Search Results (3,250)

Corneal alkali burn induces severe inflammation and tissue damage, leading to loss of corneal transparency and vision impairment. In this study, we evaluated the therapeutic potential of rapamycin (RAPA) compared with cyclosporine A (CsA) in a mouse model of corneal alkali burn, focusing on nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)–mediated inflammatory signaling and its impact on corneal wound healing and repair. Notably, RAPA robustly suppressed NF-κB activation, reduced infiltration of F4/80 macrophages and MPO neutrophils, and downregulated pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6. RAPA also markedly inhibited corneal neovascularization, as evidenced by decreased VEGF expression, reduced CD31 vessel formation, and suppression of Ang-2. RAPA substantially inhibited pathological fibrotic remodeling by reducing TGF-β1 expression, attenuating myofibroblast activation (α-SMA), decreasing collagen III deposition, and modulating matrix remodeling through suppression of MMP-9. Crucially, RAPA preserved epithelial barrier integrity by maintaining occludin expression, supported proper epithelial differentiation through sustained expression of CK12, and enhanced mucin layer stability by increasing MUC1 expression. It also restored tear production, reduced apoptotic cell death (TUNEL), and decreased dysregulated epithelial proliferation (Ki67). In conclusion, RAPA showed superior efficacy compared with CsA, primarily by enhancing corneal wound healing and facilitating structural and functional outcomes in the burned cornea. These findings underscore RAPA as a promising therapeutic candidate for ocular surface repair and vision restoration in extensive corneal injury. Full article

Exercise adaptation and training maladaptation arise from overlapping metabolic, redox, inflammatory, endocrine, and tissue-remodeling processes, so the translational question is not whether biomarkers change but when, where, and for which decision they become informative. This narrative review develops a decision-linked framework for minimally invasive biomarkers across the recovery–overload continuum and treats biomarker meaning as a molecule–matrix–time–decision relationship rather than as a stand-alone peak. The framework is organized around five coupled layers: stimulus architecture, signaling and release biology, sampling matrix and pre-analytics, bout-relative kinetics, and the monitoring decision to be supported. Current evidence indicates that no single biomarker reliably separates productive remodeling from delayed recovery, tissue strain, non-functional overreaching, or early maladaptation. Classical chemistry remains useful for bounded tasks, especially delayed tissue strain and stress reactivity; cfDNA appears promising for rapid load sensitivity; targeted metabolite panels are strongest for recovery phenotyping; and circulating RNAs and extracellular-vesicle cargo add mechanistic depth but remain constrained by pre-analytical fragility and incomplete standardization. The central practical implication is that overload is better interpreted as progressive loss of signal resolution than as threshold-crossing and that sparse temporally staggered panels are more likely to aid monitoring decisions than isolated markers or untimed high-dimensional profiles. Progress will depend on purpose-specific panels, transparent analytical standards, and prospective validation against symptoms, performance, and established measures across sex, hormonal, circadian, and training contexts. Full article

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by persistent joint inflammation and systemic immune dysregulation. While bone marrow activation has been linked to RA pathogenesis, direct access to bone marrow tissue for progenitor analysis remains limited by ethical and technical constraints. Analysis of progenitor cells in peripheral blood can serve as a surrogate reflecting bone marrow activation. In this study, we analysed peripheral blood cells from 12 RA patients and 9 healthy controls using high-dimensional spectral flow cytometry with a nine-marker panel (CD45, CD31, CD235, CD133, CD34, CD105, CD271, CD90, PDPN). Flow Self-Organizing Map (FlowSOM) clustering identified 20 distinct cell populations. Additionally, a complementary flow cytometry panel was used to assess CD31 expression on immune subsets in peripheral mononuclear cells (PBMCs) from 9 RA and 9 healthy donors of this cohort. RA patients showed increased CD45⁺CD31⁻ immune cells, but not their putative progenitors. Conversely, putative CD45⁺CD31^int progenitors and CD45⁺CD31^int mature cells were reduced, along with CD31 expression on T cells. Levels of CD235a⁺ putative erythroid precursors and CD45⁺CD31⁺ progenitors were significantly increased in RA patients. Three putative stromal cell populations were detected in circulation. Together, these findings reveal expanded erythroid precursor populations and reduced CD31 expression on T cells in RA. Our data underscore broad systemic alterations in cellular homeostasis in RA patients. In conclusion, our results suggest that the loss of CD31 expression on immune cell precursors plays a role in age-associated immune remodelling and immune activation in RA and provides the rationale for further studies on erythroblast differentiation and the functional role of erythroblasts in chronic inflammation. Full article

The retinal pigment epithelium (RPE) is a long-lived, highly polarised epithelial monolayer that performs essential functions in retinal homeostasis, including outer blood–retina barrier maintenance, visual cycle activity, metabolic exchange, phagocytic clearance of photoreceptor outer segments, and regulation of oxidative and immune balance. Because RPE cells persist for decades under conditions of sustained oxidative, metabolic, and phagocytic stress, this tissue provides a valuable model for examining how long-lived post-mitotic cells preserve function over time and how age-related dysfunction emerges when that balance weakens. Although much of the current literature on RPE ageing has been shaped by age-related macular degeneration (AMD), age-dependent change in the RPE should not be understood solely as a preclinical stage of disease. Rather, the ageing RPE offers a broader framework for studying cellular maintenance under chronic physiological load. In this review, we synthesise current evidence on RPE ageing across four interrelated domains: structural remodelling, mitochondrial and metabolic imbalance, proteostatic and lysosomal burden, and chronic inflammatory dysregulation. Across these processes, ageing in the RPE is expressed less as widespread cell loss than as progressive decline in cellular organisation, buffering capacity, and functional precision. Structural irregularity, altered mitochondrial regulation, incomplete degradative clearance, and persistent low-grade inflammatory signalling together reduce the ability of the RPE to maintain long-term homeostasis and increase vulnerability to age-related retinal dysfunction. We further argue that ageing in the RPE is best understood not as abrupt failure of isolated pathways, but as gradual loss of system coherence among interacting homeostatic systems that remain active while operating under increasing constraint. This view helps integrate diverse cellular and molecular findings and highlights the RPE as an informative model for understanding ageing in long-lived post-mitotic tissues. Full article

Ovarian function relies on a network of well-coordinated molecular mechanisms that regulate follicular development, oocyte maturation, ovulation, and corpus luteum function. When these processes are disrupted, infertility can result. Extracellular matrix (ECM) remodeling represents a central regulatory component in these processes and is essential for follicle rupture and oocyte release. This mechanism involves metalloproteinases (MMPs), mainly MMP-2 and MMP-9, which degrade the ECM and allow the necessary structural changes. Other ECM-modulating proteases, such as ADAM and ADAMTS families, also contribute to this process. Their activity is tightly regulated by tissue inhibitors of metalloproteinases (TIMPs), ensuring that tissue remodeling occurs in a controlled manner. Disruption of the balance between MMPs and TIMPs increases the risk of infertility-related conditions such as polycystic ovary syndrome (PCOS), endometriosis, luteinizing hormone (LH) deficiency syndrome, and ovarian aging. In addition to the ECM, other factors, including intracellular signaling pathways, oxidative stress (OS), and mitochondrial function, contribute to ovarian physiology and directly affect oocyte quality and viability. This narrative review focuses on the molecular mechanisms governing ovarian function, with particular emphasis on the remodeling of the ECM by MMPs during ovulation, and examines how their disorders contribute to infertility. A deeper understanding of these mechanisms may lead to the identification of new therapeutic targets and the improvement of assisted reproduction outcomes. Full article

Chronic wounds resulting from bacterial infection remain one of the main challenges in clinical practice. There is a pressing need to develop an injectable hydrogel sealant with multifunctional properties, including remodeling capabilities, self-healing, painless removal, and antibacterial activity, to promote tissue remodeling. In this work, aldehyde carboxymethylated agarose (ACMA) is employed for the first time as a bio-template. Dopamine (DA) is introduced onto the ACMA template via a reversible Schiff-base reaction, endowing it with biomineralization properties to synthesize DA-modified ACMA-Ag nanoparticles (ACMA-DA-Ag). Further, the prepared ACMA-DA-Ag, which possesses both antibacterial activity and injectable behavior, is incorporated into a guar gum hydrogel through the formation of borate/diol bonds, thereby forming a multiple-dynamic-bond crosslinked network. This hydrogel demonstrates adequate mechanical strength, injectability, remodeling capabilities, and self-healing performance. It can reassemble into a new hydrogel within 4 ± 0.6 min upon simple physical contact, and supports tissue adhesion. Furthermore, the hydrogel effectively covers irregular-shaped wound and can be removed without causing secondary injury. More importantly, this multifunctional hydrogel is cost-effective, easy to synthesize, and simple to use, significantly accelerating skin regeneration and promoting the formation of skin appendages, such as hair follicles. The outcome of this research not only serves a tissue sealant for wound healing, but also presents a new strategy for creating novel polysaccharide-based biomaterials. Full article

Non-infectious cardiac failure in feedyard cattle has become more frequently diagnosed. There is limited research assessing gross and histologic lesions in grossly abnormal hearts of harvested cattle. Cases were stratified by heart score (HS) using a scale of 1–5, with 1 representing a normal heart and 5 representing severely remodeled ventricles. Cattle were evaluated for gross lesions of the heart, lung, and liver. Samples collected from each animal for histology included cardiac (n = 4), pulmonary (n = 4), and hepatic (n = 1) tissues. Histologic evaluation scored cardiac and hepatic fibrosis and necrosis, embedded myocardial protozoal cysts (EMPCs) were quantified, and pulmonary lesions were categorized based on histologic patterns. Of 103 cases, 40 had normal HSs (NHSs) (1 or 2), and 63 had abnormal HSs (AHSs) (3, 4, or 5). There were 64 cases with normal lung deflation scores, and 39 cases with abnormal lung deflation scores. At least one cardiac section contained EMPCs in 67 cases. Cattle with abnormal lung deflation scores were more likely to have an AHS (0.76 ± 0.07, p ≤ 0.01) compared with cattle with normal deflation scores (0.52 ± 0.06). Cattle with EMPCs present in at least one cardiac section were more likely to also have an AHS (0.73 ± 0.05, p ≤ 0.1) compared with cattle without EMPCs (0.39 ± 0.08). No histological findings for the lungs or liver were associated with abnormal heart score; however, lung deflation and EMPCs were associated with abnormal heart score. Full article

Phospholipid transfer protein (PLTP) is a lipid transfer protein classically studied in the context of plasma lipoprotein metabolism, high-density lipoprotein (HDL) remodeling, and cardiovascular disease risk. PLTP facilitates phospholipid transfer between lipoproteins and regulates HDL particle size and composition through interactions with apolipoprotein A-I and apolipoprotein A-II. While its systemic roles in cholesterol handling, reverse cholesterol transport, and inflammatory signaling are well established, the cell-autonomous functions of PLTP within cardiomyocytes remain poorly defined, particularly in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Extensive experimental and clinical studies demonstrate that PLTP enhances ABCA1-dependent cholesterol efflux primarily by stabilizing ABCA1 at the plasma membrane and by promoting the generation of lipid-poor apolipoprotein A-I and pre-β HDL particles, which serve as efficient cholesterol acceptors; the magnitude of these effects depends on cellular context, PLTP expression levels, and the availability of lipid acceptors. PLTP expression is metabolically regulated and widely distributed across tissues, including macrophages and other non-hepatic cells, supporting roles beyond circulating lipoprotein remodeling. Altered PLTP activity has been linked to atherosclerosis, cardiovascular disease, and inflammatory pathways, underscoring its relevance to cardiac pathophysiology. Emerging evidence further suggests that intracellular cholesterol distribution, rather than total cholesterol content alone, critically influences mitochondrial membrane composition, bioenergetics, and stress signaling in cardiomyocytes. These observations raise the possibility that PLTP-regulated lipid flux may indirectly shape mitochondrial function by modulating cellular cholesterol homeostasis. This review synthesizes current knowledge of PLTP biology, cholesterol metabolism, and lipoprotein remodeling, and integrates these concepts with emerging frameworks in cardiomyocyte lipid metabolism and mitochondrial physiology. We highlight human iPSC-derived cardiomyocytes as a strategic and translationally relevant platform to investigate PLTP’s non-canonical, cell-intrinsic roles, identify critical knowledge gaps, and propose future directions for elucidating how PLTP may influence mitochondrial function in human cardiac cells. Full article

Male reproductive aging is increasingly recognized as a systemic process in which inflammaging drives progressive dysfunction of urogenital tissues. Key mechanisms include immune–metabolic alterations, activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, as well as epigenetic remodeling. Evidence from experimental and clinical studies suggests that these processes are often investigated independently, and integrative models in humans remain limited. Here, we propose a conceptual framework linking the prostate, testis, and skeletal muscle, in which oxidative stress may act as a mediator amplifying systemic dysregulation at different levels during the aging process. Lifestyle and metabolic interventions, including caloric restriction, resistance exercise, and selected nutraceuticals, may act as key modulators of inflammaging pathways, thus highlighting new potential targets for precision medicine approaches. Full article

Photoacoustic imaging (PAI) is an emerging hybrid biomedical imaging modality that combines the high molecular contrast of optical excitation with the deep tissue penetration of ultrasound detection. This review presents recent advances in PAI-based techniques for the detection and characterization of gynecological diseases in women, with particular focus on endometriosis and uterine-related disorders. We summarize the application of PAI across preclinical and translational studies, highlighting progress in photoacoustic microscopy, spectroscopic photoacoustic imaging, and endoscopic and probe-based implementations for non-invasive, high-resolution tissue evaluation. The role of functional and contrast-enhanced PAI approaches is discussed, emphasizing their ability to enhance diagnostic sensitivity, enable longitudinal monitoring, and provide detailed information on vascular, biochemical, and structural tissue characteristics. Furthermore, the expanding applications of PAI in assessing uterine, cervical, and ovarian pathologies, including tumor detection and tissue remodeling, are reviewed. Finally, current challenges, limitations, and future directions toward clinical translation are addressed. Collectively, this review underscores the potential of photoacoustic imaging as a powerful, non-invasive platform for early diagnosis, disease monitoring, and improved management of women’s health conditions. Full article

Background/Objectives: Advanced glycation end products (AGEs) accumulate in long-lived extracellular matrix proteins and have been implicated in skin aging and tissue remodeling, particularly in photo-exposed skin. High-frequency ultrasound (HFU) offers a non-invasive assessment of structural skin parameters that may reflect these changes. This study aimed to explore the associations between serum AGEs and HFU-derived structural parameters of cervico-facial skin, with a focus on UV-exposed dermal tissue. Methods: This cross-sectional study included 113 adults recruited in Cluj-Napoca, Romania. Fasting serum samples were analyzed for fructosyl-lysine (FruLys), pyrraline (Pyr), methylglyoxal-derived hydroimidazolone-1 (MG-H1), carboxyethyl-lysine (CEL), carboxymethyl-lysine (CML), arginine (Arg), and lysine (Lys). HFU, using a 22 MHz probe, was performed on the left zygomatic area to assess epidermal depth and density, UV-exposed dermal damage depth and density, dermis depth and density, and subcutaneous tissue depth and density. Associations between serum AGEs and HFU parameters were evaluated using Spearman correlation, with Benjamini–Hochberg false discovery rate (FDR) correction for multiple testing. Results: After FDR correction, epidermal depth was inversely correlated with serum CML (r = −0.402, adjusted p = 0.018). UV-exposed dermal density was inversely correlated with serum Pyr (r = −0.547, adjusted p < 0.019), Arg (r = −0.369, adjusted p < 0.019), and Lys (r = −0.270, adjusted p < 0.019). Subcutaneous tissue depth was also inversely correlated with serum CML (r = −0.290, adjusted p = 0.020). Conclusions: The study showed that higher levels of specific serum AGEs were associated with selected HFU-derived structural alterations in cervico-facial skin, particularly in UV-exposed dermal tissue. These exploratory findings support the biological plausibility that systemic glycation may be reflected by non-invasive skin ultrasound parameters. Full article

Wound healing involves the coordinated regulation of inflammation, angiogenesis, and extracellular matrix remodeling, processes modulated by natural bioactives. In this context, Chelidonium majus L. (C. majus), a plant rich in alkaloids and flavonoids, remains mechanistically underexplored. This study, therefore, investigates its metabolites using an integrated computational–experimental approach and evaluates their applicability in sericin-based wound-healing systems. A curated database of 83 C. majus bioactive compounds was analyzed using cheminformatics and molecular docking against key wound-healing targets (iNOS, VEGF, MMP-3, and tyrosinase), followed by ADMET and toxicity prediction (StopTox). Selected plant–sericin formulations were subsequently evaluated for wound-healing activity using an in vitro fibroblast scratch assay. Docking revealed strong binding affinities for several metabolites, particularly protopine, kaempferol-3-rutinoside, cynaroside, hesperidin, quercetin-3-rhamnosylrutinoside, and vitexin, indicating multi-target modulation across inflammatory, proliferative, and remodeling phases of tissue repair. ADMET and toxicity analyses predicted favorable dermal safety and pharmacokinetic profiles for most compounds. Consistently, in vitro assays demonstrated that C. majus–sericin systems had fibroblast migration and wound closure in a concentration- and ratio-dependent manner, with improved healing kinetics observed at 150 µg/mL and for formulations containing higher relative proportions of both components. The experimental outcomes supported the pro-angiogenic and matrix-stabilizing mechanisms predicted in silico. Overall, C. majus metabolites exhibit polypharmacological wound-healing activity, supporting their integration into sericin-based systems as a promising strategy for topical therapies. Full article

Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide, underscoring the need to better define the molecular mechanisms that govern cardiovascular homeostasis and disease progression. Among post-transcriptional regulators, microRNAs have emerged as important modulators of endothelial function, vascular smooth muscle cell plasticity, cardiomyocyte integrity, and cardiac fibroblast activity. This narrative review examines how microRNAs orchestrate molecular networks linking cellular homeostasis to inflammation, oxidative stress, mitochondrial dysfunction, apoptosis, fibrosis, angiogenesis, and pathological remodeling across major cardiovascular cell types. It further discusses how these regulatory programs are reflected in specific cardiovascular diseases, including atherosclerosis, hypertension, acute myocardial infarction, heart failure, and arrhythmias. In addition, the review addresses the growing relevance of circulating and extracellular vesicle-associated microRNAs as candidate biomarkers for diagnosis, prognosis, and disease monitoring, as well as their therapeutic potential through mimics, inhibitors, antagomirs, and emerging delivery systems. Finally, current translation barriers are considered, including methodological heterogeneity, limited tissue specificity, delivery challenges, safety concerns, and the need for large-scale clinical validation. Overall, microRNAs are presented as integrative regulators connecting cardiovascular cell biology with disease mechanisms and clinical applications. Full article

Background/Objectives: Nuclear receptor corepressors NCOR1 and NCOR2 are key regulators of transcriptional repression, chromatin remodelling, and immunometabolic signalling. While NCOR1 has already been linked to vascular biology, its relevance in abdominal aortic aneurysm (AAA) remains unclear, particularly for NCOR2. This study aimed to investigate the expression, cellular localisation, and molecular interactions of NCOR1/2 in human AAA tissue. Methods: Human AAA samples (elective and ruptured) (n = 45) and non-aneurysmal control aortas (n = 18) were obtained from our Swiss Vascular Biobank. Transcriptomic profiling was performed using ribosomal RNA-depleted RNA sequencing. Differential expression and correlation analyses were performed using DESeq2/EdgeR and Spearman rank correlation with Benjamini–Hochberg correction. Cellular localisation was assessed through immunohistochemistry (IHC). Results: Bulk transcriptomic analyses showed no significant differences in NCOR1 or NCOR2 expression between AAA and controls. IHC revealed that NCOR1 was found in endothelial cells (ECs), smooth muscle cells (SMCs), and inflammatory infiltrates, while NCOR2 was primarily associated with macrophages. Correlation analyses suggest that NCOR1 interacts with various cellular markers, proteolytic enzymes, inflammatory mediators, and epigenetic regulators, including the lncRNA MALAT1. NCOR2 showed distinct associations with remodelling enzymes, TGFB1 signalling, selective epigenetic modifiers, and lncRNA H19. Conclusions: The lack of transcriptional differences in NCOR1 and NCOR2 between AAA and controls does not exclude cell-type-specific regulation or functional relevance. The specific cellular distributions and molecular associations in human AAA imply that NCOR1 and NCOR2 play non-redundant roles in vascular remodelling, inflammation, and epigenetic regulation. Our findings highlight NCOR pathways as potential modulators of AAA pathophysiology and promising targets for future therapies. Full article

Thyroid hormones regulate a complex and interconnected network of metabolic signaling. Thyroid dysfunction is, at present, defined and monitored through circulating thyroid-stimulating hormone (TSH) and free thyroid hormones. However, biochemical normalization does not entirely indicate restoration of metabolic homeostasis. This discrepancy highlights a critical limitation of the current TSH-centric paradigm, which also fails to explain the heterogeneity in cardiometabolic outcomes observed among patients with similar biochemical profiles. Metabolomics, through the analysis of tissue-specific biofluids, could aid in capturing the complex metabolic perturbations that characterize this disease. In this review, we summarize metabolomic signatures typical of thyroid dysfunction, perform a critical evaluation of limitations and variability across studies, and explore the clinical and translational implications of metabolomics in thyroid pathology. In addition, five metabolic hubs influenced by thyroid hormone activity are summarized: (i) lipid and lipoprotein remodeling; (ii) mitochondrial energetics and redox balance; (iii) amino acid metabolism and protein turnover; (iv) gut–liver–thyroid axis and (v) biological impact of subclinical thyroid diseases. Taken together, these findings challenge the sufficiency of a diagnostic model based on TSH measurement and pose metabolomics as a promising tool to refine risk stratification, uncover subclinical vulnerability and guide patient-centered management of thyroid disease. Despite its promise, clinical adoption of metabolomics is hindered by a lack of standardization and complex data interpretation. To overcome these limitations, coupling metabolomics with genomics and transcriptomics may allow its translation into practical application. Full article