Pubertal development is associated with changes in hypothalamic-pituitary-adrenal (HPA) axis reactivity, which may contribute to the increase in stress-related vulnerabilities observed during adolescence. In particular, prepubertal rats show significantly protracted stress-induced HPA responses compared to adults. However, the neuroendocrine mechanisms responsible for this developmental change are unclear. In adults, the orexigenic neuropeptide orexin-A has been shown to be a potent modulator of HPA reactivity, and activation of orexin-A neurons aligns with the magnitude of the hormonal stress response. However, it is currently unknown whether pubertal differences in HPA reactivity are associated with changes in orexin-A neurons. We examined the hormonal stress response and the number of activated orexin-A neurons in the lateral hypothalamus by co-labeling with c-Fos, a marker of cellular activation, before, during, or after stress exposure in prepubertal (30d) and adult (70d) male and female rats. The number of immunoreactive orexin-A neurons was also quantified in prepubertal (30d), mid-pubertal (45d) and adult (70d) males and females. We found significantly prolonged stress-induced hormonal responses in prepubertal males and females compared to their adult counterparts. However, we found no developmental differences in either the number of orexin-A cells or their stress-induced activation in either sex. These data suggest minimal association between stress-induced activity of orexin-A neurons and pubertal-related differences in hormonal stress reactivity. However, these data indicate that the number of orexin-A cells is relatively stable throughout adolescent development, and that orexin-A neurons are sensitive to stressors prior to pubertal maturation.

Background: The circadian rhythm is an intrinsic, approximately 24-h cycle of physiological, behavioral, and psychological changes formed through organisms’ long-term evolutionary adaptation to the 24-h light-dark cycle on Earth. It regulates the body’s homeostatic processes according to a daily schedule, ensuring the proper execution of physiological processes and the stability of the internal environment. In recent years, numerous studies have indicated crosstalk between the circadian rhythm and neuroinflammation. Disruption of the circadian rhythm can influence the onset and progression of various acute and chronic central nervous system diseases. Summary: This review outlines the basic components and mechanisms of the circadian timing system and divides the development of neuroinflammation into several parts: initiation of neuroinflammation, glial cell activation, disruption of the neurovascular unit, oxidative stress response, and cellular energy metabolism. By revealing the role of circadian mechanisms in each part, the relationship between the biological clock and neuroinflammation is analyzed from a molecular biology perspective, aiming to provide a new theoretical basis for the clinical intervention of neuroinflammation and the treatment of related diseases. Key Messages: Disrupted circadian rhythms participate in various stages of neuroinflammation through “crosstalk,” making them a factor that cannot be ignored in the treatment of neurological disorders.

Background: Acute mountain sickness (AMS) strikes people who travel too quickly to high altitude, outstripping their ability to acclimatize. Individual susceptibility to AMS remains unpredictable. The aim of study was to investigate the neuroendocrine mechanisms regulation of corticotropin-releasing hormone (CRH) and associated with AMS. Methods: Volunteers performed exercise by cycling or by running, and the other was assigned to ascend from low to high altitude. CRH and cortisol levels were tested. AMS questionnaires were answered by volunteers. Rats were exposed in a hypobaric chamber for altitude hypoxia. CRH, Crhr1mRNA, and corticosterone levels were measured. LDH and O2 saturation were evaluated. Results: In rats, hypobaric hypoxia resulted in increased CRH release and mRNA expression in the paraventricular nucleus (PVN). Hypobaric hypoxia also upregulated Crhr1mRNA in the pituitary and PVN in a hypoxia exposure-dependent manner, along with activation of apoptotic gene mRNA and neuronal apoptosis in cortex. These effects were associated with activation of CRHR1. Hypoxia-enhanced plasma CRH levels were negatively correlated with brain CRH level but positively with plasma corticosterone in rats. In humans, exercise at low altitude increased CRH and cortisol levels in both plasma and saliva. The increased levels in plasma correlated with increased salivary CRH. Significantly, lowlanders with high plasma CRH at low altitude developed AMS after rapid ascent to the Tibet plateau. At high altitude, lowlanders with high AMS scores had high salivary and plasma CRH levels. Conclusions: Hypobaric hypoxia is associated with high plasma CRH in rats. In humans, strong activation of CRH and CRHR1 is positively linked to AMS. CRH levels in saliva or plasma appear to predict individual responses to hypoxia.

Background: N-methyl-D-aspartate receptors (NMDARs) are widely distributed in the brain and pancreas. Preliminary evidence indicates that aberrant NMDAR-mediated glutamatergic signaling may disrupt pancreatic islet function and glucose-insulin homeostasis. The frequent comorbidity of depression and diabetes underscores the potential role of NMDAR signaling in pancreatic function as a shared pathophysiological mechanism. Herein, this systematic review aims to evaluate the effects of NMDAR antagonism on pancreatic cells (i.e., alpha, beta, delta) viability and function (i.e., activation, hormone production, and release). Methods: We performed a systematic search on PubMed and Ovid databases from inception to September 11, 2024. A manual search was also conducted on Google Scholar and Scopus databases. Eligible studies were primary, controlled in vitro or in vivo studies investigating the effects of NMDAR antagonism on pancreatic islet function and viability. Results were synthesized and presented descriptively. Risk of bias was assessed independently by two reviewers using a modified SYRCLE risk of bias tool. Results: We reviewed 14 studies evaluating NMDA receptor antagonism in whole islets, beta and alpha cells; however, no studies evaluated delta cells. Within beta cells, NMDAR antagonism improved glucose-stimulated insulin secretion and increased cell proliferation and viability. Similarly, alpha cells were protected against stress-induced apoptosis. Conclusion: Our results suggest that NMDAR antagonism improves alpha and beta cell function and viability, which may have translational relevance to comorbid metabolic dysfunction in depression. These mechanisms may subserve the antidepressant effects of select NMDA antagonists (e.g., ketamine/esketamine, dextromethorphan). Further research should aim to investigate the effects of subanesthetic doses of ketamine/esketamine on pancreatic function and on delta cells.

Background: Autoimmune thyroid disease is an autoimmune disease. Observational studies have shown that individuals with thyroid dysfunction have dyslipidaemia. However, it is uncertain whether there is a causal relationship between the two. Therefore, the purpose of this study was to evaluate the causal relationship between plasma liposomes and autoimmune thyroid disease, thereby providing new insights into disease mechanisms and potential therapeutic targets. Method: We used two-sample Mendelian randomization (MR) to elucidate the causal relationship between plasma liposomes and autoimmune thyroid disease. We divide autoimmune thyroid disease into three types: autoimmune hyperthyroidism, autoimmune hypothyroidism, and autoimmune thyroiditis. The IVW method is the main analysis method, and Cochran Q test is used. MR-Egger intercept, leave-one-out test, and other tests are used to explore whether there are heterogeneity and pleiotropy in MR results. Result: MR analysis revealed causal relationships between eight plasma lipoproteins and autoimmune hyperthyroidism. Eleven causal relationships were identified between plasma lipoproteins and autoimmune hypothyroidism, including cholesterol ester (27:1/16:0) and cholesterol ester (27:1/18:2). Sixteen plasma lipoproteins have been confirmed to have causal relationships with autoimmune thyroiditis, including cholesterol ester (27:1/20:3) and sphingosine (d40:2) levels, which are associated with an increased risk of autoimmune thyroiditis, while phosphatidylethanolamine (18:2:0:0) levels are associated with a reduced risk of autoimmune thyroiditis. A series of sensitivity tests also confirmed the reliability of the results. Conclusion: According to this MR study, an established study, there is a causal relationship between plasma liposomes and autoimmune thyroid disease, which provides fresh insights into the potential mechanisms of autoimmune thyroid disease that may contribute to the development, prevention, and treatment of autoimmune thyroid disease.

Introduction: Metastatic liver pancreatic neuroendocrine tumors (PNETs) can be treated with ischemia-based trans-arterial embolization/trans-arterial chemo-embolization or radiation-based trans-arterial radioembolization (TARE). Guidelines for treatment selection are limited. The purpose of this study was to measure the effect of loss of DAXX/ATRX protein expression on ischemia and radiation sensitivity in Bon-1 and QGP-1 cells, and to compare TARE response in PNETs with and without a DAXX/ATRX mutation. Methods: This was a laboratory investigation and retrospective review of an institutional database of TARE-treated PNET patients. Ischemia and radiation sensitivity were tested on Bon-1 and QGP-1 cells and CRISPR-generated DAXX (C16/C45) and ATRX (QAX12/QAX24) knockouts. Post-ischemia and postradiation cell viability, survival fraction, and caspase-3 expression were measured. Local progression-free survival (LPFS) was measured from time of TARE to local progression or death and estimated using Cox proportional hazards. Results: Post-ischemia DAXX (C16/C45) and ATRX (QAX12/QAX24) knockouts had increased cell viability compared with Bon-1 wild-type cells (p < 0.0001, days 3, 5) and QGP-1 wild-type cells (p < 0.0001, days 3, 5, 7). Postradiation C16/C45 and QAX12/QAX24 had decreased survival fraction compared with respective wild type (p < 0.0001, all cell lines). C16/C45 had decreased apoptotic activity post-ischemia and increased apoptotic activity postradiation compared with wild type (p < 0.0001, all cell lines). Presence of DAXX/ATRX mutation was associated with longer LPFS after TARE (p < 0.001). Median LPFS after TARE was 6 months in wild type compared with 22 months in patients with DAXX/ATRX mutation. Conclusion: Loss of DAXX/ATRX protein expression is associated with ischemia resistance and radiation sensitivity in Bon-1 and QGP-1 cells and longer LPFS after TARE in PNET patients.

Plain Language SummaryPatients with lung carcinoids (a type of lung cancer) are rare, which makes research challenging. Current tools to understand the risks these patients face and how long they might survive with the cancer are limited to the basic diagnosis and tools for managing patients with more common lung cancers. This limits the information available to aid clinical management of patients with lung carcinoids. We collected information from more than 360 patients from two hospitals: the Christie (UK) and Vall d’Hebron (Spain); we believe this is the largest study of this kind. We set out to understand how useful various types of information are to predict how long these patients are likely to live. This information may help inform treatment decisions for future patients. We present our results and propose a new tool to estimate how likely a patient is to live before their disease spreads (called metastasis-free survival) and also how long they are likely to live overall when the tumour has spread in the body (called overall survival). We identified lactate dehydrogenase (a protein measured in blood) as a promising biomarker for metastasis-free survival and discovered that a history of smoking means a patient is likely to live for a shorter time than a patient without a smoking history. To our knowledge, this is the first time that such an association between smoking and overall survival is described in this rare cancer that is currently classified as not related to smoking history. We believe these findings to be important to inform decision-making with patients.

Plain Language SummaryIn the last decades, increasing relevance has been recognized for gender as a key determinant in human pathologies and cancer, paving the way for the Gender Medicine field. The role of sex has emerged as fundamental in oncology, with clear differences in cancer epidemiology, biology of the tumors, clinical presentation, and response to treatments. L-NETs account for approximately 30% of well-differentiated NET and are characterized by extreme heterogeneity in terms of biologic aggressiveness and clinical course. A role has been reported for gender, suggesting the existence of differences between males and females with these tumors, but a critical review of this issue is missing. Our review aimed to fill this gap by exploring the available data about the role of sex in L-NETs, providing a detailed analysis of the current literature and a critical overview. We believe our findings could serve as a valuable resource for both researchers and clinicians.

Introduction: Peripheral nerve injuries, such as sciatic nerve transection (SNT), are often associated with significant sensory and motor deficits. Growth hormone (GH) and gonadotropin-releasing hormone (GnRH) have been shown to exert neurotrophic effects that can promote nerve regeneration and functional reinnervation. However, the combined impact of these hormones on peripheral nerve repair remains poorly understood. Methods: This study aimed to analyze the individual and combined effects of GH and GnRH in a rat model of SNT, using orchiectomized male rats to prevent steroid-mediated neuroregeneration and neuroprotection. Treatments included GH, GnRH, or a combination of both, with subsequent assessments of motor and sensory function, as well as histological and molecular analyses of the nerve tissue and associated muscles. Results: The results revealed that both GH and GnRH significantly enhanced nerve regeneration and neural function when administered individually. Treated animals exhibited improved axonal growth, myelination, and sensory and motor functional recovery. In addition, GH and GnRH reduced neuroinflammation/reactive gliosis, as evidenced by the downregulation of TNFα, IL-1β, Iba-1, and GFAP, which are typically elevated following nerve injury. These findings indicate that each hormone independently supports critical aspects of nerve repair and functional restoration after injury. Surprisingly, when GH and GnRH were administered together, their beneficial effects were not additive. Instead, the combination of the two treatments led to diminished outcomes in comparison to either treatment alone. Specifically, animals receiving the combined therapy showed reduced axonal organization, impaired myelination, and less functional improvement. Conclusion: GH and GnRH demonstrate considerable potential as individual therapeutic agents for promoting peripheral nerve regeneration, each providing significant benefits in terms of axonal growth, functional recovery, and reduction of neuroinflammation.

Background: Adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH) are essential regulators of cortisol production within the hypothalamic-pituitary-adrenal (HPA) axis. Elevated cortisol levels, resulting from excessive ACTH, can lead to Cushing’s syndrome, a condition associated with significant morbidity. Neuroendocrine tumors (NETs) can ectopically produce both ACTH and CRH, a rare phenomenon that further contributes to this syndrome. Summary: This review discusses the pathophysiology, types, clinical presentation, diagnosis, and management of NETs that ectopically secrete CRH and ACTH. Particular emphasis is placed on the importance of identifying dual CRH/ACTH secretion, which complicates diagnosis and treatment. Furthermore, the review highlights the prognosis, common complications, and future directions for research in this area. We further report the case of a 53-year-old female patient who presented with severe Cushing’s syndrome and was diagnosed with ectopic ACTH syndrome. Despite initial findings suggesting pituitary-dependent hypercortisolism, further investigations revealed the presence of a highly differentiated, atypically located tumor in the lung. Immunohistochemistry of the tumor tissue demonstrated not only ACTH but also CRH and CRH-R1 expression. The simultaneous expression of these molecules supports the hypothesis of a positive endocrine feedback loop within the NET, in which the release of CRH stimulates ACTH expression via binding to CRH-R1. Key Messages: This case report highlights the challenges in diagnosing and managing ectopic ACTH syndrome, emphasizing the importance of a comprehensive diagnostic approach to identify secondary factors influencing cortisol production, such as CRH secretion and other contributing neuroendocrine mechanisms. Recognizing the dual secretion of CRH and ACTH in NETs is crucial for accurate diagnosis and optimizing patient management.