RESUMEN

Marfan syndrome (MFS) is a hereditary condition accompanied by disorders in the structural and regulatory properties of connective tissue, including elastic fibers, due to a mutation in the gene encodes for fibrillin-1 protein (FBN1 gene) and the synthesis of abnormal fibrillin-1 glycoprotein. Despite the high potential of mast cells (MCs) to remodel the extracellular matrix (ECM), their pathogenetic significance in MFS has not been considered yet. The group of patients with Marfan syndrome included two mothers and five children (three girls aged 4, 11, and 11 and two boys aged 12 and 13). Normal skin was examined in two children aged 11 and 12. Histochemical, monoplex, and multiplex immunohistochemical techniques; combined protocols of simultaneous histochemical and immunohistochemical staining (the results of staining were assessed using light, epifluorescence, and confocal microscopy); and bioinformatics algorithms for the quantitative analysis of detected targets were used to evaluate mast cells and their relationship with other cells from extracellular structures in the skin dermis. Analysis of the skin MC population in children with Marfan syndrome revealed a considerably increased number of intra-organic populations with the preservation of the specific Tryptase+Chymase+CPA3+ protease profile typical of the skin. The features of the MC histotopography phenotype in MFS consisted of closer colocalization with elastic fibers, smooth muscle cells, and fibroblasts. MCs formed many intradermal clusters that synchronized the activity of cell functions in the stromal landscape of the tissue microenvironment with the help of spatial architectonics, including the formation of cell chains and the creation of fibrous niches. In MCs, the expression of specific proteases, TGF-ß, and heparin increased, with targeted secretion of biologically active substances relative to the dermal elastic fibers, which had specific structural features in MFS, including abnormal variability in thickness along their entire length, alternating thickened and thinned areas, and uneven surface topography. This paper discusses the potential role of MCs in strain analysis (tensometry) of the tissue microenvironment in MFS. Thus, the quantitative and qualitative rearrangements of the skin MC population in MFS are aimed at altering the stromal landscape of the connective tissue. The results obtained should be taken into account when managing clinical signs of MFS manifested in other pathogenetically critical structures of internal organs, including the aorta, tendons, cartilage, and parenchymal organs.

Asunto(s)

Dermis , Tejido Elástico , Síndrome de Marfan , Mastocitos , Humanos , Síndrome de Marfan/metabolismo , Síndrome de Marfan/patología , Síndrome de Marfan/genética , Mastocitos/metabolismo , Mastocitos/patología , Niño , Masculino , Femenino , Tejido Elástico/metabolismo , Tejido Elástico/patología , Preescolar , Dermis/patología , Dermis/metabolismo , Adolescente , Fibrilina-1/metabolismo , Fibrilina-1/genética , Piel/metabolismo , Piel/patología , Matriz Extracelular/metabolismo , Adipoquinas

RESUMEN

Fibronectin (Fn) is a ubiquitous extracellular matrix (ECM) glycoprotein that acts as an ECM scaffold organizer and is essential in many biological functions, including tissue repair, differentiation or cancer dissemination. Evidence suggests that the amount of Fn changes during aging. However, how these changes influence the aging process remains unclear. This study aims to understand Fn influence on cell aging. First, we assess the relative level of Fn abundance in both different biopsies of skin donors and replicative senescence cellular model. In skin biopsies, we observed that Fn level decreases with aging in the reticular dermis, while its expression remains relatively stable in the papillary dermis, likely to sustain the dermis-epidermis junction. During replicative senescence, in BJ skin fibroblasts, while intracellular Fn increases, we found that secretion and Fn fibrils formation are less effective. Reduced Fn fibrils leads to disorganization of the ECM. This could be explained by the expression of different Fn isoforms observed in the secretome of senescent cells. Surprisingly, the knockdown of Fn delays the onset of senescence while cultivating cells onto a Fn-coated support promotes it. Taken together, these new insights on the role of Fn during aging may emerge new therapeutic strategies on aged-related diseases.

RESUMEN

PURPOSE: To explore the phenotype of sclera macrophages in form-deprivation (FD) myopia mice and the effects of M2 macrophage in FD myopia development. METHODS: C57BL/6 mice were under 2 weeks of unilateral FD treatment. and they were separated into two groups, including an intraperitoneally injected(IP) vehicle group and Panobinostat (LBH589) (10 mg/kg per body weight) treatment group. All biometric parameters were measured before and after treatments, and the type and density of sclera macrophages were identified by immunofluorescence and RT-qPCR. In vitro, we analyzed the M2 macrophage and primary human sclera fibroblast (HSF) co-culture system by using the transcriptome sequencing method. Gene ontology (GO) and KEGG enrichment analyses were used to pinpoint the biological functions and pathways associated with the identified Differentially Expressed Genes (DEGs). The hub genes were investigated using the STRING database and Cytoscape software and were confirmed using RT-qPCR. RESULTS: We found that the M2-type sclera macrophage density and expression increased in FD-treated eyes. The results showed that LBH589 inhibited the M2 macrophage polarization, and reduced FDM development. GO and KEGG analyses revealed that the DEGs were predominantly involved in the synthesis and breakdown of the extracellular matrix (ECM), as well as in pathways related to ECM-receptor interaction and the PI3K-Akt signaling pathway. Five hub genes (FN-1, MMP-2, COL1A1, CD44, and IL6) were identified, and RT-qPCR validated the variation in expression levels among these genes. CONCLUSION: M2 macrophage polarization occurred in the sclera in FDM mice. Panobinostat-mediated inhibition of M2 macrophage polarization may decrease FDM progression, as M2 macrophages are crucial in controlling ECM remodeling by HSFs.

RESUMEN

Background: Hepatocellular carcinoma accounts for 80% of primary liver cancers, is the most common primary liver malignancy. Hepatocellular carcinoma is the third leading cause of tumor-related deaths worldwide, with a 5-year survival rate of approximately 18%. Chemotherapy, although commonly used for hepatocellular carcinoma treatment, is limited by systemic toxicity and drug resistance. Improving targeted delivery of chemotherapy drugs to tumor cells without causing systemic side effects is a current research focus. Chitosan, a biopolymer derived from chitin, possesses good biocompatibility and biodegradability, making it suitable for drug delivery. Enhanced chitosan formulations retain the anti-tumor properties while improving stability. Chitosan-based biomaterials promote hepatocellular carcinoma apoptosis, exhibit antioxidant and anti-inflammatory effects, inhibit tumor angiogenesis, and improve extracellular matrix remodeling for enhanced anti-tumor therapy. Methods: We summarized published experimental papers by querying them. Results and Conclusions: This review discusses the physicochemical properties of chitosan, its application in hepatocellular carcinoma treatment, and the challenges faced by chitosan-based biomaterials.

RESUMEN

The absence of dystrophin protein causes cardiac dysfunction in boys with Duchenne Muscular Dystrophy (DMD). However, the common mouse model of DMD (B10-mdx) does not manifest cardiac deficits until late adulthood limiting our understanding of the mechanism and therapeutic approaches to target the pediatric-onset cardiac pathology in DMD. We show the mdx mouse model on the DBA/2J genetic background (D2-mdx) displays juvenile-onset cardiomyopathy. Molecular and histological analysis revealed heightened leukocyte chemotactic signaling and failure to resolve inflammation, leading to chronic inflammation and extracellular matrix (ECM) fibrosis, causing cardiac pathology in juvenile D2-mdx mice. We show that pharmacologically activating the N-formyl peptide receptor 2 (FPR2) - a receptor that physiologically resolves acute inflammation, mitigated chronic cardiac inflammation and fibrosis, and prevented juvenile onset cardiomyopathy in the D2-mdx mice. These studies offer insights into pediatric onset of cardiac damage in DMD, a new therapeutic target, and identify a drug-based potential therapy.

RESUMEN

CONTEXT: Abnormal endometrial extracellular matrix (ECM) remodeling compromises endometrial receptivity and diminishes the probability of a successful live birth. Serum amyloid A1 (SAA1), a modulator of inflammation, is elevated in the circulation of polycystic ovary syndrome (PCOS) patients and involved in ECM remodeling during tissue repair. However, the specific role of SAA1 in endometrial ECM remodeling and subsequent risk of pregnancy loss in PCOS patients remains unclear. OBJECTIVE: To examine the role and underlying mechanism of SAA1 in ECM remodeling in the endometrium of PCOS patients. DESIGN: Serum samples from PCOS and control patients were utilized to investigate the relationship between the abundance of SAA1 and pregnancy loss. Human endometrial tissues and primary human endometrial stromal cells were used to examine the role and underlying mechanism of SAA1 in ECM remodeling. RESULTS: Serum SAA1 concentration was elevated and could serve as an independent risk of pregnancy loss in PCOS patients. Increased SAA1 abundance was also observed in endometrium obtained from these patients. Further mechanistic studies showed that SAA1 stimulated collagen I chains synthesis (COL1A1 and COL1A2) in endometrial stromal cells, suggesting excessive SAA1 may contribute to endometrial ECM remodeling, resulting in a non-supportive environment for ongoing pregnancy. This effect was abolished by either a toll-like receptors 2/4 antagonist or a nuclear factor κB inhibitor. CONCLUSIONS: The locally elevated levels of SAA1 in endometrium contribute to ECM over-deposition by inducing collagen I synthesis in PCOS patients, which may hamper embryo implantation and increase the risk of pregnancy loss. These observations highlight the crucial role of heightened SAA1 in orchestrating endometrial dysfunction and shed light on potential therapeutic avenues for improving reproductive outcomes in PCOS patients.

RESUMEN

BACKGROUND: Extracellular matrix (ECM) remodeling in skeletal muscle is a significant factor in the development of sarcopenia. This study aims to evaluate changes in ECM remodeling in the lumbar paravertebral muscles of sarcopenic rats using diffusion-tensor magnetic resonance imaging (DT-MRI) and compare them with histology. METHODS: Twenty 6-month-old female Sprague Dawley rats were randomly divided into the dexamethasone (DEX) group and the control (CON) group. Both groups underwent 3.0T MRI scanning, including Mensa, T2WI, and DT-MRI sequences. The changes in muscle fibers and extracellular matrix (ECM) of the erector spinal muscle were observed using hematoxylineosin and sirius red staining. The expressions of collagen I, III, and fibronectin in the erector spinae were detected by western blot. Pearson correlation analysis was employed to assess the correlation between MRI quantitative parameters and corresponding histopathology markers. RESULTS: The cross-sectional area and fractional anisotropy values of the erector spinae in the DEX group rats were significantly lower than those in the CON group (p < 0.05). Hematoxylin eosin staining revealed muscle fiber atrophy and disordered arrangement in the DEX group, while sirius red staining showed a significant increase in collagen volume fraction in the DEX group. The western blot results indicate a significant increase in the expression of collagen I, collagen III, and fibronectin in the DEX group (p < 0.001 for all). Correlation coefficients between fractional anisotropy values and collagen volume fraction, collagen I, collagen III, and fibronectin were - 0.71, -0.94, -0.85, and - 0.88, respectively (p < 0.05 for all). CONCLUSIONS: The fractional anisotropy value is strongly correlated with the pathological collagen volume fraction, collagen I, collagen III, and fibronectin. This indicates that DT-MRI can non-invasively evaluate the changes in extracellular matrix remodeling in the erector spinal muscle of sarcopenia. It provides a potential imaging biomarker for the diagnosis of sarcopenia.

Asunto(s)

Matriz Extracelular , Ratas Sprague-Dawley , Sarcopenia , Animales , Femenino , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Ratas , Sarcopenia/diagnóstico por imagen , Sarcopenia/metabolismo , Sarcopenia/patología , Imagen de Difusión Tensora/métodos , Músculos Paraespinales/diagnóstico por imagen , Músculos Paraespinales/patología , Músculos Paraespinales/metabolismo , Fibronectinas/metabolismo , Modelos Animales de Enfermedad , Dexametasona

RESUMEN

Small-cell lung cancer (SCLC) is the most aggressive and lethal type of lung cancer, characterized by limited treatment options, early and frequent metastasis. However, the determinants of metastasis in SCLC are poorly defined. Here, we show that estrogen-related receptor gamma (ERRγ) is overexpressed in metastatic SCLC tumors, and is positively associated with SCLC progression. ERRγ functions as an essential activator of extracellular matrix (ECM) remodeling and cell adhesion, two critical steps in metastasis, by directly regulating the expression of major genes involved in these processes. Genetic and pharmacological inhibition of ERRγ markedly reduces collagen production, cell-matrix adhesion, microfilament production, and eventually blocks SCLC cell invasion and tumor metastasis. Notably, ERRγ antagonists significantly suppressed tumor growth and metastasis and restored SCLC vulnerability to chemotherapy in multiple cell-derived and patient-derived xenograft models. Taken together, these findings establish ERRγ as an attractive target for metastatic SCLC and provide a potential pharmacological strategy for treating this lethal disease.

Asunto(s)

Matriz Extracelular , Neoplasias Pulmonares , Receptores de Estrógenos , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Carcinoma Pulmonar de Células Pequeñas/genética , Matriz Extracelular/metabolismo , Matriz Extracelular/efectos de los fármacos , Animales , Receptores de Estrógenos/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Metástasis de la Neoplasia , Línea Celular Tumoral , Ratones , Adhesión Celular/efectos de los fármacos , Modelos Animales de Enfermedad

RESUMEN

In crowded microenvironments, migrating cells must find or make a path. Amoeboid cells are thought to find a path by deforming their bodies to squeeze through tight spaces. Yet, some amoeboid cells seem to maintain a near-spherical morphology as they move. To examine how they do so, we visualized amoeboid human melanoma cells in dense environments and found that they carve tunnels via bleb-driven degradation of extracellular matrix components without the need for proteolytic degradation. Interactions between adhesions and collagen at the cell front induce a signaling cascade that promotes bleb enlargement via branched actin polymerization. Large blebs abrade collagen, creating feedback between extracellular matrix structure, cell morphology, and polarization that enables both path generation and persistent movement.

RESUMEN

Extracellular matrix (ECM) remodeling is strongly linked to Alzheimer's disease (AD) risk; however, the underlying mechanisms are not fully understood. Here, it is found that the injection of chondroitinase ABC (ChABC), mimicking ECM remodeling, into the medial prefrontal cortex (mPFC) reversed short-term memory loss and reduced amyloid-beta (Aß) deposition in 5xFAD mice. ECM remodeling also reactivated astrocytes, reduced the levels of aggrecan in Aß plaques, and enhanced astrocyte recruitment to surrounding plaques. Importantly, ECM remodeling enhanced the autophagy-lysosome pathway in astrocytes, thereby mediating Aß clearance and alleviating AD pathology. ECM remodeling also promoted Aß plaque phagocytosis by astrocytes by activating the astrocytic phagocytosis receptor MERTK and promoting astrocytic vesicle circulation. The study identified a cellular mechanism in which ECM remodeling activates the astrocytic autophagy-lysosomal pathway and alleviates AD pathology. Targeting ECM remodeling may represent a potential therapeutic strategy for AD and serve as a reference for the treatment of this disease.

Asunto(s)

Enfermedad de Alzheimer , Astrocitos , Autofagia , Modelos Animales de Enfermedad , Matriz Extracelular , Lisosomas , Trastornos de la Memoria , Animales , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Astrocitos/metabolismo , Ratones , Matriz Extracelular/metabolismo , Lisosomas/metabolismo , Trastornos de la Memoria/metabolismo , Ratones Transgénicos , Masculino

RESUMEN

Chronic inflammatory lung diseases are characterized by disease-specific extracellular matrix accumulation resulting from an imbalance of matrix metalloproteinases (MMPs) and their inhibitors. Zinc is essential for the function of MMPs, and zinc deficiency has been associated with enhanced tissue remodeling. This study assessed if zinc iodide (ZnI) supplementation through dimethyl sulfoxide (DMSO) modifies the action of MMPs in isolated human lung fibroblasts. The expression and activity of two gelatinases, MMP-2 and MMP-9, were determined by gelatin zymography and enzyme-linked immuno-sorbent assay (ELISA). Collagen degradation was determined by cell-based ELISAs. Collagen type I and fibronectin deposition was stimulated by human recombinant tumor growth factor ß1 (TGF-ß1). Untreated fibroblasts secreted MMP-2 but only minute amounts of MMP-9. TGF-ß1 (5 ng/mL) reduced MMP-2 secretion, but stimulated collagen type I and fibronectin deposition. All the effects of TGF-ß1 were significantly reduced in cells treated with ZnI-DMSO over 24 h, while ZnI and DMSO alone had a lower reducing effect. ZnI-DMSO alone did not increase MMP secretion but enhanced the ratio of active to inactive of MMP-2. ZnI alone had a lower enhancing effect than ZnI-DMSO on MMP activity. Furthermore, MMP-2 activity was increased by ZnI-DMSO and ZnI in the absence of cells. Soluble collagen type I increased in the medium of ZnI-DMSO- and ZnI-treated cells. Blocking MMP activity counteracted all the effects of ZnI-DMSO. Conclusion: The data suggest that the combination of ZnI with DMSO reduces fibrotic processes by increasing the degradation of collagen type I by up-regulating the activity of gelatinases. Thus, the combination of ZnI with DMSO might be considered for treatment of fibrotic disorders of the lung. DMSO supported the beneficial effects of ZnI.

RESUMEN

Tissue engineered heart valves (TEHVs) demonstrates the potential for tissue growth and remodel, offering particular benefit for pediatric patients. A significant challenge in designing functional TEHV lies in replicating the anisotropic mechanical properties of native valve leaflets. To establish a biomimetic TEHV model, we employed melt-electrowriting (MEW) technology to fabricate an anisotropic PCL scaffold. By integrating the anisotropic MEW-PCL scaffold with bioactive hydrogels (GelMA/ChsMA), we successfully crafted an elastic scaffold with tunable mechanical properties closely mirroring the structure and mechanical characteristics of natural heart valves. This scaffold not only supports the growth of valvular interstitial cells (VICs) within a 3D culture but also fosters the remodeling of extracellular matrix of VICs. The in vitro experiments demonstrated that the introduction of ChsMA improved the hemocompatibility and endothelialization of TEHV scaffold. The in vivo experiments revealed that, compared to their non-hydrogel counterparts, the PCL-GelMA/ChsMA scaffold, when implanted into SD rats, significantly suppressed immune reactions and calcification. In comparison with the PCL scaffold, the PCL-GelMA/ChsMA scaffold exhibited higher bioactivity and superior biocompatibility. The amalgamation of MEW technology and biomimetic design approaches provides a new paradigm for manufacturing scaffolds with highly controllable microstructures, biocompatibility, and anisotropic mechanical properties required for the fabrication of TEHVs.

Asunto(s)

Válvulas Cardíacas , Hidrogeles , Ratas Sprague-Dawley , Ingeniería de Tejidos , Andamios del Tejido , Ingeniería de Tejidos/métodos , Animales , Andamios del Tejido/química , Anisotropía , Ratas , Hidrogeles/química , Materiales Biocompatibles/química , Prótesis Valvulares Cardíacas , Poliésteres/química , Células Cultivadas , Humanos , Matriz Extracelular/química , Masculino

RESUMEN

We previously reported that extracellular matrix protein 1 isoform a (ECM1a) promotes epithelial ovarian cancer (EOC) through autocrine signaling by binding to cell surface receptors αXß2. However, the role of ECM1a as a secretory molecule in the tumor microenvironment is rarely reported. In this study, we constructed murine Ecm1-knockout mice and human ECM1a-knockin mice and further generated orthotopic or peritoneal xenograft tumor models to mimic the different metastatic stages of EOC. We show that ECM1a induces oncogenic metastasis of orthotopic xenograft tumors, but inhibits early-metastasis of peritoneal xenograft tumors. ECM1a remodels extracellular matrices (ECM) and promotes remote metastases by recruiting and transforming bone marrow mesenchymal stem cells (BMSCs) into platelet-derived growth factor receptor beta (PDGFRß+) cancer-associated fibroblasts (CAFs) and facilitating the secretion of angiopoietin-like protein 2 (ANGPTL2). Competing with ECM1a, ANGPTL2 also binds to integrin αX through the P1/P2 peptides, resulting in negative effects on BMSC differentiation. Collectively, this study reveals the dual functions of ECM1a in remodeling of TME during tumor progression, emphasizing the complexity of EOC phenotypic heterogeneity and metastasis.

Asunto(s)

Proteína 2 Similar a la Angiopoyetina , Fibroblastos Asociados al Cáncer , Proteínas de la Matriz Extracelular , Ratones Noqueados , Neoplasias Ováricas , Microambiente Tumoral , Animales , Femenino , Humanos , Ratones , Proteínas Similares a la Angiopoyetina/metabolismo , Proteínas Similares a la Angiopoyetina/genética , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Carcinoma Epitelial de Ovario/patología , Carcinoma Epitelial de Ovario/metabolismo , Carcinoma Epitelial de Ovario/genética , Línea Celular Tumoral , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Proteínas de la Matriz Extracelular/metabolismo , Proteínas de la Matriz Extracelular/genética , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Metástasis de la Neoplasia , Neoplasias Ováricas/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo

RESUMEN

Matrix metalloproteinase-1 (MMP-1) plays a pivotal role in the pathogenesis of periodontal diseases, particularly periodontitis, by virtue of its collagenolytic activity targeting collagen type I, the primary component of periodontal tissues. This review abstract elucidates the intricate involvement of MMP-1 in periodontal tissue homeostasis and its dysregulation in disease states. Elevated MMP-1 levels, observed in gingival tissues and crevicular fluid of individuals with periodontitis, correlate with the degradation of collagen fibers within the periodontium. This degradation contributes to the detachment of teeth from surrounding tissues and exacerbates alveolar bone resorption, hallmark features of periodontal breakdown. Therapeutically, targeting MMP-1 activity emerges as a promising strategy, prompting ongoing research into MMP inhibitors and host modulation therapies. Understanding MMP-1's nuanced role in periodontal diseases paves the way for personalized treatment approaches and holds promise in reshaping periodontal disease management for improved patient outcomes and periodontal health.

RESUMEN

This study aimed to investigate the changes in oxidative stress, adenosine monophosphate-activated protein kinase (AMPK), connexin43 (Cx43), nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) expression, and extracellular matrix (ECM) in the gastric smooth muscle tissues of rats with diabetic gastroparesis (DGP) and high glucose-cultured gastric smooth muscle cells, determine the existence of oxidative stress-AMPK-Cx43-NLRP3 pathway under high glucose condition, and the involvement of this pathway in ECM remodeling in DGP rats. The results showed that with increasing duration of diabetes, oxidation stress levels gradually increased, the AMPK activity decreased first and then increased, NLRP3, CX43 expression, and membrane/cytoplasm ratio of Cx43 expression were increased in the gastric smooth muscle tissues of diabetic rats. Changes in ECM of gastric smooth muscle cells were observed in DGP rats. The DGP group showed higher collagen type I content, increased expression of Caspase-1, transforming growth factor-beta 3 (TGF-ß3), and matrix metalloproteinase-2 (MMP-2), decreased tissue inhibitor of metalloproteinase-1 (TIMP-1) expression, and higher interleukin-1 beta content when compared with the control group. For gastric smooth muscle cells cultured under higher glucose, the MMP-2 and TGF-ß3 expression was decreased, TGF-ß1 and TIMP-1 expression was increased, the interleukin-1 beta content was decreased in cells after inhibition of NLRP3 expression; the NLRP3 and Caspase-1 expression was decreased, and adenosine triphosphate content was lower after inhibition of Cx43; the expression of NLRP3, Caspase-1, P2X7, and the membrane/cytoplasm ratio of CX43 expression was decreased in cells after inhibition of AMPK and oxidative stress, the phospho-AMPK expression was also decreased after suppressing oxidative stress. Our findings suggest that high glucose induced the activation of the AMPK-Cx43-NLRP3 pathway through oxidative stress, and this pathway was involved in the ECM remodeling of gastric smooth muscles in DGP rats by regulating the biological functions of TGF-ß3, TGF-ß1, MMP-2, and TIMP-1.

Asunto(s)

Proteínas Quinasas Activadas por AMP , Conexina 43 , Diabetes Mellitus Experimental , Matriz Extracelular , Gastroparesia , Miocitos del Músculo Liso , Proteína con Dominio Pirina 3 de la Familia NLR , Estrés Oxidativo , Transducción de Señal , Animales , Masculino , Ratas , Proteínas Quinasas Activadas por AMP/metabolismo , Conexina 43/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/patología , Matriz Extracelular/metabolismo , Gastroparesia/metabolismo , Gastroparesia/patología , Glucosa/metabolismo , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ratas Sprague-Dawley , Estómago/patología

RESUMEN

Fibroblast activation protein (FAP) is a known promoter of tumor development and is associated with poor clinical outcome for various cancer types. Being specifically expressed in pathological conditions including multiple types of fibrosis and cancers, FAP is an optimal target for diagnostics and treatment. Treatment strategies utilizing the unique proteolytic activity of FAP are emerging, thus emphasizing the importance of biomarkers to directly assess FAP activity. FAP is a type II transmembrane serine protease that has been shown to cleave collagens and other ECM components. In this study, we developed an ELISA assay (C3F) targeting a circulating type III collagen fragment derived from FAP cleavage to reflect FAP activity. We demonstrated that C3F was specific to the neoepitope of the cleavage site and that the fragment was generated through FAP cleavage of type III collagen. We measured C3F in serum from a cohort of patients with non-small cell lung cancer (NSCLC) (n = 109) matched to healthy subjects (n = 42) and a cohort of patients with spondyloarthritis (SpA) (n = 17) matched to healthy subjects (n = 19). We found that C3F was significantly elevated in patients with NSCLC and in patients with SpA compared to healthy controls (p < 0.0001 and p = 0.0015, respectively). These findings suggest that C3F is a promising non-invasive biomarker reflecting FAP activity, which may aid in understanding tumor heterogeneity and potentially FAP-targeted therapies.

RESUMEN

Aging is a primary risk factor for degenerative tendon injuries, yet the etiology and progression of this degeneration is poorly understood. While aged tendons have innate cellular differences that support a reduced ability to maintain mechanical tissue homeostasis, the response of aged tendons to altered levels of mechanical loading has not yet been studied. To address this question, we subjected young and aged murine flexor tendon explants to various levels of in vitro tensile strain. We first compared the effect of static and cyclic strain on matrix remodeling in young tendons, finding that cyclic strain is optimal for studying remodeling in vitro. We then investigated the remodeling response of young and aged tendon explants after 7 days of varied mechanical stimulus (stress-deprivation, 1%, 3%, 5%, or 7% cyclic strain) via assessment of tissue composition, biosynthetic capacity, and degradation profiles. We hypothesized that aged tendons would show muted adaptive responses to changes in tensile strain and exhibit a shifted mechanical setpoint, at which the remodeling balance is optimal. Interestingly, we found 1% cyclic strain best maintains native physiology while promoting ECM turnover for both age groups. However, aged tendons display fewer strain-dependent changes, suggesting a reduced ability to adapt to altered levels of mechanical loading. This work has significant impact in understanding the regulation of tissue homeostasis in aged tendons, which can inform clinical rehabilitation strategies for treating elderly patients.

RESUMEN

Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer (LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha (FAPα) expression in LNM-CRC cells. Gain- or loss-function experiments demonstrated that FAPα enhanced tumor cell migration, invasion, epithelial-mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAPα in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis (CRCLNM). Z-GP-DAVLBH, a FAPα-activated prodrug, inhibited CRCLNM by targeting FAPα-positive LNM-CRC cells. Our study highlights the role of FAPα in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM.

RESUMEN

Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer (LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha (FAPα) expression in LNM-CRC cells. Gain- or loss-function experiments demonstrated that FAPα enhanced tumor cell migration, invasion, epithelial-mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAPα in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis (CRCLNM). Z-GP-DAVLBH, a FAPα-activated prodrug, inhibited CRCLNM by targeting FAPα-positive LNM-CRC cells. Our study highlights the role of FAPα in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM.

RESUMEN

The structural and biomechanical properties of collagen-rich ocular tissues, such as the sclera, are integral to ocular function. The degradation of collagen in such tissues is associated with debilitating ophthalmic diseases such as glaucoma and myopia, which often lead to visual impairment. Collagen mimetic peptides (CMPs) have emerged as an effective treatment to repair damaged collagen in tissues of the optic projection, such as the retina and optic nerve. In this study, we used atomic force microscopy (AFM) to assess the potential of CMPs in restoring tissue stiffness in the optic nerve head (ONH), including the peripapillary sclera (PPS) and the glial lamina. Using rat ONH tissue sections, we induced collagen damage with MMP-1, followed by treatment with CMP-3 or vehicle. MMP-1 significantly reduced the Young's modulus of both the PPS and the glial lamina, indicating tissue softening. Subsequent CMP-3 treatment partially restored tissue stiffness in both the PPS and the glial lamina. Immunohistochemical analyses revealed reduced collagen fragmentation after MMP-1 digestion in CMP-3-treated tissues compared to vehicle controls. In summary, these results demonstrate the potential of CMPs to restore collagen stiffness and structure in ONH tissues following enzymatic damage. CMPs may offer a promising therapeutic avenue for preserving vision in ocular disorders involving collagen remodeling and degradation.

Asunto(s)

Disco Óptico , Animales , Disco Óptico/metabolismo , Esclerótica/metabolismo , Roedores/metabolismo , Metaloproteinasa 1 de la Matriz/metabolismo , Colágeno/metabolismo , Presión Intraocular , Fenómenos Biomecánicos