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Choroid plexus enlargement is negatively associated with cognitive performance in a DTI-ALPS-dependent manner.
Front Aging Neurosci
Nicole I Y Z Tan, Thomas Welton, Yi Jayne Tan +11 more
Disturbances in brain fluid homeostasis are increasingly implicated in neurodegeneration. Imaging measures of structural alterations of the choroid plexus (CP) and impaired glymphatic transport have each been associated with cognitive decline, yet their potential interaction in humans remains poorly understood.
Stress management by benzodiazepines in septic shock and critical illness: mechanistic and clinical evidence supporting alternative sedative strategies.
Cell Stress
Flavia Lambertucci, David Skurnik, Damien Roux +4 more
Critical care involves the management of organismal stress by sedation. Benzodiazepines remain widely used for anxiolysis and sedation in critical care, including in septic shock. Yet converging mechanistic, preclinical and clinical evidence suggests that benzodiazepines and the endogenous ligand of benzodiazepine-binding sites, the "endozepine" acyl-CoA binding protein/diazepam binding inhibitor (ACBP/DBI), may impair host immune defenses, exacerbate organ dysfunction and contribute to long-term morbidity after intensive care. A unifying framework is that benzodiazepines may accelerate "iatrogenic aging" by antagonizing adaptive stress responses (notably autophagy) and favoring cellular senescence, chronic inflammation, immunosuppression and neurocognitive perturbations. Here, we synthesize evidence supporting benzodiazepine avoidance in sepsis-heavy intensive care populations. We propose that replacing benzodiazepines with alternative sedative strategies may improve both short-term outcomes and long-term trajectories of post-sepsis disability. We hypothesize that post-intensive-care syndrome (PICS), including -as a specific case- post-sepsis syndrome (PSS), is caused by premature aging of the organism and that PICS/PSS might be attenuated by the avoidance of benzodiazepine administration during and after critical care.
Sex as a Missing Moderator in the Dual-Pathway Neuroprotection Hypothesis.
Aging Dis
Zehui Gong, Liang Xiang, Jianrong Yuan +1 more
The Dual-Pathway Neuroprotection Hypothesis, recently proposed by Badea and colleagues, distinguishes voluntary from enforced exercise and links each to distinct neural pathways, moving beyond the unitary view of exercise as a homogeneous intervention. However, the hypothesis does not consider sex as a biological variable. Given that AD is a sex-biased disease affecting approximately 65-70% women, and that the neuroprotective effects of exercise are sexually dimorphic, we argue that sex may function as a critical moderator of this framework. We propose three testable predictions: (1) voluntary exercise's cortico-limbic effects may be potentiated in females through estrogen-BDNF signaling, but this effect may be constrained by menopausal status; (2) structured/supervised exercise may yield sex-divergent outcomes-with preliminary observations suggesting Aβ clearance in females versus neurotrophic upregulation in males-though evidence remains preliminary and derives from a limited number of heterogeneous studies; and (3) stress burden may reduce the net benefit of enforced exercise, but this will require direct testing. These predictions converge on a formal revision in which sex is not a confounder to be controlled for, but a core biological moderator that may moderate modality-specific neuroprotection. This extended model provides a hypothesis-generating framework for designing future sex-aware exercise studies in AD, but does not yet support sex-stratified clinical prescriptions. This framework is predominantly based on preclinical and indirect evidence from heterogeneous models, necessitating cautious interpretation and rigorous validation.
Mitochondrial Inflammation and Muscle Aging: Targeting the Inflammatory Microenvironment in Sarcopenic Muscle.
Aging Dis
Xuesong Wang, Shannah Erasmus, Zewen Chu +4 more
Sarcopenia is an age-related progressive degenerative disorder of skeletal muscle characterized by declining muscle mass, strength, and function. Increasing evidence indicates that chronic low-grade inflammation plays an important contributory role in its pathogenesis. The inflammatory microenvironment contributes to sarcopenia through complex interactions involving cellular senescence, mitochondrial dysfunction, and sustained inflammatory signaling, forming a self-reinforcing pathological cycle within skeletal muscle. This review synthesizes current evidence on the molecular mechanisms underlying inflammation-driven sarcopenia, with particular emphasis on how inflammatory signaling disrupts protein turnover and satellite cell metabolism. In addition, exercise is examined as a precision "hormone-like" intervention tailored to different sarcopenia phenotypes, highlighting the distinct mechanisms through which resistance training, aerobic exercise, and combined training modulate the senescence-associated phenotype and inflammatory responses. The review further evaluates anti-inflammatory therapeutic strategies, including nutritional interventions, pharmacotherapy, and acupuncture. These approaches improve muscle health by restoring immune balance, enhancing mitochondrial function, modulating the gut-muscle axis, reducing oxidative stress, and promoting the clearance of senescent cells. Finally, emerging precision medicine frameworks and multi-omics strategies that may support individualized sarcopenia management are discussed. Overall, this review provides an integrated perspective on inflammatory signaling in sarcopenia and outlines potential therapeutic strategies targeting the inflammatory microenvironment, offering insights for future research and clinical management.
Glymphatic System Function and Cognition: Converging Evidence from DTI-ALPS Imaging - A Narrative Review.
Aging Dis
Anna B Marcinkowska, Małgorzata Grzywińska, Paweł J Winklewski
The glymphatic system, a brain-wide perivascular network mediating cerebrospinal fluid-interstitial fluid exchange, has emerged as a candidate determinant of cognitive health through its role in clearing metabolic waste, neurotoxic proteins, and neuroactive metabolites. The diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index provides a non-invasive means to assess glymphatic activity in vivo, yet no synthesis has consolidated what this marker captures, how reliably it predicts cognitive outcomes, and what pathways may account for observed associations. This narrative review, informed by selected principles from the PRISMA 2020 framework but not constituting a formal systematic review, synthesizes evidence linking DTI-ALPS to domain-specific cognitive performance in healthy aging and neurological disease, encompassing the Alzheimer's disease continuum, cerebral small vessel disease, Parkinson's disease, multiple sclerosis, stroke, and HIV-associated neurocognitive disorder. Lower DTI-ALPS values were consistently associated with worse cognitive performance. The strongest associations were observed for memory and global cognition, followed by executive functions and processing speed; evidence for language and visuospatial abilities was less consistent. Longitudinal data indicate that DTI-ALPS decline may precede detectable amyloid pathology, positioning this index as a candidate early prognostic marker. Three mechanistic pathways are discussed: disruption of sleep-dependent waste clearance; compromise of gray matter integrity through neurotoxic metabolite accumulation; and facilitation of amyloid-β and tau pathology via impaired perivascular protein clearance. Limitations include the indirect nature of DTI-ALPS as a clearance measure, predominance of cross-sectional designs, small samples, and absence of sex-stratified analyses despite known hormonal modulation of glymphatic function. Longitudinal studies, randomized trials of glymphatic-targeting interventions, and acquisition protocol standardization represent priority directions for future research.
Baseline biochemical evaluation for etiologic differentiation in ACTH-dependent Cushing's syndrome: machine learning and composite score analysis in a multicenter cohort of 566 patients.
Eur J Endocrinol
Mario Detomas, Juan P Prada Salcedo, Barbara Altieri +11 more
Limited availability of corticotropin-releasing hormone (CRH) currently complicates the differentiation of adrenocorticotropin (ACTH)-dependent Cushing's syndrome (CS). The diagnostic value of common screening tests in distinguishing Cushing's disease (CD) from ectopic CS (ECS) remains unclear.
Efficacy, Safety, and Pharmacokinetics of Macitentan in Japanese Pediatric Patients With Pulmonary Arterial Hypertension: Prospective, Multicenter, Open-Label Study.
Circ Rep
Ryo Inuzuka, Taku Ishii, Toru Iwasa +15 more
Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR), imposing an increased workload on the right ventricle and ultimately leading to right heart failure. Macitentan is a potent dual endothelin receptor antagonist that blocks both endothelin receptor subtypes A and B, and is approved for adult patients with PAH, but evidence in pediatric PAH patients is limited.
Dramatic sex differences leading to different brain disease presentation: The requirement for sex-specific medications with ADNP/davunetide as a case study.
Front Neuroendocrinol
Alexandra Lobyntseva, Liri Sophia Guz, Artur Galushkin +1 more
Focusing on the brain-essential gene revealed in our laboratory, activity-dependent neuroprotective protein (ADNP) and its neuroprotective site, the investigational drug davunetide (NAP), we discuss ADNP regulating steroid hormone biosynthesis and sex chromosome genes coupled with sex-dependent shuttling between the nuclei and cytoplasm. Further coupled with sex-dependent transcriptional control, ADNP/davunetide cytoplasmic microtubule/Tau targeting is translated into differential sex regulation of key cellular processes including neurogenesis, synaptic function, and axonal transport, then decoded into sexual dichotomy in multicellular processes directing sex-dependent behavioral outcomes. ADNP regulation of these sex-specific processes serves as a target for davunetide intervention, toward sex-directed precision medicine, revealing sexually dichotomized neuroprotection against tauopathy risk and progression spanning from coronary artery bypass grafting (CABG) to prodromal Alzheimer's disease, progressive supranuclear palsy (PSP), and schizophrenia, as well as the pediatric ADNP syndrome. Sex-specific intranasal bioavailability of davunetide, regulated by the estrous cycle, provides a mechanistic foundation for these differential outcomes.
Efficacy and safety of once-weekly semaglutide 2·4 mg in Chinese adults with overweight or obesity (STEP 12): a randomised, double-blind, placebo-controlled, multicentre, phase 3b trial.
Lancet Diabetes Endocrinol
Lixin Guo, Xiaolei Bao, Kuo-Chin Huang +6 more
Semaglutide 2·4 mg is a GLP-1 receptor agonist that reduces bodyweight, and provides other cardiometabolic benefits, among people with a BMI at least 30 kg/m2 or at least 27 kg/m2 and with weight-related comorbidities. This trial aimed to evaluate the efficacy, tolerability, and safety of semaglutide 2·4 mg in adults from mainland China and Taiwan with overweight or obesity according to locally defined, BMI thresholds.
AI Patient Support and 6-Month Medication Adherence in a Digital Obesity Program: A Retrospective Analysis.
Diabetes Obes Metab
Louis Talay, Connie Xu, John Alderete +3 more
Real-world glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapies face substantial attrition rates in commercial digital weight loss services (DWLSs). Conversational artificial intelligence (AI) has been proposed to enhance patient support at production scale, but robust evidence of its effectiveness in improving medication retention is scarce.
Tirzepatide Persistence and Associated Changes in Clinical Outcomes in US Adults With Obesity or Overweight: A 6-Month Claims Database Analysis.
Diabetes Obes Metab
Theresa Hunter Gibble, Malvika Venkataraman, Donna Mojdami +5 more
Tirzepatide is a once-weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist (GLP-1 RA) approved in the US for the treatment of Type 2 diabetes (T2D), weight loss and obstructive sleep apnoea. This study aimed to assess the utilisation and effectiveness of tirzepatide among individuals in a large US commercially insured population.
Changes in recorded background glucose-lowering therapy after initiation of a GLP-1 receptor agonist or dual GIP/GLP-1 receptor agonist in adults with type 2 diabetes.
Diabetes Res Clin Pract
Artur Dziewierz, Natalia Kulicka, Krzysztof Łupina +5 more
To evaluate changes in recorded background glucose-lowering active-substance counts after initiation of a glucagon-like peptide-1 (GLP-1) or dual GIP/GLP-1 receptor agonist.
CAR T cell therapy beyond cancer: current status, challenges and future prospects.
Signal Transduct Target Ther
Saurabh Upadhyay, Sungwoo Cho, Kirti Upmanyu +1 more
Chimeric antigen receptor (CAR) T-cell therapy has revolutionized oncology, and its foundational logic-precise antigen recognition coupled with durable effector activity-extends naturally to chronic non-malignant diseases sustained by long-lived pathological cells. These include viral reservoirs, autoreactive B and plasma cells, activated fibroblasts, alloimmune clones, and senescent cells that remodel tissue niches and evade clearance by conventional therapies. This review highlights how CAR-based strategies can be adapted across diverse disease settings by redirecting engineered immune responses toward disease-sustaining cellular compartments. Co-stimulatory domains such as CD28, 4-1BB, and OX40 enhance persistence and effector function; programmed cell death protein 1 (PD-1)-CD28 switch receptors reverse inhibitory signaling; and cytokine-resistant CARs incorporating dominant-negative transforming growth factor-β (TGF-β) receptors maintain activity within suppressive microenvironments. We discuss these approaches across infections, including human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV); autoimmunity involving CD19- and B-cell maturation antigen (BCMA)-directed depletion strategies and CAR-engineered regulatory T cells (CAR-Tregs); fibrosis targeting fibroblast activation protein (FAP); hemophilia using B-cell antibody receptor (BAR)-CARs against factor VIII and factor IX inhibitors; transplantation employing human leukocyte antigen (HLA)-specific CAR-Tregs; and senescence-associated pathologies targeting urokinase plasminogen activator receptor (uPAR) and natural killer group 2D ligands (NKG2DLs). Early clinical experiences in systemic lupus erythematosus, systemic sclerosis, myositis, and multiple sclerosis, together with preclinical successes in chronic infections and fibrotic disease, demonstrate both feasibility and durable disease modification. By extending CAR-T therapy beyond oncology, these applications position programmable cellular immunotherapy as a broadly adaptable platform for eliminating persistent pathological cells, remodeling diseased tissue environments, and restoring long-term immune homeostasis.
Augmented Skin Beneficial Effects of Thermus Thermophilus and Bacillus Subtilis Mixed-Culture Ferment Extract by Tripeptide GHK-Cu.
Skin Res Technol
Jingyi Wang, Kan Tao, Hu Huang +1 more
Skin aging is a complex process driven by multiplex factors, including chronic inflammation and UV exposure. It has become common practice for cosmetic formulations to counteract skin aging by targeting different pathways simultaneously with a pool of active ingredients. The present study aims to explore the skin protective effects of a novel extract of ferment in combination with copper tripeptide-1 GHK-Cu from an anti-inflammation perspective.
Perioperative management of GLP-1 receptor agonists: a structured narrative review with considerations relevant to neurosurgical patients.
J Endocrinol Invest
Utkan Topçu, Ferhat Oto
The use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) is increasing in the treatment of obesity and type 2 diabetes mellitus. Some patients taking these medications undergo cranial or spinal surgical procedures. Delayed gastric emptying is a key mechanism of action for these medications. Despite the standard preoperative fasting period, there is a risk of residual gastric contents remaining in the perioperative period. Since neurosurgical patients face a risk of postoperative complications such as aspiration, delayed extubation, and postoperative nausea and vomiting, there is a need for a clinically focused review.
GLP-1-Based Therapies in Pain Medicine: A Narrative Review and Expert Opinion on Obesity-Related Low Back and Knee Pain.
Curr Pain Headache Rep
Jamal Hasoon, Anvinh Nguyen, Omar Viswanath +2 more
Obesity is highly prevalent among patients with chronic musculoskeletal pain and is associated with low back pain, knee osteoarthritis, reduced mobility, and poorer functional outcomes. Glucagon-like peptide-1 (GLP-1) receptor agonists and related therapies have transformed obesity medicine and may become more relevant to pain medicine specialists. This narrative review examines whether GLP-1-based medications should be considered within pain practice, particularly for obesity-associated low back pain and knee osteoarthritis.
Glucagon-like peptide-1 receptor agonist-based regimens compared with metformin-based regimens for preventing cardiovascular disease in adults with type 2 diabetes mellitus.
Cochrane Database Syst Rev
Sana Ahmed, Sandra P McCollin, Arturo Martí-Carvajal +8 more
This is a protocol for a Cochrane review (intervention). The objectives are as follows: To assess the clinical benefits and adverse effects of glucagon-like peptide-1 receptor agonist-based regimens, compared with metformin-based glucose-lowering regimens, for preventing cardiovascular events including all-cause mortality, cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, and metabolic adverse events (including transient hypoglycemia) in adults with type 2 diabetes mellitus across primary and secondary prevention settings.
Ferroptosis and Iron Dyshomeostasis as Drivers of Wound Chronicity in Diabetic Foot Ulcers: Pathophysiological Mechanisms and Targeted Therapeutic Strategies.
Int J Low Extrem Wounds
Terry Hao-Yu Qin, Sulu Shen, Atiqah Aziz +6 more
Backgrounddiabetic foot ulcers (DFUs) carry 5-year mortality rates of 50%-70% and recurrence rates of 65% at three to five years. Standard-of-care protocols fail to resolve wound chronicity in a substantial proportion of patients, reflecting incomplete understanding of the cellular mechanisms sustaining non-healing. This narrative review examines trace element dyshomeostasis as a mechanistically distinct driver of ferroptotic cell death across wound-bed cell populations and evaluates targeted therapeutic strategies within this framework.MethodsLiterature was identified through narrative searches of PubMed and Web of Science; emphasis was placed on DFU-relevant experimental models and clinical populations.ResultsLabile iron pool expansion, arising from hemolysis-derived Fe2+ release, vasa nervorum compromise, ferritinophagy dysregulation, and SASP-mediated ferroportin suppression, sustains iron-catalyzed lipid peroxidation across Schwann cells, endothelial cells, fibroblasts, and macrophages. Three upstream metabolic axes, comprising AGEs/RAGE-mediated SLC7A11 suppression, eNOS uncoupling with BH4 depletion, and macrophage iron overload-driven polarization arrest, collectively lower the ferroptotic threshold at the wound margin. AGE-induced ECM stiffening further impairs fibroblast antioxidant capacity via mechanotransduction, while impaired NCOA4-dependent ferritinophagy renders senescent fibroblasts ferroptosis-resistant, sustaining SASP-driven iron retention in neighboring cells. Localized deferoxamine delivery stabilizes HIF-1α and restores angiogenic signaling in preclinical models; selenium supplementation restores GPX4-mediated lipid hydroperoxide clearance. Stimuli-responsive biomaterials coordinating DFO and antioxidant release in response to pathological ROS, MMP, and pH signatures represent a tractable delivery framework.ConclusionIron dyshomeostasis and ferroptosis constitute a therapeutically actionable axis in DFU pathology unaddressed by current standard of care. Large animal model validation and pharmacokinetic profiling in the DFU wound environment remain necessary before clinical translation.
Clinical Profile, Biochemical Characteristics, and Surgical Outcomes in Cushing Disease: An Age-Stratified Analysis of a Large Tertiary-Care Cohort.
Clin Endocrinol (Oxf)
Rakhi Pooja, Vivek Jha, Kavyanjali Kundu +8 more
To characterize the clinical, biochemical, radiological, and surgical profile of Cushing disease in a large tertiary-care cohort, with emphasis on age-stratified differences.
TNFR2 Agonism as a Sex-Specific Therapy for Novel Osteoarthritis-Induced Cardiac Dysfunction.
bioRxiv
Pranav Prasoon, Kelly Tammen, Rebekah Russo +11 more
Osteoarthritis (OA), a degenerative joint disease, is associated with increased systemic inflammation, chronic pain, and cardiovascular dysfunction. Epidemiological evidence establishes that OA increases the risk of cardiovascular disease (CVD) threefold, yet the causal role of OA's contributions remains underexamined. We assessed cardiac function longitudinally following destabilization of the medial meniscus (DMM) surgery to induce osteoarthritis in mice. DMM-mice exhibited significant, sexually dimorphic alterations in echocardiographic parameters. Female DMM mice developed impaired relaxation with altered E/A ratios, increased E/e' ratios, and prolonged intraventricular relaxation time with no change in ejection fraction, while male DMM mice showed progressive systolic dysfunction with decreasing ejection fraction, increased E/e' ratio, and prolonged intraventricular contraction time. Transcriptomic profiles and biochemical analyses demonstrated divergent cellular responses involving fibrosis and oxidative stress in female mice, whereas autophagic and apoptotic responses were observed in male mice. Using a tumor necrosis factor 2 (TNFR2) agonist shown to reduce systemic inflammation, we investigated its potential therapeutic role in the context of OA-induced cardiovascular dysfunction. TNFR2 agonism proved to be effective both prophylactically and therapeutically for female diastolic dysfunction. While prophylactic and therapeutic administration delayed male systolic dysfunction, the efficacy declined over time. Our findings demonstrate evidence of a novel sexually dimorphic model of OA-induced CVD that recapitulates the sexually dimorphic pattern of patient phenotypes and a promising new therapeutic approach to CVD.