Through the formation of covalent connections with hyaluronic acid (HA), the inter-α-trypsin inhibitor (IαI) family collaborates to preserve the stability of the extracellular matrix (ECM). The five distinct homologous heavy chains (ITIH) and one type of light chain make up the IαI family. ITIH alone or in combination with bikunin (BK) has been proven to have important impacts in a number of earlier investigations. This implies that BK and ITIH might be crucial to both physiological and pathological processes. The functions of BK and ITIH in various pathophysiological processes are discussed independently in this paper. In the meanwhile, this study offers suggestions for further research on the roles of BK and ITIH in the course of disease and summarizes the plausible mechanisms of the previous studies.

UNASSIGNED: There is a growing body of evidence indicating a potential association between circular RNA and the pathogenesis of human osteoarthritis (OA). Nevertheless, the precise extent of their involvement in OA remains largely unexplored. Hence, the objective of this investigation is to elucidate the function of Circular (Circ) RELL1 in the context of OA.
UNASSIGNED: 24 OA tissue samples and 11 normal tissue samples were collected. The inflammatory OA-like conditions were established by Destabilized Medial Meniscus (DMM) operation in mice and LPS-induced C28/I2 cells. OA severity and articular cartilage degradation were assessed by Safranin-O staining, hematoxylin-eosin (H&E) staining, and International Society for Osteoarthritis Research (OARSI) criteria. CircRELL1, miR-200c-3p, and TCF4 were measured by RT-qPCR and Immunoblot. The cell viability and apoptosis rate were measured by MTT and flow cytometry, respectively. The levels of cytokines interleukin (IL)-1β, IL-6, and TNF-α were determined by ELISA. Apoptosis-associated proteins (cleaved caspase-3, Bax, and Bcl-2) and extracellular matrix (ECM) degradation-associated proteins (MMP13, collagen II, and Aggrecan) were detected by Immunoblot. The interaction between miR-200c-3p and circRELL1 or TCF4 was verified by dual luciferase reporter assay and RIP assay.
UNASSIGNED: CircRELL1 expression was upregulated in OA patients, and the results were consistent in DMM mice and LPS-treated C28/I2 cells. Silencing circRELL1 improved cartilage injury caused by DMM and contributed to a lower OARSI score. Silencing CircRELL1 increased the activity of OA chondrocytes in vivo and in vitro and inhibited cellular inflammatory responses and ECM degradation. In terms of mechanism, circRELL1 functioned by targeting miR-200c-3p, leading to the suppression of inflammatory factor production, cell apoptosis, and ECM degradation, thus inhibiting the progression of OA.
UNASSIGNED: CircRELL1 may promote the progression of OA by regulating the miR-200c-3p.

The maturation of brain microvascular endothelial cells leads to the formation of a tightly sealed monolayer, known as the blood-brain barrier (BBB). The BBB damage is associated with the pathogenesis of age-related neurodegenerative diseases including vascular cognitive impairment and Alzheimer\'s disease. Growing knowledge in the field of epigenetics can enhance the understanding of molecular profile of the BBB and has great potential for the development of novel therapeutic strategies or targets to repair a disrupted BBB. Histone deacetylases (HDACs) inhibitors are epigenetic regulators that can induce acetylation of histones and induce open chromatin conformation, promoting gene expression by enhancing the binding of DNA with transcription factors. We investigated how HDAC inhibition influences the barrier integrity using immortalized human endothelial cells (HCMEC/D3) and the human induced pluripotent stem cell (iPSC)-derived brain vascular endothelial cells. The endothelial cells were treated with or without a novel compound named W2A-16. W2A-16 not only activates Wnt/β-catenin signaling but also functions as a class I HDAC inhibitor. We demonstrated that the administration with W2A-16 sustained barrier properties of the monolayer of endothelial cells, as evidenced by increased trans-endothelial electrical resistance (TEER). The BBB-related genes and protein expression were also increased compared with non-treated controls. Analysis of transcript profiles through RNA-sequencing in hCMEC/D3 cells indicated that W2A-16 potentially enhances BBB integrity by influencing genes associated with the regulation of the extracellular microenvironment. These findings collectively propose that the HDAC inhibition by W2A-16 plays a facilitating role in the formation of the BBB. Pharmacological approaches to inhibit HDAC may be a potential therapeutic strategy to boost and/or restore BBB integrity.

Tumor extracellular matrices (ECM) exhibit aberrant changes in composition and mechanics compared to normal tissues. Proteoglycans (PG) are vital regulators of cellular signaling in the ECM with the ability to modulate receptor tyrosine kinase (RTK) activation via their sulfated glycosaminoglycan (sGAG) side chains. However, their role on tumor cell behavior is controversial. Here, it is demonstrated that PGs are heavily expressed in lung adenocarcinoma (LUAD) patients in correlation with invasive phenotype and poor prognosis. A bioengineered human lung tumor model that recapitulates the increase of sGAGs in tumors in an organotypic matrix with independent control of stiffness, viscoelasticity, ligand density, and porosity, is developed. This model reveals that increased sulfation stimulates extensive proliferation, epithelial-mesenchymal transition (EMT), and stemness in cancer cells. The focal adhesion kinase (FAK)-phosphatidylinositol 3-kinase (PI3K) signaling axis is identified as a mediator of sulfation-induced molecular changes in cells upon activation of a distinct set of RTKs within tumor-mimetic hydrogels. The study shows that the transcriptomic landscape of tumor cells in response to increased sulfation resembles native PG-rich patient tumors by employing integrative omics and network modeling approaches.

Ovarian cancer (OC) is a common and lethal gynaecological malignancy. RNA-binding proteins (RBPs) play a crucial role in governing RNA metabolism and have been implicated in the development and progression of diverse cancer types. Slight alterations in RBPs\' expression or activity can induce substantial modifications in the regulatory network. THUMPD2, as member of the RBP family, was found to have differential expression in ovarian cancer, with the mechanism has not been studied yet. In this study, THUMPD2 protein was found to be weakly expressed in the early (I + II) stages of OC (P = 0.013), with a low expression rate of 78.6 %, and highly expressed in late (III + IV) stages (P = 0.009), with a high expression rate of 84.8 %. The shRNA-mediated knockdown of THUMPD2 in OVCAR3 and SKOV3 cells resulted in increased cell proliferation but inhibited metastasis, whereas THUMPD2 overexpression had the opposite effect. THUMPD2 overexpression suppressed tumour growth in vivo. Conversely, low THUMPD2 expression promoted tumour growth. Furthermore, we identified the potential target genes and pathways of THUMPD2 using GO and KEGG analyses, which were related to the centrosome, microtubules, cell cycle, and extracellular matrix. We demonstrated that low expression of THUMPD2 in the early stage promoted tumour growth and high expression in the late stage promoted tumour metastasis. Our findings reveal the dual function of THUMPD2 in OC and suggest that THUMPD2 may serve as a therapeutic target for the treatment of OC.

UNASSIGNED: Periodontal disease is a common oral infection which affects the tooth-supportive tissues directly. Considering the limitation of present regenerative treatments for severe periodontal cases, cytotherapies have been gradually introduced. Human periodontal ligament-derived mesenchymal stromal cells (hPDLMSCs), while identified as one of the promising cell sources for periodontal regenerative therapy, still hold some problems in the clinical application especially their limited life span. To solve the problems, human induced pluripotent stem cells (hiPSCs) are taken into consideration as a robust supply for hPDLMSCs.
UNASSIGNED: The induction of hPDLMSCs was performed based on the generation of neural crest-like cells (NCLCs) from hiPSCs. Fibronectin and laminin were tested as coating materials for NCLCs differentiation when following previous protocol, and the characteristics of induced cells were identified by flow cytometry and RT-qPCR for evaluating the induction efficiency. Subsequently, selected dental ectoderm signaling-related cytokines were applied for hPDLMSCs induction for 14 days, and dental mesenchyme-related genes, dental follicle-related genes and hPDL-related genes were tested by RT-qPCR for the evaluation of differentiation.
UNASSIGNED: Compared to the 58% in laminin-coated condition, fibronectin-coated condition had a higher induction efficiency of CD271high cells as 86% after 8-day induction, while the mesenchymal potential of induced NCLCs was similar between two coating materials.It was shown that the gene expressions of dental mesenchyme, dental follicles and hPDL cells were significantly enhanced with the stimulation of the combination with fibroblast growth factor 8b (FGF8b), FGF2, and bone morphogenetic protein 4 (BMP4).
UNASSIGNED: FN coating was more effective in NCLCs induction, and the FGF8b+FGF2+BMP4 growth factor cocktail was effective in hPDLMSC-like cell generation. These findings underscored the likely regenerative potential of hiPSCs as an applicable and promising curative strategy for periodontal diseases.

UNASSIGNED: Chimeric antigen receptor (CAR) T-cells have emerged as a ground-breaking therapy for the treatment of hematological malignancies due to their capacity for rapid tumor-specific killing and long-lasting tumor immunity. However, the same success has not been observed in patients with solid tumors. Largely, this is due to the additional challenges imposed by safe and uniform target selection, inefficient CAR T-cell access to sites of disease and the presence of a hostile immunosuppressive tumor microenvironment.
UNASSIGNED: Literature was reviewed on the PubMed database from the first description of a CAR by Kuwana, Kurosawa and colleagues in December 1987 through to the present day. This literature indicates that in order to tackle solid tumors, CAR T-cells can be further engineered with additional armoring strategies that facilitate trafficking to and infiltration of malignant lesions together with reversal of suppressive immune checkpoints that operate within solid tumor lesions.
UNASSIGNED: In this review, we describe a number of recent advances in CAR T-cell technology that set out to combat the problems imposed by solid tumors including tumor recruitment, infiltration, immunosuppression, metabolic compromise, and hypoxia.

Background: Age and sex are the most significant risk of factors for advanced Fuchs dystrophy. Nevertheless, few data are available on the hormone\'s receptor pattern expressed in adult and advanced fuchs endothelial corneal dystrophy (FECD). We investigated the impact of gender, growth factors and extracellular matrix (ECM) regulatory proteins expressed by the dystrophic endothelia. Methods: Ten dystrophic endothelial tissues and 10 normal endothelial sheets (corneoscleral specimens; Eye Bank) were used for this characterization study. Hormones\' receptors (ERα, AR, PR, SHBG), few growth factors (VEGFA, βNGF, TGFβ1), some ECM regulators (MMP1, MMP7) and few inflammatory cytokines (IFNγ, IL10) were analyzed by real-time RT-PCR. Results: ERα transcripts were significantly increased, AR and SHBG transcripts were decreased in Fuchs endothelia from female patients, and no changes were detected for PR transcripts. VEGFA, βNGF and TGFβ1 transcripts were upregulated in Fuchs\' endothelia, but not significantly linked to gender. High MMP1 and low MMP7 transcripts\' expression were detected in Fuchs\' specimens, mainly in males than females. An increased IFNγ (Th1) transcript expression was observed in females than males, and a trend to increase for IL10 (Th2) transcripts was detected in males than females. Conclusions: Our findings clearly indicate that hormone receptors, growth factors and matrix mediators as well as a Th1 pathway are predominant in Fuchs\' dystrophy, displaying a pattern of expression specific for the female phenotype. The differential expression of hormones\' receptors and the Th1/Th2 ratio might prompt to new theories to be tested in vitro and in vivo models, such as the use of hormonal substitute for counteracting this endothelial cell lost.

Ductal carcinoma in situ (DCIS) is a heterogeneous breast disease that remains challenging to treat due to its unpredictable progression to invasive breast cancer (IBC). Contemporary literature has become increasingly focused on extracellular matrix (ECM) alterations with breast cancer progression. However, the spatial regulation of the ECM proteome in DCIS has yet to be investigated in relation to IBC. We hypothesized that DCIS and IBC present distinct ECM proteomes that could discriminate between these pathologies. Tissue sections of pure DCIS, mixed DCIS-IBC, or pure IBC (n = 22) with detailed pathological annotations were investigated by multiplexed spatial proteomics. Across tissues, 1,005 ECM peptides were detected in pathologically annotated regions and their surrounding extracellular microenvironments. A comparison of DCIS to IBC pathologies demonstrated 43 significantly altered ECM peptides. Notably, eight fibrillar collagen peptides could distinguish with high specificity and sensitivity between DCIS and IBC. Lesion-targeted proteomic imaging revealed heterogeneity of the ECM proteome surrounding individual DCIS lesions. Multiplexed spatial proteomics reported an invasive cancer field effect, in which DCIS lesions in closer proximity to IBC shared a more similar ECM profile to IBC than distal counterparts. Defining the ECM proteomic microenvironment provides novel molecular insights relating to DCIS and IBC.

Artificial vascular graft (AVG) fistula is widely used for hemodialysis treatment in patients with renal failure. However, it has poor elasticity and compliance, leading to stenosis and thrombosis. The ideal artificial blood vessel for dialysis should replicate the structure and components of a real artery, which is primarily maintained by collagen in the extracellular matrix (ECM) of arterial cells. Studies have revealed that in hepatitis B virus (HBV)-induced liver fibrosis, hepatic stellate cells (HSCs) become hyperactive and produce excessive ECM fibers. Furthermore, mechanical stimulation can encourage ECM secretion and remodeling of a fiber structure. Based on the above factors, we transfected HSCs with the hepatitis B viral X (HBX) gene for simulating the process of HBV infection. Subsequently, these HBX-HSCs were implanted into a polycaprolactone-polyurethane (PCL-PU) bilayer scaffold in which the inner layer is dense and the outer layer consists of pores, which was mechanically stimulated to promote the secretion of collagen nanofiber from the HBX-HSCs and to facilitate crosslinking with the scaffold. We obtained an ECM-PCL-PU composite bionic blood vessel that could act as access for dialysis after decellularization. Then, the vessel scaffold was implanted into a rabbit\'s neck arteriovenous fistula model. It exhibited strong tensile strength and smooth blood flow and formed autologous blood vessels in the rabbit\'s body. Our study demonstrates the use of human cells to create biomimetic dialysis blood vessels, providing a novel approach for creating clinical vascular access for dialysis.
人工血管的移植（AVG）造瘘被广泛用于肾衰竭患者的血液透析治疗。然而，目前临床使用的人工血管的弹性和顺应性较差，容易导致狭窄，形成血栓。用于透析的理想人造血管应模拟天然血管的结构和成分，而天然血管主要由血管内细胞分泌的细胞外基质（ECM）中的胶原蛋白维持。研究发现，在乙型肝炎病毒（HBV）诱导的肝纤维化中，肝星状细胞（HSCs）变得异常活跃，并产生过多的 ECM 纤维。此外，机械刺激可促进 ECM分泌并重塑ECM的纤维结构。基于上述因素，我们用乙型肝炎病毒X基因（HBX）转染HSCs细胞，在体外模拟HBV病毒感染的过程。随后，将HBX-HSCs细胞种植入由聚己内酯-聚氨酯（PCL-PU）制备的内层致密、外层多孔的双层支架，通过机械力刺激HBX-HSCs分泌大量的胶原纤维，并促进其与血管支架的多孔结构进行交联。由此，我们获得了一种ECM-PCL-PU复合仿生血管，其在脱细胞后可作为透析用血管。最后，我们将制备得到的血管支架植入兔颈部动静脉瘘模型。该血管支架具有很强的拉伸强度和顺畅的血流，并在兔子体内形成了自体血管。综上，我们的研究展示了利用人体细胞创建仿生透析血管的方法，为创建临床透析血管通路提供了一种新方法。.