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Ectopic ACTH-dependent Cushing syndrome due to mature ovarian teratoma.
BMJ Case Rep
Naseem Eisa
Ectopic adrenocorticotropic hormone (ACTH) secretion accounts for 10%-20% of ACTH-dependent Cushing syndrome, with ovarian teratomas being an exceptionally rare source. We present a female in her early 40s with severe Cushing syndrome due to ectopic ACTH secretion from a mature ovarian teratoma. She presented with progressive weight gain, moon facies, dorsocervical fat pad, proximal muscle weakness, hypertension and new-onset diabetes. Biochemical evaluation confirmed ACTH-dependent hypercortisolism with elevated cortisol, plasma ACTH, late-night salivary cortisol, urinary free cortisol and failure of dexamethasone suppression. Bilateral inferior petrosal sinus sampling (IPSS) confirmed an ectopic source. After negative pituitary and thoracoabdominal imaging, pelvic imaging identified a large right ovarian mass. Laparoscopic salpingo-oophorectomy was performed, and histopathology confirmed a mature cystic teratoma with ACTH-positive neuroendocrine cells. Postoperatively, the patient achieved complete clinical and biochemical remission with full hypothalamic-pituitary-adrenal axis recovery at 1 year follow-up. This case underscores the systematic diagnostic approach required for ectopic ACTH syndrome-including biochemical confirmation, IPSS to distinguish pituitary from ectopic sources and comprehensive imaging-as well as the importance of considering uncommon tumour sites, including ovarian teratomas, when standard thoracoabdominal imaging is unrevealing.
Growth hormone-releasing hormone attenuates amyloid deposition and neuroinflammation in Alzheimer's disease models.
Cell Death Dis
Francesca Pedrolli, Giulia Morello, Iacopo Gesmundo +8 more
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, tau hyperphosphorylation, neuroinflammation, and synaptic loss. Existing therapies provide only modest symptomatic relief and fail to slow disease progression. Beyond its role in promoting pituitary growth hormone (GH) secretion, growth hormone-releasing hormone (GHRH) has shown neuroprotective effects in experimental ischemic stroke and spinal muscular atrophy. Here, we explored the therapeutic potential of GHRH and its agonist MR-409 in AD models. In vitro, GHRH(1-44)NH₂ promoted survival, proliferation, and neuronal differentiation of rat hippocampal neural stem cells (NSCs) and human SH-SY5Y neuroblastoma cells under growth factor deprivation and amyloid beta (Aβ)1-42 exposure. These effects involved the cAMP/PKA/CREB, ERK1/2, and PI3K/Akt signaling pathways. GHRH also attenuated Aβ-induced neurotoxicity by reducing apoptosis, suppressing GSK-3β activity and tau phosphorylation, restoring nuclear β-catenin, and inhibiting NF-κB-mediated inflammation. In vivo, subcutaneous administration of MR-409 in 5xFAD mice reduced Aβ deposition, tau phosphorylation, gliosis, and proinflammatory cytokine expression. In addition, MR-409 mitigated neuronal and synaptic loss, activated survival and neurogenic pathways, and improved cognitive performance, without altering systemic GH and IGF1 levels. MR-409 also elevated NRF2 mRNA expression while reducing its negative regulator KEAP1. Overall, these findings indicate that GHRH and its analog MR-409 exert neuroprotective effects by modulating key pathological features of AD, including neurodegeneration, impaired neurogenesis, neuroinflammation, and oxidative stress. Given their ability to modulate multiple pathological pathways, GHRH agonists may represent promising therapeutic candidates for AD and other neurodegenerative disorders.
Astrocytic K+ regulation during neurodegenerative diseases.
Front Aging Neurosci
Evgeniia Samokhina, Yossi Buskila
Neurodegenerative diseases are a group of chronic, progressive disorders characterized by the gradual loss of neurons in specific areas of the central nervous system. Historically, a "neurocentric" paradigm viewed glial cells, such as astrocytes, as cells that provided adequate support for neuronal energy metabolism and controlled local cerebral blood flow. However, studies from the past two decades found that astrocytes are involved in synaptic function through different mechanisms, including the uptake of extracellular glutamate molecules and potassium ions following synaptic neuronal transmission. Also, astrocytes respond to neurotransmitters and neuromodulators through alterations of intracellular ion concentrations (e.g., Na+, Ca2+, K+) and the release of gliotransmitters. Astrocytes play a pivotal role in preserving potassium homeostasis within the central nervous system through their potassium channels, a process known as "potassium clearance." Impaired astrocytic potassium clearance mechanisms can result in neuronal hyperexcitability, leading to increased glutamate release, overactivation of glutamate receptors, and cytotoxicity. Recent studies suggest that these factors can cause cell death and neurodegeneration, and further indicate a region-specific glial dysfunction in neurodegeneration, which reflects the heterogeneity of glial cell function and sensitivity across different brain regions. Overall, this manuscript offers novel insights into a relatively new concept that glial cells can actively shape neuronal activity and survival.
Exploring Early Antifungal Activity of Rezafungin as a Stepping-Stone for Shorter Treatment Duration for Candidemia: Pooled Analysis of 2 Randomized Trials.
Open Forum Infect Dis
Luis Ostrosky-Zeichner, Jalal A Aram, Mark Redell +5 more
Guidelines recommend ≥2 weeks of antifungal therapy after candidemia clearance and for invasive candidiasis (IC). This post-hoc analysis evaluates Day 7 pooled data from the phase 2 STRIVE and phase 3 ReSTORE trials to explore early antifungal activity.
Redox signaling in chronic airway diseases: pathogenic mechanisms and therapeutic implications.
Front Physiol
Mario Cazzola, Paola Rogliani, Luigino Calzetta +3 more
Chronic airway diseases, including asthma, chronic obstructive pulmonary disease (COPD), and bronchiectasis, impose a significant global health burden. A central unifying feature of these diseases is redox imbalance, which is characterized by an excess of reactive oxygen and nitrogen species (ROS/RNS) that overwhelms the body's antioxidant defenses, causing cellular dysfunction, inflammation, and tissue damage. Physiological ROS/RNS are essential for immune regulation and transcriptional control, but chronic oxidative stress disrupts these processes, driving disease progression. In asthma, eosinophil- and epithelial-derived ROS worsen airway hyperresponsiveness, induce mucus overproduction, and reduce steroid effects. COPD involves neutrophil-dominated inflammation, mitochondrial dysfunction, protease- and oxidant-mediated extracellular matrix degradation, and accelerated senescence. Bronchiectasis features persistent neutrophilic oxidative injury, microbial colonization, impaired mucociliary clearance, and progressive airway destruction. Exogenous oxidants, cigarette smoke, biomass fuels, pollutants, and pathogens further burden antioxidant systems, including superoxide dismutases, catalase, glutathione peroxidase, and Nrf2-regulated pathways. Redox dysregulation also contributes to post-COVID sequelae, promoting ongoing airway inflammation, fibrosis, and systemic complications. Therapeutic strategies targeting redox imbalance, mainly thiol-based antioxidants, Nrf2 activators, NADPH oxidase inhibitors, and mitochondria-targeted antioxidants, show mechanistic promise but face challenges in specificity, bioavailability, and clinical translation. Advancing precision redox medicine requires biomarker-guided patient stratification, high-resolution redox proteomics, single-cell and organoid models, and spatial imaging to identify disease-specific redox endotypes. Modulating pathological oxidative stress while preserving physiological signaling offers a novel avenue to improve outcomes. Understanding redox biology in airway disease highlights the potential of precision antioxidant strategies as adjuncts to conventional therapies, representing a paradigm shift in managing chronic airway disorders.
Life Cycle and Circadian Rhythms in Central Resident Immunity and Neuropsychiatric Pathology.
Neurosci Bull
Zhixin Lim, Ha Linh Nguyen, Yuanyuan Zeng +12 more
The central resident immune system, commonly known as the glial system, comprises various glial cells that play a critical role in neuropsychiatric disorders. However, a systematic review exploring the relationships between the life cycles and daily rhythms of these immune cells and the pathological features of neuropsychiatric disorders is lacking. These immune cells exhibit unique developmental origins and circadian characteristics, resulting in rhythmic variations in functions such as phagocytosis, immune clearance, neurogenesis, and neurotransmitter recycling. These properties are crucial for understanding the pathological mechanisms underlying developmental disorders like major depressive disorder, autism spectrum disorder, and schizophrenia, as well as age-related conditions such as Alzheimer's and Parkinson's diseases. The daily rhythms of these immune cells correlate with diurnal variations in emotion, cognition, and motor function, involving shared processes like oxidative stress and neuroinflammation. This article systematically reviews the composition, life cycle changes, and circadian characteristics of central immune cells, highlighting their roles in neuropsychiatric diseases.
Thymosin α1 improves the outcomes of patients with hepatitis B virus-related acute-on-chronic liver failure by restoring immune balance.
Immunopharmacol Immunotoxicol
Zhi-Hui Li, Li-Li Wu, Yuan-Qiang Zhu +8 more
Thymosin α1 (Tα1) has been shown to improve survival in patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF), but its immunomodulatory mechanisms remain unclear. This study investigated how Tα1 restores immune homeostasis to confer a survival benefit in these patients.
Tirzepatide attenuates mesolimbic cocaine-evoked dopamine levels and reduces cocaine taking, motivation and seeking behaviours in male rodents.
EBioMedicine
Christian E Edvardsson, Xinming Zhang, Thaynnam A Emous +5 more
Cocaine use disorder (CUD) remains among the most treatment-resistant addictions, characterised by high relapse rates even following extended abstinence periods. Dopamine signalling in mesocorticolimbic circuits contributes to cocaine's reinforcing effects and remains an important target for therapeutic intervention. Growing evidence suggests appetite-regulating peptides may influence central dopamine transmission. Whether recently approved incretin polyagonists can modulate cocaine-related behaviours through their capacity to simultaneously engage multiple appetite-regulating peptide receptor pathways remains unexplored.
Tirzepatide-Induced Liver Injury: A Rare Complication.
AACE Endocrinol Diabetes
Lauren D Spaeth, Kim M Jordan, Mariah P Barlow +1 more
Tirzepatide is widely prescribed and generally considered safe. The objective of this report is to describe a patient with tirzepatide-induced liver injury and increase awareness of this rare complication.
Real-World Effectiveness and Safety of Tirzepatide, Semaglutide, and Liraglutide in Adults with Overweight or Obesity without Diabetes: A Comparative Study.
Diabetes Metab Syndr Obes
Serap Cetiner
Obesity is a chronic metabolic disease associated with substantial cardiometabolic risk and long-term morbidity. Although randomized controlled trials have demonstrated the efficacy of incretin-based therapies, real-world comparative data in adults with overweight or obesity without diabetes remain limited. Real-world studies provide complementary evidence by capturing treatment effectiveness, tolerability, dose escalation, and adherence in routine clinical practice.
Glucagon-like peptide-1 receptor agonist use and clinical outcomes after posterior cervical spinal fusion for degenerative pathologies: A large cohort retrospective analysis.
N Am Spine Soc J
Christian Rajkovic, Ankita Jain, Mahnoor Shafi +6 more
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as potentially impactful agents in improving spinal fusion outcomes. While several recent studies have investigated the effect of these agents on lumbar spinal procedures, the current evidence of the impact of these agents on cervical spinal fusion is limited. This study aims to investigate the impact of GLP-1RA use on perioperative clinical outcomes of posterior cervical spinal fusion.
B-type natriuretic peptide attenuates TLR-induced cytokine and chemokine secretion in monocyte-derived Langerhans cells.
Front Immunol
Dorottya Horváth, Zsófia Pénzes, Petra Molnár +6 more
B-type natriuretic peptide (BNP) is a well-known cardiac hormone and biomarker of heart failure, but emerging evidence suggests that it also possesses immunomodulatory properties, including a role in inflammatory skin conditions like atopic dermatitis (AD). Langerhans cells (LCs), specialized epidermal antigen-presenting cells, orchestrate cutaneous immunity and are targets of neuropeptides. In the present study, we investigated how BNP treatment during differentiation affects the activation, cytokine profile, and interaction of immune cells with moLCs subsequently activated via Toll-like receptors (TLRs).
A pilot study on the role of the oxytocinergic system in gut microbiome composition in children with autism: baseline associations and effects of intranasal oxytocin.
Brain Behav Immun
Evenepoel Margaux, Tuerlinckx Elise, Derrien Muriel +8 more
Autistic children often experience behavioral difficulties alongside nutritional and gastro-intestinal (GI) problems, including gut dysbiosis. Recent research has highlighted important interactions between the oxytocinergic system and gut microbiome compositions, however, insights into how exogenous administration of oxytocin may influence GI health remain largely unexplored. Here, we first examined whether nutrition, GI symptoms and microbiome compositions vary in autistic versus non-autistic children, and how alterations link to clinical-behavioral difficulties and oxytocinergic signaling. Next, we examined the effect of a four-week intranasal oxytocin administration regimen on GI health/dysbiosis in autistic children enrolled in a randomized placebo-controlled trial. Compared to non-autistic children, autistic children consumed more soft drinks, and fewer vegetables and experienced abdominal pain more frequently over the past three months. Notably, epigenetic variations in the oxytocin receptor gene (OXTR) were associated with stool consistency, indicating that children with looser stools exhibited lower OXTR methylation levels, indicative of increased receptor expression. Additionally, a higher abundance of Romboutsia was associated with OXTR hypo-methylation and more anxiety-like behavior. In autistic children, the four-week oxytocin regimen had no effect on bacterial diversity but did modify stool consistency, leading to less dense stools with an overall more normal stool consistency, and an increased abundance of the potentially anti-inflammatory genus Fusicatenibacter. To conclude, this study provides novel insights into the role of the oxytocinergic system in GI symptoms and gut microbiome compositions in autistic children, and preliminary evidence suggesting a modulatory effect of exogenously administered oxytocin on these parameters.
Obesity and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Literature Review on Pathophysiology and Treatment.
Diabetes Obes Metab
Michael Romanos, Juan M Garcia Cordova, Jose Villamarin +2 more
Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a key hepatic manifestation of obesity and systemic metabolic dysfunction and is a leading cause of chronic liver disease worldwide. Obesity-driven mechanisms, including adipose tissue dysfunction, insulin resistance and increased free fatty acid flux to the liver, promote ectopic lipid accumulation and lipotoxic injury. These processes trigger mitochondrial and endoplasmic reticulum stress, inflammation, immune activation and disturbances in the gut-liver axis, driving disease progression from simple steatosis to metabolic dysfunction-associated steatohepatitis, fibrosis and cirrhosis. MASLD is a highly heterogeneous condition, with differences in fat distribution, body composition and genetic susceptibility giving rise to distinct clinical phenotypes, including lean and non-lean MASLD, which have important implications for disease risk, progression and therapeutic response. Clinical outcomes are determined primarily by fibrosis stage, which represents the strongest predictor of liver-related and all-cause mortality, underscoring the importance of early disease recognition and risk stratification. Therapeutic strategies, therefore, increasingly target upstream metabolic drivers rather than hepatic steatosis alone. Lifestyle interventions remain foundational but are often limited by challenges in long-term adherence. Pharmacologic therapies, particularly incretin-based agents such as glucagon-like peptide-1 receptor agonists and dual incretin agonists, as well as bariatric and endoscopic metabolic procedures, have demonstrated substantial metabolic and hepatic benefits. Recognition of disease heterogeneity supports phenotype-guided approaches that integrate metabolic risk, adiposity, body composition and fibrosis assessment to personalise treatment strategies and improve long-term outcomes across the MASLD spectrum.
Norepinephrine neurons in the locus coeruleus and the nucleus of the solitary tract drive different stress-related behavioral outputs in mice.
Neurobiol Stress
Raoni Conceição Dos-Santos, Maria W Najjar, Carly Friedman +5 more
Norepinephrine (NE) is one of the main neuromodulators that regulate the stress response. NE-expressing neurons in the locus coeruleus (LC) and the nucleus of the solitary tract (NTS) project to the corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) to regulate the hypothalamic-pituitary-adrenal (HPA) axis response to stress. NE neurons also project to other brain regions to regulate stress outputs, including throughout the limbic system and the medial prefrontal cortex. The NE circuits, therefore, are well-positioned to regulate an integrated stress response that coordinates the activation of the HPA axis with different behavioral responses appropriate to distinct stressors. Here, we show that chemogenetic activation of LC-NE neurons induces affective stress behaviors while activation of NTS-NE neurons stimulates sickness-like behaviors. Selective activation of NE neurons in the NTS caused an increase in immobility, a decrease in mechanical nociception threshold, and reduced exploratory, grooming, and feeding behaviors. Activation of LC-NE neurons, on the other hand, caused an increase in grooming and a decrease in exploratory behaviors, but no change in immobility. Stimulation of either the NTS-NE or LC-NE neurons elicited an increase in activation of the HPA axis. Taken together, our results show that the activation of NTS-NE and LC-NE neurons stimulates both redundant and distinct aspects of the stress response, perhaps via stimulation of both discreet and overlapping populations of PVN neurons.
Post-ACTH peak cortisol response is associated with genotype in children with nonclassic congenital adrenal hyperplasia.
Front Endocrinol (Lausanne)
Allie N Dayno, Marissa J Kilberg, Erin Gonter +4 more
Suboptimal cortisol levels after ACTH stimulation have been recently reported in approximately 30% of patients with nonclassic congenital adrenal hyperplasia (NCCAH). There is little information on the role of genotype on cortisol secretion in NCCAH. The aim of this study is to investigate the association between genotype (i.e compound heterozygote for one mild and one severe CYP21A2 variant vs. homozygous for two mild variants) and peak cortisol response after ACTH stimulation in a pediatric population with NCCAH.
Unruptured Giant Internal Carotid Artery Aneurysm Compressing the Pituitary Gland Leading to Panhypopituitarism.
AACE Endocrinol Diabetes
Sapna Sharma, Madhav Acharya, Sara Bean +2 more
Internal carotid artery aneurysms are rare and can lead to hypopituitarism due to their mass effect. Hypopituitarism triggered by aneurysmal compression may persist, and postsurgical restoration of pituitary function is challenging, often necessitating long-term hormone replacement therapy. We herein report a case of hypopituitarism caused by intrasellar aneurysm.
A Rare Case of Takotsubo Cardiomyopathy Responsive to Fludrocortisone in Secondary Adrenal Insufficiency.
Cureus
Waqar Khalid, Muhammad Usman Khan, Maheen Khoso +3 more
We present a case of a middle-aged woman with a prolonged history of diarrhea, vomiting, and abdominal pain. Upon admission to the ICU, she exhibited hypotension and hypoglycemia. Based on presenting gastrointestinal complaints, she was initially treated for acute gastroenteritis; however, continuous refractory hypotension led to an echocardiographic assessment. A left ventricular ejection fraction (LVEF) of 30-35% with apical akinesis and distinct apical ballooning was visualized on a transthoracic echocardiogram, suggestive of takotsubo cardiomyopathy. An increasing inotropic demand raised concerns regarding alternative etiologies. Further evaluation revealed decreased adrenocorticotropic hormone and cortisol levels, leading to a diagnosis of secondary adrenal insufficiency. Treatment with fludrocortisone significantly improved her adrenal insufficiency and her cardiomyopathy. This case highlights secondary adrenal insufficiency as a rare but potential cause of takotsubo cardiomyopathy in Pakistan, with the use of fludrocortisone as a treatment option in a carefully selected patient.
Diagnostic challenges of Cushing's syndrome in pregnancy.
BMJ Case Rep
Fariha Tahir, Brendan Browne, Melina Kostoula +1 more
SummaryWe report a rare case of Cushing's syndrome in a pregnant woman carrying twins. Interestingly, the patient did exhibit many of the classic clinical features typically associated with hypercortisolism, including Cushingoid facies, violaceous striae, insulin-dependent diabetes, raised central adiposity, chronic hypertension and peripheral myopathy. Her case was less straightforward given her previous gastric sleeve bariatric surgery, which led to rapid weight loss prior to pregnancy. The occurrence of an atraumatic fracture of the femoral neck in a young woman with a medical history of type 2 diabetes mellitus, chronic hypertension and possible severe osteoporosis raised clinical suspicion of a unifying diagnosis, prompting further evaluation.Biochemical testing, including elevated cortisol and suppressed adrenocorticotropic hormone levels, alongside imaging studies, confirmed the diagnosis of adrenal Cushing's syndrome. This case prompted a deeper investigation into the physiological changes of the hypothalamic-pituitary-adrenal axis during normal pregnancy, as well as the unique challenges in diagnosing and managing Cushing's syndrome during pregnancy.This case highlights the need for a high index of suspicion and a multidisciplinary approach in diagnosing and managing complex presentations in pregnancy. Early recognition and treatment of Cushing's syndrome are critical to optimising maternal and fetal outcomes.Cushing's syndrome during pregnancy is a rare but serious hormonal syndrome characterised by elevated cortisol levels. This hypercortisolism may be a result of functional adrenal or pituitary tumours, or iatrogenic. Though uncommon, it poses a significant threat to both maternal and fetal health due to the high risk of complications. This case study aims to provide a current overview of the diagnosis and management of Cushing's syndrome in pregnancy, with an emphasis on minimising associated maternal and fetal morbidity. The case report highlights missed differential diagnoses of Cushing's syndrome in the pre-pregnancy period despite the presence of type 2 diabetes, hypertension and morbid obesity in a young patient. Bariatric surgery further complicated the differential diagnosis.
Development of NAFLD-Specific Human Liver Organoid Models on a Microengineered Array Chip for Semaglutide Efficacy Evaluation.
Cell Prolif
Xiao-Yan You, Xiang-Yang Li, Hui Wang +1 more
Progressive non-alcoholic fatty liver disease (NAFLD) may culminate in severe complications, including fibrosis, cirrhosis and hepatocellular carcinoma, yet therapeutic breakthroughs remain elusive, necessitating novel pharmacological strategies. Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist clinically approved for type 2 diabetes and obesity management, has demonstrated pleiotropic effects in preclinical NAFLD models. In this study, we investigated semaglutide's therapeutic efficacy and mechanisms in a human liver organoids (hLOs) model of NAFLD. Utilising microengineered array chips, human induced pluripotent stem cells (hiPSCs) were differentiated into hLOs with functional hepatic properties. NAFLD pathology was induced via free fatty acid (FFA) exposure, recapitulating disease hallmarks such as steatosis, inflammatory cytokine elevation and fibrogenic activation. Semaglutide treatment at 50 nM significantly attenuated lipid deposition caused by FFAs and reduced triglyceride levels by 8-fold and cholesterol levels by 1.8-fold. It also inhibited the expression of pro-inflammatory markers (IL-6, IL-8, TNF-α) by about 1.5-2 fold and increased the level of lipolytic genes by about 45%. These findings elucidate the therapeutic potential of semaglutide in attenuating key NAFLD-associated pathologies and establish a robust in vitro platform for preclinical drug evaluation. The study provides critical insights into targeted NAFLD interventions and supports the translation of GLP-1-based therapies into clinical practice, addressing an unmet need in hepatology.