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Glial cells in neuropathic pain.
Physiol Rev
Temugin Berta, Arkady Khoutorsky, Jing Xu +1 more
Neuropathic pain is a chronic, debilitating condition that affects approximately 78% of the global population and remains difficult to treat due to limited therapeutic options. Over the past two decades, mounting preclinical evidence has highlighted the crucial role of glial cells in the development, maintenance, and resolution of neuropathic pain. Conditions such as peripheral nerve injury are associated with reactive responses of glial cellsnamely microglia and astrocytes in the central nervous system, and satellite glial cells in the peripheral ganglia. Under physiological conditions, glial cells contribute to homeostatic regulation of spinal nociceptive circuits, preserving normal pain sensitivity. However, neuropathic pain is increasingly recognized as a form of gliopathy, wherein dysregulated glial activity contributes to pain hypersensitivity through enhanced excitability of primary sensory neurons (peripheral sensitization) and neuronal plasticity in the central pain circuits (central sensitization). In this review, we provide a comprehensive overview of glial cell research in neuropathic pain, with a specific focus on microglia, astrocytes, and satellite glial cells, the most extensively studied glial types in this context. We also highlight the critical involvement of glial cells in neuroinflammation and neuro-glial interactions and evaluate emerging therapeutic strategies targeting glial mechanisms of neuropathic pain.
Isolation and Therapeutic Application of Extracellular Vesicles Derived from Self-Assembled Mesenchymal Stem Cell Aggregates.
J Vis Exp
Jun-Xi He, Si-Yu Lan, Li-Heng Ren +10 more
Extracellular vesicles (EVs) are vital mediators of intercellular communication and promising cell-free agents for regenerative medicine. Among EV subpopulations, large extracellular vesicles (LEVs) are particularly suited for tissue repair due to their enriched pro-regenerative cargo. However, standardized and reproducible methods to generate functional dental stem cell-derived LEVs for downstream characterization and therapeutic evaluation remain limited. Utilizing the exceptional osteogenic potential of stem cells from the apical papilla (SCAPs), we developed a 3D culture model under low-adhesion conditions to induce self-assembled SCAP aggregates. This model mimics physiological mesenchymal condensation, significantly enhancing cell-cell interactions and boosting LEV secretion. Key culture parameters and handling notes are provided to improve aggregate consistency and maximize LEV output while maintaining cell viability. Here, we present a standardized protocol for the efficient production of functional SCAP-derived LEVs, encompassing 3D aggregate generation, isolation via differential centrifugation, nanoparticle tracking analysis (NTA)-based particle size distribution and concentration analysis, and therapeutic delivery using a thermally crosslinked hydrogel for mandibular bone defect repair. This approach streamlines LEV production for downstream mechanistic studies and preclinical evaluation in craniofacial regeneration. This optimized workflow ensures the reproducible preparation of bioactive LEVs with consistent yields and enriched pro-osteogenic cargo, facilitating fundamental research and accelerating the clinical translation of EV-mediated craniofacial reconstruction. In representative applications, hydrogel-loaded LEVs provide a localized depot at defect sites and facilitate convenient handling during implantation. Collectively, this method provides a scalable platform to prepare SCAP-derived LEVs and highlights key considerations for standardized reporting and translational study design. This approach supports broader adoption across craniofacial EV laboratories.
Aggregation-State Dynamics Drive Double Cooperativity Between Antimicrobial Peptides LL-37 and HNP1.
Angew Chem Int Ed Engl
Yuge Hou, Jing Zhang, Koh Takeuchi +7 more
The double cooperative effect between two major antimicrobial peptides, LL-37 and HNP1, where their combination enhances antimicrobial efficiency while reducing cytotoxicity, offers a promising strategy for developing safer and more effective antibiotics against antimicrobial resistance. However, the molecular mechanism driving this effect has remained unclear. In this study, a combination of total internal reflection fluorescence (TIRF) microscopy, Förster resonance energy transfer (FRET), nuclear magnetic resonance (NMR), and molecular dynamic simulation (MD) revealed that the double cooperative effect arises from the dynamic assembly and disassembly of LL-37/HNP1 aggregates, where the degree of aggregation governs membrane toxicity and therefore influences the cell fate. The aggregation is driven primarily through hydrophobic interactions between several amino acids within LL-37 and HNP1. Interestingly, in membranes, this aggregation state is regulated by the lipid composition, where only anionic lipids can break up the aggregates and disperse peptides in the membranes, leading to the gain of peptides' function. Taking the advantage of the lipid composition difference, this enables the aggregates to destroy bacterial membranes, whereas protect eukaryotic cell membranes.
Molecular interaction modes of the host-defense peptide cathelicidin LL-37 and its mutants dictate diverse antimicrobial activities.
Nanoscale
Xiaofei Jin, Huipan Wang, Huayuan Tang
The host-defense peptide cathelicidin LL37 is an innate immune defense peptide with broad-spectrum antimicrobial effects. Experiments showed that the antimicrobial activity of LL37(17-29), the active core of LL37, was associated with peptide aggregation and fibrillization. Although wild-type (WT) LL37(17-29) aggregated into densely packed fibrils with strong antimicrobial activity, the F17S mutation exhibited a weaker antimicrobial effect, and I24K totally abolished the antimicrobial activity, with no fibrils formed. To uncover the mechanisms of the distinct antimicrobial activities, we explored the structures and aggregation dynamics of LL37(17-29) and its mutants using discrete molecular dynamics (DMD) simulations, an efficient molecular dynamics algorithm with accurate predictions. The results showed that the LL37(17-29) peptides formed helix-helix contacts driven by hydrophobic interactions, which further aggregated into fibrils of densely packed helices. The F17S peptides, with a monomeric structure similar to that of WT peptides, were more flexible and formed weak interpeptide contacts between short helices, ultimately inhibiting aggregation. In comparison, although the helix structure of the monomeric I24K peptide was promoted compared with that of the WT peptide, the helix-helix contacts between I24K peptides were diminished due to the reduced hydrophobic interactions and enhanced electrostatic repulsions, resulting in suppressed aggregation and antimicrobial activity. Together, our results elucidated the molecular mechanisms of the diverse aggregation and antimicrobial activities of the LL37(17-29) WT and its mutants, offering valuable insights for the rational design of novel antibacterial agents.
IL-15 Plus Thymosin α1 Reduces Senescent Hepatic CD8+ T Cells in Hepatocellular Carcinoma via PI3K/AKT Suppression.
J Gastroenterol Hepatol
Fengtian Wu, Zixuan Guo, Jun Guan +3 more
CD8+ T cell immunosenescence drives hepatocellular carcinoma (HCC) progression and impedes therapeutic efficacy. We hypothesized that combining interleukin-15 (IL-15), which rescues senescent CD8+ T cells peripherally, with thymosin alpha 1 (Tα1), which replenishes the T cell pool via thymic rejuvenation, may synergistically overcome immunosenescence and enhance antitumor immunity in HCC.
Do GLP-1 receptor agonists improve insulin sensitivity and reduce lipid accumulation in skeletal muscles and the liver independent of weight loss?
Endokrynol Pol
Adrian Kołakowski, Monika Karczewska-Kupczewska
Increased body mass index and excessive lipid accumulation are associated with enhanced production of toxic lipid species and impairedoxidation of free fatty acids (FFAs), a phenomenon defined as lipotoxicity. It is an important predictor of etabolic disorders such astype 2 diabetes (T2D). Increased lipid accumulation leads to decreased glucose uptake in skeletal muscle and enhanced hepatic glucoseproduction. Thus, ectopic fat accumulation impairs insulin signalling and decreases insulin sensitivity (IS). Scientific data demonstratethat glucagon-like peptide-1 receptor agonists (GLP-1 RAs) can improve IS and decrease lipid accumulation in peripheral tissues mainlythrough weight loss. However, experimental studies indicate that GLP-1 RAs exert direct effects on glucose and lipid metabolic pathways,although the precise mechanisms remain incompletely understood. GLP-1 RAs may directly modulate fatty acid β-oxidation, lipogenesis,and 5'-AMP-activated protein kinase (AMPK) phosphorylation. In this review, we discuss the mechanisms by which liraglutide and subcutaneoussemaglutide affect IS and lipid accumulation in key insulin-responsive tissues.
Age- and sex-related glymphatic differences and hemispheric asymmetry in healthy adults at 7.0T magnetic resonance imaging.
Psychoradiology
Yumei Yue, Xiaocui Tang, Ting Shen +5 more
The glymphatic system plays a critical role in cerebral waste clearance and has been implicated in neurodegenerative and cerebrovascular disorders. However, normative variations in glymphatic structure and function across age, sex, and hemispheric organization in healthy adults remain incompletely characterized.
The common pathological network of inflammation, extracellular matrix imbalance, and senescence in intervertebral disc degeneration and osteoarthritis.
Mol Biol Rep
Wenbo Xie, Chao Song, Lei Yang +5 more
As representatives of degenerative orthopedic diseases, intervertebral disc degenerative disease (IVDD) and osteoarthritis (OA) involve the spine and peripheral articular cartilage, respectively. Their comorbidity rate in individuals over 60 years exceeds 40%, suggesting overlapping pathological and physiological features. Age-related "inflammaging" and cellular senescence, obesity-mediated mechanical load and metabolic disorders, and genetic/epigenetic abnormalities (e.g., COL2A1, ADAMTS5) constitute a shared risk factor network. Extracellular matrix (ECM) imbalance is a core initiating event: the MMPs/ADAMTS enzyme system, together with inflammatory cytokines such as IL-1β and TNF-α, drives excessive degradation of type II collagen and aggrecan, forming a "degradation-inflammation" positive feedback loop. In the chronic inflammatory microenvironment, damage-associated molecules activate TLR/NLRP3 pathways, triggering M1 macrophage polarization and Th17 cell infiltration, further disrupting ECM and inducing cell apoptosis. Cellular senescence releases pro-inflammatory mediators and degradation enzymes via the senescence-associated secretory phenotype (SASP). Abnormal mechanical loading exacerbates mechanobiological dysregulation through the integrin-YAP/TAZ signaling axis, while hypoxia/acidification-induced mitochondrial dysfunction creates a "mechanical-metabolic" double hit. Innate and adaptive immune cells recognize degenerated fragments and amplify local tissue damage. The interweaving of these mechanisms contributes to the comorbid progression of IVDD and OA through mechanical conduction, inflammatory diffusion, and neural sensitization. Importantly, we also discuss key differences between the two diseases, including the avascular nature of the intervertebral disc, the distinct roles of nutrient supply and disc herniation subtypes, and the etiological heterogeneity of OA across different joints. Future research should move beyond single-disease frameworks, analyze multi-tissue interactions from a systemic degeneration perspective, and develop combined strategies targeting senescent cell clearance, inflammatory blockade, and ECM repair. The concept of "spine-joint integrated diagnosis" - defined as concurrent evaluation of spinal and peripheral joint degeneration - is proposed to guide integrated management and improve clinical outcomes in comorbid patients.
Senescent cells in systemic aging: SASP heterogeneity, immune escape, and endocrine modulation.
Biogerontology
Louay Abo Qoura, Alexey V Churov, O N Maltseva +2 more
Aging is characterized by progressive loss of physiological resilience accompanied by increased susceptibility to chronic diseases. Among the interconnected hallmarks of aging, cellular senescence has emerged as a central driver of systemic inflammation through the senescence-associated secretory phenotype (SASP). Senescent cells accumulate across multiple tissues with advancing age and secrete complex mixtures of cytokines, growth factors, and proteases that reshape tissue microenvironments and propagate inflammatory signaling locally and systemically. Increasing evidence indicates that SASP composition is highly heterogeneous and depends on cell lineage, metabolic state, and the nature of the senescence-inducing stressor. Recent discoveries further demonstrate that inflammatory signaling in senescent cells is sustained by multiple nucleic acid-sensing pathways, including both cGAS-STING-dependent DNA sensing and mitochondrial RNA-mediated activation of RIG-I-like receptors. Concurrently, senescent cells deploy immune-evasion mechanisms that limit clearance by cytotoxic lymphocytes and natural killer cells, facilitating their persistence within aging tissues. Accumulation of senescent cells therefore represents a critical mechanistic link between molecular damage and the systemic inflammatory state known as inflammaging. This review synthesizes current understanding of tissue-specific SASP programs across immune, vascular, metabolic, hepatic, and neural systems. Particular emphasis is placed on mechanisms that amplify local senescence into organism-wide inflammation, including endocrine signaling, extracellular vesicle trafficking, and sex-dependent modulation of senescence pathways.
Cheyne-Stokes respiration detected via CPAP devices as a digital biomarker for heart failure in obstructive sleep apnoea: systematic review.
Sleep Adv
Nashe Marshall Mutombe, Kanchana Ekanayake, Chin Moi Chow
To synthesize evidence on the diagnostic, prognostic, surveillance, and monitoring potential of Cheyne-Stokes respiration (CSR) ventilatory patterns, as detected by continuous positive airway pressure (CPAP) devices, in patients with heart failure (HF) or at risk of HF-often with comorbid obstructive sleep apnoea.
Neuroprotective Effects of Cerebrolysin in Moderate Traumatic Brain Injury with Nonoperative Lesions: A 6-Month Prospective Cohort Analysis.
Asian J Neurosurg
Panu Boontoterm, Siraruj Sakoolnamarka, Karanarak Urasyanandana
Moderate traumatic brain injury (TBI) with nonoperative intracerebral hemorrhage (ICH) presents a significant challenge in neurorehabilitation, often lacking targeted pharmacological interventions. Cerebrolysin, a neuropeptide compound with proposed neurotrophic and neuroprotective properties, may support recovery in this population. This study aimed to evaluate the clinical efficacy and safety of Cerebrolysin in adults with moderate TBI and nonoperative ICH over a 6-month period.
Thyroid Dysfunction Following Tirzepatide Use in a Post-thyroidectomy Patient on Stable Levothyroxine Therapy: A Case Study.
Cureus
Emily W Adams, Alex Somers, Emmanuel Garrido-Cortes +1 more
Tirzepatide, a dual glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, is increasingly prescribed for obesity and glycemic control. Its effects on gastric emptying, appetite regulation, and rapid weight loss may influence thyroid hormone homeostasis and the pharmacokinetics of narrow-therapeutic-index medications such as levothyroxine. Emerging clinical experience suggests that GLP-1-based therapies can suppress thyroid-stimulating hormone (TSH), alter thyroid hormone dynamics, and precipitate symptoms of thyrotoxicosis in patients receiving thyroid hormone replacement. As use of incretin therapies expands, understanding their potential interaction with thyroid physiology is increasingly important. We describe a 52-year-old woman with a history of thyroidectomy complicated by postoperative hypothyroidism, maintained on stable doses of levothyroxine for several years. After six months of tirzepatide therapy, she experienced 48 pounds of intentional weight loss and developed dizziness, tachycardia, weakness, and confusion. Laboratory evaluation showed a markedly suppressed TSH and elevated free T4, consistent with significant over-replacement with levothyroxine. She required emergent dose reduction and supportive care, with gradual resolution of symptoms after adjustment of her thyroid regimen. Key contributing factors included substantial weight loss without proportional levothyroxine dose reduction, delayed gastric emptying altering levothyroxine absorption, and absence of endogenous thyroid reserve following thyroidectomy. These changes created a clinical environment highly susceptible to pharmacologic fluctuations and rapid shifts into iatrogenic thyrotoxicosis. Additionally, GLP-1 therapy-associated decreases in blood pressure and appetite likely amplified her acute presentation. This case highlights the importance of vigilant monitoring in post-thyroidectomy patients who begin tirzepatide or other incretin-based medications. Clinicians should anticipate the need for levothyroxine dose adjustments as weight decreases and gastrointestinal motility changes. Early follow-up, routine thyroid function testing, and prompt evaluation of new cardiovascular or neurocognitive symptoms are essential to prevent avoidable morbidity related to drug-hormone interactions.
NGF administration is associated with increased GnRH immunoreactivity and a GnRH-associated phenotype in hypothalamic NSCs of aging mice.
Front Endocrinol (Lausanne)
Jiao Luo, Junhai Jiang, Tiantian Zhang +5 more
Age-related decline in testosterone is closely associated with hypothalamic gonadotropin-releasing hormone (GnRH) neuron dysfunction. Nerve growth factor (NGF) has emerging roles in reproductive system. However, its effect on the differentiation of hypothalamic neural stem cells (htNSCs) into GnRH-associated phenotype remains unexplored.
HPA axis function during adjunctive high-dose dexamethasone use in chemotherapy: a prospective pilot study.
Front Endocrinol (Lausanne)
Elżbieta Turska, Krzysztof Lewandowski, Igor Symonowicz +5 more
Glucocorticoid-induced adrenal insufficiency is a well-known adverse effect of glucocorticoid therapy, occurring not only with oral administration but also with intramuscular, inhaled, and other routes of administration. However, the impact of intermittent high-dose glucocorticoids used during chemotherapy on hypothalamic-pituitary-adrenal (HPA) axis function remains incompletely understood.
Selexipag for the treatment of schistosomiasis-associated pulmonary arterial hypertension: the SELSCH study.
ERJ Open Res
Caio Julio Cesar Dos Santos Fernandes, Susana Hoette, José Leônidas Alves-Jr +3 more
Schistosomiasis-associated pulmonary arterial hypertension (Sch-PAH) is one of the most prevalent forms of PAH in Brazil. However, no prospective data are available for evaluating the efficacy of PAH drugs in the treatment of Sch-PAH. Does selexipag improve pulmonary vascular resistance (PVR) in Sch-PAH patients?
The impact of automated insulin delivery on glucose management in people with diabetes and advanced chronic kidney disease.
Diabetologia
Jean C Lu, Christine L Meyer-Olesen, Bella Halim +15 more
Chronic kidney disease (CKD) complicates insulin dosing and increases glycaemic instability in diabetes. We aimed to compare feasibility, safety and efficacy of automated insulin delivery (AID) with usual care in people with diabetes and advanced CKD.
Estimated Oral Semaglutide Exposure Has Distinct Relationships With Glycaemic Response, Weight Loss and Gastrointestinal Tolerability.
Diabetes Obes Metab
Gian Paolo Fadini, Mario Luca Morieri, Carlotta Boscaro +2 more
Oral semaglutide absorption is subject to inter-individual variability. We investigated whether estimated individual exposure (eCavg) provides predictive information beyond the prescribed dose in a real-world cohort of patients with type 2 diabetes (T2D).
Effect of Tirzepatide on Health-Related Quality of Life in Japanese Patients With Obesity Disease: Patient-Reported Outcomes From the SURMOUNT-J Study.
Diabetes Obes Metab
Hiroaki Masuzaki, Hirotaka Nagashima, Tomotaka Shingaki +2 more
We evaluated the impact of tirzepatide on health-related quality of life (HR-QoL) in Japanese individuals with obesity disease from the phase 3 SURMOUNT-J trial.
Anti-Inflammatory and Anabolic Effects of Liraglutide on 3D Inflammatory Osteoarthritic Spheroid and Scaffold Models of Human Chondrocytes.
Osteoarthritis Cartilage
Eda Ciftci, Sophie C Eberlein, Sibylle Grad +3 more
Osteoarthritis (OA) is a prevalent age-related joint disease characterized by low-grade inflammation and progressive cartilage degeneration. Liraglutide, a glucagon-like peptide-1 receptor agonist approved for diabetes and obesity, has shown anti-inflammatory and chondroprotective effects in preclinical OA models, but its effects in human 3D chondrocyte systems remain unclear.
In Situ Engineered "Cascade-Amplified" Drug-Loaded Vesicles for Enhanced Cancer Stem Cell Therapy.
J Extracell Vesicles
Tiantian Zhang, YuanYuan Wei, Zimai Liu +9 more
Cancer stem cells (CSCs) characterized by the capacity of self-renewal and drug resistance, are a major cause of tumour recurrence and metastasis. However, CSCs are mainly localized in the deep and hypoxic regions of the tumour microenvironment that hinder drug penetration. Furthermore, their overexpression of the CD24/Siglec10 immune checkpoint axis markedly suppresses immune clearance, severely limiting the efficacy of current therapeutic strategies. To address this challenge, this study developed an in situ engineered "cascade-amplified" drug-loaded vesicle delivery system, aiming to achieve deep drug delivery into CSC-enriched regions and enhance anti-tumour immune responses. Based on a biomimetic "core-shell" nanoplatform (siXkr8/Dox@PMLC), this system initiates a cascade within the TME where Doxorubicin (Dox) induces tumour cells to generate drug-loaded apoptotic bodies (ApoBDs). These ApoBDs serve as primary vesicles that, upon uptake by adjacent tumour cells, trigger secondary apoptosis, establishing a "cascade-amplified" cycle of enhanced drug delivery. Meanwhile, the silencing of the phospholipid scramblase Xkr8 via siRNA inhibits phosphatidylserine (PS) exposure on the surface of ApoBDs, thereby preventing their recognition and clearance by M2-type macrophages and facilitating immune phenotype remodelling. Furthermore, through targeted blockade of the CD24/Siglec-10 immune axis, the nanoplatform enhances macrophage-mediated phagocytosis of CSCs. In summary, this strategy achieves deep eradication of CSCs and synergistically enhances anti-tumour immunotherapy, demonstrating significant translational potential.