Neuroendocrinology最新文献

Introduction: Hypothyroidism and its induced neurological-associated disorders greatly affect the health-related quality of patients' life. Meanwhile, microglia in brain have essential regulatory functions on neurodegeneration, but the underlying link between hypothyroidism and microglia function is largely ambiguous.

Methods: We deciphered how hypothyroidism modulates the polarization of microglia by constructing methimazole-induced mice model and checking the expression pattern of biomarkers of microglia M1 polarization. Then, we used lipopolysaccharide (LPS)-treated BV2 cells to explore the effecting factors on microglia M1 polarization. Finally, global transcriptome sequencing (RNA-seq) was utilized to identify the underlying regulatory mechanisms.

Results: We detected that biomarkers of microglia M1 polarization and pro-inflammatory cytokines were significantly increased in hypothyroidism mice brain; hypothyroidism could also repress the expression of BDNF and TrkB, and the anti-inflammatory cytokine such as IL-10. In BV2 cells, LPS treatment decreased expression of BDNF, IL-10, and Arg1, while BDNF overexpression (BDNF-OE) significantly reversed the inflammation induced by LPS. BDNF-OE significantly repressed expression of iNOS and TNF-α, but increased expression of IL-10 and Arg1. For mechanism, RNA-seq analysis demonstrated that BDNF-OE could globally regulate transcriptome profile by affecting gene expression. In LPS-treated BV2 cells, BDNF-OE significantly altered expression pattern of genes involved in PI3K-Akt signaling pathway, including Thbs3, Myc, Gdnf, Thbs1, and Ccnd1 as upregulated genes, and Gnb4, Fgf22, Pik3r3, Pgf, Cdkn1a, and Pdgfra as downregulated genes. Myc, Gdnf, Thbs1, and Ccnd1 showed much higher expression levels than other genes in PI3K-Akt signaling pathway and could be promising targets of BDNF in reversing microglia M1 polarization.

Conclusion: Our study demonstrated a sound conclusion that hypothyroidism promotes microglia M1 polarization by inhibiting BDNF expression in brain; BDNF could inhibit the M1 polarization of microglia by activating PI3K-Akt signaling pathway, which could serve as a promising therapeutic target for microglia-induced neurodegenerative or emotional disorders in future.

Introduction: Hypothyroidism and its induced neurological-associated disorders greatly affect the health-related quality of patients' life. Meanwhile, microglia in brain have essential regulatory functions on neurodegeneration, but the underlying link between hypothyroidism and microglia function is largely ambiguous.

Methods: We deciphered how hypothyroidism modulates the polarization of microglia by constructing methimazole-induced mice model and checking the expression pattern of biomarkers of microglia M1 polarization. Then, we used lipopolysaccharide (LPS)-treated BV2 cells to explore t

Background: Many experimental data in several species clearly demonstrate the important genetic contribution to variations in HPA axis activity. The influence of corticosteroid hormones on adaptive processes and on production traits such as growth rate, feed efficiency, carcass composition, and meat quality is a strong impetus to the search for the molecular bases of these differences for efficient genetic selection.

Summary: Three main sources of genetic variability have been documented so far in farm animal species, the adrenal cortex sensitivity to ACTH-regulating corticosteroid hormone production, the bioavailability of corticosteroid hormones and especially corticosteroid-binding globulin capacity, and glucocorticoid receptor function. The effect of single mutations may be dependent on the genetic background, and genetic variation of cortisol levels may have different functional consequences depending on the molecular mechanisms responsible for this change.

Key messages: Understanding the genetic basis of HPA axis activity allows the development of genomic tools and breeding technologies aimed at improving adaptive capacity and stress tolerance in farm animals and their use as valuable models for the genetic study of the HPA axis and the correlation with adaptation, metabolism, and other functions regulated by adrenal hormones, and associated pathologies (obesity, cardiovascular, etc.). The next step will be to explore HPA axis variability from a system genetics perspective including the multiple sources of variation and their interactions. This multifactorial approach is a prerequisite to the use of the HPA axis phenotypes in the genetic selection for more productive and robust animals, with a high level of production of quality products.

Introduction: The gut microbiome, allegedly involved in both healthy homeostasis and development of disease, is found to be associated with several types of cancer. Short-chain fatty acids (SCFAs), important metabolites derived from the gut microbiota, are described to carry both protective and promoting features in cancer development. Limited research exists on neuroendocrine tumors (NETs) and their association with microbiota-derived SCFAs. The aim of this study was to investigate possible alterations in plasma SCFAs/organic acids in NET patients compared to healthy controls.

Methods: We quantified 11 organic acids, including SCFAs, in plasma from 109 NET patients (49 curatively operated patients and 60 patients with distant metastasis) as well as 20 healthy controls. Acids were quantified using liquid chromatography tandem mass spectrometry.

Results: We found that levels of 3OH-propionic acid, 3OH-butyric acid, lactic acid, formic acid, acetic acid, glyoxylic acid, and glycolic acid were significantly altered in NET patients with metastatic disease, as well as curatively operated NET patients, compared to healthy controls (p < 0.05). In addition, a trend displaying increased acid level alterations from healthy controls in curatively operated patients with future recurrence, compared to patients with no documented recurrent disease, was detected.

Conclusion: Our results demonstrating significantly altered levels of multiple organic acids in NET patients represents a novel finding implicating further research on their role in NET pathophysiology.

Introduction: Obesity may lead to cognitive impairment and neuropsychiatric disorders, which are associated with changes in the brain cortical structure, particularly in cortical thickness. However, the exact genetic association between obesity and brain cortical thickness remains inconclusive. We aimed to identify the relationship between obesity-related traits (body mass index [BMI], waist-hip ratio [WHR], and waist-hip ratio adjusted for BMI [WHRadjBMI]) and brain cortical thickness.

Methods: Leveraging summary statistics of large-scale GWAS(s) conducted in European-ancestry populations on BMI (N = 806,834), WHR (N = 697,734), WHRadjBMI (N = 694,649), and brain cortex thickness (N = 33,709), we performed GWAS combining genetic correlation, multi-trait meta-analysis, and Mendelian randomization analysis.

Results: Our findings revealed a strong genetic correlation between BMI and brain cortical thickness (rg = -0.0542, p = 0.0435), and a significant result was also observed for WHR and brain thickness (rg = -0.0744, p = 0.009). In addition, we identified three loci between obesity-related traits. Mendelian randomization analysis supported the causal role of BMI (inverse-variance-weighted [IVW] beta = -0.006, 95% CI = -0.011 to -3.85E-04; weighted median beta = -0.006, 95% CI = -0.013 to -0.002), WHR (IVW beta = -0.011, 95% CI = -0.018 to -0.005; weighted median beta = -0.008, 95% CI = -0.018 to -0.003), and WHRadjBMI (IVW beta = 0.011, 95% CI = -0.018 to -0.005; weighted median beta = -0.008, 95% CI = -0.018 to -0.002) in brain cortical thickness.

Conclusion: This study has shown that genetically predicted obesity-related traits have a causal relationship with reduced cortical thickness. These findings provide genetic evidence for a link between obesity and structural changes in the brain and suggest that obesity may be associated with neuropsychiatric disorders by affecting brain structure, particularly cortical thickness.

Introduction: During malnutrition, mammalian reproductive functions are suppressed by inhibition of the pulsatile release of gonadotropin-releasing hormone (GnRH)/gonadotropins. This study aimed to investigate whether nociceptin-opioid-related nociceptin receptor 1 (OPRL1) signaling mediates glucoprivic suppression of luteinizing hormone (LH) pulses in female rats.

Methods and results: RNA sequencing analysis of tdTomato-positive arcuate (ARC) kisspeptin neurons obtained from Kiss1 (kisspeptin gene)-Cre/Cre-dependent tdTomato reporter female rats showed that Oprl1 messenger RNA expression was evident in ARC kisspeptin neurons. Double in situ hybridization for Kiss1 and Oprl1 or prepronociceptin gene (Pnoc) revealed that approximately 20% of Kiss1-expressing cells co-expressed Oprl1, but not Pnoc in ovariectomized (OVX) wild-type rats treated with diestrus levels of estradiol-17β (low E2). Administration of [N-Phe1]-orphanin FQ (1-13) amide (NC13), a selective OPRL1 antagonist, to the third ventricle (3V) transiently reversed the suppression of LH pulses induced by intravenous (iv) 2-deoxy-D-glucose (2DG), an inhibitor of glucose utilization, in OVX + low E2 rats. The frequency of LH pulses during the first hour of the 3-h sampling period was significantly higher in 3V NC13-treated rats than in vehicle-treated controls. In contrast, 3V NC13 administration failed to affect LH pulses in OVX + low E2 rats without iv 2DG treatment. Furthermore, iv 2DG treatment significantly increased the percentage of fos-positive ARC Pnoc-expressing cells in OVX + low E2 rats.

Conclusion: These results indicate that ARC nociceptin-OPRL1 signaling partly mediates the glucoprivic suppression of LH pulses and that nociceptin may directly suppress ARC kisspeptin neurons, the GnRH/LH pulse generator in female rats.

Introduction: A growing body of evidence demonstrates that gastrointestinal motility disorder (GIMD) and gastric stress ulcers can be induced by chronic stress, whereas melatonin (MT) elicits anti-inflammatory and antioxidant effects. The present study investigated the mechanisms of MT-mediated protection against chronic restraint stress-induced GIMD.

Methods: Sixty 8-week-old male Institute of Cancer Research mice were divided into four groups: control, restraint stress, restraint stress + MT, and MT (positive control). MT (20 mg/kg) or vehicle was administered intraperitoneally 60 min before chronic restraint stress (5 h/day) once daily for 30 days. Biochemical parameters, intestinal mucosal integrity, tissue antioxidant ability, and autophagic protein levels were determined.

Results: Mice subjected to restraint stress presented elevated CORT and NE levels of 141.41% and 151.24%, respectively, and a decreased plasma MT content of 37.12%. Consistent with the decrease in MT levels, we observed a reduction in antioxidant ability and autophagic proteins and increased apoptotic protein levels in the gut, resulting in injury to the intestinal mucosa, which manifested as reductions in the villus height and the V/C ratio; the number of goblets; the number of mast and PCNA-positive cells; and the expression of tight junction proteins (ZO-1, occludin and claudin-1). In contrast, MT reversed these changes caused by chronic restraint stress and improved intestinal mucosal injury. However, there was no significant difference between the MT (positive control) and control groups.

Conclusion: Our results suggest that MT effectively mitigates chronic psychological stress-induced intestinal mucosa injury, providing evidence demonstrating the potential for the use of MT as a therapy for intestinal impairment associated with chronic psychological stress.

Background: Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors arising from neuroendocrine cells, exhibiting a wide range of behaviors from indolent to highly aggressive forms. Treatment options remain limited, particularly for progressive cases. Cabozantinib, a multitarget tyrosine kinase inhibitor, has demonstrated potential in targeting key pathways related to tumor growth, angiogenesis, and metastasis.

Summary: This review provides a comprehensive analysis of cabozantinib's therapeutic role across various NEN subtypes, including gastroenteropancreatic NENs, lung NENs, pheochromocytomas/paragangliomas, Merkel cell carcinoma, presacral NENs, pituitary neuroendocrine tumors, and neuroendocrine prostate cancer.

Key messages: The paper discusses several preclinical and clinical studies that demonstrate the efficacy of cabozantinib in slowing tumor progression and improving progression-free survival, particularly in patients with progressive, well-differentiated NENs. However, cabozantinib's complex toxicity profile limits its broad application, necessitating further research to optimize dosing, particularly in syndromic NENs. Ongoing trials are investigating cabozantinib in combination with somatostatin analogs, peptide receptor radionuclide therapy, temozolomide, and immunotherapies in order to overcome treatment resistance and expanding therapeutic strategies for advanced NENs.

Introduction: Gender difference may affect lung neuroendocrine tumor (L-NET) onset, progression, and outcomes as emerged in other cancers. This study aimed to analyze gender difference in L-NET to identify potential prognostic factors, to improve patient follow-up and therapeutic strategies.

Methods: Patients with histologically confirmed L-NEN diagnosis referred to the ENETS CoE of the Endocrinology Unit, Federico II University of Naples, from 2013 to 2023, were retrospectively evaluated.

Results: Among 48 patients with L-NEN, 38 (79.2%) with sporadic L-NET were enrolled: 22 typical (57.9%) and 16 atypical (42.1%) carcinoids, 22 (57.9%) female and 16 (42.1%) male, mean age at diagnosis 57.3 years (range 16-84). Median follow-up was 70.5 months (range 12-305). No statistical difference resulted regarding smoking habit, BMI, primary site (left/right and central/peripheral), and histological characteristics, between cohorts. Metastasis at diagnosis was found in 20 patients (52.3%), 10 female (10%) and 10 male (10%) (p: 0.20). Progressive disease (PD) was observed in 14 (36.8%) patients, and male sex developed PD more frequently 9/14 (64.3%) than female 5 (35.7%), p: 0.05. Male sex seemed to show more frequently bone metastasis without reaching statistical difference, 7 male/10 (70%), p: 0.06. Among 9 deaths (23.7%), 7 (77.8%) were men and 7 died for PD, p < 0.03. Male had a poorer prognosis than female regarding progression-free survival (PFS) (p: 0.04) and overall survival (p: 0.001), also when sub-groups of patient metastatic at diagnosis were compared (p: 0.02 and p: 0.02).

Conclusions: This study showed a worse prognosis in male than female with L-NET, despite similar clinical features, tumor type, stage, and treatment, with regard to PFS, OS, and metastatic spread. These findings may suggest a closer follow-up in men, with potential positive impact on outcomes.

Introduction: 17-α-hydroxyprogesterone caproate (17-OHPC) is prescribed to pregnant individuals at risk for preterm birth during critical periods of fetal cortical maturation. Yet the potential long-term effects of 17-OHPC on neural and behavioral development in children are unknown. Nuclear progesterone receptor (PR) is expressed in all functional regions of rat cortex during development. The hypothesis that developmental exposure to 17-OHPC alters sensorimotor development was tested.

Methods: Sensorimotor behaviors were observed in neonates administered 17-OHPC from the day of birth through postnatal day 11, and PR was quantified in cortex at P11.

Results: 17-OHPC administration resulted in a disruption in sensorimotor indicators of typical brain development, without affecting gross motor function. 17-OHPC-exposed rats had significantly fewer PR-immunoreactive nuclei in somatosensory cortex.

Conclusions: These findings demonstrate that 17-OHPC exposure during critical periods of cortical development may impact sensorimotor development and cortical sensitivity to progestins, highlighting the need for further investigation on the clinical implications of this progestin.

Introduction: Because prolactin excess and hyperthyroidism are often complicated by hyperglycemia and impaired insulin sensitivity, many patients with both these disorders are treated with metformin. This drug inhibits secretory function of overactive anterior pituitary cells, including lactotrophs. The purpose of the current study was to investigate whether metformin action on prolactin oversecretion is impacted by coexisting hyperthyroidism.

Methods: Our prospective, cohort study included two groups of women in reproductive age requiring metformin therapy with mild or moderate hyperprolactinemia. Patients with concomitant grade 1 subclinical hyperthyroidism (group A) and individuals without thyroid pathology (group B) were matched for age, insulin sensitivity, and total prolactin levels. Glucose homeostasis markers, thyroid-stimulating hormone (TSH), free thyroid hormones, total and monomeric prolactin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, adrenocorticotropic hormone, IGF-1, and peripheral markers of thyroid hormone action (ferritin and osteocalcin) were measured before and after 6-month metformin therapy.

Results: At baseline, both groups differed in levels of TSH, free thyroid hormones, ferritin, and osteocalcin. Although metformin reduced glucose, improved insulin sensitivity and reduced total and monomeric prolactin in both groups, these effects were more pronounced in group A than group B. The impact on prolactin in group A correlated with concentrations of free thyroid hormones. Only in group A, did metformin slightly increase FSH and LH concentrations. In women with hyperthyroidism and without thyroid pathology, there were no statistical differences between baseline and follow-up levels of the remaining variables.

Conclusion: The study results suggest that hyperthyroidism potentiates the impact of metformin on secretory function of overactive lactotrophs in reproductive-age women.