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Reversible Nephrogenic Diabetes Insipidus Induced by Lithium: A Case Report.
Case Rep Nephrol
Sevil Uygun İlikhan, Gülin Dilken, Gökhan Hazıroğlu +2 more
Lithium is an effective mood stabilizer but may cause nephrogenic diabetes insipidus (NDI) by impairing the renal collecting duct response to arginine vasopressin (AVP). We report a 52-year-old woman on long-term lithium therapy who presented with diarrhea, fatigue, polyuria, and confusion. Initial evaluation showed hypernatremia (serum sodium 156-159 mmol/L), low urine osmolality (101 mOsm/kg) despite serum osmolality of 286 mOsm/kg, daily urine output of 6.5-7.5 L, and a lithium level of 1.65 mmol/L. Renal function was preserved. Intravenous 5% dextrose was administered for free-water replacement. Bicarbonate and potassium supplementation were initiated based on blood gas and biochemical findings consistent with metabolic acidosis (pH: 7.33 and serum bicarbonate: 22.1 mmol/L) and hypokalemia, requiring potassium supplementation. Lithium was discontinued, and a thiazide-containing regimen was initiated. Without desmopressin, serum sodium normalized to 140 mmol/L within 72 h, urine output decreased to approximately 2 L/day, and mental status fully recovered. This case demonstrates that timely recognition and management of lithium-induced NDI may allow recovery of urinary concentrating ability.
Comparative Efficacy and Safety of Resmetirom and Efruxifermin for Metabolic Dysfunction-Associated Steatohepatitis: A Network Meta-Analysis of Randomized Controlled Trials.
Endocrinol Diabetes Metab
Doha Jaber, Inas Jaber, Ayah Abu Lehia +2 more
Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver condition and a major cause of cirrhosis, hepatocellular carcinoma, and liver transplantation. Resmetirom, a thyroid hormone receptor β agonist, and Efruxifermin, a fibroblast growth factor 21 analogue, have shown promise in improving hepatic fat fraction (HFF) and liver enzyme levels. This study systematically compares the efficacy and safety of Resmetirom and Efruxifermin in treating MASH.
Efficacy of GLP-1 analog peptides, semaglutide, tirzepatide, and retatrutide on MC4R deficient obesity and their comparison.
Int J Obes (Lond)
Kosuke Hitaka, Takumi Sugawara, Mitsuharu Matsumoto +1 more
Melanocortin 4 receptor (MC4R) is a G-protein-coupled receptor expressed in the hypothalamus, playing a key role in regulating feeding behavior and energy homeostasis. MC4R is integral to the POMC-MC4R and leptin-MC4R pathways, which control food intake and body weight. Mutations in the POMC gene lead to severe early-onset obesity and increased food consumption. Recently, glucagon-like peptide-1 (GLP-1) analogs, including semaglutide, tirzepatide, and retatrutide, have been explored as potential anti-obesity therapies.
High-linear energy transfer radiation disrupts natural killer cell surveillance of senescent intestinal cells in the mouse intestine.
Mol Biomed
Santosh Kumar, Shubhankar Suman, Heng-Hong Li +3 more
High-Linear Energy Transfer (LET) ion radiation, such as 28Si ions, is densely ionizing and poses a significant risk to astronauts during long-duration space missions. We previously showed that mice exposed to high-LET ionizing radiation (IR) exhibit greater accumulation of senescent cells in the intestine than those exposed to equivalent doses of low-LET γ-rays. However, the mechanisms driving this persistent senescence remain unclear. Given the role of Natural killer (NK) cells in senescent cell clearance, we investigated the impact of IR on intestinal NK cell function. At 60 days post-irradiation, intestinal tissues from 28Si-exposed mice showed a significant reduction in NKp46⁺ NK cells and decreased expression of molecules associated with NK activation and epithelial interactions. NK cell subtype analysis further revealed a decline in functionally mature populations involved in recognizing stressed cells. In parallel, intestinal epithelial cells (IECs) displayed altered expression of NK cell regulatory ligands, including reduced activating signals and increased inhibitory signaling associated with Qa-1b (non-classical MHC class Ib). Mechanistically, these changes were linked to activation of p38 Mitogen-Activated Protein Kinase (MAPK) signaling. Using irradiated intestinal organoids, we observed that pharmacological inhibition of the p38 MAPK pathway decreased Qa-1b expression and enhanced NK cell cytotoxic activity. Causality experiments further demonstrated that Qa-1b directly regulates NK cell-mediated cytotoxicity against senescent IECs. Collectively, these findings indicate that high-LET IR compromises intestinal immune surveillance by impairing NK cell function through a p38 MAPK-Qa-1b signaling axis, providing mechanistic insight into radiation-induced immune dysregulation.
Galectin-9high Neutrophils Exacerbate Radiation-Induced Frailty.
Aging Cell
Zhuo Cheng, Le Ma, Yan Chen +11 more
Local radiation injury-induced frailty seriously impacts the quality of life of patients undergoing radiotherapy or nuclear accident casualties and causes a significant medical and economic burden. However, the underlying mechanisms of the frailty remain unknown. In this study, a unique population of hyperactive GAL-9high neutrophils is identified with characteristics of elevated ROS, NETs, and IFN-γ, prolonged lifespan, etc. These neutrophils infiltrate into multiple organs to induce injuries, also disrupt the bone marrow microenvironment, drive sustained bone marrow myeloid-biased differentiation, and resist clearance by bone marrow macrophages, serving as a crucial factor to exacerbate frailty. GAL-9 protein is demonstrated to play a vital role in the regulation of neutrophil hyperactivity. EccDNA shedding after skin radiation injury is shown to activate the JAK1/2-STAT1 pathway in splenic GMP cells, which is a potential origin of GAL-9high neutrophils. In summary, our results highlight the significance of the previously unrecognized hyperactive GAL-9high neutrophils to exacerbate frailty through a 'skin-spleen-bone marrow-multiple organs' axis after local radiation injury.
DNA O-MAP uncovers the molecular neighborhoods associated with specific genomic loci.
Elife
Yuzhen Liu, Christopher D McGann, Conor P Herlihy +14 more
The accuracy of crucial nuclear processes such as transcription, replication, and repair depends on the local composition of chromatin and the regulatory proteins that reside there. Understanding these DNA-protein interactions at the level of specific genomic loci has remained challenging due to technical limitations. Here, we introduce a method termed 'DNA O-MAP', which uses programmable peroxidase-conjugated oligonucleotide probes to biotinylate nearby proteins. We show that DNA O-MAP can be coupled with label-free or sample multiplexed quantitative proteomics, targeted chemical perturbations, and next-generation sequencing to quantify DNA-proximal proteins and DNA-DNA interactions at specific genomic loci in human and murine cells. Furthermore, we establish that DNA O-MAP is applicable to both repetitive and unique genomic loci of varying sizes, from kilobase HOX gene clusters to megabase alpha-satellite repeats, and that DNA O-MAP can measure proximal molecular effectors in a homolog-specific manner.
Semaglutide-Induced Weight Loss Is the Main Determinant for the Improvement of Hepatic Biochemistry and Elastographic Repeated Measurements with FibroScan® in Patients with Type 2 Diabetes Mellitus and Metabolic Dysfunction-Associated Steatotic Liver Disease.
Metab Syndr Relat Disord
Savvoula Savvidou, Elektra Augousti-Varela, Aikaterini Damianakou +2 more
Semaglutide is currently being investigated for its effectiveness in metabolic dysfunction-associated steatotic liver disease (MASLD), irrespective of type 2 diabetes mellitus (T2DM) presence, even though its action on hepatic fibrosis is still debated. The aim of this study was to examine the effect of semaglutide on hepatic parameters in patients with both T2DM and MASLD in real-world clinical practice, and to further assess the significance of weight loss during treatment.
Preoperative GLP-1 Receptor Agonists and Thromboinflammatory Markers in Patients Undergoing Abdominoplasty: A Prospective Monocentric Study.
Aesthetic Plast Surg
Agostino Bruno, Marco Schirosi, Riccardo Foti
Abdominoplasty in patients with obesity carries a heightened risk of venous thromboembolism (VTE) due to a proinflammatory and hypercoagulable baseline. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used for weight loss and have demonstrated anti-inflammatory and antithrombotic properties, but their role in aesthetic surgery remains unexplored.
Molecular Characterization of the Effect of Glucagon-Like Peptide-1 Receptor Agonist Semaglutide in the Nephrotoxic Serum Nephritis Mouse Model.
Kidney360
Jaime Moreno Martinez, Maria Ougaard, Tanya Grancharova +7 more
CKD is a significant public health issue, affecting approximately half a billion people globally. Key risk factors for CKD include obesity, hypertension, cardiovascular diseases and diabetes. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are effective treatments for obesity and diabetes. The FLOW trial recently showed that treatment with the GLP-1RA semaglutide significantly reduced the incidence of clinically important kidney outcomes in patients with type 2 diabetes and CKD, likely via beneficial effects on kidney blood flow, inflammation and fibrosis as well as effects mediated by improvement of glycemic control. This study aimed to characterize the effects of semaglutide in the mouse nephrotoxic serum nephritis model, a non-obese and non-diabetic mouse model of CKD.
Real-World Clinical Evidence of Tirzepatide for Metabolic Abnormalities in Subjects With Type 2 Diabetes: The Multicenter Retrospective Observational Hokkaido-TZP Study.
Diabetes Obes Metab
Fumika Maruyama, Hiroya Kitsunai, Naoyuki Kitao +12 more
Tirzepatide has demonstrated potent glucose-lowering efficacy and metabolic benefits in subjects with type 2 diabetes (T2D) in Phase III clinical trials. However, its efficacy in real-world clinical practice, particularly among patients receiving various antidiabetic therapies, remains to be elucidated.
Early intervention with tirzepatide or semaglutide influences anti-atherosclerotic effects in ApoE knockout mice.
Sci Rep
Kazunori Dan, Junpei Sanada, Tomohiko Kimura +10 more
This study aimed to investigate the anti-atherosclerotic properties of tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist, in comparison with semaglutide, a selective GLP-1 receptor agonist. ApoE knockout mice were divided into early diabetes (dosed from 10 to 22 weeks of age), late diabetes (dosed from 18 to 30 weeks of age), and non-diabetic groups after streptozotocin treatment, and each group received semaglutide, tirzepatide, or saline for 12 weeks. In the early diabetes group, both agents significantly suppressed aortic plaque formation compared with control, while modestly improving glycemia and lipid levels. No significant vascular effects were observed in late diabetes or non-diabetic groups. Tirzepatide markedly reduced inflammatory mediators, including Mcp-1, Il-6, I-cam, and Cd68, whereas semaglutide showed partial overlap. Notably, these anti-inflammatory effects were also detected in non-diabetic mice, suggesting vascular protection may involve arterial actions independently of metabolic control. Taken together, our findings demonstrate that tirzepatide exerts anti-atherosclerotic effects comparable to semaglutide, supporting the concept that GIP and GLP-1 signaling can confer vascular benefits. These results highlight the potential clinical relevance of dual incretin receptor agonism for cardiovascular risk reduction, although further studies are required to clarify the specific role of GIP signaling.
Analyzing Vital Sign Variability in Remote Monitoring as a Predictor of 31-Day Heart Failure Readmission: A Retrospective Cohort Study.
Telemed J E Health
Adeel Arif, Anshul Kumar, Michelle Elsener +2 more
Heart failure (HF) is a major cause of morbidity and early hospital readmission in the United States. Remote patient monitoring (RPM) is increasingly used to support postdischarge care, but evidence remains mixed, and the prognostic value of day-to-day vital sign variability is unclear. This study evaluated whether physiologic variability and patient engagement during RPM were associated with 31-day HF readmission.
Tirzepatide-induced ketoacidosis with hyperglycemia in a patient without diabetes.
Arch Endocrinol Metab
Mendel Shloush, Vania Rodriguez, Victor Guillen +1 more
Tirzepatide,a dual GLP-1 and GIP receptor agonist, is increasingly used for weight management in both patients with diabetes and patients without diabetes. While gastrointestinal side effects such as nausea are common, severe metabolic complications like ketoacidosis are rare and often overlooked. We report the case of a 38-year-old woman with congenital heart disease who developed acute ketoacidosis with hyperglycemia following five months of tirzepatide therapy. Laboratory findings confirmed high anion gap metabolic acidosis, elevated ketones, and significant hyperglycemia. With supportive care, including intravenous fluids, insulin infusion, and electrolyte replacement, she recovered fully. This represents a rare case of tirzepatide-induced hyperglycemic ketoacidosis in a patient without diabetes. In contrast, the two previously reported cases by Singh and cols. and Iqbal and cols. involved patients without diabetes who developed euglycemic ketoacidosis with normal glucose levels while on tirzepatide. This case underscores the importance of vigilant monitoring for metabolic complications, including hyperglycemia and ketoacidosis, in patients without diabetes, particularly those with comorbidities.
Beyond the HPA axis: Synaptic circuits of PVNCRH neurons in stress-related psychiatric disorders.
Pharmacol Res
Jiayuan Zheng, Na Yue, Zhanzhuang Tian +2 more
Chronic psychosocial stress is a major risk factor for anxiety, depression and related disorders, yet a hypothalamic-pituitary-adrenal (HPA) axis centric framework alone is insufficient to explain stress-induced vulnerability and phenotypic heterogeneity. Paraventricular nucleus corticotropin-releasing hormone (PVNCRH) neurons are classically regarded as the neuroendocrine entry point for driving glucocorticoid secretion. However, accumulating evidence indicates that, beyond this endocrine role, they also use fast transmitters and CRH co-transmission to form functional projections to diverse brain regions and pre-sympathetic circuits, thereby regulating stress dimensions that extend beyond HPA axis output, including defensive behaviors, reward and motivation, arousal-sleep regulation, autonomic output and glucose homeostasis. In this review, we integrate anatomical, electrophysiological, and behavioral evidence across representative PVNCRH pathways, compare their stress-related functional specialization and shared mechanisms across synaptic and endocrine timescales, and discuss translational implications for circuit-informed pharmacological and neuromodulatory strategies in stress-related psychiatric disorders.
Absent nocturnal cortisol decline in Pheochromocytoma: A retrospective study.
Steroids
Yahan Sun, Mitsuhiro Kometani, Ko Aiga +5 more
Pheochromocytoma is a catecholamine-producing tumor that may exhibit atypical hormonal profiles. Emerging evidence suggests an association with cortisol dysregulation in the absence of overt Cushing syndrome; however, systematic cortisol evaluation is not routinely performed. This study investigated the prevalence and clinical characteristics of absent nocturnal cortisol decline in pheochromocytoma. This retrospective study included 53 patients with histologically confirmed pheochromocytoma treated between 2011 and 2024. All eligible patients diagnosed during the study period were included. Among them, 22 had paired morning (8:00 AM) and midnight serum cortisol measurements for analysis of nocturnal cortisol decline. Adrenocorticotropic hormone (ACTH) and the 1-mg dexamethasone suppression test (DST) were assessed when available. Patients were stratified by midnight cortisol level (≥1.8 µg/dL vs < 1.8 µg/dL). Among the 22 patients, 18 (82%) had elevated midnight cortisol, indicating absent nocturnal decline (mean midnight, 5.1 µg/dL; mean morning, 13.7 µg/dL). The elevated group (n = 18) was older than the normal group (n = 4) (median, 64 vs 43 years). Metabolic comorbidities were more frequent in the elevated group, including diabetes (50% vs. 25%), dyslipidemia (61% vs. 25%), and cardiovascular disease (44% vs. 0%). DST was performed in 10 patients and showed adequate suppression in 7 of 8 patients with paired cortisol measurements, arguing against autonomous cortisol secretion. No patients had clinical features of overt Cushing syndrome. Absent nocturnal cortisol decline was common and may reflect a pseudo-Cushing state associated with catecholamine excess. These findings support further evaluation of cortisol regulation and its clinical implications.
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.