]Tc-mebrofenin-based functional liver volumetry. Functional liver volumetry based on dynamic [^99mTc]Tc-mebrofenin SPECT/CT facilitated precise surgical planning and reliable assessment of the efficacy of parenchymal modulation, thereby aiding in the prevention of post-hepatectomy liver failure. Liver fibrosis was non-invasively evaluated using two-dimensional shear wave elastography (2D-SWE). Tumor progression was monitored using somatostatin receptor scintigraphy, chromogranin A, and contrast-enhanced CT. Recurrent disease was treated with somatostatin analogues (SSAs) and [¹⁷⁷Lu]Lu-DOTA-TATE peptide receptor radionuclide therapy (PRRT). Despite progression to grade 3 disease (Ki-67 from 1% to 30%), the patient remains alive 53 months post-diagnosis, in complete remission, with an ECOG (Eastern Cooperative Oncology Group) status of 0. Conclusions: Functional imaging played a pivotal role in guiding therapeutic decisions throughout the disease course. This case not only underscores the clinical utility of advanced nuclear imaging but also illustrates the dynamic nature of pancreatic neuroendocrine tumors. The transition from low-grade to high-grade disease highlights the need for further studies on tumor progression mechanisms and the potential role of adjuvant therapies in managing PanNETs. Full article

The sympathetic nervous system (SNS) is crucial for stress response regulation and immune modulation. Prolonged SNS activation, often induced by stress exposure, disrupts immune homeostasis and intensifies inflammatory processes, contributing to periodontal disease progression. This study investigates the relationship between SNS activity and periodontitis severity, utilizing salivary biomarkers chromogranin A (CgA) and alpha-amylase (sAA) alongside pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-6 (IL-6). Saliva samples from 67 patients, categorized by periodontitis severity (Stages I/II and III/IV), were analyzed using enzyme-linked immunosorbent assay (ELISA). The results revealed significantly higher median levels of CgA (9.45 vs. 3.93 pmol/mL) and IL-1β (257.81 vs. 220.11 pg/mL) in patients with Stage III/IV periodontitis compared with those with Stage I/II, indicating heightened SNS activity and inflammatory response. Correlations between these biomarkers and clinical periodontal parameters, such as probing depth and clinical attachment loss, further support these findings. Despite elevated sAA levels in severe cases, statistical significance was not achieved. IL-6 levels also showed no significant variation across disease stages, although trends aligned with increased severity. This study highlights the interplay between SNA activation and periodontal inflammation, as evidenced by elevated salivary levels of CgA and IL-1β in patients with advanced periodontitis. By integrating neuroendocrine and inflammatory biomarkers into the diagnostic process, clinicians may be able to better identify patients at increased risk for periodontal breakdown and to consider adjunctive interventions such as stress management, thereby supporting more personalized approaches to periodontitis treatment. Full article

Prostate cancer with bone metastasis exhibits significant heterogeneity, complicating prognosis, and treatment. This study explores the potential of plasma, serum, and urine biomarkers to stratify patients and evaluate their prognostic value. Using two-step clustering, we analyzed baseline levels of Platelet-derived growth factor-BB (PDGF-BB), Insulin-like growth factor-binding protein 1 (IGFBP-1), Bone Morphogenetic Protein 2 (BMP-2), Vascular endothelial growth factor (VEGF) (plasma and urine), prostate-specific antigen (PSA), neuron-specific enolase (NSE), chromogranin A (CgA) and bone-specific alkaline phosphatase (BAP) (serum) and creatinine (Cr), and type I collagen-cross-linked N telopeptide (NTx) (urine) in 29 patients with prostate cancer and bone metastasis. Longitudinal biomarker dynamics were assessed at baseline, 6 months, and 12 months. Clinical outcomes were evaluated using Kaplan–Meier and multivariate analyses. Three distinct groups (C1, C2, and C3) were identified. C1 exhibited elevated pPDGF-BB and pVEGF levels, C3 had increased pBAP and uNTx/Cr, and C2 showed lower biomarker levels. Prior treatments influenced biomarker levels, with bisphosphonates reducing bone turnover markers and radiotherapy correlating with long-term changes in growth factors. Longitudinal analysis revealed unique biomarker dynamics within each group, with a tendency for pPDGF-BB and pVEGF levels to decrease over time in C1, and distinct trends in uNTx/Cr between groups. Despite individual biomarkers failing to predict survival, C3 patients demonstrated significantly worse survival than C1 and C2. Molecular clustering of peripheral blood and urinary biomarkers identifies distinct subgroups with metastatic castration-resistant prostate cancer patients outperforming traditional models in outcome prediction and supporting its potential for personalized treatment and prognosis. Full article

Neuroendocrine neoplasms (NENs) comprise a heterogeneous tumor group arising from neuroendocrine cells, commonly originating in the gastroenteropancreatic tract and bronchopulmonary system. Their incidence has risen significantly, owing to improved diagnostic techniques and increased clinical recognition. While previous reviews have explored the molecular and genetic basis of NENs, limited attention has been given to the role of epigenetic modifications, particularly DNA methylation, in tumorigenesis and disease progression. This review focuses on lung, pancreas, and thyroid well-differentiated neuroendocrine tumors (NETs), highlighting epigenetic mechanisms, particularly DNA methylation, as promising biomarkers for early diagnosis and risk stratification. Aberrant DNA methylation can silence key tumor suppressor genes, including RASSF1A and CDKN2A, thereby promoting tumorigenesis. Integrating DNA methylation profiles with conventional biomarkers such as chromogranin A (CgA) may enhance diagnostic accuracy and inform therapeutic strategies. Emerging epigenetic therapies offer potential avenues for personalized treatment based on molecular profiling. Unlike prior reviews that broadly cover genetic and epigenetic changes in NENs, this review uniquely emphasizes the translational potential of epigenetic biomarkers in clinical practice. By synthesizing recent findings and evaluating their clinical implications, we aim to bridge the gap between molecular research and practical applications in diagnosis, prognosis, and therapy. Full article

Rheumatoid arthritis (RA) is a chronic autoimmune disease that not only causes joint inflammation but also significantly increases the risk of cardiovascular disease (CVD), leading to a higher morbidity and mortality. RA patients face an accelerated progression of atherosclerosis, attributed to both traditional cardiovascular risk factors and systemic inflammation. This review focuses on emerging biomarkers for cardiovascular risk assessment in RA, aiming to enhance early detection and treatment strategies. Specifically, we examine the roles of interleukin-32 (IL-32), Dickkopf-1 (DKK-1), galectin-3 (Gal-3), catestatin (CST), and fetuin-A (Fet-A) as potential markers for CVD in this patient population. IL-32, a proinflammatory cytokine, is elevated in RA patients and plays a significant role in inflammation and endothelial dysfunction, both of which contribute to atherosclerosis. DKK-1, a Wnt signaling pathway inhibitor, has been associated with both synovial inflammation and the development of atherosclerotic plaques. Elevated DKK-1 levels have been linked to an increased CV mortality and could serve as a marker for CVD progression in RA. Gal-3 is involved in immune modulation and fibrosis, with elevated levels in RA patients correlating with disease activity and cardiovascular outcomes. Catestatin, a peptide derived from chromogranin A, has protective anti-inflammatory and antioxidative properties, though its role in RA-related CVD remains under investigation. Finally, Fet-A, a glycoprotein involved in vascular calcification, shows potential as a biomarker for CV events in RA, though data on its role remain conflicting. These biomarkers provide deeper insights into the pathophysiology of RA and its cardiovascular comorbidities. Although some biomarkers show promise in improving CV risk stratification, further large-scale studies are required to validate their clinical utility. Currently, these biomarkers are in the research phase and are not yet implemented in standard care. Identifying and incorporating these biomarkers into routine clinical practice could lead to the better management of cardiovascular risk in RA patients, thus improving outcomes in this high-risk population. This review highlights the importance of continued research to establish reliable biomarkers that can aid in both diagnosis and the development of targeted therapies for cardiovascular complications in RA. Full article

Introduction: Bronchopulmonary Neuroendocrine Neoplasms (NEN) occur in 2–7% of patients with multiple endocrine neoplasia type 1 (MEN1). Precursor lesions have been identified for MEN1-related pancreatic, duodenal, and gastric NEN. The aim of the current study using a MEN1 mouse model was to define the precursor lesions of bronchopulmonary NEN and evaluate the potential prophylactic antitumor effects of somatostatin analogues in a transgenic MEN1 mouse model. Methods: Fifteen mice, germline heterozygous for Men1(+/T), were treated with subcutaneous injections of lanreotide autogel (Somatuline Autogel^®, IPSEN Pharma), while 15 mice were treated with subcutaneous injections of physiologic sodium chloride as the control group. Five mice from each group were euthanized after 12, 15, and 18 months, respectively. The complete lungs were resected and evaluated after hematoxylin and eosin staining and immunohistochemistry for synaptophysin and chromogranin A. Results: In the lungs of the 30 evaluated mice, whether treated or placebo treated, no bronchopulmonary neuroendocrine cell hyperplasia nor neuroendocrine neoplasia was detected through histopathology. However, pulmonary adenocarcinoma developed in 2 (13%) of the 15 untreated mice and in 1 (7%) of the 15 lanreotide-treated mice. Conclusions: Heterozygous Men1(+/T) knockout mice do not develop bronchopulmonary NEN or precursor lesions, but pulmonary adenocarcinoma. This surprising result needs to be investigated in more detail. Full article

Microalgae, a marine-derived natural ingredient, has emerged as a rich source of bioactive compounds with the potential to modulate gut–brain axis activities. The objective of this study was to investigate whether supplementation with a microalgae extract from Tetradesmus obliquus strain Mi175.B1.a (TOME) influences gut health and reduces stress and anxiety in healthy adults experiencing mild to moderate gastrointestinal (GI) distress. Methods: Fifty-six healthy adults (age: 31.9 ± 7.7 years; body weight: 71.8 ± 12.6 kg; BMI: 24.6 ± 2.8 kg/m²) were enrolled in a randomized, double-blind, placebo-controlled, parallel-arm clinical trial. Participants were randomly allocated to receive capsules containing either 250 mg/day of TOME or a placebo for four weeks. Primary outcomes included the assessment of GI symptoms using the Gastrointestinal Symptom Rating Scale (GSRS) and Bristol Stool Scale (BSS). Secondary outcomes focused on subjective evaluation of mood, stress, and anxiety, as well as blood pressure responses to sympathetic nervous system activation induced by the cold pressor test (CPT). In addition, stool, plasma, and saliva samples were collected to assess biomarkers associated with stress, sympathetic activation, intestinal permeability, and GI health. 16S rRNA sequencing was performed to analyze changes in gut microbial populations. Results: Daily supplementation for four weeks with TOME was safe and well tolerated in the study population. In addition, TOME significantly reduced GSRS global scores (p = 0.02), as well as constipation (p = 0.05) and indigestion (p = 0.03) subcomponent scores compared to Placebo. There was also a significant increase in Shannon’s index before FDR correction (p = 0.05; FDR = 0.12) and stool butyrate level was significantly lower in the TOME group than in Placebo after 4 weeks of supplementation (p = 0.039). Both groups showed a significant reduction in perceived stress scores, but the TOME intervention group also had reduced Negative Affect scores (p < 0.001). In addition, plasma chromogranin A, a stress biomarker, was significantly reduced after TOME intervention (p = 0.03). There were no negative effects on blood lipids or other parameters related to sympathetic activation or cardiovascular health. Conclusions: Overall, these results suggest that 4-week supplementation with T. obliquus strain Mi175.B1.a improves GI symptoms, potentially through effects on the gut microbiota, and may promote positive effects on mental health. Additional research should follow up on mental health outcomes in populations with increased stress and anxiety and investigate mechanisms underlying improvements in GI health. This trial was registered at clinicaltrials.gov as NCT06425094. Full article

Immunohistochemically, ameloblastomas often express CD56; however, novel neuroendocrine markers such as synaptophysin (SYP), insulinoma-associated protein 1 (INSM1), and chromogranin A (CgA) remain unexplored. We analyzed 36 ameloblastoma specimens for CD56, SYP, CgA, and clusterin (CLU) and examined limited samples for INSM1 expression by performing immunohistochemistry, transmission electron microscopy, and reverse transcriptase-polymerase chain reaction. Our findings indicate that the limited cells were positive for CD56, SYP, CgA, INSM1, and CLU expression in 72% (26/36), 14% (5/36), 0% (0/40), 80% (4/5), and 22% (8/36) of the cases, respectively. CD56 expression correlated with older age, but not with subtype, SYP, and CLU expression. However, SYP-positive cases were exclusively found in CD56- and CLU-positive cases, and SYP and CLU expression were significantly correlated. Selected cases had dense-core granules and NCAM1 and SYP mRNA expression. This study is the first to suggest neuroendocrine differentiation in ameloblastomas, as indicated by SYP and INSM1 immunoexpression and the presence of dense-core granules, which are consistent with the recent World Health Organization classification of Head and Neck Tumors guidelines. SYP-positive and CgA-negative phenotypes may characterize neuroendocrine differentiation in ameloblastoma. Although the underlying molecular mechanism remains unclear, CLU expression may be associated with neuroendocrine differentiation. Full article

Background: Hypoglycemia in the case of persons without diabetes is a rare event, being usually, initially misinterpreted based on the symptoms that can mimic various diseases, especially of a neuro-psychiatric nature. In the case of the identification of insulin-mediated hypoglycemia, the evaluation of pancreatic neuroendocrine tumors, which represent the most common and worrisome causes of non-diabetic insulin-mediated hypoglycemia, must be considered. Case Report: We present the case of a 57-year-old patient, hospitalized for a history of approximately one month of recurrent episodes of symptoms suggestive for severe hypoglycemia. The biological evaluation performed during an episode of hypoglycemia showed a plasma glucose value of 44 mg/dL, insulinemia 16.3 µU/mL, C peptide 3.72 ng/mL, HbA1c 4.99%, absence of urinary ketone bodies and anti-insulin antibodies <0.03 U/mL. The CT and MRI examination showed a 15.3/15 mm rounded tumor in the pancreatic corporeo-caudal region. The pancreatic tumor formation was enucleated and the histopathological and immunohistochemical analysis confirmed the diagnosis of the pancreatic neuroendocrine tumor with a positive reaction for chromogranin A, synaptophysin and insulin, without malignancy features (Ki 67 positive in 1% of the tumor cells). The postoperative evolution was favorable, without episodes of hypoglycemia, the fasting insulinemia one day after surgery being 4.1 µU/mL and HbA1c at three weeks postoperatively being 5.51%. Conclusions: The management of patients with hyperinsulinemic hypoglycemia secondary to insulinoma involves multidisciplinary collaboration with an important role in recognizing symptoms suggestive of hypoglycemia in a person without diabetes, initiating biological and imaging evaluation, establishing the optimal therapeutic option and histopathological confirmation. Full article

Neuroendocrine neoplasms (NENs) are a diverse group originating from endocrine cells/their precursors in pancreas, small intestine, or lung. The key serum marker is chromogranin A (CgA). While commonly elevated in patients with NEN, its prognostic value is still under discussion. Secretion/posttranslational proteolytic cleavage of CgA results in multiple bioactive fragments, which are essential regulators of the cardiovascular and immune system. miR-223, regulator of Nrlp3 inflammasome and neutrophil activation, was recently found to have decreased in patients with NEN. We performed flow cytometry of circulating neutrophils in a patient cohort (n = 10) with NEN, microdissection and histology of tumor tissue. Subsequently, in vitro transfections using the well-established human pancreatic NEN cell line (BON), and co-culture experiments with primary macrophages and neutrophils were performed. Serum miR-223 in patients correlated with the expression of the neutrophil activation marker CD15 in circulating cells. Neutrophilic CD62L/CD63 showed good discrimination compared to healthy controls. Immune cell-derived miR-155, miR-193 and miR-223 colocalize with neutrophil in the extra-tumoral tissue alongside Nlrp3-associated caspase-1 activation. miR-223 knockdown in BON decreased the CgA intracellularly, increased in cellular granularity and caspase-1 activation. Plasmin inhibitor a2-aP reverted those effects. Western Blot showed fragmented CgA following miR-223 knockdown, which altered the inflammatory potential of neutrophils. Our data hence provide initial insights into an immunoregulatory mechanism via miR-223 and CgA in NEN cells, as regulation of miR-223 in NEN may affect tumor-associated inflammation. Full article

Introduction: Neuroendocrine tumors are a diverse group of tumors predominantly found in the gastrointestinal tract or respiratory system. Methods: This retrospective study aimed to measure the serum concentrations of LRP6 (low-density lipoprotein receptor-related protein 6), SFRP3 (secreted frizzled-related protein 3), and DVL1 (segment polarity protein dishevelled homolog) using the ELISA method in patients with NETs (N = 80) and a control group (N = 62). We evaluated the results against various demographic, clinicopathological, and biochemical characteristics. Results: Our analyses revealed that the concentration of SFRP3 in patients with neuroendocrine tumors was significantly elevated (p < 0.001) compared to the control group. Additionally, DVL1 concentrations were significantly higher (p < 0.01) in patients with BP-NETs compared to GEP-NETs. Furthermore, DVL1 analysis showed a moderate negative correlation with chromogranin A (p < 0.001) and weak negative correlations with serotonin (p < 0.05) and 5-HIAA (p < 0.05). Significant negative correlations were also observed between DVL1 and age in the control group (p < 0.01), and between LRP6 and Ki-67 in the study group. Conclusions: These results suggest that changes in the SFRP3 and DVL1 pathways play a key role in NET development. Elevated levels of these proteins highlight their importance in tumor biology, with SFRP3 and DVL1 potentially being crucial in NET molecular mechanisms. Further research is needed to explore their roles and potential in diagnosis and treatment. Full article