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Astrocytic Ferroptosis: An Integrative Hub Linking Metabolic Dyshomeostasis, Glial Crosstalk, and Neurodegeneration in Alzheimer's Disease.
Aging Dis
Zhimin Lu, Chang Meng, Xiaoyan Ren +5 more
Alzheimer's disease (AD) is a widespread age-related neurodegenerative disorder. Current therapies targeting Aβ plaques and hyperphosphorylated Tau show limited efficacy. The core pathology of AD involves neuroglial metabolic network collapse, which is tightly associated with brain iron dyshomeostasis and abnormal ferroptosis. As the main iron storage and antioxidant cells in the CNS, astrocytes transform into disease-associated astrocytes under AD conditions. Metabolic reprogramming switches them from a neuroprotective to a pro-ferroptotic phenotype, contributing to thereby exacerbating systemic metabolic dyshomeostasis. This review systematically elaborates the regulatory mechanisms of astrocytic ferroptosis in AD: disordered iron metabolism (e.g., aberrant DMT1/FPN1 expression) induces iron accumulation as the initiation prerequisite; excessive oxidative stress (Ang II/HIF-1α-NOX4 axis-mediated ROS generation) and impaired antioxidant defense (Nrf2-SLC7A11/GPX4 inactivation, ApoE4 dysfunction) serve as core regulatory modules; FTH1 and SAT1 dysregulation elevates the labile iron pool, while AQP4 dysfunction impairs metabolite clearance, amplifying ferroptosis. Moreover, aberrant crosstalk among astrocytes, microglia and oligodendrocytes exacerbates AD-related neurodegeneration. Collectively, astrocytic ferroptosis acts as a key integrative mechanism linking iron dysmetabolism, oxidative stress, neuroinflammation and Aβ/Tau pathology, offering a potential new avenue for decoding AD pathogenesis. Targeting astrocytic ferroptosis is expected to overcome the long-standing therapeutic limitations of conventional AD treatments, providing theoretical support and new directions for developing disease-modifying AD therapies. While individual components including disease-associated astrocytes, brain iron dyshomeostasis, NOX4- and NRF2-related ferroptosis have been documented separately, this review represents the first comprehensive synthesis that identifies astrocytic ferroptosis as a central hub that unifies these fragmented mechanisms into a cohesive pathogenic cascade driving AD.
Utility of N-terminal pro-Brain Natriuretic Peptide Immunostaining of the Kidney in Forensic Diagnosis.
Am J Forensic Med Pathol
Shojiro Takasu, Sari Matsumoto
N-terminal pro-brain natriuretic peptide (NT-proBNP) is secreted by ventricular myocardial cells and released in response to ventricular wall stress conditions such as congestive heart failure (CHF). We previously reported the potential diagnostic efficacy of postmortem urine NT-proBNP concentrations for acute myocardial infarction, CHF, heat stroke, and sepsis. As urine is often unavailable in autopsy cases, alternative diagnostic methods are required. In this study, we conducted NT-proBNP immunostaining of the kidney, evaluated NT-proBNP positivity in the renal tubule in a series of forensic autopsy cases (n = 30), and compared the results to the urinary levels of NT-proBNP and urine Hounsfield unit (HU) values in postmortem computed tomography conducted before the autopsy. The results showed significantly higher urinary NT-proBNP levels in the CHF, sepsis, and heat stroke groups than in the control group. NT-proBNP positivity was also significantly higher in these groups. Moreover, a correlation between urinary NT-proBNP concentration and immunostaining results was observed. These results suggest that NT-proBNP immunostaining of the kidney could be considered as an alternative to NT-proBNP measurement in urine, which may, in turn, improve postmortem diagnosis. However, the association with postmortem urine HU values should be evaluated in further large-scale studies.
Neuroimmune programming of childhood trauma: comorbid mechanisms and developmental origins of depression and autoimmune diseases.
J Neuroinflammation
Jiajia Wang, Qinglu Xu, Xinge Tang +3 more
Adverse childhood experiences (ACEs) represent a critical environmental trigger for the adult comorbidity of depression and autoimmune diseases. This review synthesizes evidence showing that ACEs induce persistent dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system, thereby promoting a chronic low-grade inflammatory state. This state is characterized by elevated pro-inflammatory cytokines (e.g., IL-6, TNF-α), immune cell dysfunction, and epigenetic modifications. Facilitated by microglial activation and monocyte-mediated disruption of the blood–brain barrier, this pro-inflammatory milieu disrupts central nervous system homeostasis, contributing to the pathogenesis of both depressive symptoms and autoimmune disorders. Aberrant neuroimmune crosstalk emerges as a core mechanism underlying this comorbidity. Future research must delineate developmental windows of vulnerability and the differential effects of adversity types to translate these insights into novel therapeutic strategies targeting the neuroimmune axis—such as anti-cytokine therapies or vagus nerve stimulation—for high-risk populations.
Advances in pharmacological treatment for congenital adrenal hyperplasia.
Curr Opin Pediatr
Lara E Graves, Henrik Falhammar
Congenital adrenal hyperplasia (CAH), most commonly caused by 21-hydroxylase deficiency, remains associated with substantial morbidity despite life-saving glucocorticoid replacement. This review is timely because several novel therapies have recently emerged with the potential to improve disease control while reducing glucocorticoid burden.
Associations of episodic and tonic appetite-related signals with malnutrition and appetite dysregulation in end-stage liver disease.
Clin Res Hepatol Gastroenterol
François Le Calvez, James King, Alexis Couret +3 more
Malnutrition is highly prevalent in end-stage liver disease (ESLD), while being strongly associated with sarcopenia and poor prognosis in this population. The physiological regulation of energy intake is influenced by tonic signals, reflecting body composition and metabolic demands, and episodic signals, arising from gastrointestinal peptides, that remain to be better explored in the context of ESLD. The present narrative review analyzed 94 studies that characterises circulating concentrations of ghrelin, CCK, PYY, GLP-1 and leptin in cirrhosis and hepatocellular carcinoma. Overall, in patients with ESLD, orexigenic signaling, particularly from ghrelin and Fat-Free Mass (FFM) appears blunted, while anorexigenic peptides (CCK, PYY, GLP-1) are frequently elevated, prolonging satiety. Leptin regulation is inconsistent, reflecting both inflammation-driven increases and fat mass-related decreases. These disturbances converge toward a mismatch between elevated metabolic requirements and insufficient energy intake. Understanding how ESLD disrupts appetite-regulating pathways may help design new strategies to restore nutritional balance and improve clinical outcomes.
Exploring the therapeutic potential of GLP-1 receptor agonists in pulmonary arterial hypertension.
ERJ Open Res
Benoit Aguado, Thomas Lacoste-Palasset, Grégoire Ruffenach +5 more
Pulmonary hypertension (PH) is a progressive and multifactorial disease marked by elevated pulmonary arterial pressure and right ventricular (RV) dysfunction. Among its subtypes, pulmonary arterial hypertension (PAH) is characterised by profound vascular remodelling, inflammation and fibrosis. Despite therapeutic advances targeting the endothelin, nitric oxide, prostacyclin, and, more recently, the activin signalling pathway via sotatercept, outcomes in PAH remain suboptimal, particularly in patients with cardiovascular comorbidities. This has prompted growing interest in novel metabolic-based interventions, such as glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs). GLP-1RAs, initially developed for type 2 diabetes and obesity, exhibit pleiotropic properties including vasodilation, anti-inflammatory, antifibrotic and endothelial-protective effects. In experimental models of PAH GLP-1RAs administration attenuates the severity of PH. Additional studies highlight their ability to protect against lung fibrosis and preserve endothelial function. Indirect enhancement of GLP-1 signalling through dipeptidyl peptidase-4 (DPP-4) inhibition similarly improves pulmonary haemodynamics and mitigates fibrosis and inflammation, underscoring the relevance of this pathway. Although no clinical trials have specifically evaluated GLP-1RAs in PH, observational studies in patients with heart failure with preserved ejection fraction suggest potential cardiopulmonary benefits. GLP-1RAs emerge as promising candidates bridging metabolic, vascular and cardiac domains in PH, warranting rigorous clinical validation. These findings support further translational research and randomised clinical trials to evaluate GLP-1RAs as a disease-modifying therapy in PAH.
Decidualization-empowered ECM hydrogel integrating sustained Tβ4 release drives endometrial regeneration in intrauterine adhesions.
Nat Commun
Yuxiang Liang, Zhaowei Yu, Shaobo Du +15 more
Intrauterine adhesions (IUA), a leading cause of female infertility, result from a pathological switch in the uterine injury response from regeneration to fibrotic scarring. Current treatments are often inadequate as they fail to address this fundamental shift. Here, we report a "decidualization-empowered" hydrogel that reverses this pathology by synergistically combining a bioactive extracellular matrix from decidualized endometrium (DEndo-UdECM) with the sustained release of the anti-fibrotic peptide Thymosin β4 (Tβ4). In a murine IUA model, a single administration of the hydrogel restores endometrial architecture, resolves fibrosis, and, most critically, leads to a near-complete recovery of fertility. Mechanistically, the hydrogel orchestrates a pro-regenerative niche by reprogramming macrophages to an M2 phenotype while dually inhibiting pyroptosis-driven inflammation and the canonical TGF-β/Smad3 fibrotic cascade. Together, these findings demonstrate that mimicking the biological intelligence of a physiological niche can resolve complex fibrotic diseases and restore organ function.
Pathophysiology of orofacial neuropathic pain: A narrative review on the multi-level cascade of neuro-glial plasticity.
J Oral Biosci
Ryuji Terayama, Kenta Uchibe, Shohei Kohno
Orofacial neuropathic pain has a complex pathophysiology beyond simple neuronal hyperexcitability. In this review, recent evidence is synthesized on the multi-level cascade of neuro-glial plasticity-from the trigeminal ganglion (TG) to higher brain centers-and its role in pain chronicity and affective distress is examined.
Dietary monoalkyldiacylglycerol enhances muscle regeneration and induces type Ⅱb myofiber formation in cardiotoxin-injury mice.
Biochem Biophys Res Commun
Kyosuke Imamura, Naoki Takatani, Masashi Hosokawa +1 more
Monoalkyldiacylglycerols (MADG), ether-type glycerolipids found in deep-sea fish animals, promote myotube formation in C2C12 myoblasts. In this study, we investigated the effects of MADG on skeletal muscle regeneration in a mouse model of cardiotoxin-induced muscle injury. Male C57BL/6J mice were fed a diet supplemented with 0.5% MADG for 2 weeks, followed by cardiotoxin injection into the tibialis anterior muscle, and maintained on the experimental diets for up to an additional 2 weeks. The MADG diet increased the number and total area of myofibers 7 and 14 days post-injury compared with the normal diet group. mRNA levels of the myogenic regulatory factors MyoD and Myogenin increased, whereas those of inflammatory factors and satellite cell marker, remained unchanged. Immunohistochemical staining for myofiber type markers showed that dietary MADG promoted a shift toward a more fast-type phenotype, characterized by an increase in the number and proportion of MHC4-positive type Ⅱb fibers. In C2C12 myoblasts and mouse satellite cells, treatment with batyl alcohol, a MADG metabolite, increased Myh4 mRNA expression and decreased Myh2 mRNA expression. Overall, MADG promotes skeletal muscle regeneration and has the potential to induce a fast-twitch shift, accompanied by an increased proportion of type IIb myofibers during muscle repair. These results contribute to a better understanding of the regulation of myofiber types underlying skeletal muscle function and homeostasis.
Glucagon-like peptide 1 receptor agonist use and risk of arthroplasty for knee osteoarthritis: retrospective database analysis.
Reg Anesth Pain Med
Victoria Carter, Ethan Desverreaux, Idris Amin +4 more
Knee osteoarthritis (OA) is a leading cause of chronic pain and disability, with limited disease modifying therapies. While glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have established cardiometabolic benefits and have been associated with reductions in knee OA related pain, it is unclear whether they can reduce progression to total knee arthroplasty (TKA).
Beyond weight loss: How metabolism in human adipocytes is shaped by GLP-1R agonists and dual GIPR/GLP-1R agonists.
Pharmacol Res
Roberto Curto, Claudia Giglione, Rossella Cannarella +6 more
Obesity is a chronic disease leading to multiple comorbidities, including type 2 diabetes mellitus (T2DM), cardiovascular disease, and several cancers. Its prevalence has dramatically risen worldwide, making it a major global concern. Although lifestyle interventions remain the cornerstone of management, their effectiveness is often, underscoring the need for novel pharmacological approaches. In this regard, glucagon-like receptor agonists (GLP-1RAs) and the novel dual glucose-dependent insulinotropic polypeptide receptor (GIPR)/GLP-1R agonist, tirzepatide, have shown significant benefits on obesity-related outcomes. Clinical evidence consistently supports their efficacy and safety in promoting weight loss. Furthermore, these agents appear to exert pleiotropic effects by modulating the function of multiple systems, including the cardiovascular, nervous, and gastrointestinal systems. However, the cell type-specific molecular mechanisms underlying their actions in target tissues, particularly adipose tissue, remain incompletely understood. Hence, this review aims to summarize current preclinical evidence on the effects of GLP-1R and dual GIPR/GLP-1R agonists on the function of human-and animal-derived adipocytes. Available data indicate that most studies have been conducted in animal models, both in vivo and in vitro models, which may not fully recapitulate human adipose tissue pathophysiology. Therefore, future studies should prioritize human-derived cell models to better elucidate and address the pathophysiological and pharmacological downstream effects of GLP-1, GIP, and their agonists in humans.
Semaglutide and Neovascular Age-Related Macular Degeneration Among Adults with Type 2 Diabetes: An OHDSI Network Study.
Ophthalmology
Cindy X Cai, Brian Toy, Benjamin Martin +44 more
or Purpose: To investigate the potential association of semaglutide and neovascular age-related macular degeneration (NVAMD) DESIGN: Retrospective study across 12 databases in the Observational Health Data Sciences and Informatics (OHDSI) network during the study period from 12/1/2017-12/31/2024 SUBJECTS, PARTICIPANTS, AND/OR CONTROLS: Adults with type 2 diabetes (T2D) on semaglutide, other glucagon-like peptide-1 receptor agonists (GLP-1RAs) (dulaglutide, exenatide), or non-GLP-1RAs (empagliflozin, sitagliptin, glipizide) METHODS, INTERVENTION OR TESTING: The association between semaglutide and NVAMD was assessed using two approaches: an active-comparator cohort design and a self-controlled case-series (SCCS) analysis. The cohort design used propensity score-adjusted Cox proportional hazards models to estimate hazard ratios (HRs). The SCCS used conditional Poisson regression models to estimate incidence rate ratios (IRRs). A random-effects meta-analysis was used to generate network-wide HR and IRR estimates.
Dynamic modulation of LH secretion by continuous kisspeptin infusion in healthy men.
Hormones (Athens)
Amna Naveed, Margaret F Lippincott, Maria Stamou +3 more
Kisspeptin stimulates gonadotropin-releasing hormone (GnRH) release and, by extension, gonadotropin secretion. Although continuous kisspeptin administration has been shown to dampen kisspeptin-induced GnRH release in non-human primates [1, 2], this has not been replicated in the limited human studies reported to date. The objective of this study was to examine the effects of continuous kisspeptin administration on luteinizing hormone (LH) secretion in healthy men.
Population pharmacokinetics of polymyxin B: an individual participant data meta-analysis.
Clin Microbiol Infect
Saikumar Matcha, Gauri G Rao, Patrick O Hanafin +22 more
Small-scale studies often lack sufficient statistical power to identify clinically relevant covariates affecting drug pharmacokinetics (PK) and dosing. To overcome these limitations, we pooled data from clinical trials and performed a population PK analysis using individual participant data meta-analysis (IPDMA) approach for polymyxin B. The aim was to uncover covariate-parameter relationships that may remain unidentifiable in isolated analyses of data from smaller studies.
Nucleophagy removes cytotoxic trapped PARP1.
Nat Cell Biol
Gwendoline Hoslett, Sara Tribble, Pauline Lascaux +21 more
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) induce cytotoxicity in homologous recombination repair (HR)-deficient (HRD) cancers by trapping PARP1 on chromatin, thereby causing irreparable replication-associated DNA damage. Although increased clearance of trapped PARP1 from chromatin reduces the sensitivity of cancer cells to PARPi, details surrounding this process remain unclear. PARPi exposure is known to cause increased autophagy flux, whereas autophagy inhibition can hypersensitize cells to PARPi. Our study reveals that trapped PARP1 is cleared via nucleophagy, with the selective autophagy receptor TEX264 and its partner segregase p97 (also known as VCP) orchestrating this process. TEX264 interacts directly with trapped PARP1, linking it to the autophagosomal protein LC3 for degradation. Disrupting this pathway, either chemically or genetically, increases PARP1 trapping, resulting in protein aggregates, DNA damage and cell lethality, ultimately re-sensitizing PARPi-resistant cells. We conclude that nucleophagy serves a cytoprotective role by targeting PARPi-induced trapped PARP1 for degradation.
Determination of the relationship between thymoquinone and apelin in isoproterenol-induced myocardial infarction.
Tissue Cell
Rifat Özmen, Derya Karabulut, Aysun Çetin +5 more
Experimental MI models induced by isoproterenol (ISO) are frequently used because they show many similarities to the human heart attack model. Thymoquinone (THQ) is a biologically active compound known for its antioxidant and anti-inflammatory properties. This study aimed to induce experimental MI using ISO and to investigate the effects of THQ through its relationship with apelin.
Plasma proteomics enhances heart failure risk prediction among individuals with type 2 diabetes: a prospective cohort study.
Am J Clin Nutr
Hancheng Yu, Jijuan Zhang, Frank Qian +17 more
Heart failure (HF) is a severe complication of type 2 diabetes (T2D), yet the association between plasma proteins and HF in individuals with T2D remains underexplored.
Risk factors for adrenal insufficiency after adrenalectomy for mild autonomous cortisol secretion.
Surgery
Akanksha Aggarwal, Ali Osman Balkan, Divya Sistla +9 more
Although unilateral adrenalectomy can improve metabolic outcomes associated with mild autonomous cortisol secretion, it can also be associated with postoperative adrenal insufficiency. We aimed to look at the incidence and risk factors of suspected adrenal insufficiency in these patients.
Psychiatric Symptoms in Women with Mild Autonomous Cortisol Secretion Versus Non-Functioning Adrenal Adenomas: A Cross-Sectional Study.
Horm Metab Res
Ilkay Cakir, Fuat Mısıroğlu, Zeynep Elustu Belten +7 more
The potential association between mild autonomous cortisol secretion and psychopathological symptoms remains inadequately studied. This study aimed to investigate whether women with mild autonomous cortisol secretion exhibit greater psychological symptom severity and distress compared with patients with nonfunctional adrenal adenomas, as assessed by multidimensional self-report scales including the Beck Depression Inventory-II, Beck Anxiety Inventory, and Symptom Checklist‑90. A cross-sectional study was conducted at the endocrinology department of a tertiary-care hospital in Turkey between June 2022 and 2025. The study cohort included 91 women with adrenal adenomas, comprising 50 patients with mild autonomous cortisol secretion and 41 patients with nonfunctional adrenal adenoma. Questionnaire-derived scores from the 10 subscales and Global Severity Index of the Symptom Checklist-90, as well as the Beck Anxiety Inventory and Beck Depression Inventory-II, along with hormonal parameters, including morning cortisol, adrenocorticotropic hormone, dehydroepiandrosterone sulfate, 1-mg dexamethasone-suppressed cortisol, 24-hour urinary free cortisol, the dehydroepiandrosterone sulfate ratio, and the cortisol/dehydroepiandrosterone sulfate ratio, were compared between the groups. Women with mild autonomous cortisol secretion exhibited higher overall psychological distress, as measured by the Global Severity Index of the Symptom Checklist-90. Depressive (Beck Depression Inventory-II) and anxiety (Beck Anxiety Inventory) symptoms did not differ significantly between groups, although a non-significant pattern suggested that depressive symptom severity may increase with higher basal cortisol levels. No significant associations were found between hormonal parameters and psychological scores. These findings indicate that patients with mild autonomous cortisol secretion may experience increased general psychological distress, highlighting the importance of considering mental health in their clinical evaluation and warranting further research into the relationship between mild cortisol excess and specific psychiatric symptoms.
Quadruple Non-Insulin Therapy for Advanced Type 2 Diabetes Mellitus With Cognitive Impairment: A Case Report.
Cureus
Stjepan Skudar
Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder that often requires treatment intensification over time. In complex patients with multiple comorbidities and cognitive impairment, therapeutic decisions must balance glycemic control with safety and feasibility. We present a 59-year-old male with long-standing T2DM, marked body weight fluctuations, and emerging neurocognitive decline. Baseline glycated hemoglobin (HbA1c) was 9.4%, with progressive improvement to 7.1% under quadruple non-insulin therapy consisting of metformin, sitagliptin, glimepiride, and semaglutide. Insulin therapy was avoided due to cognitive impairment and a high risk of dosing errors. Sustained glycemic control was achieved without severe hypoglycemia. This case highlights the importance of individualized, multidisciplinary management in advanced T2DM and demonstrates that non-insulin strategies may be a viable and safe alternative in selected high-risk patients.