Neuroendocrinology最新文献

Introduction: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a diverse group of tumors arising from neuroendocrine cells, often characterized by slow growth and subtle symptoms, leading to advanced-stage diagnoses. The gut microbiota (GM) has been implicated in various gastrointestinal malignancies, but its relationship with GEP-NENs remains unclear.

Methods: A two-sample MR analysis was employed using genome-wide association study data to explore causal associations between GM and GEP-NENs. Genetic variants significantly associated with GM traits were selected as instrumental variables. Forward MR analysis identified significant GM traits associated with GEP-NENs, followed by reverse analysis to exclude reverse causation. Bayesian-weighted Mendelian randomization was employed for verification. Mediation analysis was conducted using a two-step approach to evaluate the mediating role of immune cell traits in these causal relationships. Sensitivity analyses, including heterogeneity and pleiotropy tests, were conducted to ensure the robustness of the findings.

Results: Our analysis identified significant causal associations between 45 GM traits and GEP-NENs, involving 25 bacterial taxa and 20 metabolic pathways. Specifically, s_Paraprevotella_xylaniphila showed the strongest association with pancreatic NEN (OR: 0.473, p: 0.005); metabolic pathway PWY.6588 (pyruvate fermentation to acetone) exhibited the strongest association with gastric NEN (OR: 2.706, p: 0.003); pathway PWY0.845 (super pathway of pyridoxal 5'-phosphate biosynthesis and salvage) had the strongest association with small intestine NEN (SI-NEN, OR: 1.898, p: 0.001); and g_Roseburia displayed the strongest association with colorectal NEN (OR: 0.504, p: 0.007). Furthermore, mediation analyses revealed that specific immune cell traits significantly mediated these associations, with CD3- lymphocyte absolute count showing a notable mediation effect (12.187%, p: 0.019) between g_Clostridium and G-NEN, highlighting the crucial role of immune modulation in GEP-NEN pathogenesis.

Conclusions: Our MR analysis provides robust causal evidence that specific GM taxa significantly influence the risk of GEP-NENs, and that this effect is partially mediated through discrete subsets of circulating immune cells. These findings underscore the GM-immune axis as a novel preventive and therapeutic target in GEP-NENs.

Background: The number of patients with type 2 diabetes (T2D) and type 1 diabetes (T1D) is on the rise, partly due to a global increase in new T1D cases among children. Beyond the well-documented microvascular and macrovascular complications, there is now substantial evidence indicating that diabetes also impacts the brain, leading to neuropsychological impairments. The risk of developing neuropsychiatric symptoms is notably higher in childhood due to the ongoing maturation of the brain, which makes it more susceptible to damage. Despite this awareness, the specific effects of diabetes on cognitive function remain poorly understood.

Summary: This review synthesizes literature on the impact of diabetes on cognition and its relationship with brain structural changes. It presents data and hypotheses to explain how T1D contributes to cognitive dysfunction, with a particular focus on children and adolescents. The emphasis on the pediatric population is intentional, as young diabetic patients typically have fewer comorbidities, reducing confounding factors and simplifying the investigation of cognitive alterations.

Key message: We examine the roles of hypo- and hyperglycemia, as well as the emerging role of glucocorticoids in the development of neuropsychological disorders. When specific mechanisms related to T1D are available, they are highlighted; otherwise, data and hypotheses applicable to both T1D and T2D are discussed.

Objective: This study aimed to elucidate the effect and mechanism of hyperoside on blood-brain barrier (BBB) damage in bacterial meningitis (BM) by regulating the microRNA-155 (miR-155)/brain-derived neurotrophic factor (BDNF) pathway.

Methods: A rat model of meningitis was established via intracisternal injection of Streptococcus pneumoniae (SPN), while an in vitro BBB injury model was created by treating human cerebral microvascular endothelial cells (hCMEC/D3) with lipopolysaccharide (LPS). Hyperoside was administered in both models. Evans blue staining was used to assess BBB permeability in rats. Brain water content was determined using the wet-dry weight method. Transendothelial electrical resistance (TEER) was measured with an endothelial resistance meter. RT-qPCR, Western blotting, and ELISA were conducted to assess the expression of tight junction proteins (ZO-1, Claudin-5, and AQP4) in brain tissues and cell supernatants. ELISA was also used to measure inflammatory cytokines (TNF-α, IL-1β, IL-6) in cerebrospinal fluid and cell culture supernatants. Bioinformatics analysis and dual-luciferase reporter assays were employed to predict and validate the regulatory relationship between miR-155 and BDNF.

Results: Hyperoside treatment reduced BBB permeability, alleviated brain edema, and suppressed inflammatory cytokine expression in SPN-infected rats. In LPS-induced hCMEC/D3 cells, hyperoside significantly increased TEER values. Furthermore, hyperoside markedly downregulated miR-155 and upregulated BDNF expression. miR-155 was confirmed to directly target BDNF and negatively regulate its expression in hCMEC/D3 cells. Importantly, the administration of a miR-155 mimic or BDNF knockdown (sh-BDNF) partially reversed the protective effects of hyperoside on TEER, tight junction protein expression (ZO-1, Claudin-5, AQP4), and inflammatory cytokine levels (TNF-α, IL-1β, IL-6) in LPS-induced hCMEC/D3 cells.

Conclusion: Hyperoside mitigates BBB damage in BM via reducing miR-155 expression and upregulating BDNF expression, leading to an increase in tight junction-related protein expression, a reduction in inflammatory factor secretion, and a decrease in BBB permeability.

Background: Obesity is a major risk factor for noncommunicable diseases and is associated with a reduced life expectancy of up to 20 years, as well as with other consequences such as unemployment and increased economic burden for society. It is a multifactorial disease, and physiopathology of obesity involves dysregulated calorie utilization and energy balance, disrupted homeostasis of appetite and satiety, lifestyle factors including sedentary lifestyle, lower socioeconomic status, genetic predisposition, epigenetics, and environmental factors. Some endocrine-disrupting chemicals (EDCs) have been proposed as "obesogens" that stimulate adipogenesis leading to obesity. In this review, definition of obesogens, their adverse effects, underlying mechanisms, and metabolic implications will be updated and discussed.

Summary: Disruption of lipid homeostasis by EDCs involves multiple mechanisms including increase in the number and size of adipocytes, disruption of endocrine-regulated adiposity and metabolism, alteration of hypothalamic regulation of appetite, satiety, food preference and energy balance, and modification of insulin sensitivity in the liver, skeletal muscle, pancreas, gastrointestinal system, and the brain. At a cellular level, obesogens can exert their endocrine disruptive effects by interfering with peroxisome proliferator-activated receptors and steroid receptors. Human exposure to chemical obesogens mainly occurs by ingestion and, to some extent, by inhalation and dermal uptake, usually in an unconscious manner. Persistent pollutants are lipophilic features; thus, they bioaccumulate in adipose tissue.

Key messages: Although there are an increasing number of reports studying the effects of obesogens, their mechanisms of action remain to be elucidated. In addition, epidemiological studies are needed in order to evaluate human exposure to obesogens.

Introduction: The purpose of this study was to evaluate longitudinal changes in Ki-67 indices of SI-NETs and assess the impact of these in overall survival (OS).

Methods: We screened 551 patients with SI-NETs diagnosed from 1993, through 2021, identified using the SI-NET databases from five European referral centres. Only patients with well-differentiated tumours and available baseline tumour samples and follow-up re-biopsies were included. For tumour grading, apart from 2017 WHO classification system, we applied a recently proposed SI-NET site-specific modified histopathological grading system with Ki-67 cut-offs of 5 and 10%. Uni- and multivariable regression analyses were used to determine whether there was a difference between OS in SI-NET patients stratified by increment of Ki-67 indices over time and/or progression to a higher grade.

Results: We included 45 patients. Median Ki-67 index at SI-NET diagnosis was 2% (range: 0.5-15%). Thirty-three patients had Ki-67 indices <5% (70.2%), 6 had Ki-67: 5-10% (12.8%), and 8 had Ki-67 ≥10% (17%). Mean time to re-biopsy was 48.8 months (SD: ±162.5). At re-biopsy, the median change in Ki-67 index (absolute value; follow-up minus time of diagnosis) was 1% (range: -10 to +38%). An increase in Ki-67 occurred in 20 patients (42.6%); in 14 patients, the change in Ki-67 resulted in progression to higher tumour grade following the modified grading system. Patients with an increment in Ki-67 ≥1% had a median OS of 32.9 months versus 80.5 months in patients without (HR = 5.6, 95% CI: 1.42-22.02; p = 0.014). When applying the novel modified histopathological grading system for SI-NETs, patients with grade progression had a median OS of 32.9 months versus 53.7 months in those without (HR = 4.61, 95% CI: 1.22-13.54; p = 0.022). At multivariable analysis, grade progression was confirmed as an independent predictor for death (HR = 7.2, 95% CI: 1.58-32.82; p = 0.011).

Conclusions: Metachronous increment in Ki-67 indices and related grade progression over time following a site-specific modified histopathological grading system with Ki-67 cut-offs of 5 and 10% is observed in approximately 1/3 of SI-NETs subjected to re-biopsy and it is associated with worse survival outcomes.

Introduction: Multiple endocrine neoplasia type 1 (MEN-1) is the most common inherited syndrome associated with NET development and gender-specific differences are emerging in neuroendocrine tumors (NETs). This study aimed to analyze gender difference in a single cohort of MEN-1 patients focusing on duodeno-pancreatic (DP)-NET and survival rates.

Methods: MEN-1 patients referred to the Endocrinology Unit of the "Federico II" University of Naples, ENETS CoE, were retrospectively evaluated.

Results: Among 100 MEN-1 patients enrolled, 59 (59%) were female and 41 (41%) male, and mean age at diagnosis was 39.4 years (range 5-86). No statistically significant association was identified between MEN-1 clinical manifestations and gender (primary hyperparathyroidism [PHPT] p: 1.0, DP-NET p: 0.83, pituitary adenoma [PA] p: 0.84, lung NET p: 0.64, and thymic NET p: 0.10), and similarly, age at diagnosis of MEN-1 and its individual manifestations was similar between genders. Survival analysis revealed no statistically significant difference between genders in DP-NET patients regarding progression disease p: 1.0 and death p: 1.0. Mean progression-free survival (PFS) of patients with DP-NET was 98.6 months (range 3-288), and mean overall survival (OS) was 130.1 months (range 3-444 months), without differences between genders (PFS p: 0.67 and OS p: 0.60). The Kaplan-Meier survival curves for PFS and OS showed no differences between genders (PFS p: 0.92; OS p: 0.87).

Conclusion: In this MEN-1 cohort, no gender differences in the occurrence of PHPT, PA, DP-NET, lung NET, and thymic NET, nor in survival outcomes including PFS and OS within the DP-NET subcohort, emerged. Therefore, this study supports similar screening and follow-up for both male and female MEN-1 patients.

Introduction: The efferent vestibular system (EVS) originates in brainstem efferent vestibular nuclei (EVN) and modifies afferent vestibular signals at their source, in peripheral vestibular organs. Recent evidence suggests that EVS is also involved in the development of motion sickness symptoms, including vertigo and nausea, but the underlying mechanism is unknown. One possible link between EVN and motion sickness symptoms is through the neuropeptide calcitonin gene-related peptide (CGRP). CGRP often co-exists with substance P and pituitary adenylate cyclase-activating polypeptide (PACAP), two neuropeptides with similar vasodilatory effects. Collectively, these sensory neuropeptides have been associated with vestibular migraine pathophysiology and motion sickness. While CGRP and the fast EVS neurotransmitter, acetylcholine (ACh), have previously been identified in EVN neurons and their peripheral terminals, the presence of substance P and PACAP in the EVN has not yet been described.

Methods: We used fluorescent immunohistochemistry combined with confocal microscopy to examine the distribution of these three neuropeptides in the mouse EVN. In transgenic choline acetyltransferase (ChAT)-gCaMP6f mice, EVN neurons were positively identified using the fluorescent expression of gCaMP6f. In wild-type C57/BL6 mice, EVN neurons were confirmed using ChAT immunolabelling.

Results: Consistent with previous studies, CGRP was labelled in a subset of cholinergic EVN neurons. Additionally, we also show evidence for substance P and PACAP expression in EVN of transgenic and wild-type mice.

Conclusion: The presence of CGRP, substance P, and PACAP in EVN neurons suggests a complex peptidergic modulation of cholinergic signalling, whose release into local blood vessels may contribute to motion sickness symptoms.

Introduction: Indoleamine 2,3-dioxygenase (IDO) converts L-tryptophan (T) to L-kynurenine (K) resulting in an immunosuppressive microenvironment. The aim of the current study was to evaluate in patients with neuroendocrine tumor (NET) (1) T and K concentrations; (2) correlation with clinical outcome; (3) relationship between IDO activity and inflammatory cytokines.

Methods: A cross-sectional study was performed to investigate the IDO pathway in patients in follow-up for NET. Clinicopathological features, serum levels of K and T through liquid chromatography, and serum assay of cytokines (IL-6, IL-10, IL-17A, IL-22, IL-23, TNF-α) through MAGPIX were evaluated.

Results: Seventy-eight NET patients were enrolled (66 lung, 12 pancreatic): 69.2% were in postoperative remission, 14.1% in stable disease, and 16.7% in disease progression. T was significantly lower in patients older than 65 years (p = 0.003). K and T were significantly lower in patients with progression (p = 0.03, p = 0.004, respectively). T was an independent predictor factor of progression in multivariable analysis (p = 0.041). A cutoff of 7.74 μg/mL significantly differentiates patients with progression and those with stable disease. IL-6 and IL-10 were significantly associated with tumor progression in univariate analysis (p = 0.005, p = 0.001, respectively) but not in the multivariable analysis. A statistically significant negative correlation was found between T and IL-10 (r = -0.366, p value = 0.04).

Conclusion: The K/T pathway may play a role as a potential predictor of tumor progression in NET. These findings need to be validated in large prospective studies investigating its metabolites as both prognostic and predictive factors for treatment response.

Introduction: The glymphatic system is regarded as a key factor in the pathogenesis of neurodegenerative diseases. Given the heightened risk of cognitive impairment in patients with type 2 diabetes mellitus (T2DM), the possible alterations in the glymphatic system in T2DM patients remain to be explored. Diffusion tensor imaging (DTI) analysis along the perivascular space (ALPS) index can be utilized to model the glymphatic system in humans. Our aim was to explore the relationship between the ALPS index and cognitive function in patients with T2DM and whether this relationship is modulated by gray matter (GM) integrity anchored by the ALPS index.

Methods: All participants underwent evaluation using a comprehensive cognitive assessment scale to determine their neurocognitive status. The ALPS index was calculated based on DTI data, and the disparity in ALPS index values between patients with T2DM and healthy controls (HCs) was examined. Furthermore, multiple linear regression analysis was conducted in the T2DM group to identify the GM regions associated with the ALPS index, and the volumes of the GM partitions were extracted. The volume of GM partitions was used as the regulating variable, the ALPS index was used as the independent variable, and cognitive test scores were used as the dependent variable in our analysis.

Results: The ALPS index differed significantly between the two groups, and the ALPS index in patients with T2DM was significantly lower than that in HCs. In addition, our analysis revealed a correlation between the ALPS index and GM volume in the insular region, consistent with the observed GM atrophy in the patient cohort. Moreover, a significant negative correlation was observed between the ALPS index in patients and performance on the Trail-Making Test-A (TMT-A), and this relationship was moderated by GM integrity. In patients with more severe GM atrophy, the ALPS index was more strongly correlated with cognitive function.

Conclusions: In this study, a decreased ALPS index was found in T2DM patients, indicating impaired glymphatic function in this population. Furthermore, a significant association was detected between the ALPS index and cognitive performance in T2DM patients, and this correlation was influenced by GM integrity. Therefore, the ALPS index has the potential to be used as a biomarker of cognitive impairment in diabetic patients. Further studies are needed to investigate the diagnostic and therapeutic implications of glymphatic dysfunction in T2DM patients with cognitive impairment.