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Microglia Rank signaling regulates GnRH neuronal function and the hypothalamic-pituitary-gonadal axis.
Science
Alejandro Collado-Sole, Nozha Borjini, Jing Zhai +23 more
The hypothalamic-pituitary-gonadal axis (HPG) controls pubertal development, sexual maturation, and fertility. We identified a role of hypothalamic microglia in controlling the HPG axis through receptor activator of nuclear factor κβ (Rank) signaling. Whole-body and microglia Rank depletion led to hypogonadotropic hypogonadism (HH) resulting from an alteration in gonadotropin-releasing hormone (GnRH) neuron function. In addition, we identified rare gene variants of RANK in patients with HH. Transcriptional profiling upon Rank loss revealed defective microglia activation and morphological alterations in the median eminence, decreasing the contacts and engulfment of GnRH terminal projections and impairing GnRH neuronal responses to kisspeptin. Overall, our data uncover the microglia as regulator of GnRH neuronal function through Rank signaling, with potential implications for reproductive maturation and fertility.
Exendin-4 enhances GLP-1 signaling and reduces anxiety-like behaviors in male heroin withdrawal mice.
PLoS One
Yang Xiang, Xiaowei Yan, Rongrong Li +7 more
Anxiety and depression significantly contribute to heroin relapse, and addressing these issues could lower relapse rates. The basolateral amygdala (BLA) and nucleus tractus solitarius (NTS) are involved in regulating these emotions, but the molecular mechanisms during heroin withdrawal are not yet understood. Subcutaneous injection of heroin into C57BL/6J mice to simulate chronic dependence, withdrawal, and Exendin-4 treatment. Assess anxiety and depression-like behaviors using open field test (OFT), elevated plus maze (EPM), forced swimming test (FST), and tail suspension test (TST). Analyze neuronal and protein expression changes in the BLA brain area with Western blotting (WB) and immunofluorescence staining. Heroin dependence reduces glutamatergic neurons in BLA without affecting anxiety and depression-like behaviors, due to the inhibitory effect of heroin reward. During withdrawal, GLP-1 secretion by the NTS rises, increasing c-Fos and GLP-1 receptor expression in glutamatergic neurons of BLA, linked to heightened anxiety but not depression. A 7-day treatment with Exendin-4 (2 µg/kg) alleviates anxiety in withdrawal mice by downregulating GLP-1 signaling in the NTS-BLA circuit, indicating GLP-1's role in regulating anxiety during heroin withdrawal. GLP-1 receptors within BLA may serve as molecular targets for modulating emotional states, thereby offering empirical support for strategies aimed at preventing heroin relapse.
Clinical Outcomes Following Supply-Driven Transition From Intranasal to Oral Desmopressin in AVP-Deficiency-A Single Centre Experience Including The Pituitary Foundation Desmopressin Shortage Impact Report.
Clin Endocrinol (Oxf)
Trevor Tam, Amy Mach, Alam Wahid +6 more
Arginine vasopressin deficiency (AVP-D) requires lifelong desmopressin replacement. In March 2025, the national suspension of intranasal desmopressin necessitated urgent transition to oral alternatives. However, optimal conversion ratios and clinical response remain undefined. We evaluated clinical outcomes following this supply-driven transition.
The Use of Glucagon-Like Peptide 1 Agonists Among Non-Diabetics: Evidence From Medicare Part D.
Health Serv Res
Minji Kim, Kieran Allsop, Joseph F Levy
To assess the extent of off-label glucagon-like peptide-1 receptor agonist (GLP-1) prescribing among individuals without diabetes in Medicare Part D.
Incretin and Glucagon Signalling in MASLD and MASH: Integrating Metabolic Pathways With Disease Progression.
Diabetes Obes Metab
Evangelia E Tsakiridis, Gregory R Steinberg
Metabolic dysfunction-associated steatotic liver disease (MASLD) arises from dysregulated interactions between nutrient delivery, adipose tissue lipid handling and liver lipid metabolism, which collectively coalesce to drive inflammatory signalling leading to metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis. Recent clinical success of incretin- and glucagon-based therapies in both diabetes and obesity has intensified interest into how these hormonal pathways modify liver disease progression. In this review, we integrate preclinical and clinical data to examine how glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon engage key pathogenic nodes, including the gut-liver and adipose-liver axes, hepatic lipid synthesis and oxidation, mitochondrial function and nonparenchymal inflammatory responses. GLP-1-based therapies consistently improve steatosis and steatohepatitis through reductions in nutrient flux to the liver, improved adipose tissue insulin sensitivity and weight-independent anti-inflammatory effects, despite limited direct action in hepatocytes. GIP signalling appears to modulate adipose tissue lipid handling and expandability, thereby limiting fatty acid spillover to the liver, although its role in hepatic inflammation remains incompletely defined. In contrast, glucagon receptor activation directly targets hepatocytes to enhance oxidative metabolism and reduce hepatocellular stress. Across studies, improvements in fibrosis appear secondary to sustained reductions in metabolic and inflammatory injury suggesting the addition of anti-fibrotic combination therapies may exert further benefits. Looking ahead, a key challenge will be defining how these hormonal pathways interact within distinct metabolic states and how this greater mechanistic understanding can be leveraged to rationally combine therapies and expand the proportion of patients who respond across the MASLD spectrum.
Neuroendocrine effects of exogenous adropin administration on the hypothalamic pituitary testicular axis in male rats.
Turk J Med Sci
Ersen Eraslan, Ayhan Tanyeli, Mustafa Can Güler +6 more
Obesity impairs male fertility through metabolic dysfunction, oxidative stress, and disruption of the hypothalamic-pituitary-testicular (HPT) axis. Adropin (ADR), a peptide hormone whose circulating levels are reduced in obesity, plays emerging roles in metabolic homeostasis; however, its involvement in reproductive endocrine regulation remains unclear. The present study was conducted in healthy, nonobese male rats and aimed to investigate the neuroendocrine and testicular effects of exogenous ADR administration, focusing on circulating reproductive hormones, hypothalamic regulatory peptides, and testicular antioxidant pathways.
Region and Cell-Selective Induction of Zbtb16/Plzf by Multiple Stressors in the Adult Murine Hypothalamus.
Eur J Neurosci
Mina Roueinfar, Pardis Mohammadzadeh, Luke A Schwerdtfeger +2 more
Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, a neuroendocrine system that regulates responses related to feeding, reproduction, and aggression, among other homeostatic functions. Stressors significantly impact gene expression along the HPA axis and in hypothalamic nuclei that drive it, including the paraventricular nucleus (PVN). To identify genetic regulators of stress responses in the PVN, adult mice underwent 2 h of multi-modal stress before gene expression profiles were analyzed using bulk RNA sequencing. A transcription factor zinc finger and BTB domain containing 16 (Zbtb16), also known as PLZF, was identified as a stress responsive, glucocorticoid receptor (GR) target in the PVN. Zbtb16 mRNA expression was increased by two-fold in male and female mice within 2 h of restraint stress or injection of a synthetic glucocorticoid, dexamethasone (DEX). Immunohistochemistry (IHC) confirmed Zbtb16 protein expression and localization in the PVN following 20 min of restraint stress and 4 h of recovery. Cellular analyses revealed that Zbtb16 was highly expressed in CRH neurons in the PVN, neurons routinely activated post-stress as indicated by colocalization with c-FOS. Adult mice were also exposed to an immune stress by injection of tumor necrosis factor alpha (TNFα) to assess Zbtb16 regulation. Expanded analyses indicated that the cell specificity of Zbtb16 expression was region-specific, colocalizing with CRH neurons in the mid-PVN but more in astrocytes surrounding the PVN. These findings identify Zbtb16 as a glucocorticoid- and cytokine-inducible transcriptional regulator with region- and cell type-specific roles in PVN stress circuitry.
Metachronous Bilateral Adrenal Adenomas Causing Adrenocorticotropic Hormone-Independent Cushing's Syndrome: A Case Report.
Cureus
I-Ting Hsiao, Chieh-Hua Lu
Bilateral adrenal adenomas (BAAs) represent an uncommon etiology of adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome (CS); however, metachronous BAAs, where the adenomas present years apart, are exceptionally rare, with only a few cases previously reported. We present the case of a 53-year-old woman who developed ACTH-independent CS from a left adrenal cortical adenoma 19 years ago, treated successfully with a left-sided adrenalectomy. Nineteen years after the first episode, she presented with classic hypercortisolism symptoms, including central obesity, striae, and osteoporosis. Workup confirmed recurrent ACTH-independent CS with a low baseline ACTH level and a failure of both low- and high-dose dexamethasone suppression tests to suppress cortisol. Laparoscopic-assisted right-sided adrenalectomy was performed after image confirmation. Adrenal cortical adenoma was diagnosed by histological examination. Following the adrenalectomy, the patient required permanent glucocorticoid and mineralocorticoid replacement therapy. Serial brain magnetic resonance imaging (MRI) scans were initiated for Nelson's syndrome (NS) surveillance. Over 38 months of follow-up, the patient's clinical symptoms improved, and no signs of NS were noted. This case represents the longest detailed reported case with an interval of 19 years between the diagnosis and surgical treatment of metachronous BAAs causing ACTH-independent CS. This rarity highlights the critical importance of long-term and regular follow-up for patients with unilateral adrenal adenoma to monitor for subsequent contralateral masses.
VGLL4 modulates Paneth cells and sustains intestinal homeostasis.
EMBO Rep
Haoen Zhang, Zuoyun Wang, Xiaodong Wang +22 more
Paneth cells are defensive cells in the intestinal tract, which secrete niche factors and antimicrobial peptides (AMPs) to maintain the small intestinal stem cell niche and immune homeostasis. Here, we show that Vestigial-like family member 4 (VGLL4) plays a pivotal role in maintaining small intestinal homeostasis and in regulating Paneth cells. VGLL4 expression is downregulated in response to irradiation and DSS-induced colitis. Consistently, public datasets of human colitis show reduced VGLL4 expression. Loss of VGLL4 in the intestinal epithelium decreases Paneth cell numbers and AMPs production, and triggers gut microbiota dysbiosis, impairing intestinal regenerative capacity. Mechanistically, VGLL4 forms a complex with TEAD4 and ATOH1, stimulating GFI1 expression and promoting Paneth cell differentiation. Furthermore, VGLL4 forms a complex with TEAD4 and TCF4 to induce defensin expression, thereby maintaining microbiota composition. Collectively, our findings uncover novel roles for VGLL4 in intestinal homeostasis.
Hypothalamic-Pituitary-Gonadal Axis Disorders Impacting Fertility in Both Sexes and the Potential of Kisspeptin-Based Therapies to Treat Them.
Handb Exp Pharmacol
Maricedes Acosta-Martínez
Impaired function of the hypothalamic-pituitary-gonadal (HPG) axis can lead to a vast array of reproductive disorders some of which are inherited or acquired, but many are of unknown etiology. Among the clinical consequences of HPG impairment, infertility is quite common. According to the latest report from the World Health Organization, the global prevalence of infertility during a person's lifetime is a staggering 17.5% which translate into 1 out of every 6 people experiencing it. In both sexes, infertility is associated with adverse health events, and if unresolved, infertility can cause substantial psychological stress, social stigmatization, and economic strain. Even though significant advances have been made in the management and treatment of infertility, low or variable efficacy of treatments and medication adverse effects still pose a significant problem. However, the discovery that in humans inactivating mutations in the gene encoding the kisspeptin receptor (Kiss1R) results in pubertal failure and infertility has expanded our understanding of the mechanisms underlying the neuroendocrine control of reproduction, opening up potential new therapies for the treatment of infertility disorders. In this chapter we provide an overview of common infertility disorders affecting men and women, their recommended treatments, and the potential of kisspeptin-based pharmacotherapies to treat them.
Influence of N- and O-glycosylation on structural properties and biological activity of a C-terminal LL-37 fragment.
Carbohydr Res
Daria Grzywacz, Francesca Nuti, Krzysztof Żamojć +5 more
Glycosylation represents a versatile strategy in peptide glycoengineering to modulate the structural, physicochemical, and biological properties of antimicrobial peptides (AMPs). In this study, we report the synthesis and characterization of O- and N-glycosylated analogues of the C-terminal fragment of human cathelicidin LL-37 (Ac-DFLRNLVPRTES-COOH), achieved via solid-phase peptide synthesis using Fmoc-Thr(β-d-Glc) and Fmoc-Asn(β-d-Glc) as glycosylated building blocks. The metal-binding affinity of these glycopeptides (N163 and T168) and the unmodified reference peptide (hCAP) toward Cu2+ and Mn2+ ions were evaluated by steady-state fluorescence spectroscopy. All peptides formed non-permanent complexes (Ka = 102 -104 M-1), with the native hCAP exhibiting the highest affinity. Molecular dynamics (MD) simulations revealed that glycosylation reduced conformational flexibility without significantly altering the overall shape of the peptide. Occasional sugar-metal contacts were observed, indicating transient carbohydrate participation in metal coordination. Cytotoxicity studies using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assays confirmed the biocompatibility of all tested peptides, showing low toxicity against human fibroblasts, keratinocytes, and T-cells up to 100 μM. Our results demonstrate that carbohydrate conjugation subtly reshapes peptide-metal ion interactions, and structural dynamics. In this study, glycosylation serves primarily as a chemical model of post-translational modification, designed to probe how the presence of a carbohydrate moiety influences peptide conformation and coordination behaviour, rather than a strategy for enhancing antimicrobial function.
Retatrutide in type 2 diabetes mellitus and obesity: an overview.
Expert Rev Clin Pharmacol
Theodoros Panou, Evanthia Gouveri, Djordje S Popovic +1 more
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used for T2DM and obesity.
Comparative Analysis of Efficacy and Safety of the Glucagon-Like-Peptide-1 Receptor Agonists Tirzepatide and Semaglutide in Solid-Organ Transplant Recipients.
Exp Clin Transplant
Omar El Khatib, Maguy Chiha, Ola Jarad +5 more
Diabetes mellitus, including new-onset diabetes after transplant, is a prevalent complication in solid-organ transplant recipients, often necessitating complex glycemic management. Glucagon-like peptide-1 receptor agonists, including semaglutide and tirzepatide, have shown promising outcomes in the general population, but comparative data in solid-organ transplant recipients are limited. In this study, we evaluated and compared the efficacy and safety of semaglutide and tirzepatide in a diverse cohort of solid-organ transplant recipients.
Novel GLP-1-based Medications for Type 2 Diabetes and Obesity.
Endocr Rev
Jang Won Son, Carel W le Roux, Matthias Blüher +2 more
The approvals of semaglutide and tirzepatide have set new benchmarks in the treatment of type 2 diabetes and obesity. Building on their success, novel glucagon-like peptide-1 (GLP-1)-based therapeutics are rapidly advancing. These next-generation agents engage not only GLP-1 receptors but also those for other gastro-entero-pancreatic hormones such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, amylin, and peptide YY to enhance energy uptake, storage, and expenditure through synergistic mechanisms. Both GIP receptor agonism and antagonism, particularly in combination with GLP-1 receptor agonism, have shown promise. Maridebart cafraglutide, combining GLP-1 receptor agonism with GIP receptor antagonism, exemplifies this innovative approach. Glucagon coagonists like survodutide and mazdutide have demonstrated significant weight loss and improved glycemic control. Amylin-based agents, including CagriSema (cagrilintide + semaglutide) and amycretin, enhance satiety and glycemic outcomes through complementary actions. Further innovation is seen in triple agonists such as retatrutide, which targets GIP, GLP-1, and glucagon receptors to amplify metabolic effects. Meanwhile, the emergence of orally active small-molecule GLP-1 receptor agonists like danuglipron and orforglipron, which are resistant to enzymatic degradation, marks a major advance in patient-friendly drug delivery. This review explores the mechanisms, clinical development, and therapeutic potential of these novel agents, excluding already approved drugs like liraglutide, semaglutide, and tirzepatide. We highlight how multireceptor agonists and oral GLP-1-based therapies may reshape the future landscape of obesity and type 2 diabetes treatment by offering more effective and better-tolerated options.
The Association Between Suicidal Ideation, Personality Traits, and Stress Hormones in Final-Year Medical Students.
Early Interv Psychiatry
Feyza Nur Ozbahar, Hamit Sirri Keten, Seyithan Taysi
This study aims to investigate the relationship between suicide risk, personality traits, and stress-related hormone levels among final-year medical students.
A rare case report of familial glucocorticoid deficiency type 4 (GCCD4) with dilated cardiomyopathy: a 3-year follow-up study.
Transl Pediatr
Zeli Xun, Yan'an Du, Ting Zhao +1 more
Familial glucocorticoid deficiency type 4 (GCCD4), caused by nicotinamide nucleotide transhydrogenase (NNT) gene mutations, represents a rare multisystem disorder with poorly characterized cardiac manifestations.
Characterization of membrane-interaction mechanisms of proteins using vacuum-ultraviolet circular dichroism spectroscopy.
Chirality
Munehiro Kumashiro, Koichi Matsuo
Protein-membrane interactions play an important role in various biological phenomena, such as material transport, demyelinating diseases, and antimicrobial activity. We combined vacuum-ultraviolet circular dichroism (VUVCD) spectroscopy with theoretical (e.g., molecular dynamics and neural networks) and polarization experimental (e.g., linear dichroism and fluorescence anisotropy) methods to characterize the membrane interaction mechanisms of three soluble proteins (or peptides). α1 -Acid glycoprotein has the drug-binding ability, but the combination of VUVCD and neural-network method revealed that the membrane interaction causes the extension of helix in the N-terminal region, which reduces the binding ability. Myelin basic protein (MBP) is an essential component of the myelin sheath with a multi-layered structure. Molecular dynamics simulations using a VUVCD-guided system showed that MBP forms two amphiphilic and three non-amphiphilic helices as membrane interaction sites. These multivalent interactions may allow MBP to interact with two opposing membrane leaflets, contributing to the formation of a multi-layered myelin structure. The antimicrobial peptide magainin 2 interacts with the bacterial membrane, causing damage to its structure. VUVCD analysis revealed that the M2 peptides assemble in the membrane and turn into oligomers with a β-strand structure. Linear dichroism and fluorescence anisotropy suggested that the oligomers are inserted into the hydrophobic core of the membrane, disrupting the bacterial membrane. Overall, our findings demonstrate that VUVCD and its combination with theoretical and polarization experimental methods pave the way for unraveling the molecular mechanisms of biological phenomena related to protein-membrane interactions.
Antimicrobial Peptides (AMPs) Are Not Increased in Asymptomatic Bacteriuria in Healthy Older Adult Patients.
J Am Geriatr Soc
Katherine M Hunold, Andrew Schwaderer, Julie A Stephens +8 more
Antimicrobial peptides have demonstrated promise as biomarkers for urinary tract infection (UTI) in older adults (age ≥ 65 years). However, it is unknown if urinary AMP levels also increase in asymptomatic bacteriuria. Our objective was to determine if AMP levels vary between older adult patients with and without asymptomatic bacteriuria.
Body Weight Support Treadmill Training Combined With Sciatic Nerve Electrical Stimulation Ameliorating Motor Function by Enhancing PI3K/Akt Proteins Expression via BDNF/TrkB Signaling Pathway in Rats with Spinal Cord Injury.
World Neurosurg
Qingqin Xu, Zhen Li, Junhong Su +5 more
To investigate the effects of body weight support treadmill training (BWSTT) and sciatic nerve electrical stimulation (SNES) on motor function recovery in spinal cord injury (SCI) rats and its possible mechanism.
Cholinergic neurons in the dorsal nucleus of the vagus nerve are involved in the mechanism of action of electroacupuncture at HT7 in a mouse model of chronic heart failure.
Acupunct Med
Shi-Yue Wang, Hao-Sheng Wu, Sheng-Bing Wu +1 more
To investigate the role and mechanism of the dorsal motor nucleus of the vagus nerve (DMV) in the effects of electroacupuncture (EA) at HT7 in a mouse model of chronic heart failure (CHF).