Journal of Neuroendocrinology最新文献

Locally advanced neuroendocrine neoplasms (NENs) are defined by extensive local invasion in the absence of distant metastases, although specific definitions may vary among study groups. While most patients with NENs present with localized or metastatic disease, a smaller subset is diagnosed with locally advanced tumors. Management of this subgroup remains particularly challenging, owing to the limited evidence base and lack of consensus regarding optimal therapeutic strategies. This guidance document synthesizes the current evidence and expert knowledge on the management of locally advanced NENs of the small intestine and pancreas, addressing four clinically relevant key questions that aim to inform best practice in these patients.

Osmoregulation is an essential homeostatic process that maintains the osmolality of the extracellular fluid (ECF) close to a physiological setpoint. Vasopressin (VP) plays a key role in osmoregulation and is secreted by the magnocellular neurosecretory cells (MNCs) of the hypothalamus. MNC electrical activity and VP release increase with elevations of ECF osmolality. MNC osmosensitivity depends on a mechanosensitive N-terminal variant of the transient receptor potential vanilloid type 1 (ΔN-TRPV1) channel that activates in response to osmotically induced cell shrinkage. ΔN-TRPV1 mechanosensitivity depends on their association with microtubules in the MNC cytoskeleton and is modulated by a dense layer of submembranous actin in MNC somata. MNCs exposed to sustained increases in osmolality, however, undergo marked somatic hypertrophy, which suggests that other mechanisms may be important to maintain VP release. Recent evidence suggests that the translocation of ΔN-TRPV1 (and possibly other channels) to the MNC cell surface could contribute to osmotically induced long-term increases in MNC excitability. Osmotically induced ion channel translocation is dependent on MNC firing, Ca²⁺ influx through L-type Ca²⁺ channels, the activation of phospholipase C δ1 and protein kinase C, and soluble N-ethylmaleimide-sensitive factor attachment protein receptor-dependent exocytotic fusion. Other recent work has explored osmotically induced changes in the MNC cytoskeleton that may be related to hypertrophy and ion channel translocation. MNCs may also be activated by elevations in extracellular Na⁺ through the activation of the Na⁺-sensitive Na⁺ channel, Na_X. This review highlights recent advancements in our understanding of long-term MNC regulation at the cellular level.

Benzophenones (BPs) are widely used as ultraviolet (UV) filters in personal care products, plastics, and food packaging. Although they serve as effective photoprotective agents, growing evidence suggests that BPs can act as endocrine-disrupting chemicals (EDCs), interfering with hormone regulation and reproductive functions. This review summarizes the current knowledge on BP exposure, metabolism, and their potential effects on reproductive health. We discuss the mechanisms by which BPs interact with hormonal receptors, alter steroid metabolism, and influence the hypothalamic–pituitary–gonadal axis. Special attention is given to BP-2 and BP-3, which have been detected in human biological samples, including urine, blood, and fetal tissues. Additionally, we highlight recent findings from in vitro and in vivo studies demonstrating their estrogenic activity and potential impact on reproduction. The review also addresses regulatory concerns, emphasizing the need for stricter policies to limit human and environmental exposure to BPs. Understanding the effects of these chemicals is essential for assessing their safety and developing alternatives to mitigate potential health risks.

The maintenance of extracellular fluid (ECF) osmolality and sodium concentration ([Na⁺]_o) near optimal “set point” values sustains physiological functions and prevents pathological states such as hypo- and hypernatremia. The peptide hormones vasopressin (antidiuretic hormone) and oxytocin (a natriuretic hormone in rats) play key roles in this process. These hormones are synthesized by hypothalamic magnocellular neurosecretory cells (MNCs) that project to the neurohypophysis and are released into the systemic circulation in response to rises in ECF osmolality or [Na⁺]_o. These homeostatic responses are highly sensitive. For example, vasopressin release is elicited by an increase in ECF osmolality as small as ≥1%. The osmotic and sodium-dependent control of vasopressin and oxytocin release at the neurohypophysis is directly regulated by the electrical activity of MNCs. This regulation involves an array of mechanisms that include synaptic inputs from the brain and periphery, the effects of chemicals released by glial cells, and intrinsic sensory properties of MNCs. These overlapping mechanisms may offer an important degree of redundancy for the homeostatic control of vasopressin and oxytocin release and contribute to the high sensitivity of these responses. Recent work has shown that the intrinsic sodium sensitivity and osmosensitivity of MNCs play an important role in the control of these neurons in vivo. This review provides an update of our current understanding of the molecular and cellular mechanisms that contribute to the cell-autonomous sensory properties of MNCs.

In most species, individuals must be able to identify threats, peers, and potential mates to survive. The distinction of kin from non-kin and novel conspecifics from familiars is essential to the successful categorization of these identities. Although oxytocin (OXT) signaling has been implicated in social recognition, little is known about the contributions of distinct OXT-producing cell groups to distinguishing conspecific type. To determine whether OXT-producing neuronal populations differentially respond to novelty or kinship status, we conducted immediate early gene tests in male spiny mice (Acomys dimidiatus), a communally breeding species that we previously showed distinguishes between novelty and kinship status. Immunohistochemical analysis of brain tissue revealed that the OXT cell populations in the paraventricular nucleus of the hypothalamus and the anterior hypothalamus did not differentially respond to the kinship or novelty status of same-sex conspecifics. However, while OXT-producing neurons in the bed nucleus of the stria terminalis did not distinguish between kin and non-kin spiny mice, this cell group was more responsive to familiar than novel conspecifics. These results suggest that extrahypothalamic OXT neurons may be involved in aspects of processing the novelty status of a conspecific.

Sleep and circadian rest-activity rhythm alterations are recognised as inherent clinical features of various neurodegenerative diseases. Traditionally viewed as secondary manifestations of neurodegeneration, recent studies have revealed that disruptions in circadian rhythm and sleep–wake cycles can precede clinical symptoms and significantly contribute to the underlying pathophysiological progression. In this review, we summarise recent research on the impact of sleep and circadian rhythm alterations in ageing and major neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and frontotemporal dementia, highlighting the roles of melatonin, orexin, and melanin-concentrating hormone (MCH) systems as key regulators at the intersection of sleep and neurodegeneration. We argue that sleep and circadian alterations may serve as early biomarkers and therapeutic targets for these diseases.

In hippocampus, androgens and estrogens influence neuronal plasticity via a range of nuclear or membrane-bound receptors. While much work has focused on determining their functions, a certain vagueness about the cellular expression of established receptors has remained. Moreover, novel candidates, such as the androgen-responsive zinc-transporter ZIP9, need to be inserted into the emerging picture. We used highly-sensitive RNAscope in situ hybridization and quantitative real-time PCR to examine the cellular and total hippocampal mRNA expression of androgen (AR, ZIP9) and estrogen receptors (ERα, ERβ, GPER1) in adult mouse hippocampus, considering sex and estrous cycle as variables. (1) Androgen receptors are more abundantly expressed than estrogen receptors. (2) AR and ZIP9 mRNA regularly co-localize in hippocampal neurons, but ZIP9 mRNA is more homogenously distributed and also expressed in astrocytes and microglia. (3) ERα and GPER1 are the predominant estrogen receptors (ERβ mRNA was very low), but exhibit differential expression patterns: GPER1 mRNA is preferentially expressed in glutamatergic neurons, while ERα is specifically expressed in a subpopulation of GABAergic interneurons. Both receptors were barely detectable in astrocytes and microglia. (4) ZIP9 mRNA expression varies during the estrous cycle, being significantly down-regulated if serum E2 is high, whereas ERα mRNA expression was generally higher in females. We provide a comprehensive cellular and quantitative expression analysis of androgen and estrogen receptors in adult mouse hippocampus, including for the first time mRNA expression data on ZIP9. Our data underline the necessity to consider sex and estrous cycle when studying sex hormone functions.

Neuroendocrine neoplasms (NENs), once considered rare, are now increasingly diagnosed worldwide, with gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) accounting for the majority of cases (55%–70%). NENs are characterized by considerable heterogeneity, driven by factors such as tumor differentiation, Ki-67 index, primary tumor location, somatostatin receptor status, and disease stage. International guidelines advocate for a multidisciplinary approach to ensure individualized treatment strategies. Given the disease's complexity, artificial intelligence (AI) may offer substantial support in the management of NENs. AI is playing an increasingly prominent role in medicine by enabling advanced diagnostic capabilities through machine learning and deep learning algorithms, particularly in imaging. However, current literature on AI applications in NENs is limited, and their routine use in clinical practice has yet to be established. This narrative review aims to provide a comprehensive overview of the potential roles of AI in the diagnosis of GEP-NENs, while also addressing the associated biases and ethical considerations of medical AI implementation.

Corticotropin-releasing factor (CRF) plays roles in stress-related responses through its type 1 (CRF₁) and type 2 receptors. Both CRF and CRF₁ are expressed in the rat colon. Peripheral CRF administration and various stressors increase colonic motility and defecation. Stress induces CRF release in the colon, suggesting CRF may mediate stress-related responses of the colon. The vagal nodose ganglion (NG) transduces visceral information, including colonic sensation, to the brain. However, it remains unclear whether the CRF/CRF₁ system is involved in vagal afferent functions. This study, therefore, aimed to clarify the involvement of the CRF/CRF₁ system in relaying visceral sensory information to the brain and the effect of stress exposure on vagal nerve function. The experiments were conducted in male rats. First, CRF₁-like immunoreactivity (CRF₁-LI) was characterized in the NG. Second, the effects of vagotomy on CRF₁-LI in the NG, intraperitoneally administered CRF-induced fecal output, and c-Fos expression in the nucleus tractus solitarius (NTS) were evaluated. Subsequently, a fast blue retrograde tracer was microinjected into the proximal colon. Finally, we analyzed CRF- or stress-induced phosphorylation of cyclic AMP-response element-binding protein (pCREB) in the NG. CRF₁ mRNA and CRF₁-LI were detected, and CRF₁-LI accumulated on the proximal side of the ligated region of the nerve trunk, and CRF₁-LI was detected in most cholinergic neurons. CRF₁ siRNA suppressed the expression of CRF₁-LI in the NG. Subdiaphragmatic vagotomy decreased the number of CRF₁-positive cells in the NG while it did not affect CRF-induced fecal output. CRF-induced c-Fos expression in the NTS was suppressed by vagotomy. A neuronal tracing study showed that approximately half of CRF₁-positive cells expressed fast blue in the NG. Intraperitoneal CRF, a selective CRF₁ agonist, or immobilization stress induced pCREB expression and increases in CRF₁-positive cells in the NG. In contrast, a CRF₁ antagonist reduced the immobilization-induced increase in the expression of pCREB in the NG. These results suggest that the CRF/CRF₁ system is involved in the signal transduction of colonic sensory information to the central nervous system via the NG.

In patients with gastroenteric and pancreatic neuroendocrine neoplasms (GEP-NENs), the risk of liver metastases is high, but the accuracy of standard imaging for detecting small hepatic nodules is limited. This raises concerns about the adequacy of staging in cM0 patients. This study aims to determine the percentage of cM0 GEP-NEN patients with occult liver metastases that can be identified using intraoperative ultrasound (IOUS) during surgery for the primary tumor. A prospective study was conducted at three high-volume centers between October 2020 and December 2023. Patients who underwent surgery for GEP-NENs staged as cM0 based on CT and PET/CT (MRI in selected cases) were included. IOUS was systematically performed, in combination with contrast-enhanced IOUS (CE-IOUS) and biopsy when necessary. The ground truth was the result of a contrast-enhanced CT or MRI performed 6 months after surgery. A total of 51 cM0 GEP-NEN patients were enrolled. IOUS detected suspicious liver nodules in seven patients (14%). Three were classified as metastatic based on the IOUS pattern, CE-IOUS pattern, and biopsy, respectively, while four were classified as non-metastatic based on biopsy (n = 2) or CE-IOUS pattern (n = 2). At six-month follow-up imaging, two patients (4%) were confirmed as metastatic (the suspicious metastasis at CE-IOUS was not confirmed). GEP-NENs G3 and those with necrosis had a higher risk of metastases (one-third of patients, p < 0.05 compared to G1-2 and non-necrotic neoplasms). IOUS, combined with CE-IOUS and biopsy, achieved 100% sensitivity, 98% accuracy, and 100% negative predictive value. IOUS, along with CE-IOUS and biopsy, provides accurate staging in GEP-NENs, identifying occult metastases in approximately 4% of cM0 cases. Due to the low incidence of occult metastases, routine use of IOUS cannot be recommended. It should be considered selectively in aggressive tumors, which have shown a significantly higher risk of liver involvement.