Search Results (409)

Endometriosis is traditionally conceptualized as a pelvic lesion–centered disease; however, mounting evidence indicates it is a chronic, systemic, and multifactorial inflammatory disorder. This review examines the molecular dialog between ectopic endometrial tissue, the immune system, and peripheral organs, highlighting mechanisms that underlie disease chronicity, symptom variability, and therapeutic resistance. Ectopic endometrium exhibits distinct transcriptomic and epigenetic signatures, disrupted hormonal signaling, and a pro-inflammatory microenvironment characterized by inflammatory mediators, prostaglandins, and matrix metalloproteinases. Immune-endometrial crosstalk fosters immune evasion through altered cytokine profiles, extracellular vesicles, immune checkpoint molecules, and immunomodulatory microRNAs, enabling lesion persistence. Beyond the pelvis, systemic low-grade inflammation, circulating cytokines, and microRNAs reflect a molecular spillover that contributes to chronic pain, fatigue, hypothalamic–pituitary–adrenal axis dysregulation, and emerging gut–endometrium interactions. Furthermore, circulating biomarkers—including microRNAs, lncRNAs, extracellular vesicles, and proteomic signatures—offer potential for early diagnosis, patient stratification, and monitoring of therapeutic responses. Conventional hormonal therapies demonstrate limited efficacy, whereas novel molecular targets and delivery systems, including angiogenesis inhibitors, immune modulators, epigenetic regulators, and nanotherapeutics, show promise for precision intervention. A systems medicine framework, integrating multi-omics analyses and network-based approaches, supports reconceptualizing endometriosis as a systemic inflammatory condition with gynecologic manifestations. This perspective emphasizes the need for interdisciplinary collaboration to advance diagnostics, therapeutics, and individualized patient care, ultimately moving beyond a lesion-centered paradigm toward a molecularly informed, holistic understanding of endometriosis. Full article

Background and Objectives: This study aims to analyze the effects of levetiracetam (LEV) and valproic acid (VPA) administration on oxidative stress, inflammation, apoptosis, extracellular matrix dynamics, and bone remodeling parameters in rat alveolar bone exposed to orthodontic force. Materials and Methods: Four experimental groups were designed for this study: Control, Force, Force + LEV, and Force + VPA. LEV (150 mg/kg/day) or VPA (300 mg/kg/day) was administered intraperitoneally to the experimental groups daily for 6 weeks. At the end of the experimental period, the alveolar bone tissues were used for molecular analyses. RT-PCR analysis was performed to assess the expression levels of antioxidant markers [superoxide dismutase, (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH)], inflammatory cytokines [tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β)], apoptosis-related genes (Bax, Bcl-2, and Caspase-3), matrix remodeling genes [matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and metallopeptidase inhibitor 1 (TIMP-1)], and bone metabolism regulators [receptor activator of nuclear factor kappa-Β ligand (RANKL) and osteoprotegerin (OPG)]. Oxidative stress and inflammatory measurements were also confirmed via ELISA assays. Results: The results demonstrated that orthodontic force application increased oxidative stress, inflammation, and apoptosis compared to the Control group, disrupted extracellular matrix homeostasis, and increased bone resorption, while LEV administration (LEV + Force) markedly mitigated these abnormalities. In other words, LEV administration increased levels of antioxidant markers, decreased levels of inflammatory cytokines and pro-apoptotic genes, restored extracellular matrix balance (decrease in MMP-2 and MMP-9 with concurrent upregulation of TIMP-1), and limited tissue destruction (decrease in RANKL along with elevation in OPG). In contrast to LEV, VPA did not correct these molecular alterations induced by orthodontic force and, in several parameters, further exacerbated them. Conclusions: In conclusion, molecular data from the animal model indicate that LEV plays a protective role against orthodontic force by reducing excess levels of oxidative stress, apoptosis, and inflammation and homeostatic pathways. Full article

Breast cancer is a heterogeneous disease that exists in multiple subtypes, some of which still lack targeted and effective therapy. A major challenge is to unravel their underlying molecular mechanisms and bring to light novel therapeutic targets. In this study, we investigated the role of WNT-inducible signaling pathway protein 1 (WISP1) matricellular protein in the acquirement of an invasive phenotype by breast cancer cells. To this aim, we treated non-invasive MCF7 cells with WISP1 and assessed the expression levels of macrophage migration inhibitory factor (MIF) and its cellular receptor CD74. Next, we examined the expression of epithelial-to-mesenchymal transition (EMT) markers as well as molecular effectors of the tumor microenvironment, such as CD44, the main hyaluronan receptor that also acts as a co-receptor for MIF, the hyaluronan oncogenic network, and specific matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs). The results showed that WISP1 potently induces the expression of MIF cytokine and affects the expression of specific extracellular matrix molecules with established roles in the promotion of malignant properties. Notably, Src kinases and MIF are critically involved in these processes. Collectively, the present study demonstrates for first time a WISP1/Src/MIF axis as well as its ability to induce an invasive phenotype in MCF7 cells and highlights novel cellular and molecular processes involved in the epithelial-to-mesenchymal transition and the development of invasive breast cancer. This suggests that specific cues from the tumor microenvironment can activate a migratory/invasive phenotype in a subpopulation of cells residing within the heterogeneous breast tumor. Full article

Vasculitides are a heterogeneous group of disorders characterized by inflammation of blood vessel walls, leading to tissue ischemia and organ injury. Traditional inflammatory markers such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are widely used but lack diagnostic specificity. This has driven the search for more informative biomarkers across vasculitis subtypes. This review summarizes current evidence for validated and emerging biomarkers in large-, medium-, small-, and variable-vessel vasculitis, as well as single-organ vasculitis. Key analytes reflect systemic inflammation, such as serum amyloid A (SAA) and interleukin-6 (IL-6), as well as endothelial activation, complement pathways, neutrophil and macrophage activation, and organ-specific damage. Promising candidates include pentraxin-3 (PTX3) and matrix metalloproteinase-9 (MMP-9) in large-vessel vasculitis; N-terminal pro-B-type natriuretic peptide (NT-proBNP) and S100 proteins in Kawasaki disease; galactose-deficient immunoglobulin A1 (Gd-IgA1) and urinary angiotensinogen (AGT) in IgA vasculitis; and tissue inhibitor of metalloproteinases-1 (TIMP-1), S100 proteins, complement C3, and PTX3 in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Although these biomarkers provide mechanistic insight, most lack disease-specificity, external validation, or standardized assays. Future progress will require multicenter studies, harmonized testing, and integrated biomarker panels combined with imaging modalities to improve diagnosis, activity assessment, and monitoring. Full article

Background/Objectives: Osteoarthritis (OA) is a pervasive chronic joint disease characterized by the triad of persistent articular cartilage degeneration, debilitating synovial inflammation, and sustained chronic pain. Although salmon nasal cartilage proteoglycan (SPG) is recognized for supporting joint health, the precise molecular mechanism underlying its effects during OA progression remains to be fully elucidated. This study evaluated the therapeutic efficacy of SPG using a monosodium iodoacetate (MIA)-induced mouse model. Methods: A total of 180 male C57BL/6J mice (six-week-old) were utilized, organized into three independent cohorts to analyze distinct analytical endpoints: (1) pain assessment, histology, and immunohistochemistry; (2) mRNA expression analysis for early-stage OA (Day 3); and (3) mRNA expression analysis for the late-stage OA (Day 28). All subjects received daily oral treatment via gavage, commencing 5 days prior to OA induction and continuing until the designated experimental termination points (either Day 3 or Day 28). Each cohort comprised five experimental groups (n = 10–12 per group): a saline-injected Sham group, an MIA-induced Control group, a positive comparator receiving celecoxib (CLX, 20 mg/kg/day), and two groups administered SPG at a dose of 50 or 100 mg/kg/day. Results: Our findings demonstrated that SPG, particularly at the 100 mg/kg dose, significantly mitigated joint pain symptoms, performing comparably to CLX. Histopathological assessments confirmed that SPG effectively preserved the structural integrity of the cartilage matrix and substantially reduced pathological damage, as evidenced by lower Mankin scores. Mechanistically, SPG treatment led to a marked downregulation of degradative enzymes, including matrix metalloproteinase-3 (MMP-3) and a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4), while concurrently normalizing the levels of tissue inhibitors of metalloproteinases (TIMPs). Furthermore, SPG prevented the aberrant, over-compensatory expression of anabolic markers such as SRY-box transcription factor 9 (SOX-9), type II collagen alpha 1 chain (COL2A1), and aggrecan (ACAN) typically observed in the disease’s later stages. While SPG demonstrated a limited impact on broadly pro-inflammatory cytokine profiles, it specifically and significantly reduced interleukin-6 (IL-6) gene expression during the chronic phase. Conclusions: These results suggest that SPG serves as a promising natural agent that maintains articular homeostasis by balancing matrix metabolic pathways, positioning it as a scientifically validated functional food candidate for the management of joint health. Full article

Background: Matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs), regulate the extracellular matrix. This study examined messenger RNA transcripts of TIMP2 before and after kidney transplantation. Methods: Transcripts were measured in peripheral blood mononuclear cells from 105 kidney transplant recipients, including AB0-incompatible, AB0-compatible, and deceased donor transplantation patients. Quantitative real-time polymerase chain reaction was utilized. Results: Kidney transplant recipients (72 male; 33 female) were a median of 55 (44–63) years old. The median (interquartile range) of pretransplant TIMP2 transcripts was 0.68 (0.50–0.87) in kidney transplant recipients. In total, 9 out of 72 patients (13%) showed delayed graft function, i.e., need for dialysis within 1 week after transplantation. Preoperative TIMP2 transcripts were significantly lower in kidney transplant recipients who experienced delayed graft function compared to patients with immediate graft function (0.40 (0.32–0.62) vs. 0.68 (0.56–0.87); p = 0.01). There was no association between TIMP2 transcripts and age or gender. TIMP2 median transcripts were 0.73 (0.58–0.88) on the first postoperative day. TIMP2 transcripts were similar on the first postoperative day in patients with delayed graft function and immediate graft function. Conclusions: Preoperative TIMP2 transcripts were lower in patients with delayed allograft function. Future investigations are needed to establish the role of TIMP2 transcripts in transplant pathophysiology. Full article

This study aimed to explore the association between genetic variants of matrix metalloproteinases (MMP-1 rs1799750, MMP-9 rs17576, and rs17577) and their tissue inhibitors (TIMP-1 rs4898, TIMP-2 rs2277698, and rs55743137) in the development of bronchopulmonary dysplasia (BPD) in infants from a Polish population. Methods: A cohort consisting of 100 premature infants (47% female) was analyzed, in which there were 38 BPD cases and 62 controls without BPD. Genotype distributions were analyzed, and their relationship with BPD risk was assessed after adjustment for potential confounders. Results: Application of Bonferroni correction for multiple testing showed that none of the single-nucleotide polymorphisms (SNPs) reached the adjusted significance threshold (p < 0.008). However, analysis of allele frequencies using adjusted p-values identified a statistically significant difference for MMP1 rs17999750 (p = 0.038). Conclusion: These findings do not support a significant role of TIMP-2 and MMP-9 genetic variations in the pathogenesis of BPD among preterm infants. While these results are informative, a limitation of this study is the small sample size, and larger studies are needed to confirm these observations. Full article

Background/Objectives: Early detection of pancreatic ductal adenocarcinoma (PDAC) can improve patient survival and biomarkers to facilitate this are greatly needed. We recently reported a serum biomarker signature comprising tissue inhibitor of metalloproteinase 1 (TIMP1), intercellular adhesion molecule 1 (ICAM1), cathepsin D (CTSD), thrombospondin 1 (TSP1/THBS1), and carbohydrate antigen 19-9 (CA 19-9), that detected Stage I and II PDAC with high sensitivity and specificity. In this assay, CA 19-9 is measured with a commercial instrument and individual ELISAs were developed to measure TIMP1, ICAM1, CTSD, and THBS1. Here, we report the analytical performance of these four analytes in their ELISA formats. Methods: Biomarker precision, linearity, algorithm precision, matrix effects, hook effect, method comparison, interference, and analyte stability were evaluated against acceptance criteria per CLSI guidelines. Results: High, medium, and low concentrations of each biomarker met acceptance criteria for inter- and intra-day precision (%CVs < 14%) and for linearity (%CVs < 11%). Matrix effects did not impact quantitation of any analyte nor was hook effect present. All analytes met acceptance criteria for accuracy and stability (all biases < 11.2% and <16.5%, respectively). For interference, two CTSD measurements and one ICAM1 measurement in HAMA-spiked samples showed 20.7–29% biases, falling slightly outside of acceptance criteria (<20% bias). All other analyte concentrations met interference acceptance criteria. In total, 94.1% of all diagnostic calls were made with 100% certainty, indicating high precision of the assay’s algorithm. Conclusions: All analytes demonstrated acceptable analytical precision, linearity, accuracy, and stability, showing high overall analytical performance of each analyte. Full article

The premetastatic niche (PMN) represents a specialized microenvironment established in distant organs before the arrival of metastatic cells. This concept has fundamentally altered our understanding of cancer progression, shifting it from a random event-driven process to an orchestrated one. This review examines the critical role of extracellular proteases in PMN formation, focusing on matrix metalloproteinases (MMPs), serine proteases, and cysteine cathepsins that collectively orchestrate extracellular matrix remodeling, immune modulation, and vascular permeability changes essential for metastatic colonization. Key findings demonstrate that MMP9 and MMP2 facilitate basement membrane degradation and the recruitment of bone marrow-derived cells. At the same time, tissue inhibitor of metalloproteinase-1 (TIMP-1) promotes organ-specific hepatic PMN recruitment through neutrophil recruitment mechanisms. The plasminogen–plasmin system emerges as a master regulator through its broad-spectrum proteolytic activity and ability to activate downstream proteases, with S100A10-mediated plasmin generation providing mechanistic pathways for remote PMN conditioning. Neutrophil elastase and cathepsin G contribute to the degradation of anti-angiogenic proteins, thereby creating pro-metastatic microenvironments. These protease-mediated mechanisms represent the earliest interventional window in metastatic progression, offering therapeutic potential to prevent niche formation rather than treat established metastases. However, significant methodological challenges remain, including the need for organ-specific biomarkers, improved in vivo methods for measuring protease activity, and a better understanding of temporal PMN dynamics across different target organs. Full article

Inguinal hernia represents a multifactorial condition driven by extracellular matrix (ECM) dysregulation, collagen imbalance, and oxidative stress. Across studies, a consistent reduction in the collagen I:III ratio, coupled with altered expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), underpins weakened fascia and hernia susceptibility. Aging further impairs ECM remodeling through fibroblast senescence, cross-linking deficits, and elastic fiber attrition, while oxidative stress and inflammation amplify tissue degradation and impair repair mechanisms. Evidence from clinical and experimental studies underscores the interplay between surgical technique, mesh choice, redox balance, and recurrence risk. Understanding the combined impact of aging and oxidative stress provides a mechanistic framework for targeted therapeutic and surgical strategies aimed at preventing hernia development and recurrence. Full article

Wound healing is a complex process involving coordinated actions of multiple cell types. Therefore, when developing therapeutics to promote wound healing, it is essential to consider the synergistic contributions of various cells at different stages of the healing process. In this study, we evaluated the potential of different extracts of Botryocladia leptopoda as wound-healing agents by examining their effects on antioxidant activity, cytotoxicity, cell migration, anti-inflammatory properties, and expressions of specific biomarkers associated with wound healing. Results indicated that the ethanol extract (FE) and hexane extract (HE) exhibited the highest DPPH radical scavenging activity, reaching up to 94%. The alkaline extract (AE) showed the strongest antioxidant ability in the FICA assay, with a maximum of 99%. In addition, the FE and AE provided anti-inflammatory actions that inhibited tumor necrosis factor (TNF)-α and interleukin (IL)-6 in lipopolysaccharide (LPS)-treated RAW 264.7 cells. Further analyses suggested that the FE and AE enhanced cell proliferation (210% and 112%) and migration (442.2% and 535.6%) and regulated wound healing-related genes, including matrix metalloproteinase 2, MMP9, and tissue inhibitor of metalloproteinase 2 (TIMP2) to avoid scar formation and accelerate wound healing. Lastly, the identification of potential compounds within the extract using the UHPLC system further supports its prospective medical applications. Taken together, these findings indicated that the FE and AE from B. leptopoda exhibited remarkable in vitro wound-healing properties, highlighting their potential for applications in pharmaceutical industries and health food development. Full article

Age-related changes in facial ligaments contribute to altered facial shape and soft tissue descent. Radiofrequency (RF) has been utilized for skin rejuvenation by promoting collagen fiber contraction and synthesis through increased expression of heat shock proteins (HSPs). The primary component of ligamentous collagen fibers undergoes structural modifications with age, exhibiting increased fragmentation and a reduced collagen type I/III ratio. This study aimed to investigate whether RF irradiation alleviates senescence-related changes in facial ligaments through HSP70-mediated molecular remodeling using a UV-induced photoaging rat model. In senescent fibroblasts, RF enhanced the interaction between HSP70 and IκBα kinase (IKK)γ while reducing IκBα phosphorylation, which was associated with decreased nuclear factor-kappa B (NF-κB) activation. These RF-mediated changes were attenuated by an HSP70 inhibitor, suggesting that RF reduces NF-κB activity via HSP70 modulation. RF also suppressed expression levels of matrix metalloproteinases and SMAD7 in senescent fibroblasts. Consistent with in vitro findings, RF increased the interaction between HSP70 and IKKγ while decreasing IκBα phosphorylation and NF-κB activity in the UV-induced photoaging (senescent) facial ligaments of rat models. Furthermore, RF enhanced the collagen type I/III ratio and increased collagen fiber density within the ligaments. Scanning electron microscopy revealed that RF irradiation increased collagen fiber bundle diameter and enhanced the helical structure of those fibers. Overall, RF mitigates senescence-related changes in facial ligaments through HSP70 modulation. Considering that facial ligament laxity contributes to soft tissue descent, facial ligament-targeting approaches may promote a more youthful facial structure. RF demonstrates the possibility in reducing senescence-associated changes within facial ligaments. Full article

Matrix metalloproteinase-9 (MMP-9) is a zinc-dependent endopeptidase that plays a central role in extracellular matrix (ECM) remodeling, angiogenesis, immune cell trafficking, and cytokine activation. Dysregulated MMP-9 activity has been implicated in the pathogenesis of diverse conditions, including atherosclerosis, aneurysm formation, chronic obstructive pulmonary disease (COPD), asthma, neurodegeneration, and malignancy. Although broad-spectrum synthetic MMP inhibitors were initially developed as therapeutic agents, clinical trials failed due to lack of selectivity, poor tolerability, and impairment with physiological tissue repair. This outcome has shifted attention toward indirect pharmacological modulation of MMP-9 using drugs that are already approved for other indications. In this paper, we review the evidence supporting MMP-9 modulation by established therapeutics and adjunctive strategies. Cardiometabolic agents such as statins, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), metformin, and pioglitazone reduce MMP-9 expression and enzymatic activity, contributing to vascular protection, improved insulin sensitivity, and attenuation of aneurysm progression. Anti-inflammatory and respiratory drugs, including glucocorticoids, phosphodiesterase-4 (PDE4) inhibitors, macrolide antibiotics, montelukast, and nonsteroidal anti-inflammatory drugs (NSAIDs), suppress MMP-9-driven airway inflammation and pathological tissue remodeling in asthma, COPD, and acute lung injury. Tetracycline derivatives, particularly sub-antimicrobial dose doxycycline, directly inhibit MMP-9 activity and are clinically validated in the treatment of periodontal disease and vascular remodeling. Hormone-related therapies such as rapamycin, estradiol, and tamoxifen exert tissue- and disease-specific effects on MMP-9 within endocrine and oncologic pathways. In parallel, nutritional interventions—most notably omega-3 polyunsaturated fatty acids and antioxidant vitamins—provide adjunctive strategies for mitigating MMP-9 activity in chronic inflammatory states. Taken together, these findings position MMP-9 as a modifiable and clinically relevant therapeutic target. The systematic integration of approved pharmacologic agents with lifestyle and nutritional interventions into disease-specific treatment paradigms may facilitate safer, context-specific modulation of MMP-9 activity and unveil novel opportunities for therapeutic repurposing. Full article

Background: The human acellular amniotic membrane (HAAM) is widely used as a decellularized bioscaffold in tissue engineering to promote wound healing, but its clinical application is limited by poor mechanical properties, rapid degradation, and handling difficulties. This study aimed to develop a modified amniotic membrane-based composite material loaded with vascular endothelial growth factor (VEGF) and the Notch signaling inhibitor N-[N-(3,5-difluorophenacetyl)-Lalanylhydrazide]-Sphenylglycine t-butyl ester (DAPT) to enhance wound healing by modulating macrophage polarization and cytokine secretion. Methods: VEGF-loaded gellan gum-hyaluronic acid (GG-HA) hydrogels (VEGF-GG-HA) and DAPT-loaded HAAM (DAPT-HAAM) were prepared and combined to form a novel composite material (VEGF-GG-HA & DAPT-HAAM). The morphology and microstructure of the materials were characterized using scanning electron microscopy. In vitro studies were conducted using the human monocytic cell line (Tohoku Hospital Pediatrics-1, THP-1) to evaluate the effects of the materials on cell viability, cytokine secretion, and protein expression. Assessments included CCK-8 assays, ELISA, quantitative real-time PCR, Western blot analysis, and immunohistochemical staining. Results: The composite material VEGF-GG-HA & DAPT-HAAM exhibited good biocompatibility and significantly promoted THP-1 cell proliferation compared to control and single-component groups. It enhanced the secretion of IL-10, TNF-α, TGF-β, MMP1, and MMP3, while suppressing excessive TGF-β overexpression. The material also modulated macrophage polarization, showing a trend toward anti-inflammatory M2 phenotypes while maintaining pro-inflammatory signals (e.g., TNF-α) for a balanced immune response. Conclusions: The modified amniotic membrane hydrogel composite promotes wound healing through a phased immune response: it modulates macrophage polarization (balancing M1 and M2 phenotypes), enhances cytokine and matrix metalloproteinase secretion, and controls TGF-β levels. These effects contribute to improved vascular remodeling, reduced fibrosis, and prevention of scar formation, demonstrating the potential for enhanced wound management. Full article

Glioblastoma (GB) is the most aggressive form of brain cancer. However, despite intensive intervention, GB almost invariably recurs due to the highly invasive nature of its tumor cells, which infiltrate surrounding healthy brain tissue, underscoring the urgent need for more effective therapies. One such approach could be based on targeting matrix metalloproteinase-9 (MMP-9), an enzyme that plays a crucial role in GB progression and is closely associated with enhanced invasiveness and poor prognosis. Previously, we engineered a potent and selective MMP-9 inhibitor derived from the N-terminal domain of the endogenous tissue inhibitor of metalloproteinases-2 (N-TIMP2). In this study, we evaluate the efficacy and toxicity of this engineered N-TIMP2 variant (REY) in adult GB U251 and normal Vero cells using multiple in vitro assays. Our results demonstrate that REY significantly inhibits colony formation and cell invasion, and markedly reduces spheroid spreading at nanomolar concentrations. Importantly, the engineered variant, which is highly specific for MMP-9, consistently outperforms the wild-type N-TIMP2, which broadly targets multiple MMPs, and exhibits no cytotoxicity toward healthy cells. Together, these findings support MMP-9 as a viable therapeutic target in GB and highlight the potential of our engineered N-TIMP2 variant as a promising candidate for further therapeutic development. Full article