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Critical illness impairs coordinated myogenesis: a prospective longitudinal study of skeletal muscle progenitor cell biology using serial muscle biopsies (SATELLITE study).
Crit Care
Adéla Krajčová, Vlasta Němcová, Pavel Škrha +5 more
Critical illness often causes prolonged weakness, possibly due to impaired skeletal muscle regeneration, but the timing and nature of satellite cell (SC) dysfunction remain unclear. We aimed to determine whether SC depletion and dysfunction are detectable early after intensive care unit admission and describe their pathophysiological nature.
Early life social isolation stress and pain vulnerability: unraveling neuroimmune mechanisms and central sensitization.
Front Pharmacol
Carmela Belardo, Maria Consiglia Trotta, Federica Ricciardi +11 more
Chronic pain is increasingly recognized as a multidimensional condition in which neuroimmune interactions shape disease vulnerability and persistence. Among the emerging pain phenotypes, nociplastic pain (defined as an alteration of nociceptive processing in the absence of clear tissue damage or somatosensory lesion) remains mechanistically elusive and therapeutically challenging. Emerging evidence suggests that early life stress, particularly social isolation, may be a potent psychosocial stressor associated with an increased risk of nociplastic pain. However, this relationship remains incompletely understood and is largely inferred from indirect, model-dependent, or related lines of research. Preclinical and clinical studies indicate that prolonged social isolation can induce sustained activation of the hypothalamic-pituitary-adrenal (HPA) axis, systemic low-grade inflammation, and immune changes. These changes have been shown to promote persistent microglial activation, astrocytic reactivity, and dysregulated neuron-glia communication within pain-processing regions, including the spinal dorsal horn and supraspinal affective circuits. In parallel, peripheral neuroimmune alterations, particularly involving satellite glial cells and Schwann cells may contribute to increased sensory neuron excitability and processes consistent with central sensitization. Notably, much of this evidence derives from studies on stress-related conditions, neuroinflammation, and disorders such as fibromyalgia, rather than being specific to nociplastic pain per se. Early life social isolation stress has also been associated with changes in limbic and prefrontal networks implicated in the affective components of pain, suggesting a potential interaction between emotional dysregulation and pain amplification, although causal pathways remain to be clarified. Sex-dependent differences in neuroimmune signalling further add complexity to this framework, suggesting that biological sex may influence vulnerability to isolation-induced pain states and response to glial-targeted interventions. This narrative review proposes a putative neuroimmune model linking early life social isolation stress to nociplastic pain vulnerability and persistence. By integrating evidence from stress biology, glial dysfunction, and central sensitization, we aim to outline a conceptual model that may help guide future research and inform therapeutic strategies targeting central and peripheral neuroinflammatory processes.
Crosstalk Between Probiotics and Host Immunity: Antimicrobial Peptides-Mediated Health Benefits.
Compr Physiol
Shuanshan Ren, Muhammad Asif Arain, Atique Ahmed Behan +1 more
The intricate crosstalk between probiotics and the host immune system is increasingly recognized as a central determinant of mucosal integrity, resistance to infection, and systemic homeostasis. This narrative review synthesizes current evidence identified through comprehensive searches of major scientific databases, including PubMed, Scopus, and Web of Science, using targeted keywords related to probiotics, antimicrobial peptides (AMPs), and immune modulation. Emerging evidence indicates that, beyond their traditional metabolic roles, probiotics exert significant immunomodulatory effects through the induction and regulation of AMPs, including bacteriocins, defensins, lysozymes, and cathelicidins. Mechanistically, probiotics activate key host signaling pathways, stimulating epithelial and immune cells to enhance AMP expression. These peptides exhibit broad-spectrum antimicrobial activity by disrupting microbial membranes, inhibiting quorum sensing, and excluding pathogens, thereby strengthening mucosal barrier function and maintaining microbial homeostasis. Additionally, host immune signaling further promotes probiotic colonization and AMPs biosynthesis, establishing a tightly regulated bidirectional feedback mechanism. This review aims to highlight the current evidence on the bidirectional crosstalk between probiotics and host immunity, with particular emphasis on AMPs-mediated mechanisms underlying mucosal protection, immune modulation, and pathogen resistance.
LL-37 IgG levels are associated with clinical characteristics and T follicular cell response in acute coronary syndrome in adults.
Physiol Rep
Paul C Dimayuga, Jianchang Zhou, Xiaoning Zhao +3 more
Elevated LL-37 IgG levels are implicated in inflammatory conditions and immune complexes formed with LL-37 potentially propagate immunothrombosis in acute coronary syndrome (ACS). The reported binding of LL-37 to LDL may be relevant in this context given that LDL autoantibodies are implicated in ACS risk. In this report, three distinct cohorts were used to evaluate immunologic characteristics, clinical relevance, and potential mechanisms of elevated LL-37 IgG levels in ACS. First, evaluation of IgG reactive to native (n) LDL and LL-37 complexed with LDL (LL-37_LDL) in a cohort without acute disease demonstrated significantly higher levels of LL-37 IgG compared to LL-37_LDL IgG and nLDL IgG. Next, evaluation of LL-37 IgG levels in samples (N = 500) from the AZACS study (Azithromycin in ACS) and population-level associations with clinical characteristics showed that LL-37 IgG levels were significantly higher in subjects who had prior myocardial infarction and were negatively correlated with blood pressure. Third, an ACS cohort showed a negative association of LL-37 IgG with LVEF. There was also significantly reduced CD8+CD25+CXCR5+ T follicular (Tf) regulatory cells with constant CD8+CD137+CXCR5+ Tf-like cells in response to LL-37 stimulation of peripheral blood mononuclear cells suggesting the association of Tf cells with increased LL-37 IgG levels in ACS.
CGM-derived postprandial glucose with IcoSema versus other insulin regimens: a post hoc analysis of COMBINE 1 and 3.
EClinicalMedicine
Christophe De Block, Malik Benamar, Ariel Fu +2 more
Impaired insulin and incretin responses, alongside elevated postprandial glucose (PPG) levels after meals, are hallmarks of type 2 diabetes (T2D) and can lead to postprandial hyperglycaemia. This post hoc analysis used PPG levels derived from continuous glucose monitoring (CGM) to investigate the effect of IcoSema versus other insulin-based regimens on PPG control in T2D.
Effects of Semaglutide on Body Composition and GFR: A Prespecified Analysis of the SMART Trial.
Clin J Am Soc Nephrol
Hiddo J L Heerspink, Maria Soler, Jelle M Beernink +16 more
Treatment with semaglutide compared with placebo for 24 weeks reduced lean body mass and fat mass in adults with CKD and overweight or obesity. Changes in lean body mass or fat mass during semaglutide treatment did not correlate with changes in creatinine or cystatin C‑eGFR or measured GFR. Semaglutide significantly reduced extracellular water and BP, and changes in BP correlated with extracellular water.
Semaglutide and Risk of Adult-Onset Seizure: A Target Trial Emulation.
Neurology
Yong Eun, Suhwan Bong, Hyun Yong Koh +4 more
Adult-onset seizure reflects the burden of acquired brain insults, but established disease-modifying preventive strategies are limited. We evaluated whether semaglutide initiation is associated with a lower incidence of adult-onset seizure compared with sodium-glucose cotransporter 2 inhibitors (SGLT2i) and other glucose-lowering drugs (GLDs) in adults with type 2 diabetes.
GLP1 receptor agonists in heart failure with preserved ejection fraction (HFpEF) - beyond weight loss: a condensed scientific review.
Drugs Context
Elyzabeth Roy, Marie-Claude Parent, Anique Ducharme
More than half of cases of heart failure (HF) now occur with preserved ejection fraction (HFpEF), a heterogeneous syndrome strongly influenced by comorbidities such as obesity, hypertension, diabetes and atrial fibrillation. Despite recent evidence supporting SGLT2 inhibitors and mineralocorticoid receptor antagonists, morbidity and mortality remain substantial. GLP1 receptor agonists, initially developed for type 2 diabetes, induce profound weight loss and have demonstrated benefits across cardiovascular, renal and metabolic pathways relevant to HFpEF. Recent randomized controlled trials (RCTs) in obesity-related HFpEF showed clinically meaningful improvements in symptoms, functional capacity and inflammatory biomarkers with semaglutide in STEP-HFpEF, and a reduction in the composite of cardiovascular death or worsening HF events with tirzepatide in SUMMIT. Mechanistic evidence suggests effects on natriuresis, inflammation, cardiac remodelling, endothelial function and epicardial adipose tissue quality and volume. This review summarizes the pathophysiological rationale, clinical evidence, mechanistic insights and therapeutic positioning of GLP1 receptor agonists in HFpEF.
Imaging biomarkers of glymphatic system dysfunction in Alzheimer's disease: a systematic review and meta-analysis with a focus on DTI-ALPS index.
Front Aging Neurosci
Zulin Liao, Rui Chen, Xinyi Yang +6 more
Alzheimer's disease (AD) has been linked to impaired clearance of metabolic waste, and glymphatic dysfunction is increasingly considered a potential contributor to its pathogenesis. The diffusion tensor imaging-based analysis along the perivascular space (ALPS) index has been proposed as a non-invasive imaging marker, although findings across clinical studies remain inconsistent.
Plasma soluble triggering receptor expressed on myeloid cells 2 levels and clinical outcomes in acute decompensated heart failure: A retrospective cohort study.
J Int Med Res
Jie Li, Mengyu Wang, Jing Ma +9 more
ObjectiveEmerging evidence suggests a potential role for soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cardiovascular pathophysiology. However, plasma sTREM2 levels in patients with acute decompensated heart failure and their possible association with adverse clinical outcomes have not been fully characterized.MethodsIn this retrospective cohort study, we enrolled patients with acute decompensated heart failure between 2020 and 2023 and defined a composite endpoint comprising all-cause mortality and heart failure-related readmission. Baseline plasma sTREM2 levels were compared across clinical categories and acute decompensated heart failure phenotypes using appropriate statistical tests. The prognostic value of sTREM2 was evaluated using Kaplan-Meier survival curves, restricted cubic splines, and Cox proportional hazards regression models. Model calibration was validated using bootstrap-corrected plots with 1000 resamples. Furthermore, time-dependent receiver operating characteristic curves, net reclassification improvement, and integrated discrimination improvement were used to assess the incremental predictive value of sTREM2 over N-terminal pro-B-type natriuretic peptide. Finally, subgroup analyses were performed to assess the robustness of the findings.ResultsA total of 128 patients (median age, 75.5 years) were enrolled, with 58 (45.3%) reaching the composite endpoint during follow-up. Plasma sTREM2 levels were significantly higher in patients with acute decompensated heart failure than in healthy controls (P < 0.001) and showed a progressive increase with worsening New York Heart Association functional class. Multivariable Cox regression analysis demonstrated that each 50 pg/mL increment in sTREM2 was independently associated with an increased risk of the composite endpoint (adjusted hazard ratio: 1.594; 95% confidence interval: 1.170-2.173) and heart failure-related readmission (adjusted hazard ratio: 1.802; 95% confidence interval: 1.310-2.480). Restricted cubic spline analysis confirmed a linear association between sTREM2 levels and clinical outcomes (all P for nonlinear > 0.05). Although adding sTREM2 to N-terminal pro-B-type natriuretic peptide did not significantly increase the area under the curve, it provided incremental predictive value for heart failure-related readmission. Subgroup analyses revealed no significant interactions (all P for interaction > 0.05).ConclusionOur findings demonstrate that sTREM2 is a potential biomarker in acute decompensated heart failure. Elevated sTREM2 levels are independently associated with an increased risk of adverse clinical outcomes, particularly heart failure-related readmission, underscoring its potential utility in risk stratification and clinical management of acute decompensated heart failure.
Clinical efficacy of combined sacubitril/valsartan and the Chinese herbal preparation, Qili Qiangxin Capsules on reverse cardiac remodeling in patients with heart failure with reduced ejection fraction.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub
Fengyun Chen, Jing Gu
Heart failure with reduced ejection fraction (HFrEF) is mainly characterized by cardiac remodeling. Sacubitril/valsartan and Qili Qiangxin Capsules (QLQX a Chinese patent medicine, commonly used for the treatment of CHF with wide acceptance in Chinese patients), each benefit HFrEF alone, however, further high-quality clinical evidence is needed to confirm their combined effect on reversing cardiac remodeling.
Glucose-Dependent Insulinotropic Polypeptide Receptors Are Expressed in the Lateral Septum and Reduce Electrically-Evoked Dopamine Release as well as the Ability of Cocaine to Increase Extracellular Dopamine.
ACS Chem Neurosci
Anna Marie Buchanan, Sonja Virkus, N Dalton Fitzgerald +6 more
Tirzepatide, a dual agonist of the glucagon-like peptide 1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR), represents a new class of medication for obesity and type II diabetes treatment. Using laboratory mice, we show that GIPRs are present in the lateral septum (LS) in cells also expressing GLP-1R, particularly in the dorsolateral LS. Likewise, we show the coexpression of the dopamine (DA) D2 receptor (DRD2) in LS cells with GLP-1R in both the dorsolateral and intermediate portions of the LS. Using fast-scan cyclic voltammetry, we demonstrate that systemic GLP-1R or GIPR agonist treatment reduces both electrically evoked DA release in the LS and the ability of cocaine to increase extracellular DA levels. These data unveil a new central role for GIPR signaling and identify a potentially important cell type expressing both GLP-1R and GIPR upon which tirzepatide or other dual agonists may modulate DA homeostasis in the brain.
Chronic Exposure to 6PPD-Q Induces HPO Axis Dysfunction and Metabolic Disturbances in Female Offspring Mice.
J Agric Food Chem
Yan Jiang, Yanqi Ruan, Zihan Zeng +3 more
N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPD-Q) is an emerging environmental pollutant with limited research on its reproductive toxicity. In this study, female offspring mice were exposed to 6PPD-Q during gestation and lactation. The results revealed that 6PPD-Q exposure disrupted the hypothalamus-pituitary-ovary (HPO) axis in postnatal day (PND) 22 female offspring mice, leading to precocious puberty and estrous cycle irregularities, accompanied by substantial metabolic alterations. At PND 71, disturbances in the HPO axis and metabolic functions were observed. In both in vivo and in vitro experiments, 6PPD-Q was found to suppress hypothalamic gonadotropin releasing hormone (GnRH) secretion via the Kisspeptin/GPR54 pathway, inhibit pituitary luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion through the PKC/c-Raf/ERK1/2/IEGs pathway, and induce oxidative stress in human granulosa-like tumor cell line (KGN), resulting in a reduction in estradiol (E2) secretion. Collectively, this study provides novel theoretical insights into the potential reproductive toxicity and metabolic impact of 6PPD-Q.
Baxdrostat versus Osilodrostat: Steroid Biosynthesis in Human Adrenocortical Cells.
Endocr Connect
Yuki Taki, Takashi Kono, Ikki Sakuma +7 more
To compare the functional selectivity of baxdrostat versus osilodrostat in primary human adrenocortical cells, focusing on aldosterone suppression while preserving cortisol biosynthesis, we conducted an experimental ex vivo study using primary cells derived from aldosterone-producing adenomas, cortisol-producing tumors, and normal adrenal cortex. Cells were stimulated with adrenocorticotropic hormone (10 nM) and exposed for 72 h to baxdrostat, osilodrostat, or metyrapone (0-10 μM). Outcomes included geometric mean (GM) IC50 values for aldosterone and cortisol, LC-MS/MS steroid profiling, and molecular docking to CYP11B2/CYP11B1. In aldosterone-producing adenoma cells, baxdrostat selectively inhibited aldosterone (GM IC50 = 0.041 μM) and did not achieve 50% cortisol suppression in cortisol-producing tumor or normal adrenal cortex within 0-10 μM. Osilodrostat inhibited aldosterone (GM IC50 = 0.0022 μM) and cortisol (GM IC50 = 0.196 μM). Steroid profiling showed a modest, selective rise in 11-deoxycorticosterone with baxdrostat (+3.76-fold), whereas osilodrostat produced larger increases in 11-deoxycorticosterone (+25.4-fold) together with androgen elevations. Docking supported the mechanism: baxdrostat showed stronger predicted binding to CYP11B2 (-11.5 kcal/mol) than osilodrostat (-8.7 kcal/mol) with limited engagement of CYP11B1. Baxdrostat demonstrated greater functional selectivity for CYP11B2, with minimal cortisol-axis impact and smaller upstream precursor accumulation than osilodrostat. These human-tissue data inform dose selection and safety monitoring strategies for selective aldosterone synthase inhibition in aldosterone-mediated and treatment-resistant hypertension.
The evolving therapeutic landscape of gut-pancreatic peptide signalling in metabolic disorders: from mono- to multi-agonist therapies.
Biosci Rep
Marco Falasca, Mohan Patil, Federico Piccinini +2 more
The pharmacotherapeutic landscape for the clinical management of type-2 diabetes (T2D), obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), and steatohepatitis (MASH) is evolving swiftly in response to the escalating global prevalence and incidence of these interrelated metabolic disorders. Although insulin and metformin formulations have long constituted the foundation of diabetes care, a paradigm shift in T2D management has been observed with the advent of novel pharmacotherapies. Gut peptide analogues are at the forefront of this transformation. The emergence of glucagon-like peptide-1 (GLP-1) receptor agonists represents a watershed moment, fundamentally reshaping the therapeutic landscape for both T2D and obesity due to multifaceted metabolic benefits. The clinical success of GLP-1-based therapies has stimulated pharmaceutical interest in other metabolic peptides. Gut-pancreatic peptides such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, amylin, and peptide YY (PYY) are of particular interest due to their distinct pharmacological benefits and therapeutic promise in metabolic disorders. This review aims to provide a comprehensive and current overview of non-insulin gut-pancreatic peptide signalling-based therapies that are either clinically approved or under clinical investigation, with a focus on the emerging therapeutic convergence between T2D, obesity and associated liver disease. The review critically narrates their mechanisms of action, therapeutic efficacy, limitations, current development status, and positioning in the treatment landscape. Furthermore, the review delineates the emerging avenues in the development of novel peptide-based pharmacotherapies, offering insights into their future potential and acquainting the reader with developments in non-insulin gut-pancreatic peptide signalling-based therapies for metabolic disorders.
PROSTACYCLIN ANALOGS AND DIABETIC RETINOPATHY OUTCOMES IN PATIENTS WITH PULMONARY HYPERTENSION : A Cohort Analysis.
Retina
Natan Lishinsky-Fischer, Jaime Levy
The aim of this study was to evaluate the association between prostacyclin analog (PCA) therapy and the long-term incidence of diabetic retinopathy (DR) in patients with diabetes and pulmonary arterial hypertension.
Pan-filovirus activity of an IGF2-fused monoclonal antibody: Impairment by IGF1R cross-engagement and rescue via IGF2 Y27L mutation.
Virus Res
Wen Hu, Xiaonan Wu, Yuting Zhang +15 more
Filoviruses (Ebola and Marburg) cause severe high-mortality infectious diseases. Neutralizing antibodies represent promising antiviral candidates, but broadly reactive antibodies against multiple filoviruses are rare. Antibody-ligand fusion strategies that combine conserved glycoprotein-targeting antibodies with IGF2R ligands can mediate endosomal antibody delivery. Previously, we showed that an NPC2-fused AF-03 (an antibody to the GP1 core region) exhibited pan-filovirus neutralization. However, this NPC2 fusion faced quality control challenges and its application is limited by heterogeneous glycosylation, batch inconsistency, and poor CMC feasibility.
From autophagy to mitophagy: Quality control mechanisms in skeletal muscle.
Int Rev Cell Mol Biol
Eduardo Antuña, Nerea Menéndez-Coto, Paula Fernández-Guisasola +1 more
Autophagy is a process which is responsible for the maintenance of cellular homeostasis. This is achieved through the orchestration of both highly selective and non-selective degradation pathways, the purpose of which is the elimination of damaged structures. Recent findings have revealed that, in addition to its intracellular function, this organelle exhibits a remarkable "social life" and forms relationships with other cellular organelles. This has led to the discovery that mitochondrial quality is maintained not only through mitophagy, but also through extracellular mechanisms between cells. This has significantly expanded our understanding of tissue integrity. In skeletal muscle, autophagy, or autophagy, is a finely tuned process that plays a crucial role in maintaining physiological performance and adaptation. Disruption of autophagy has been linked to accelerated degeneration, metabolic dysfunction, and frailty. Although therapeutic manipulation of autophagy and mitophagy shows promise in restoring muscle health, major translational barriers persist. A more profound and nuanced exploration of autophagy flux in human muscle is imperative, underpinned by novel advanced cell biology technologies and predicated on satellite cells as the primary agents in muscle regeneration. The full therapeutic potential of autophagy could be harnessed to redefine interventions against muscle ageing and associated diseases. However, this would still require critical scrutiny of the long-term effects and systemic consequences.
Nuclear export of R-loop by the DDX1 and XPO1 complex promotes senescence-associated secretory phenotype and inflammaging.
Nat Aging
Xue Hao, Bo Zhao, Qingqing Yan +10 more
Cellular senescence contributes to inflammaging in part through the senescence-associated secretory phenotype (SASP). R-loops, three-stranded nucleic acid structures, contribute to innate immune response in cancers; however, the role of R-loops in senescence and inflammaging remains largely unknown. Here we show that nuclear-derived cytoplasmic R-loops promote the SASP and inflammaging. We detect an accumulation of nuclear-derived R-loops in the cytoplasm of senescent cells with an enrichment in alpha-satellite repeats. These cytoplasmic R-loops localize into cytoplasmic chromatin fragments (CCFs) and activate the cGAS-STING innate immune pathway to drive the SASP. We identify the exportin-1 (XPO1)-DEAD-Box helicase 1 (DDX1) complex as essential for the nuclear export of R-loops and their subsequent localization into CCFs. Inhibition of XPO1 with KPT-330 suppresses nuclear R-loop export and its localization into CCFs, attenuates the SASP, mitigates age-associated inflammation and extends healthspan. These findings reveal nuclear export of R-loops as a potential target for suppressing age-associated inflammation.
Association between GLP-1 receptor agonist use and NAION with optic disc drusen.
Ophthalmology
Ibrahim Abboud, Rami Madani, Joseph G Chacko +3 more
In adults with optic disc drusen and type-2-diabetes or obesity, glucagon-like peptide-1 receptor agonists exposure was not associated with increased nonarteritic anterior ischemic optic neuropathy hazard, though moderate risk increases could not be excluded statistically.