Alterations in the genes involved in the creation of the extracellular matrix (ECM) were observed in our earlier transcriptome studies of sarcoids and their cell culture model. For a complete characterization of the underlying molecular pathways, it is imperative to comprehend the involvement of ECM modifications in the oncogenic transformation of sarcoid fibroblasts. Thus, the aim of this investigation was to describe the expression patterns of a set of genes that are essential for the rearrangements of the extracellular matrix, namely collagen genes, and elucidate possible mechanisms underlying the observed disruptions. To this end, we applied the RT-qPCR method on BPV-negative skin samples and sarcoid samples (n = 6 and 7; respectively) to perform relative quantification of the expression level of eight genes belonging to the collagen family and carried out an integrative analysis of the obtained data with previously characterized epigenetic signatures. The results showed aberrations in the level of chosen collagen genes in the sarcoids compared to the control, manifesting in their elevated levels in the tumor samples (p-value≤0.05). The upregulation of Col1A2, Col11A1, Col6A3, Col5A2, Col4A1, Col6A6, Col5A1, Col6A2 genes was detected in sarcoid samples. The identified changes were statistically significant (p-value≤0.05) and ranged from 1.43 (Col6A2) to 1.88 (Col6A3). Further investigation into the potential involvement of epigenetic mechanisms in the regulation of collagen gene levels in sarcoids revealed compelling evidence of DNA methylation and microRNAs playing significant roles. The findings suggest a complex interplay between gene expression, epigenetic regulation, and the dysregulation of the ECM in sarcoid pathogenesis.

Tissue engineering and regenerative medicine approaches seek to enhance biomaterial mimicry with the goal of driving cell recruitment, proliferation, and differentiation. Decellularized extracellular matrix (dECM) biomaterials have emerged as a promising platform for biomaterials development as they capture the complexity of native tissues and offer a rich environment of signals to guide cellular responses. However, the decellularization process can affect both the structure and composition of the ECM. Recent efforts have focused on leveraging dECM as drug delivery carriers for controlled release of bioactive molecules. This review highlights current strategies for incorporating therapeutic agents into dECM which include encapsulation within hydrogel formulations, direct bulk absorption of biomolecules, and affinity-based binding and conjugation. Each method offers unique advantages for modulating release profiles, which can range from rapid initial burst to prolonged, sustained release, depending on factors such as crosslinking density, degradation rate, and specific interactions of biomolecules with dECM components such as glycosaminoglycans.

Cationic nanoparticles (NPs) are emerging as promising carriers for intra-articular drug delivery, particularly for osteoarthritis (OA) where treatment options are limited. However, the clinical translation is challenged by an incomplete understanding of NP interactions within pathological environments. While the influence of the protein coronas on NP behavior has been extensively studied, the specific role of glycoproteins in the extracellular matrix (ECM) remains underexplored, representing a significant knowledge gap. This study investigates how glycosylation-driven interactions between polymeric NPs and enzyme-degraded cartilage biomolecules such as glycosaminoglycans (GAGs) affect NP-ECM aggregate formation and subsequent inflammatory responses. Using an ex vivo model of cartilage degradation induced by catabolic enzymes- hyaluronidase, ADAMTS5 and collagenase- a novel model system was developed to specifically study the behavior of small (<10 nm) and large (∼270 nm) cationic NPs in glycoprotein-enriched environments. Atomic force microscopy and dynamic light scattering revealed distinct mesh-like structures formed by the NP aggregates following different enzymatic treatments, confirming the adsorption of glycosylated fragments onto the particles. While total protein content showed minimal differences between NP samples, smaller NPs demonstrated a prominent association with GAGs such as hyaluronic acid and aggrecan, as demonstrated by circular dichroism. These ECM-NP interactions significantly influenced the immunological response, as evidenced by differential cytokine production from macrophages exposed to the aggregates. Our findings underscore the crucial, yet underappreciated, role of glycoproteins in determining NP behavior in pathological environments. Accounting for glycoprotein interactions into the design of nanomaterial and drug delivery systems could significantly improve therapeutic outcomes by enhanced targeting precision, optimized delivery, and effectively modulating immune responses in OA and other complex diseases.

Matrix metalloproteinases (MMPs), including MMP9, play a significant role in colorectal cancer (CRC) progression, mainly by extracellular matrix remodeling. However, little is known about MMP9 role in aberrant crypt foci (ACF) cluster formation, the earliest colon preneoplastic lesions.

We conducted a bioinformatics analysis of MMPs expression in CRC using Gene Expression Profiling Interactive Analysis2 (GEPIA2). Subsequently, we investigated MMP9 expression during the early stage of colon carcinogenesis in mice and assessed the effect of doxycycline (DOX), a global inhibitor of MMPs, on ACF cluster formation. Thus, NMRI mice received two weekly injections of 1,2-Dimethylhydrazine (DMH, 20 mg/kg, subcutaneously), followed or not by DOX (100 mg/kg, orally, from the 4th to the 6th week).

GEPIA2 analysis indicated that among the 28 identified MMPs with collagenase and doxycycline-sensitive activities, MMPs 1, 3, 7, 9, and 13 were overexpressed in CRC tissues. Moreover, only MMP1 and MMP9 correlated well with collagen expression in colorectal tumors. In vivo, methylene blue-stained DMH-treated colons revealed multiple ACF clusters at week 6, associated with mucosa remodeling and sustained nitrosative stress as attested by enhanced collagen fibers, malondialdehyde level, and nitrotyrosine deposits. Pyrosequencing showed increased methylation at the tenth CpG site of the MMP9 promoter, which was associated with increased MMP9 expression. Interestingly, DOX attenuated the number and size of ACF clusters and mucosa remodeling without rebalancing nitrosative stress.

Overexpression of MMP9 occurs early during colorectal carcinogenesis, and doxycycline may control the pathological remodeling of colon mucosa into ACF clusters by attenuating MMP9 activity.

Hypoxia is a critical microenvironmental condition that plays a major role in driving tumorigenesis and cancer progression. Increasing evidence has revealed novel functions of hypoxia in intercellular communication. The hypoxia induced tumor derived exosomes (hiTDExs) released in high quantities by tumor cells under hypoxia are packed with unique cargoes that are essential for cancer cells' interactions within their microenvironment. These hiTDExs facilitate not only immune evasion but also promote cancer cell growth, survival, angiogenesis, EMT, resistance to therapy, and the metastatic spread of the disease. Nevertheless, direct interventions targeting hypoxia signaling in cancer therapy face challenges related to tumor progression and resistance, limiting their clinical effectiveness. Therefore, deepening our understanding of the molecular processes through which hiTDExs remodels tumors and their microenvironment, as well as how tumor cells adjust to hypoxic conditions, remains essential. This knowledge will pave the way for novel approaches in treating hypoxic tumors. In this review, we discuss recent work revealing the hiTDExs mediated interactions between tumor and its microenvironment. We have described key hiTDExs cargos (lncRNA, circRNAs, cytokines, etc.) and their targets in the receipt cells, responsible for various biological effects. Moreover, we emphasized the importance of hiTDExs as versatile elements of cell communication in the tumor microenvironment. Finally, we highlighted the effects of hiTDExs on the molecular changes in target cells by executing molecular cargo transfer between cells and altering signaling pathways. Currently, hiTDExs show promise in the treatment of diseases. Understanding the molecular processes through which hiTDExs influence tumor behavior and their microenvironment, along with how tumor cells adapt to and survive in low-oxygen conditions, remains a central focus in cancer research, paving the way for innovative strategies in treating hypoxic tumors and enhancing immunotherapy.

Obesity and type 2 diabetes mellitus (T2DM) are metabolic diseases at epidemic proportions. The economic burden for these diseases is at an all-time high, and as such, there is an urgent need for advancements in identifying targets for treating these complex disorders. The extracellular matrix (ECM), comprising collagen, fibronectin, laminin, elastin, and proteoglycan, surrounds skeletal muscles and plays a critical role in maintaining tissue homeostasis by providing structural support and facilitating cell-to-cell communication. Disruption of the ECM signaling results in changes to its micro/macroenvironment, thereby modifying tissue homeostasis. Skeletal muscle ECM remodeling has been shown to be associated with insulin resistance, an underlying feature of obesity and T2DM. This narrative review explores the critical components of skeletal muscle ECM and its accumulation and remodeling in metabolic diseases. In addition, we discuss potential treatments to mitigate the effects of ECM remodeling in skeletal muscle. We conclude that targeting ECM remodeling in skeletal muscle represents a promising yet underexplored therapeutic avenue in the management of metabolic disorders.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive lymphoma that is isolated in the central nervous system (CNS) or vitreoretinal space. High-dose methotrexate (HD-MTX)-based immunochemotherapy is the frontline for its treatment, with a high early response rate. However, relapsed or refractory (R/R) patients present numerous difficulties and challenges in clinical treatment. Chimeric antigen receptor (CAR)-T cells offer a promising option for the treatment of hematologic malignancies, especially in the R/R B-cell lymphoma and multiple myeloma. Despite the exclusion of most PCNSL cases from pivotal CAR-T cell trials due to their specific tumor microenvironment (TME), available preclinical and clinical studies with small cohorts suggest an overall acceptable safety profile and remarkable anti-tumor effects. In this review, we will provide the development process of CAR-T cells and summarize the research progress, limitations, and future perspectives of CAR-T cell therapy in patients with R/R PCNSL.

Gastrointestinal stromal tumors (GISTs) are a type of tumor that originates from gastrointestinal mesenchymal tissue. Although several somatic or germline mutation GIST mice were established, however, there is still a lack of an authentic mice GIST cell lines for further experimental study.

We developed a chemically induced C57BL/6 J GIST model using 3- methylcholanthrene. Tumor characteristics were confirmed through histology and IHC. Primary cells were isolated to establish the mGSTc01 cell line, and molecular profiling was conducted. Additionally, we established GIST model in immunocompetent mice to evaluate their sensitivity to imatinib.

Our study successfully developed a chemically induced murine GIST model, characterized by positive staining of c-kit and DOG-1. The mGSTc01 monoclonal cell line exhibited slender morphology and expressed the c-kit marker, Whole exome sequencing uncovered mutations of Lamb1, MMP9, and c-kit in GIST cells and provided a detailed picture of the entire genome's copy number variations. RNA sequencing indicated genes associated with cell adhesion and focal adhesion were enriched in mGSTc01 cells. The mGSTc01 cells demonstrated obvious malignant behaviors, notably elevated migration, adhesion, and proliferation. In immunocompetent mice, subcutaneous xenografts not only reserved the aggressive phenotype but also displayed a response to imatinib, underscoring the model's applicability for advancing therapeutic research.

We firstly established a mGSTc01 cell line derived from C57BL/6 J mice GIST tumor offers, which closely mimicking human disease characteristics. It is a potent platform for investigating tumor microenvironment of GIST in mice model, and provides a novel way for new therapeutic discoveries in GIST.

Pericytes, specialized mural cells residing within the basement membrane of pulmonary microvessels, participate in various biological processes, including vascular homeostasis, immunomodulation, and tissue repair. However, these beneficial physiological roles can be detrimental under pathological conditions. Numerous pulmonary fibrosis models have demonstrated pericyte differentiation into scar-forming myofibroblasts, leading to collagen deposition and matrix remodeling, thereby contributing to tissue fibrosis. Similarly, pericytes play crucial roles in inflammatory diseases. This review aims to explore the dual roles of pericytes in the lung and the underlying mechanisms of their role conversion, providing insights for developing therapeutic strategies targeting these cells.

Treatment of breast cancer (BC) remains to face clinical challenges due to poor tumor penetration of therapeutic agents, which is a direct consequence of the high content of hyaluronan (HA) within the extracellular matrix (ECM) of tumor tissues. Herein, we reported the synthesis of phototherapy liposomes which integrated hyaluronidase (HAase) conjugated with a matrix metalloproteinase 2 (MMP-2) responsive peptide in their phospholipid membrane, and preloaded with indocyanine green (ICG), CaO2, and L-buthionine sulfoximine (BSO). Under near-infrared (NIR) laser irradiation, the responsive release of HAase and photodynamic therapy (PDT) effect generated by ICG enabled the controlled degradation of HA in the ECM. Moreover, the photothermal effect of ICG inactivated the residual HAase. This sequential cascade of events facilitated the highly efficient penetration of liposomes into tumor and degrades HA into oligosaccharides (oHA) through adjusting NIR laser irradiation intensity and duration. The phototherapy liposomes also alleviated hypoxia and depleted glutathione (GSH) within the tumor microenvironment. Combined treatment with our liposomes and laser irradiation led to a cell survival rate of <20 % for both 4 T1 and MDA-MB-231 cells. In 4 T1 tumor-bearing mice, the liposome group under NIR light irradiation significantly enhanced tumor ablation, achieving an inhibition rate of 64.9 %, demonstrating that the combination of PDT/PTT with oHA improves the therapeutic efficacy. As expected, the generation of oHA reduced the adverse effects triggered by HAase. These phototherapy liposomes, by promoting the penetration of PDT/PTT drugs, offer a promising strategy to enhance the treatment effectiveness for BC.

3D Bioprinting technology has been applied to vaginal reconstruction with satisfactory results. Understanding the transcriptome and proteome of regenerated vaginas is essential for knowing how biomaterials and seed cells contribute to vaginal regeneration. There are no reports on the systemic analysis of vaginal regeneration transcriptomes or proteomes. This study aims to explore the transcriptomic and proteomic features of vaginal tissue reconstructed with 3D bioprinted scaffolds. The scaffolds were made with biomaterials and bone marrow-derived mesenchymal stem cells (BMSCs) and then transplanted into a rabbit model.rna sequencing was used to analyze the transcriptomes of reconstructed and normal vaginal tissues, identifying 11,956 differentially expressed genes (DEGs). Proteomic analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and data-independent acquisition (DIA) identified 7,363 differentially expressed proteins (DEPs). Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses were performed on DEGs and deps. Results showed that DEGs and deps.were involved in extracellular matrix remodeling, angiogenesis, inflammatory response, epithelialization, and muscle formation. This study shows that 3D bioprinted scaffolds are feasible for vaginal reconstruction and offers new insights into the molecular mechanisms involved.

The extracellular matrix (ECM) plays a critical role in cancer progression by influencing tumor growth, invasion, and metastasis. This review explores the emerging therapeutic strategies that target the ECM as a novel approach in cancer treatment. By disrupting the structural and biochemical interactions within the tumor microenvironment, ECM-targeted therapies aim to inhibit cancer progression and overcome therapeutic resistance. We examine the current state of ECM research, focusing on key components such as collagen, laminin, fibronectin, periostin, and hyaluronic acid, and their roles in tumor biology. Additionally, we discuss the challenges associated with ECM-targeted therapies, including drug delivery, specificity, and potential side effects, while highlighting recent advancements and future directions. This review underscores the potential of ECM-focused strategies to enhance the efficacy of existing treatments and contribute to more effective cancer therapies.

Pituitary adenoma (PA) is one of the most common intracranial tumors, and owing to its special biological morphology and behavior, there is currently no effective treatment. miRNAs play crucial roles as diagnostic indicators and targets for the treatment of numerous cancer types. The objective of this research was to explore how miR-29a-3p influences the development of PA. We collected 25 pairs of PA tissue and normal pituitary tissue, followed by the subcutaneous injection of 5 × 107 HP75 cells into the left axilla of nude mice, creating a heterotopic PA xenograft tumor model for experimental study. TtT/GF and HP75 cell proliferation and tumor growth in nude mice were assessed using CCK-8, Transwell, and immunohistochemistry tests. Western blotting, RT‒qPCR and RIP were used to detect the expression and interaction of related proteins and genes. The expression of miR-29a-3p was upregulated in PA. Knockdown of miR-29a-3p can inhibit the proliferation, invasion and migration of TtT/GF and HP75 cells and reduce the epithelial mesenchymal transformation (EMT) of these cells. Furthermore, reducing miR-29a-3p levels suppressed the expression of Ki-67 in the PA tissues of nude mice and slowed tumor growth. From a mechanistic standpoint, miR-29a-3p can target COL6A6 and PTEN. Knockdown of miR-29a-3p inhibits the PI3K/Akt/CUX1 signaling pathway through simultaneously increasing COL6A6 and PTEN expression, thus inhibiting the proliferation, invasion, migration and EMT of PA cells and alleviating the progression of PA. Conversely, CUX1 can promote the expression of miR-29a-3p through a positive feedback loop and accelerate the development of PA. Our study suggests that downregulating the expression of miR-29a-3p may be a new target for the treatment of PA.

Cell‒cell communication (CCC) is a fundamental biological process for the harmonious functioning of biological systems. Increasing evidence indicates that cells of the same type or cluster may exhibit different interaction patterns under varying niches, yet most prevailing methods perform CCC inference at the cell type or cluster level while disregarding niche heterogeneity. Here we introduce the Spatial Transcriptomics-based cell‒cell Communication And Subtype Exploration (STCase) tool, which can describe CCC events at the single-cell/spot level based on spatial transcriptomics (ST). STCase includes an interpretable multi-view graph neural network via CCC-aware attention to identify niches for each cell type and uncover niche-specific CCC events. We show that STCase outperforms state-of-the-art approaches and accurately captures reported immune-related CCC events in human bronchial glands. We also identify three distinct niches of oral squamous cell carcinoma that may be obscured by agglomerative methods, and discover niche-specific CCC events that could influence tumor prognosis.

Oral cancer (OC) is one of the major types of cancer and the most common cause of cancer-related mortality in Asia. In recent years, matrix stiffness in the tumor microenvironment has been found to play an important role in regulating tumor cell behavior. However, the regulatory mechanisms associated with matrix stiffness in OC cells remain unclear.

In this study, polyacrylamide gels with different stiffness were prepared to simulate low versus high matrix stiffness environments in tumor tissues by adjusting the acrylamide and cross-linker concentrations. Subsequently, the effects of different stiffness on OC cell survival, migration, invasion and invadopodia formation were explored based on cell counting kit-8 (CCK-8), Transwell and confocal microscopy. Meanwhile, the levels of markers relevant to phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), apoptosis (BAX and BCL2) as well as metastasis (Cadherin-1, CDH1; Cadherin-2, and CDH2) were calculated via western blotting and real-time quantitative PCR.

According to the results, high matrix stiffness was seen to contribute to the increased number of migrated and invaded cells as well as the enhanced viability of OC cells, along with the aggravated invadopodia formation and the up-regulation in CDH2 and BCL2 levels yet the down-regulation in CDH1 and BAX levels. Elevated PI3K/AKT phosphorylation levels were also seen in high matrix stiffness-mediated OC cells, and the intervention using LY294002 could visibly overturned the effects of high matrix stiffness on the cell migration, invasion and invadopodia formation of OC cells.

This study reveals that matrix stiffness may enhance the invasiveness and anti-apoptotic ability of OC cells by activating the PI3K/AKT pathway, which provides a new idea for exploring the microenvironmental regulation of tumor mechanics and targeted intervention strategies.

The pericellular matrix (PCM) is the immediate microniche surrounding cells in various tissues, regulating matrix turnover, cell-matrix interactions, and disease. This study elucidates the structure-mechanical properties and mechanobiology of the PCM in fibrocartilage, using the murine meniscus as the model. The fibrocartilage PCM is comprised of thin, randomly oriented collagen fibrils that entrap proteoglycans, contrasting with the densely packed, highly aligned collagen fibers in the bulk extracellular matrix (ECM). Compared to the ECM, the PCM exhibits lower modulus and greater isotropy, but has similar relative viscoelastic properties. In Col5a1+/- menisci, the reduction of collagen V results in thicker, more heterogeneous collagen fibrils, reduced modulus, loss of isotropy and faster viscoelastic relaxation in the PCM. Such altered PCM leads to impaired matrix-to-cell strain transmission, and in turn, disrupts mechanotransduction of meniscal cells, as illustrated by reduced calcium signaling activities and alters expression of matrix genes. In vitro, Col5a1+/- cells produce a weakened PCM with inferior properties and reduced protection of cells against tensile stretch. These findings highlight the PCM as a distinctive microstructure in fibrocartilage mechanobiology, underscoring a pivotal role of collagen V in PCM function. Targeting the PCM or its constituents offers potential for improving meniscus regeneration, osteoarthritis intervention and broader fibrocartilage-related therapies.

As one of the most prevalent primary brain tumors, glioblastoma (GBM) is characterized by its severe malignancy and extremely poor prognosis. Recent studies have demonstrated that targeting anoikis and malignancy showed impressed efficiency for treatment in a wide range of solid tumors, however, relevant research on GBM still remains unclarified.

In this study, genes related with malignancy and anoikis of GBM were identified by utilizing the Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA) and the Molecular Signatures Database (MSigDB). Subsequently, the role of the key gene was validated via proliferation, invasion and migration experiments both in conditions with and without attachment. Moreover, RNA sequencing analysis was employed to reveal further mechanisms.

Here, Type V collagen alpha 1 (COL5A1) was identified as a critical gene associated with anoikis and poor outcomes. Additionally, COL5A1 knockdown induced significant reduction in malignancy of GBM both in vitro and in vivo. Moreover, cell anoikis was remarkable enhanced by reduced expression of COL5A1 after low-attachment cell culture. Mechanically, RNA sequencing analysis revealed that the activity of the Wnt/β-catenin signaling pathway was diminished following COL5A1 knockdown, which indicated that COL5A1 reduced anoikis via regulating Wnt/β-catenin signaling pathway thus promoted malignancies of GBM cells.

These findings demonstrated the novel evidence that COL5A1 serves as an essential regulatory factor influencing both anoikis and malignancy of GBM cells by regulating Wnt/β-catenin signaling pathway, indicating that COL5A1 could be a novel prognosis-related biomarker and potential therapeutic target for GBM.

Matrix metalloproteinase 1 plays a pivotal role in tumor biology and immune modulation through its enzymatic remodeling of the extracellular matrix, facilitating tumor progression. In this study, we utilized large-scale single-cell RNA sequencing and spatial transcriptomics to investigate MMP1 expression, its cellular localization, and its impact on tumor progression and immune modulation. Our findings reveal that MMP1 expression is elevated in various tumor types and is strongly correlated with metastatic potential. High MMP1 expression was associated with increased activity in epithelial-mesenchymal transition signaling and TNFα/NF-κB pathways, which are known to promote tumor progression. Furthermore, MMP1+ malignant cells exhibited significant interactions with immune cells, particularly macrophages and CD8+ T cells. MMP1 expression correlated with enhanced macrophage infiltration and impaired CD8+ T-cell function, contributing to an immunosuppressive tumor microenvironment. Notably, the CXCL16-CXCR6 and ANXA1-FPR3 signaling axes were identified as key mediators of these interactions. Inhibition of MMP1 in vitro demonstrated reduced cell invasion, stemness, and proliferation, while increasing reactive oxygen species levels and promoting apoptosis. Our findings position MMP1 as a key player in the "tumor-immune" vicious cycle and a promising therapeutic target to enhance anti-tumor responses and improve patient outcomes.

The Matrix Remodeling Associated Genes (MXRAs) family, comprising eight distinct members (MXRA1-8), plays a crucial role in the development and maintenance of higher vertebrate cells. These proteins are primarily involved in the regulation of intercellular adhesion and the remodeling of the extracellular matrix (ECM). Recent investigations have highlighted the significant roles of MXRAs in the modulation of tumor growth and progression, establishing them as vital components in the oncogenic landscape. Notably, each MXRA member exhibits unique structural characteristics and functional properties, contributing to a diverse array of regulatory effects within the tumor context. This review seeks to provide a comprehensive analysis of the structural attributes, functional contributions, and activities of MXRAs within the tumor microenvironment. By elucidating the underlying mechanisms of action, this paper aims to offer novel insights and strategic approaches for the identification of early diagnostic biomarkers, as well as potential therapeutic targets that may facilitate molecular interventions aimed at inhibiting tumor development.

Myocardial remodeling plays a crucial role in determining patient outcomes after myocardial infarction (MI). Emerging evidence from both preclinical and clinical studies highlights the beneficial effects of cardiac lymphangiogenesis in improving cardiac function and prognosis post-MI. Lingguizhugan decoction (LD), a traditional Chinese medicine, is extensively used in the treatment of ischemic heart disease. Nevertheless, its potential mechanisms are still not well understood.

To determine whether LD can enhance post-MI myocardial remodeling by promoting lymphangiogenesis and to elucidate its molecular mechanisms METHODS: Surgical ligation of the left anterior descending artery (LAD) was utilized to establish MI rat model. Cardiac structure and function were assessed using histopathological staining and echocardiography. A transgenic zebrafish model was used to confirm that lymphangiogenesis plays a key role in LD's cardioprotective effects. Network pharmacology analysis was conducted to predict the potential mechanisms underlying LD's therapeutic action in MI. The expression levels of matrix metalloproteinase-9 (MMP-9) and lymphatic vessel endothelial receptor-1 (LYVE-1) were assessed in MI rats. Transcriptomic data mining from MI patients and in vitro protein interaction validation were conducted to explore the relationship between MMP-9 and LYVE-1. Key proteins involved in the interleukin-17 (IL-17) signaling pathway were analyzed using western blotting and qRT-PCR. Furthermore, mass spectrometry imaging was conducted to identify potential bioactive compounds in LD that regulate the IL-17 signaling pathway.

LD significantly improved cardiac function and mitigated adverse myocardial remodeling in left anterior descending artery-ligated rats. Notably, LD promoted cardiac lymphangiogenesis and improved cardiac function in transgenic zebrafish treated with verapamil, with further validation using lymphangiogenesis inhibitors. Based on network pharmacology findings and previous studies, MMP-9 and LYVE-1 were identified as key targets of LD. LD decreased MMP-9 expression and increased LYVE-1 levels in MI rat hearts. A strong correlation was observed between MMP-9 and LYVE-1, suggesting a potential regulatory relationship. Additionally, LD downregulated key proteins involved in the IL-17 signaling pathway, indicating its role in modulating inflammatory responses. Finally, four biologically active compounds dehydrotrametenonic acid, ethyl p-methoxycinnamate, atractylon, and licoricone were identified in cardiac tissue as potential regulators of the IL-17R/MMP-9/LYVE-1 axis, contributing to LD's lymphangiogenesis-promoting effects.

LD enhances post-MI ventricular remodeling by promoting lymphangiogenesis and modulating the IL-17R/MMP-9/LYVE-1 signaling pathway. Dehydrotrametenonic acid, ethyl p-methoxycinnamate, atractylon, and licoricone may serve as key bioactive compounds responsible for LD's therapeutic effects.

Glycation, or non-enzymatic glycosylation, has recently attracted increasing interest in the context of its impact on aging. Advanced glycation end products (AGEs) contribute to various age-related pathological conditions such as inflammation, fibrosis, and vascular calcification. However, the molecular mechanisms underlying glycation-induced disruption of cell-matrix interactions during cellular senescence are not fully understood. The aim of this study was to investigate transcriptomic changes in young and senescent dermal fibroblasts (HdFbs) cultured in 3D post-glycated collagen type I matrices after 10 and 17 days. Our findings indicate that D-ribose-mediated glycation increases the accumulation of fluorescent AGEs and the stiffness of matrices in a dose-dependent manner. The transcriptome alterations in cells encompassed the modulation of age-related genes and signaling pathways, including activation of genes related to senescence-associated secretory phenotype (SASP). Notably, the alterations in the transcriptome profiles due to glycation were more pronounced (in terms of both the number of genes and their fold changes) after 10 days of culture compared to day 17 in both passages. These findings suggest that cellular responses to glycation and resulting stiffness depend on both the concentration of reducing sugar and the time spent under those conditions.

Harnessing natural developmental programs to repair and replace damaged organs represents promising approaches in regenerative medicine. However, effective strategies are still lacking for tissue regeneration in complicated conditions, such as the periodontal bone defect. Here, human dental follicle stem cells (hDFSCs) and their aggregates (hDFSCA) are cultured and characterized, which are formed based on the inherent property of these stem cells self-assembly into compact spheroid-like structures, mimicking mesenchymal condensation in development. A periodontal tissue-specific microenvironment simulation material is then established, human decellularized alveolar bone matrix particles (hDABMPs), which possess favorable physicochemical and biological properties for regenerative use. hDFSCs co-cultured with hDABMPs exhibit improved cell function, and hDFSCA-hDABMP co-aggregates are subsequently constructed, which activate the developmental gene expression in hDFSCA and initiate hypoxic adaptation mechanisms for tissue regeneration. Indeed, hDFSCA-hDABMP co-aggregates significantly promote regeneration after implantation in alveolar bone defects with good biosafety. Interestingly, during the early stages of implantation, hDABMPs enhance hDFSC survival and expansion, thereby providing a sufficient source of cells for tissue regeneration. Collectively, this study reveals a development-inspired, engineered cell-niche co-aggregation strategy for enhancing CA therapeutic potential by simulating tissue-specific microenvironments, offering novel insights for functional tissue regeneration.

Nonalcoholic fatty liver disease (NAFLD) is characterized by increased lipid accumulation and excessive deposition of extracellular matrix (ECM) that results in tissue stiffening. The potential interplay between matrix stiffness and hepatocyte lipid accumulation during NAFLD has not been established. Here, an in vitro NAFLD model is developed using chemically defined, engineered hydrogels and human induced pluripotent stem cell-derived hepatic organoids (HOs). Specifically, dynamic covalent chemistry crosslinking, along with transient small molecule competitors, are used to create dynamic stiffening hydrogels that enable the reproducible culture of HOs. Within matrices that mimic the stiffness of healthy to diseased tissue (≈1-6 kPa), lipid droplet accumulation in HOs is triggered by exposure to an NAFLD-associated free fatty acid. These NAFLD model suggests that higher stiffness microenvironments result in increased hepatic lipid droplet accumulation, increased expression of fibrosis markers, and increased metabolic dysregulation. By targeting the ROCK mechanosignaling pathway, the synergy between matrix stiffness and lipid droplet accumulation is disrupted. The in vitro model of NAFLD has the potential to understand the role of mechanosignaling in disease progression and identify new pathways for therapeutic intervention.

Proteolysis is an irreversible posttranslational modification with immense biological impact. Owing to its high disease significance, there is growing interest in investigating proteolysis on the proteome scale, termed degradomics. We developed 'Database of Identified Cleavage sites Endemic to Disease states' (DICED; https://diced.lerner.ccf.org/), as a searchable knowledgebase to promote collaboration and knowledge sharing in degradomics. DICED was designed and constructed using Python, JavaScript, HTML, and PostgreSQL. Django (https://www.djangoproject.com) was chosen as the primary framework for its security features and support for agile development. DICED can be utilized on major web browsers and operating systems for easy access to high-throughput mass spectrometry-identified cleaved protein termini. The data was obtained using N-terminomics, comprising N-terminal protein labeling, labeled peptide enrichment, mass spectrometry and positional peptide annotation. The DICED database contains experimentally derived N-terminomics peptide datasets from tissues, diseases, or digests of tissue protein libraries using individual proteases and is searchable using UniProt ID, protein name, gene symbol or up to 100 peptide sequences. The tabular output format can be exported as a CSV file. Although DICED presently accesses data from a single laboratory, it is freely available as a Galaxy tool and the underlying database is scalable, permitting addition of new datasets and features.

The mammary gland is a modified sweat gland responsible for milk production. It is affected by diseases that reduce animals' quality of life, consequently leading to economic losses in livestock. With advancements in tissue bioengineering and regenerative medicine, studying the extracellular matrix (ECM) of the bovine mammary gland can improve our understanding of its physiology and the processes that affect it. This knowledge could also enable the development of sustainable therapeutic alternatives for both the dairy production chain and human oncology research. A common approach in regenerative medicine is decellularization, a process that removes all cells from tissue while preserving its architecture and ECM components for subsequent recellularization. The success of recellularization depends on obtaining immunologically compatible scaffolds and using appropriate cell culture sources and methods to ensure tissue functionality. However, tissue culture technology still faces challenges due to specific requirements and high costs. Here, we review the literature on biomaterials and tissue engineering, providing an overview of the ECM of the bovine mammary gland and advances in its bioengineering, with a focus on regenerative medicine for bovine species. The methodology employed consists of a structured search of scientific databases, including PubMed, Google Scholar, and SciELO, using specific keywords related to tissue engineering and the bovine mammary gland. The selection criteria prioritized peer-reviewed articles published between 2002 and 2025 that demonstrated scientific relevance and contributed to the understanding of bovine mammary gland bioengineering. Although research on this topic has advanced, vascularization, tissue maturation, and scalability remain key barriers to widespread application and economic viability.

Despite recent advancements in technology for the treatment of type 1 diabetes (T1D), exogenous insulin delivery through automated devices remains the gold standard for treatment. This review will explore progress made in pancreatic islet bioengineering within the field of beta-cell replacement for T1D treatment.

First, we will focus on the use of decellularized extracellular matrices (dECM) as a platform for pancreatic organoid development. These matrices preserve microarchitecture and essential biochemical signals for cell differentiation, offering a promising alternative to synthetic matrices. Second, advancements in 3D bioprinting for creating complex organ structures like pancreatic islets will be discussed. This technology allows for increased precision and customization of cellular models, crucial for replicating native pancreatic islet functionality. Finally, this review will explore the use of stem cell-derived organoids to generate insulin-producing islet-like cells. While these organoids face challenges such as functional immaturity and poor vascularization, they represent a significant advancement for disease modeling, drug screening, and autologous islet transplantation.

These innovative approaches promise to revolutionize T1D treatment by overcoming the limitations of traditional therapies based on human pancreatic islets.

Females' reproductive capacity is closely related to the actual metabolic status of the organism. The pituitary, an element of the regulatory hypothalamic-pituitary-ovarian axis, is one of the most important endocrine glands regulating reproductive system activity. Undisturbed functioning of pituitary ensures the regular course of pregnancy through, among others, the modulation of steroid hormones production, which is critical in the early stages of gestation. Visfatin, a hormone belonging to the adipokines family, may belong to a group of factors regulating the reproductive functions in response to the female's metabolic status. Herein we verified the hypothesis assuming a modulatory effect of visfatin on the porcine anterior pituitary transcriptome on days 15 to 16 of gestation (beginning of implantation). RNA-seq analysis of the porcine anterior pituitary cells revealed changes in the expression of 203 genes (121 up-regulated and 82 down-regulated, when compared to the non-treated controls), assigned to 325 gene ontology terms. The presence of visfatin affected the frequency of alternative splicing events (194 cases), as well as long noncoding RNA expression (64 cases). Visfatin expression and the occurrence of alternative splicing events of genes that are responsible, directly or indirectly, for regulation of the secretory functions of the pituitary, including those critical for reproductive functions suggests that the adipokine may be a key agent in ensuring the appropriate hormonal milieu during the peri-implantation period.

In this study, we aimed to uncover genes associated with stressed cardiomyocytes by combining single-cell transcriptomic data sets from failing cardiac tissue from both humans and mice.

Our bioinformatic analysis identified SORBS2 as conserved NPPA-correlated gene. Using mouse models and cardiac tissue from human heart failure patients, we demonstrated that SORBS2 expression is consistently increased during pathological remodelling, correlates to disease severity, and is regulated by GATA4. By affinity purification mass spectrometry, we showed SORBS2 to interact with the integrin-cytoskeleton connections. Cardiomyocyte-specific genetic loss of Sorbs2 in adult mice changed integrin interactions, indicated by the increased expression of several integrins and altered extracellular matrix components connecting to these integrins, leading to an exacerbated fibrotic response during pathological remodelling.

Sorbs2 is a cardiomyocyte-enriched gene that is increased during progression to heart failure in a GATA4-dependent manner and correlates to phenotypical hallmarks of cardiac failure. Our data indicate SORBS2 to function as a crucial regulator of integrin interactions and cardiac fibrosis.

Elastin stabilization has been correlated with the reversibility of fibrosis. Fibulin-1 can participate in elastin assembly, which promotes its stabilization. However, the role of Fibulin-1 in liver fibrosis remains unknown. Here, we performed a proteomics analysis to identify notable changes in Fibulin-1 expression during continuous fibrosis progression and regression. Fibulin-1 expression was dramatically increased in the plasma of patients with cirrhosis as well as in liver fibrosis models and hepatic stellate cells (HSCs) treated with TGF-β1, and significant accumulation of Fibulin-1 was observed in chronic hepatitis B (CHB)- and metabolic dysfunction-associated steatohepatitis (MASH)-related cirrhosis. Functional studies demonstrated that Fibulin-1 silencing inhibited HSC activation, while the opposite effects were observed for Fibulin-1 overexpression in vitro. Furthermore, transcriptomic analysis revealed that Fibulin-1 mediated p38 MAPK pathway activation, which was confirmed by the addition of a p38 MAPK inhibitor. More importantly, Fibulin-1 depletion in a CCl4-induced liver fibrosis model substantially ameliorated fibrosis progression, which was accompanied by decreased profibrogenic gene expression and decreased levels of insoluble elastin. Moreover, activation of the p38 MAPK pathway was inhibited in vivo. The expression of Fibulin-1D, rather than Fibulin-1C, was elevated during liver fibrogenesis, which suggested a major role for Fibulin-1D in liver fibrosis. Next, we established Fibulin-1D/elastin-coated culture models with LX-2 cells. LX-2 cells with extracellular elastin and Fibulin-1D deposition showed more significant profibrotic phenotypic alterations than those with elastin alone. Fibulin-1 deficiency alleviated liver fibrosis by reducing insoluble elastin and HSC activation, and finally, the p38 MAPK pathway might be involved in the effect of Fibulin-1 on HSCs.

Previous studies reported that preserving the anterior cruciate ligament (ACL) remnants following ACL rupture during reconstruction surgery could promote graft healing. However, the temporal proteomic expression of ACL remnants remains unclear. Based on previous reports, we have redefined the initial 6 weeks following ACL rupture as the acute phase and the subsequent 6 weeks to 6 months as the subacute phase. High-throughput proteomic sequencing on ACL remnants from the two groups was utilized. Our study unveiled a total of 381 differential expression proteins (DEPs), with 136 upregulated and 245 downregulated proteins in the acute phase. By intersecting these findings with secretory protein databases, we identified 26 upregulated secretory proteins and 19 downregulated in the acute phase. The upregulation of MMP9 and VTN and the downregulation of COL1A1 and POSTN in the acute phase were further confirmed by immunohistochemistry. These findings suggest that the elevated expression of secretory proteins in the acute phase may play crucial roles in promoting cell proliferation, angiogenesis, and tissue repair of the graft. This study not only enhances our understanding of repair mechanisms in ACL remnant preservation but also provides a theoretical foundation for guiding rational clinical surgical timing.

Long non-coding RNAs (lncRNAs) exert significant influence on the development of cancer. However, their role in colorectal cancer (CRC) is not fully clarified. The expression levels of LINC01811 in CRC samples were determined using differential expression analysis and validated by RT-qPCR assays. Transwell assays were conducted to investigate the biological function of LINC01811 in CRC. To elucidate the mechanism by which LINC01811 acts as a molecular sponge for miR-214-3p and regulates YAP1 expression, binding site analysis, Luciferase reporter assay, RT-qPCR, and Western blotting were employed. We identified a novel oncogenic lncRNA LINC01811 in CRC tissues and cell lines. Our results showed that the suppression of LINC01811 significantly reduced CRC cell invasion and migration by regulating epithelial-mesenchymal transition-related markers, including MMP2, MMP9, vimentin, and E-cadherin in vitro. Furthermore, LINCO1811 modulated YAP1 expression by sequestering miR-214-3p, thereby promoting CRC progression by suppressing its activity. In summary, this study identified a novel lncRNA LINC01811 involved in CRC progression through the miR-214-3p/YAP1 axis.

The online version contains supplementary material available at 10.1007/s13205-025-04292-8.

Tendons are vital for maintaining integrity and movement, but current treatment options are insufficient for their regeneration after injuries. Previous studies have shown that the secretome from mesenchymal stem cells (MSCs) promoted tendon regeneration. However, limited studies have explored the impact of the physical microenvironment on the secretome's efficacy of MSCs. In this study, it is shown that the topographic orientation regulates the secretome of human adipose-derived stem cells (ADSCs) and promotes tendon regeneration. Conditioned medium (CM) is collected from ADSCs cultured on the scaffolds with different topography. The results show that CM generated from aligned structure group has a potent effect in promoting cell migration and proliferation, tenogenic differentiation, macrophage polarization toward M2 phenotype, tendon structure and mechanical function recovery. Proteomic analysis revealed that the aligned structure can up-regulate the secretion of Extracellular matrix (ECM) proteins while down-regulate proinflammatory factors. This modulation activates the MAPK, GPCR and Integrin signaling pathways which may account for the enhanced effect on tendon regeneration. This study offers a promising and safer non-cell-based treatment option for tendon repair.

Defence from environmental threats is provided by physical barriers that confer mechanical protection and prevent the entry of microorganisms1. If microorganisms overcome those barriers, however, innate immune cells use toxic chemicals to kill the invading cells2,3. Here we examine immune diversity across tissues and identify a population of neutrophils in the skin that expresses a broad repertoire of proteins and enzymes needed to build the extracellular matrix. In the naive skin, these matrix-producing neutrophils contribute to the composition and structure of the extracellular matrix, reinforce its mechanical properties and promote barrier function. After injury, these neutrophils build 'rings' of matrix around wounds, which shield against foreign molecules and bacteria. This structural program relies on TGFβ signalling; disabling the TGFβ receptor in neutrophils impaired ring formation around wounds and facilitated bacterial invasion. We infer that the innate immune system has evolved diverse strategies for defence, including one that physically shields the host from the outside world.

Pancreatic ductal adenocarcinoma (PDAC) exhibits higher hypoxia level than most solid tumors, and the presence of intratumoral hypoxia is associated with a poor prognosis. However, the identification of hypoxia levels based on pathological images, and the mechanisms regulating ferroptosis resistance, remain to be elucidated. The objective of this study was to construct a deep learning model to evaluate the hypoxia characteristics of PDAC and to explore the role of Sulfide quinone oxidoreductase (SQOR) in hypoxia-mediated ferroptosis resistance.

Multi-omics data were integrated to analyze the correlation between hypoxia score of PDAC, SQOR expression and prognosis, and ferroptosis resistance level. A deep learning model of Whole Slide Images (WSIs) were constructed to predict the hypoxia level of patients. In vitro hypoxia cell models, SQOR knockdown experiments and nude mouse xenograft models were used to verify the regulatory function of SQOR on ferroptosis.

PDAC exhibited significantly higher hypoxia levels than normal tissues, correlating with reduced overall survival in patients. In slide level, our deep learning model can effectively identify PDAC hypoxia levels with good performance. SQOR was upregulated in tumor tissues and positively associated with both hypoxia score and ferroptosis resistance. SQOR promotes the malignant progression of PDAC in hypoxic environment by enhancing the resistance of tumor cells to ferroptosis. SQOR knockdown resulted in decreased cell viability, decreased migration ability and increased MDA level under hypoxic Ersatin induced conditions. Furthermore, SQOR inhibitor in combination with ferroptosis inducer has the potential to inhibit tumor growth in vivo in a synergistic manner.

This study has established a hypoxia detection model of PDAC based on WSIs, providing a new tool for clinical evaluation. The study revealed a new mechanism of SQOR mediating ferroptosis resistance under hypoxia and provided a basis for targeted therapy.