Search Results (8,740)

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

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited treatment options. Patients are treated with DNA damaging chemotherapies which act by inducing DNA damage in rapidly dividing tumor cells. Unfortunately, these tumors frequently develop treatment resistance, underscoring the need to understand resistance mechanisms in order to develop better treatment strategies. DNA damage response (DDR) detects and repairs DNA damage, and the DDR pathway has been shown to contribute to chemoresistance. Another factor known to drive chemoresistance in PDAC is the dense stroma, composed of extracellular matrix proteins secreted by cancer-associated fibroblasts (CAFs). Our recent work identified a CAF-induced resistance mechanism involving N-myc downstream regulated gene 1 (NDRG1). CAF-induced signaling resulted in the phosphorylation of NDRG1 and NDRG1-dependent DNA repair and protection from chemotherapies. Loss of NDRG1 resulted in increased chemotherapy-induced DNA damage and decreased replication fork speed and recovery. Methods: To gain insight into the molecular mechanism of NDRG1-mediated DNA repair and replication, we performed a BioID screen to identify binding partners of NDRG1. We further assessed the mechanistic roles of the identified interaction partners on DNA repair using DNA replication and repair assays such as the Comet assay and DNA fiber assays. Results: Our BioID screen identified meiotic recombination 11 (MRE11) protein, a nuclease involved in DDR, as a putative NDRG1 interacting protein. Interaction between MRE11 and NDRG1 was enriched during the late S/early G2 cell cycle phases and under replication stress. However, this interaction is likely indirect as the interaction only occurred in a cellular context and not with in vitro purified proteins. Blocking NDRG1 phosphorylation or blocking MRE11 exonuclease activity both resulted in protection of newly synthesized DNA at stalled replication forks. In NDRG1 knockout cells, blocking MRE11 led to decreased protection of nascent DNA, suggesting that NDRG1 and MRE11 may be acting in the same pathway and that NDRG1 is required for MRE11’s activity at stalled forks. Conclusions: In summary, our work has uncovered a protein complex between NDRG1 and MRE11 that may play a key role in chemoresistance due to its role in the processing of stalled replication forks. Full article

Acute kidney injury (AKI) continues to pose a significant clinical challenge due to its high morbidity rates and limited therapeutic options. Recent evidence suggests that natural compounds may provide renoprotective benefits by modulating oxidative stress and inflammation. This study examines the protective effects of a novel polysaccharide peptide extracted from Ganoderma lucidum (GL-PPQ1) against renal ischemia–reperfusion (I/R) injury, with particular emphasis on the integrin β3/Fibronectin 1 (Fn1) signaling axis. A murine model of renal I/R injury was established, and GL-PPQ1 was administered orally for seven days before surgery. The assessment included renal function, histopathology, oxidative stress markers, and inflammatory cytokines. Additionally, transcriptomic profiling and protein expression analyses were conducted to elucidate the underlying mechanisms. The results revealed that GL-PPQ1 pretreatment significantly reduced renal tubular damage, lowered serum creatinine and blood urea nitrogen levels, and diminished oxidative stress and inflammatory responses. RNA sequencing revealed that GL-PPQ1 affected gene sets associated with extracellular matrix remodeling and cell adhesion. Western blot and immunohistochemistry further confirmed that GL-PPQ1 decreased the expression of integrin β3 and Fn1, suggesting a regulatory effect on their interaction during I/R injury. These findings demonstrate that GL-PPQ1 offers substantial kidney protection by mitigating oxidative stress, inflammation, and dysregulation of the integrin β3/Fn1 signaling pathway. Thus, this study supports that polysaccharide peptides derived from Ganoderma lucidum could have the potential to serve as both a dietary supplement and a therapeutic agent in the treatment of AKI. 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

Background: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition marked by heterogeneous behavioral symptoms and systemic comorbidities, including immune and gastrointestinal dysfunctions. Emerging studies suggest that glycosylation—a fundamental post-translational modification regulating cellular communication and immune responses—may play a role in ASD pathophysiology, yet its contribution remains underexplored. Methods: In this study, we developed an integrative transcriptomic and network analysis framework to investigate glycosylation-related gene expression changes and their functional associations in ASD. Using publicly available datasets from bulk and single-cell RNA sequencing of brain and blood tissues, we focused on four prior-knowledge gene subsets: glycogenes, extracellular matrix glycoproteins, immune response genes, and autism risk genes. Results: Differential expression and pathway enrichment analyses revealed consistent dysregulation of glycosylation pathways, including mucin-type O-glycan biosynthesis, glycosaminoglycan metabolism, GPI-anchor formation, and sialylation, across ASD tissues. These transcriptional changes were functionally linked to altered immune signaling (e.g., IL-17, Toll-like receptor, and complement pathways) and synaptic development pathways, forming a distinct glyco-immune axis. Network analysis identified key glycogenes such as GALNT10, NEU1, LMAN2L, and CHST1 as central molecular nodes, interacting with immune and neuronal regulators. Linkage disequilibrium analysis further revealed ASD-associated SNPs influencing the expression of these glycogenes in both blood and brain tissues. Conclusions: Together, these findings support a model in which disrupted glycosylation contributes to ASD pathophysiology by mediating immune dysregulation and altered neuronal connectivity. This study offers a systems-level framework to understand the molecular complexity of ASD and highlights glycogenes as potential biomarkers and targets for future therapeutic exploration. Full article

Cigarette smoking contributes to vascular aging through oxidative stress, inflammation, and extracellular matrix (ECM) remodeling. Cellular senescence has been recognized as an important mechanism linking tobacco exposure to vascular dysfunction, but effective pharmacological strategies targeting this process remain scarce. In this study, we examined whether Rapalink-1, a dual inhibitor of mechanistic target of rapamycin complex 1 and complex 2 (mTORC1 and mTORC2), modulates smoke condensate (SC)-induced senescence in vascular cells. Human umbilical vein endothelial cells (HUVECs) and vascular smooth muscle cells (SMCs) were exposed to SC with or without Rapalink-1. SC increased intracellular reactive oxygen species, induced DNA damage, and promoted senescence-associated changes, including increased senescence-associated β-galactosidase (SA-β-gal) activity, reduced Lamin B1, and elevated p21 expression. These effects were accompanied by increased expression of inflammatory and matrix-remodeling genes associated with the senescence-associated secretory phenotype (SASP). Rapalink-1 co-treatment reduced oxidative stress and DNA damage, attenuated senescence markers, and partially normalized SASP-related and ECM-associated gene expression. Mechanistically, SC activated nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling and increased downstream mTOR pathway activity, whereas Rapalink-1 dampened these signaling responses. Together, these findings indicate that dual mTORC1/2 inhibition by Rapalink-1 mitigates smoke condensate-induced senescence and inflammatory responses in vascular cells. Full article

Keloid is a benign skin disease with excessive growth of fibroblasts, characterized by too much abnormal extracellular matrix deposited in the dermis. It is generally believed that transforming growth factor-β (TGF-β) is the core cytokine that causes keloid. Previously, it was thought that its pathogenic effect was mainly attributed to the classical Smad-dependent pathway. It directly shuttles signals to the nucleus to trigger pro-fibrotic gene transcription. However, accumulating evidence now points to the equally vital role of Smad-independent signaling. Unlike the direct nuclear translocation of Smads, these alternative pathways transmit signals through rapid intracellular kinase cascades. They jointly direct the proliferation, migration, anti-apoptosis, fibrogenesis, and chronic inflammation of fibroblasts in keloids. This review attempts to comprehensively clarify the molecular processes regulated by TGF-β through non-Smad pathways (such as MAPK, PI3K/Akt, Rho GTPase, Wnt/β-catenin, JAK/STAT). Translating these non-Smad insights helps to overcome the high recurrence rates of traditional therapies. Targeting these specific molecular hubs through combination and precision therapies serves to reprogram the fibrotic microenvironment. Full article

Uterine fibroids (leiomyomas) are common benign smooth muscle tumors that impose substantial symptom burden and healthcare costs worldwide. Although uterine fibroid (leiomyoma) pathogenesis is multifactorial, hypoxia has emerged as a key feature of the uterine fibroid (leiomyoma) microenvironment, particularly within poorly perfused tumor cores. Hypoxia-inducible factor-1α (HIF-1α) is a central transcriptional regulator of cellular adaptation to low oxygen and coordinates downstream programs that support angiogenesis, metabolic reprogramming, cell survival, and extracellular matrix (ECM) remodeling. In uterine fibroids (leiomyomas), these HIF-1α–dependent processes intersect with steroid hormone signaling, growth factor pathways, inflammatory mediators, and redox imbalance, together promoting tumor persistence and progressive fibrosis. This review synthesizes the molecular regulation of HIF-1α, highlights major HIF-linked effector pathways relevant to uterine fibroid (leiomyoma) biology, and emphasizes mechanistic crosstalk with estrogen- and progesterone-responsive signaling, TGF-β/SMAD-driven fibrosis, NF-κB-mediated inflammation, and metabolic checkpoint pathways including mTOR and AMPK. Finally, we evaluate emerging therapeutic strategies that target HIF-1α directly or indirectly through upstream regulators. 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

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive desmoplastic microenvironment; however, reproducible stromal-associated biomarkers linked to disease progression remain limited. This study therefore aimed to identify and validate a biologically relevant stromal/extracellular matrix (ECM)-associated candidate biomarker for PDAC. Methods: Three GEO bulk transcriptomic PDAC cohorts (GSE15471, GSE16515, and GSE62452) were integrated for differential expression, functional enrichment, protein–protein interaction, and hub-gene analyses. Candidates identified as a promising biomarker were further evaluated using the following: public proteomic and survival resources; head-to-head receiver operating characteristic (ROC) comparisons against COL1A1, COL3A1, and COL5A1; a progression cohort (GSE43288); and single-nucleus RNA sequencing data (GSE202051). Results: Among 206 shared differentially expressed genes, COL5A2 was the only consensus hub retained across multiple network-ranking methods. COL5A2 protein expression was found to be elevated in tumor tissue and associated with worse overall and disease-free survival. In ROC analyses, COL5A2 exhibited stable tumor-versus-non-tumor discrimination across GSE15471, GSE16515, and GSE62452 (AUC = 0.932, 0.760, and 0.782, respectively) and significantly outperformed COL3A1 in two cohorts. In GSE43288, COL5A2 expression increased along the normal–pancreatic intraepithelial neoplasia–PDAC axis and remained positively associated with ECM and cancer-associated fibroblast (CAF) signature scores after adjustment for disease group. Reanalysis of GSE202051 restricted to the original 18 untreated PDAC specimens revealed that COL5A2 expression was concentrated in fibroblast-lineage compartments, with CAFs accounting for the largest overall contribution and myCAFs demonstrating the strongest per-specimen expression enrichment. Conclusions: COL5A2 is a reproducible stromal/ECM-associated candidate biomarker linked to PDAC progression, with predominant expression in fibroblast/CAF compartments. Full article

Background/Objectives: Musculoskeletal soft-tissue injuries are common among physically active individuals and arise from complex interactions between environmental and biological factors. Genetic variation in genes involved in extracellular matrix (ECM) organization may contribute to individual susceptibility to such injuries. This study investigated whether polymorphisms in aggrecan (ACAN, rs2351491 and rs1042631) and fibromodulin (FMOD, rs7543148) genes are associated with susceptibility to sports-related injuries. Methods: The study included 335 physically active Caucasians, comprising 202 participants with a history of non-contact sports-related musculoskeletal injuries and 133 uninjured controls. Genotyping was performed using real-time polymerase chain reaction. Results: No significant associations were observed between the analyzed polymorphisms and overall injury occurrence after correction for multiple comparisons. A nominal association was observed for ACAN rs2351491 in the overall injury comparison under the overdominant model (p = 0.0457), where CT heterozygotes were more frequent among injured participants. The ACAN rs1042631 variant showed nominal associations with anterior cruciate ligament (ACL) injury under the codominant (p = 0.0179), recessive (p = 0.0243), and overdominant (p = 0.0346) models, with the TT genotype associated with lower odds of ACL injury under the recessive model (OR = 0.15, 95% CI: 0.02–1.22). No significant associations were observed for FMOD rs7543148 or for haplotype analysis of ACAN variants. Conclusions: No robust associations were identified between the investigated variants and susceptibility to musculoskeletal soft-tissue injury after correction for multiple testing. Nominal signals observed for ACAN variants, particularly in ACL-focused analyses, warrant further investigation but should be interpreted cautiously and confirmed in larger, independent cohorts. 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

Bone marrow(BM) is the primary site of hematopoiesis, supporting the self-renewal and differentiation of hematopoietic stem cells (HSCs). Its function depends on a highly complex microenvironment composed of stromal cells, vascular networks, extracellular matrix components, and dynamic biophysical signals. Traditional two-dimensional culture systems and animal models fail to adequately recapitulate the spatial architecture and dynamic regulatory processes of the human bone marrow niche, thereby limiting in-depth investigations into hematopoietic regulatory mechanisms, disease pathogenesis, and drug-induced bone marrow toxicity. In recent years, advances in microphysiological systems (MPS) have provided novel engineering approaches for the in vitro reconstruction of the bone marrow microenvironment. This review systematically summarizes current construction strategies for bone marrow MPS, including three-dimensional self-organized bone marrow organoids and microfluidic bone marrow-on-a-chip platforms. Particular attention is given to the roles of key cellular components, biomaterial scaffolds, vascularized architectures, and dynamic perfusion systems in biomimetic bone marrow engineering. In addition, we discuss strategies for constructing more complex models, such as vascular niches, vascularized bone tissue constructs, and bone metastasis models. Bone marrow MPS more faithfully recapitulate the hematopoietic microenvironment and provide a physiologically relevant in vitro platform for hematopoietic research, disease modeling, and drug evaluation, thereby supporting future advances in precision and regenerative medicine. Full article

Oral mucosal ulcers sustain a persistent inflammatory and oxidative microenvironment that interferes with epithelial repair and delays healing. Although hyaluronic acid (HA) is used in oral wound management due to its biocompatibility and hydrating properties, its biological activity is highly context-dependent and can be compromised under inflammatory conditions. In contrast, N-acetyl-L-cysteine (NAC) is a well-established antioxidant with documented anti-inflammatory effects, yet its rapid clearance limits its effectiveness when applied locally. In this study, the effects of HA and NAC, individually and in combination, on metabolic activity and inflammatory responses of TNF-α–stimulated human gingival keratinocytes were evaluated. In parallel, the individual immobilization of HA or NAC onto plasma-activated decellularized extracellular matrix (dECM) films was investigated as a materials-oriented approach for potential localized intraoral applications. NAC significantly attenuated TNF-α-induced IL-6 and IL-8 secretion, reducing both cytokines by approximately 99%, while preserving keratinocyte metabolic activity. HA displayed limited immunomodulatory effects. The combined HA + NAC condition did not improve the response compared with NAC alone. Plasma treatment enabled stable individual grafting of HA and NAC onto dECM films, and both functionalized surfaces retained chemical stability under saliva-like conditions. Collectively, these findings identify NAC as the most effective anti-inflammatory candidate under the tested cellular conditions and support plasma-functionalized dECM films as a feasible platform for future biological evaluation in intraoral applications. Full article

The rapid emergence of antibiotic-resistant bacteria represents one of the most critical challenges in modern healthcare and has stimulated intense research into alternative antimicrobial strategies. Antibacterial hydrogels have emerged as versatile biomaterials due to their high water content, tunable physicochemical properties, and ability to function as multifunctional platforms for drug delivery and tissue regeneration. This review analyzes recent advances in antibacterial hydrogel systems through a conceptual framework based on three complementary pillars: biological antibacterial agents, inorganic functional components, and structural material engineering. Biological strategies, particularly bacteriophage-based approaches, provide highly specific antibacterial activity capable of targeting multidrug-resistant pathogens and disrupting bacterial biofilms. Inorganic components such as hydroxyapatite nanoparticles contribute additional functionalities including drug adsorption, modulation of the ionic microenvironment, and osteoconductive behavior relevant for bone-related infections. Structural design strategies based on electrospinning enable the fabrication of fibrous architectures that enhance mechanical stability, regulate therapeutic release, and mimic extracellular matrix organization. The integration of these three pillars within multifunctional hydrogel platforms offers promising opportunities for developing advanced antibacterial biomaterials capable of addressing infection control while supporting tissue regeneration. Full article