Search Results (3,235)

Angiotensin II (AngII), the primary effector of the renin-angiotensin system, is essential for maintaining blood pressure and fluid-electrolyte homeostasis. However, elevated AngII levels are a feature of disease conditions such as heart failure and chronic kidney disease, where it is associated with pathological tissue remodeling and fibrosis. AngII-mediated fibrosis has been documented in multiple organs and is characterized by fibroblast expansion, myofibroblast differentiation, and excessive extracellular matrix deposition. Periostin has recently emerged as a marker of fibroblast activation. Notably, periostin expression is highly upregulated during fibrotic remodeling in the kidney and lung, which is strongly linked with impaired organ function. While AngII-induced activation of periostin-lineage (Postn^Lin) cells is well established in the heart, the temporal dynamics of Postn^Lin activation in response to AngII infusion in the lung and kidney remain unexplored. Here, we used a Postn-MerCreMer lineage-tracing approach, combined with continuous AngII infusion over an experimental period of one week and two weeks to assess Postn^Lin responses in lung and kidney. Our findings reveal a progressive activation of Postn^Lin cells in both organs, characterized by myofibroblast phenotype, together with increased collagen deposition and macrophage infiltration. These results highlight the potential of Postn^Lin fibroblasts as a key effector of AngII-mediated tissue remodeling and fibrosis in the lung and kidney. Full article

Background: Most immunologically “cold” tumors do not respond durably to checkpoint blockade because tumor antigen (TA) release and presentation are insufficient to prime effective T-cell immunity. While prior work demonstrated synergy between cisplatin and a TLR7/8/9 agonist (CR108) in 4T1 tumors, the underlying mechanism—particularly whether chemotherapy functions as a broad antigen-releasing agent enabling TLR-driven immune amplification—remained undefined. Methods: Using murine models of breast (4T1), melanoma (B16-F10), and colorectal cancer (CT26), we tested multiple chemotherapeutic classes combined with CR108. We quantified intratumoral and systemic soluble TAs, antigen presentation and cross-priming by antigen-presenting cells, tumor-infiltrating lymphocytes, and cytokine production by flow cytometry/ICS. T-cell receptor β (TCRβ) repertoire dynamics in tumor-draining lymph nodes were profiled to assess amplitude and breadth. Tumor microenvironment remodeling was analyzed, and public datasets (e.g., TCGA basal-like breast cancer) were interrogated for expression of genes linked to TA generation/processing and peptide loading. Results: Using cisplatin + CR108 in 4T1 as a benchmark, we demonstrate that diverse chemotherapies—especially platinum agents—broadly increase the repertoire of soluble tumor antigens available for immune recognition. Across regimens, chemotherapy combined with CR108 increased T-cell recognition of candidate TAs and enhanced IFN-γ⁺ CD8⁺ responses, with platinum agents producing the largest expansions in soluble TAs. TCRβ sequencing revealed increased clonal amplitude without loss of repertoire breadth, indicating focused yet diverse antitumor T-cell expansion. Notably, therapeutic efficacy was not predicted by canonical damage-associated molecular pattern (DAMP) signatures but instead correlated with antigen availability and processing capacity. In human basal-like breast cancer, higher expression of genes involved in TA generation and antigen processing/presentation correlated with improved survival. Conclusions: Our findings establish an antigen-centric mechanism underlying chemo–TLR agonist synergy: chemotherapy liberates a broadened repertoire of tumor antigens, which CR108 then leverages via innate immune activation to drive potent, T-cell-mediated antitumor immunity. This framework for rational selection of chemotherapy partners for TLR7/8/9 agonism and support clinical evaluation to convert “cold” tumors into immunologically responsive disease. Full article

Stem cell (SC)-based therapy exploits the ability of cells to migrate to damaged tissues and repair them. In this context, there is a strong interest in the use of mesenchymal stem cells (MSCs), multipotent SCs that are easy to obtain and are able to differentiate into various cell lineages. However, MSCs undergo cellular senescence during in vitro expansion, and may also become senescent in vivo, influenced by multiple molecular, cellular, and environmental interactions. Therefore, the development of in vitro cell models is crucial to study the mechanisms underlying senescence in MSCs. This study aimed to investigate the effects of tert-butyl hydroperoxide (t-BHP) as a senescence inducer in human dermal MSCs (hDMSCs), a promising tool for tissue repair. t-BHP induced a pro-senescent effect on hDMSCs greater than hydrogen peroxide (H₂O₂), as evidenced by ROS production, DNA damage, cell cycle arrest, inhibition of cell proliferation, changes in cellular and nuclear morphology, and cytoskeletal reorganization, as well as the increase in other senescence markers, including senescence-associated β-galactosidase (SA-β-Gal)-positive cells, and senescence-associated secretory phenotype (SASP). These results indicate that t-BHP could be a promising compound for inducing stress-induced premature senescence (SIPS) in hDMSCs, providing a valuable tool to investigate this process and evaluate the efficacy of senolytic compounds. Full article

Bone metastases continue to be a major cause of morbidity and mortality in patients with advanced cancers, driven by the dynamic remodeling of the bone marrow niche. Traditionally viewed as passive space-fillers, bone marrow adipocytes (BMAs) are now recognized as active regulators of tumor growth, therapeutic resistance, and skeletal pathology. BMAs comprise a significant portion of the adult marrow space, particularly in aging and obesity, and facilitate metastatic colonization through various mechanisms. These include metabolic coupling, where adipocyte-derived fatty acids fuel tumor oxidative phosphorylation; the secretion of adipokines such as leptin and IL-6, which promote epithelial-to-mesenchymal transition, invasion, and immune evasion; regulation of osteoclastogenesis via RANKL expression; and the release of extracellular vesicles that reprogram cancer cell metabolism. Clinical and experimental studies show that BMA expansion correlates with increased tumor burden and poorer outcomes in breast, prostate, lung cancers, and multiple myeloma. Additionally, BMAs actively promote therapeutic resistance through metabolic rewiring and drug sequestration. Experimental models, ranging from in vitro co-cultures to in vivo patient-derived xenografts, demonstrate the complex roles of BMAs and also reveal important translational gaps. Despite promising preclinical approaches such as metabolic inhibitors, PPARγ modulation, adipokine blockade, and lifestyle changes, no therapies directly targeting BMAs have yet reached clinical practice. This review compiles current evidence on the biology of BMAs, their tumor-promoting interactions, and potential therapeutic strategies, while also highlighting unresolved questions about BMA heterogeneity, lipid flux, and immunometabolic crosstalk. By revealing how bone marrow adipocytes actively shape the metastatic niche through metabolic, endocrine, and immunological pathways, this review highlights their potential as novel biomarkers and therapeutic targets for improving the management of bone metastases. Full article

Several genetic diseases affecting the human nervous system are incurable and insufficiently understood. Among them, nine rare diseases form the polyglutamine (polyQ) family: Huntington’s disease (HD), spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17, dentatorubral pallidoluysian atrophy, and spinal and bulbar muscular atrophy. In most patients, these diseases progress over decades to cause severe movement incoordination and neurodegeneration. Although their inherited genes with tandem-repeat elongations and the encoded polyQ-containing proteins have been extensively studied, the neuronal-type-specific pathologies and their long pre-symptomatic latency await further investigations. However, recent advances in detecting the single-nucleus transcriptome, alongside the length of tandem repeats in HD post-mortem brains, have enabled the identification of very high CAG repeat sizes that trigger transcriptional dysregulation and cell death in specific projection neurons. One challenge is to better understand the complexity of movement coordination circuits, including the basal ganglia and cerebellum neurons, which are most vulnerable to the high CAG expansion in each disease. Another challenge is to detect dynamic changes in CAG repeat length and their effects in vulnerable neurons at single-cell resolution. This will offer a platform for identifying pathological events in vulnerable long projection neurons and developing targeted therapies for all tandem-repeat expansions affecting the CNS projection neurons. Full article

We present a quantitative theory of contraction and expansion cycles within the Quantum Memory Matrix (QMM) cosmology. In this framework, spacetime consists of finite-capacity Hilbert cells that store quantum information. Each non-singular bounce adds a fixed increment of imprint entropy, defined as the cumulative quantum information written irreversibly into the matrix and distinct from coarse-grained thermodynamic entropy, thereby providing an intrinsic, monotonic cycle counter. By calibrating the geometry–information duality, inferring today’s cumulative imprint from CMB, BAO, chronometer, and large-scale-structure constraints, and integrating the modified Friedmann equations with imprint back-reaction, we find that the Universe has already completed $N_{\mathrm{past}}=3.6\pm 0.4$ cycles. The finite Hilbert capacity enforces an absolute ceiling: propagating the holographic write rate and accounting for instability channels implies only $N_{\mathrm{future}}=7.8\pm 1.6$ additional cycles before saturation halts further bounces. Integrating Kodama-vector proper time across all completed cycles yields a total cumulative age $t_{\mathrm{QMM}}=62.0\pm 2.5\mathrm{Gyr}$, compared to the $13.8\pm 0.2\mathrm{Gyr}$ of the current expansion usually described by $\mathrm{\Lambda }$CDM. The framework makes concrete, testable predictions: an enhanced faint-end UV luminosity function at $z\gtrsim 12$ observable with JWST, a stochastic gravitational-wave background with $f^{2/3}$ scaling in the LISA band from primordial black-hole mergers, and a nanohertz background with slope $\alpha \simeq 2/3$ accessible to pulsar-timing arrays. These signatures provide near-term opportunities to confirm, refine, or falsify the cyclical QMM chronology. Full article

Musculoskeletal disorders are a major cause of lameness in horses, often necessitating innovative regenerative strategies to restore joint function and improve quality of life. This study investigated the effects of platelet-rich plasma (PRP), ozonized PRP, hyaluronic acid, paracetamol, and polyacrylamide hydrogel (NOLTREX^®) on the behavior of mesenchymal stem cells (MSCs) derived from equine synovial fluid. Synovial fluid samples were collected under strict cytological criteria to ensure viability, followed by in vitro expansion and phenotypic characterization of MSCs. Cultures were supplemented with the tested preparations, and cellular proliferation and viability were evaluated at 24 h, 72 h, and 7 days. PRP significantly promoted MSC proliferation in a time- and dose-dependent manner, with maximal effect at 10%. Hyaluronic acid stimulated growth, most pronounced at 1 mg/mL, while paracetamol induced a concentration-dependent proliferative response, strongest at 100 μg/mL. NOLTREX displayed a biphasic effect, initially inhibitory at high concentrations but stimulatory at 7 days. Ozonized PRP showed concentration-dependent redox activity, with lower doses maintaining viability and higher doses producing an initial suppression followed by delayed stimulation. Collectively, these findings support the therapeutic potential of PRP and related biologic preparations as intra-articular regenerative therapies in equine medicine, while underscoring the importance of dose optimization and standardized protocols to facilitate clinical translation. Full article

Background: Antibody-drug conjugates (ADCs) have ushered in a new era of precision oncology by combining the targeting specificity of monoclonal antibodies with the potent cytotoxicity of chemotherapeutic drugs. However, the cellular and molecular mechanisms underlying their dose-limiting ocular toxicity remain unclear. Elahere™, the first FDA-approved ADC targeting folate receptor α (FRα), demonstrates remarkable efficacy in platinum-resistant ovarian cancer but causes keratitis and other ocular toxicities in some patients. Notably, FRα is not expressed in the corneal epithelium—the primary site of damage—highlighting the urgent need to elucidate its underlying mechanisms. The aim of this study was to identify the cell-type-specific molecular mechanisms underlying Elahere-induced ocular toxicity. Methods: Sprague-Dawley rats were treated with intravenous Elahere (20 mg/kg) or vehicle weekly for five weeks. Ocular toxicity was determined by clinical examination and histopathology. Corneal single-cell suspensions were analyzed using the BD Rhapsody single-cell RNA sequencing (scRNA-seq) platform. Bioinformatic analyses to characterize changes in corneal cell populations, gene expression, and signaling pathways included cell clustering, differential gene expression, pseudotime trajectory inference, and cell-cell interaction modeling. Results: scRNA-seq profiling of 47,606 corneal cells revealed significant damage to the ocular surface and corneal epithelia in the Elahere group. Twenty distinct cell types were identified. Elahere depleted myeloid immune cells; in particular, homeostatic gene expression was suppressed in phagocytic macrophages. Progenitor populations (limbal stem cells and basal cells) accumulated (e.g., a ~2.6-fold expansion of limbal stem cells), while terminally differentiated cells decreased in corneal epithelium, indicating differentiation blockade. Endothelial cells exhibited signs of injury and inflammation, including reduced angiogenic subtypes and heightened stress responses. Folate receptor alpha, the target of Elahere, was expressed in endothelial and stromal cells, potentially driving stromal cells toward a pro-fibrotic phenotype. Fc receptor genes were predominantly expressed in myeloid cells, suggesting a potential mechanism underlying their depletion. Conclusions: Elahere induces complex, multi-compartmental ocular toxicity characterized by initial perturbations in vascular endothelial and immune cell populations followed by the arrest of epithelial differentiation and stromal remodeling. These findings reveal a cascade of cellular disruptions and provide mechanistic insights into mitigating Elahere-associated ocular side effects. Full article

Citrus creasing is a physiological rind disorder. Satsuma mandarin (Citrus unshiu Marc.) is the most widely cultivated mandarin variety worldwide and exhibits a high susceptibility to creasing. To investigate the physiological mechanisms underlying creasing, satsuma mandarin trees were treated with different drought stress during fruit expansion, then the relationship between the soil water content and creasing incidence was analyzed, while also examining the rind morphology, oil gland distribution in the flavedo, antioxidant enzyme activities, hormone concentrations, cell wall components, mineral content of creasing fruit, and the impact of creasing on fruit quality. Results showed that severe water stress (35% SRWC) increased the creasing incidence rate by 28% compared to well-irrigated treatments (80% SRWC). The creasing fruit oil gland diameter reduced by 35.7% and the density increased by 149.7% compared to healthy fruits. Simultaneously, the content of H₂O₂ and proline elevated by 47.1% and 8.3% respectively, and the activities of SOD, POD, and CAT of the creasing rind were enhanced significantly. Additionally, the content of IAA, ZR, and MeJA decreased by 17.2%, 7.8%, and 50.2%, respectively. Cell wall components such as cellulose, hemicellulose, and protopectin content reduced by 44.6%, 31.7%, and 33.1%, while soluble pectin increased by 36.3%. Significant alterations were observed in several minerals (Al, Fe, Na, Ni, V, Ga, Zn, Ba, Sn, Hg, Sc, Y, and La). However, fruit quality remained unaffected by creasing. These results demonstrate that drought is a key factor inducing creasing. Increased oil gland density, the degradation of cell wall components, elevated oxidative stress, reductions in phytohormones, and altered mineral element content work together to contribute to rind cells’ structural instability and lead to creasing in the satsuma mandarin. Full article

β-thalassemia is a chronic genetic blood disorder characterized by defective β-globin synthesis, requiring frequent transfusions and resulting in iron overload, immune dysfunction, and increased susceptibility to infections. In these immunocompromised patients, altered immune responses lead to significant changes in the human virome, promoting viral persistence, reactivation, and expansion of pathogenic viral communities. This review explores the intricate relationship between β-thalassemia and the human virome, focusing on how clinical interventions and immune abnormalities reshape viral dynamics, persistence, and pathogenicity. Patients with β-thalassemia exhibit profound innate and adaptive immune dysregulation, including neutrophil dysfunction, T cell senescence, impaired B cell and NK cell activity, and expansion of myeloid-derived suppressor cells. These alterations create an immunological niche that favors viral reactivation and virome expansion. Iron overload enhances viral replication, while chronic transfusions introduce transfusion-transmitted viruses. Splenectomy and allo-HSCT further compromise viral surveillance. Additionally, disruptions in the gut virome, particularly bacteriophage-driven dysbiosis, may exacerbate inflammation and impair host–virus homeostasis. The human virome is not a passive bystander but a dynamic player in the pathophysiology of β-thalassemia. Understanding virome–immune interactions may offer novel insights for infection monitoring, risk stratification, and precision therapies in thalassemic patients. Full article

Adipose tissue renewal requires precise coordination of stem/progenitor cell proliferation, preadipocyte commitment, and terminal adipocyte differentiation. T-cadherin (CDH13), an atypical GPI-anchored cadherin, is expressed in adipose tissue and functions as a receptor for high-molecular-weight (HMW) adiponectin—a key adipokine produced by adipose tissue and involved in metabolic regulation. While T-cadherin is implicated in cardiovascular and metabolic homeostasis, its role in adipogenesis still remains poorly understood. In this study, we used the 3T3-L1 preadipocyte model to investigate the function of T-cadherin in adipocyte differentiation. We analyzed T-cadherin expression dynamics during differentiation and assessed how T-cadherin overexpression or knockdown affects lipid accumulation, expression of adipogenic markers, and key signaling pathways including ERK, PI3K–AKT, AMPK, and mTOR. Our findings demonstrate that T-cadherin acts as a negative regulator of adipogenesis. T-cadherin overexpression ensured a proliferative, undifferentiated cell state, delaying early adipogenic differentiation and suppressing both lipid droplet accumulation and the expression of adipogenic markers. In contrast, T-cadherin downregulation accelerated differentiation, enhanced lipid accumulation, and increased insulin responsiveness, as indicated by PI3K–AKT pathway activation at specific stages of adipogenesis. These results position T-cadherin as a key modulator of adipose tissue plasticity, regulating the balance between progenitor expansion and terminal differentiation, with potential relevance to obesity and metabolic disease. Full article

Fracture repair complications occur in 5–10% of cases, despite bone’s regenerative capacity. Bone marrow-derived (BM) stem cells have been extensively investigated for orthopedic applications but, given the critical role that periosteum plays in fracture repair, periosteal-derived (PO) cells offer a promising alternative cell source. This study compared the in vitro osteogenic capacities of equine BM and PO cells. Passage 3 cells from each source were maintained in osteogenic medium for up to 10 days. Osteogenesis was assessed by Runx2, Osterix, and alkaline phosphatase (ALP) mRNA up-regulation, induction of ALP activity, and matrix mineralization. Comparisons were made by paired t tests, repeated measures one-way or two-way ANOVAs, as indicated. BM cells proved superior to PO cells in osteogenesis assays. BM cells significantly up-regulated Runx2, Osterix, and ALP mRNAs, ALP activity, and secreted a mineralized matrix by day 10. PO cells did not. BMP-2 expression increased significantly in BM cells in osteogenic medium, whereas BMP-2 expression in PO cells was unchanged. Exogenous BMP-2 did not restore osteogenesis in periosteal cells, indicating that ex vivo expansion affects periosteal osteogenic capacity beyond BMP-2 downregulation. Clinical applications of PO cells will require the identification and exogenous provision of requisite stimulatory factors and substrates. Full article

Background: The global health burden of mosquito-borne viruses, including dengue, yellow fever, Zika, and chikungunya, is rising due to climate change and globalisation, which favour mosquito habitat expansion. The genetic diversity of these viruses complicates the development of virus-specific vaccines or antivirals, highlighting the need for pan-viral strategies. As the common vector for these pathogens, mosquitoes and specifically their salivary proteins represent a promising target for such interventions. Mosquito saliva, secreted into the skin during biting, has immunomodulatory effects that can enhance host susceptibility to infection, but these mechanisms are not well defined in humans. Methods: The objective of this study was to determine whether AGS-v PLUS, a vaccine targeting mosquito salivary antigens, could modulate the human skin immune response to mosquito biting and potentially promote antiviral bystander immunity. In a Phase I trial, healthy volunteers were vaccinated with AGS-v PLUS (with or without adjuvant) or placebo, and three weeks later, they were exposed to bites from Aedes albopictus and Aedes aegypti mosquitoes. Skin biopsies from bitten and unbitten sites were analysed by transcriptomic profiling. Results: In placebo recipients, mosquito biting elicited a marked adaptive immune response at 48 h, characterised by CD4⁺ Th1 and CD8⁺ T cell signatures and leukocyte recruitment. While responses to Ae. aegypti and Ae. albopictus bites were broadly similar, those to Ae. albopictus were stronger. Vaccination with AGS-v PLUS, particularly with adjuvant, enhanced Th1 and CD8⁺ T cell-associated gene expression while suppressing pathways linked to neutrophilic inflammation and epithelial stress, which together may provide enhanced antiviral capacity. Conclusions: These findings demonstrate that targeting the host response to mosquito saliva via vaccination can reprogram the skin’s immune response to mosquito bites, supporting a novel and broadly applicable pan-viral strategy to mitigate the impact of arboviral diseases. Full article

Background/Objectives: Biological aging phenotypes in coronary artery disease (CAD) include coronary atherosclerosis, vascular aging, and endothelial dysfunction. The aim of the present study was to investigate the potential links between aging phenotypes, regulatory immune cells, and features of the thymus in patients with CAD. Methods: A single-center, cross-sectional, comparative study was conducted. Patients were stratified according to the severity of coronary atherosclerosis: patients with a Gensini score ≥ 65 points and patients with a Gensini score < 65 points. Peripheral blood and thymus biopsy were obtained. Imaging flow cytometry, ELISA, and immunohistochemical analysis were used for analysis. Results: Thymic morphology ranged from total fatty involution to a preserved structure of the thymus (20–80% area in 31% of obtained samples) but was not associated with the severity of atherosclerosis. Meanwhile, patients with a Gensini score ≥ 65 had impaired thymus cellular composition compared to patients with a Gensini score < 65 points; increased frequency of CD8+ T lymphocytes and NK cells; and decreased frequency of CD4 + CD8+ T lymphocytes. In peripheral blood, the main determinants of a Gensini score ≥ 65 points were low absolute counts of eMDSCs and CD25^low Tregs with FoxP3 nuclear translocation, while advanced vascular aging was associated with elevated eMDSC absolute counts. Advanced coronary atherosclerosis was also associated with decreased numbers of endothelial progenitor cells in circulation. Conclusions: Thymus dysfunction accompanies CAD progression and is manifested in changes in cellular composition rather than morphology. In CAD patients, MDSC and Treg lymphocytes are equally involved in the progression of coronary atherosclerosis, which is aggravated by the decreased regulatory potential of the endothelium. Vascular aging represents a distinct phenotype of biological aging in CAD patients, characterized by the expansion of eMDSCs. Full article

Allogeneic chondrocyte therapies present an attractive alternative to existing autologous therapies for the repair of cartilage defects, enabling the selection of optimal donor cells and streamlined manufacturing processes. This study investigates the potential of juvenile chondrocytes derived from human infantile (aged 0–4 y) polydactyly digits and the iliac apophysis for cartilage repair using Good Manufacturing Practice bioreactor expansion. Iliac apophysis (n = 4) and polydactyly tissues (n = 4) were assessed histologically. Chondrocytes were isolated enzymatically and cultured using standard tissue culture plastic (TCP) methodology. Upon sufficient cell expansion, chondrocytes were seeded into the Quantum^® bioreactor system or onto TCP (±vitronectin coating). The manufactured chondrocytes growth rates, total cell yields, chondrogenic pellet forming capacity (GAG/DNA, histology), immunoprofiles (flow cytometry) and gene expression (RT-qPCR) were assessed. Equivalent chondrocyte numbers were isolated from polydactyly and iliac apophysis donors per wet weight of tissue. Quantum^®-expanded chondrocytes from both sources yielded comparable cell numbers; however, growth was slowed in the Quantum^® compared to TCP. Polydactyly and iliac apophysis-derived chondrocytes expressed chondrocyte cell surface markers (CD166, CD44, CD151, SOX9) and formed chondrogenic pellets. Quantum^® bioreactor expansion did not alter, gene expression or capacity to form glycosaminoglycans (GAGs (normalised to DNA content)) compared to matched TCP expansion. Juvenile cartilage donors are a promising chondrocyte source for the development of an allogeneic therapy. This novel study expanding juvenile chondrocytes in the Quantum^® GMP-compliant bioreactor suggests that culture conditions may need modification to improve growth, whilst retaining cartilage forming capacity. Full article