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Viruses May 2024Numerous human adenovirus (AdV) types are endowed with arginine-glycine-aspartic acid (RGD) sequences that enable them to recognize vitronectin-binding (αv) integrins.... (Review)
Review
Numerous human adenovirus (AdV) types are endowed with arginine-glycine-aspartic acid (RGD) sequences that enable them to recognize vitronectin-binding (αv) integrins. These RGD-binding cell receptors mediate AdV entry into host cells, a crucial early step in virus infection. Integrin interactions with adenoviruses not only initiate receptor-mediated endocytosis but also facilitate AdV capsid disassembly, a prerequisite for membrane penetration by AdV protein VI. This review discusses fundamental aspects of AdV-host interactions mediated by integrins. Recent efforts to re-engineer AdV vectors and non-viral nanoparticles to target αv integrins for bioimaging and the eradication of cancer cells will also be discussed.
Topics: Humans; Genetic Therapy; Integrins; Virus Internalization; Genetic Vectors; Adenoviruses, Human; Adenoviridae; Animals; Receptors, Virus; Neoplasms; Integrin alphaV; Oligopeptides
PubMed: 38793651
DOI: 10.3390/v16050770 -
Theranostics 2024Cancer cells are capable of evading clearance by macrophages through overexpression of anti-phagocytic surface proteins known as "don't eat me" signals. Monoclonal...
Cancer cells are capable of evading clearance by macrophages through overexpression of anti-phagocytic surface proteins known as "don't eat me" signals. Monoclonal antibodies that antagonize the "don't-eat-me" signaling in macrophages and tumor cells by targeting phagocytic checkpoints have shown therapeutic promises in several cancer types. However, studies on the responses to these drugs have revealed the existence of other unknown "don't eat me" signals. Moreover, identification of key molecules and interactions regulating macrophage phagocytosis is required for tumor therapy. CRISPR screen was used to identify genes that impede macrophage phagocytosis. To explore the function of Vtn and C1qbp in phagocytosis, knockdown and subsequent functional experiments were conducted. Flow cytometry were performed to explore the phagocytosis rate, polarization of macrophage, and immune microenvironment of mouse tumor. To explore the underlying molecular mechanisms, RNA sequencing, immunoprecipitation, mass spectrometry, and immunofluorescence were conducted. Then, in vivo experiments in mouse models were conducted to explore the probability of Vtn knockdown combined with anti-CD47 therapy in breast cancer. Single-cell sequencing data from the Gene Expression Omnibus from The Cancer Genome Atlas database were analyzed. We performed a genome-wide CRISPR screen to identify genes that impede macrophage phagocytosis, followed by analysis of cell-to-cell interaction databases. We identified a ligand-receptor pair of Vitronectin (Vtn) and complement C1Q binding protein (C1qbp) in tumor cells or macrophages, respectively. We demonstrated tumor cell-secreted Vtn interacts with C1qbp localized on the cell surface of tumor-associated macrophages, inhibiting phagocytosis of tumor cells and shifting macrophages towards the M2-like subtype in the tumor microenvironment. Mechanistically, the Vtn-C1qbp axis facilitated FcγRIIIA/CD16-induced Shp1 recruitment, which reduced the phosphorylation of Syk. Furthermore, the combination of Vtn knockdown and anti-CD47 antibody effectively enhanced phagocytosis and infiltration of macrophages, resulting in a reduction of tumor growth in vivo. This work has revealed that the Vtn-C1qbp axis is a new anti-phagocytic signal in tumors, and targeting Vtn and its interaction with C1qbp may sensitize cancer to immunotherapy, providing a new molecular target for the treatment of triple-negative breast cancer.
Topics: Phagocytosis; Animals; Mice; Humans; Macrophages; CD47 Antigen; Female; Cell Line, Tumor; Tumor Microenvironment; Cell Communication; Breast Neoplasms; Signal Transduction; Mice, Inbred BALB C; Carrier Proteins; Mitochondrial Proteins
PubMed: 38773982
DOI: 10.7150/thno.94537 -
Experimental Hematology May 2024Hematopoiesis occurs in the bone marrow (BM), within a specialized microenvironment referred to as the stem cell niche, where the hematopoietic stem cells (HSCs) reside... (Review)
Review
Hematopoiesis occurs in the bone marrow (BM), within a specialized microenvironment referred to as the stem cell niche, where the hematopoietic stem cells (HSCs) reside and are regulated for quiescence, self-renewal and differentiation through intrinsic and extrinsic mechanisms. The BM contains at least two distinctive HSC-supportive niches: an endosteal osteoblastic niche that supports quiescence and self-renewal and a more vascular/perisinusoidal niche that promotes proliferation and differentiation. Both associate with supporting mesenchymal stromal cells. Within the more hypoxic osteoblastic niche, HSCs specifically interact with the osteoblasts that line the endosteal surface, which secrete several important HSC quiescence and maintenance regulatory factors. In vivo imaging indicates that the HSCs and progenitors located further away, in the vicinity of sinusoidal endothelial cells, are more proliferative. Here, HSCs interact with endothelial cells via specific cell adhesion molecules. Endothelial cells also secrete several factors important for HSC homeostasis and proliferation. In addition, HSCs and mesenchymal stromal cells are embedded within the extracellular matrix (ECM), an important network of proteins such as collagen, elastin, laminin, proteoglycans, vitronectin, and fibronectin. The ECM provides mechanical characteristics such as stiffness and elasticity important for cell behavior regulation. ECM proteins are also able to bind, sequester, display, and distribute growth factors across the BM, thus directly affecting stem cell fate and regulation of hematopoiesis. These important physical and chemical features of the BM require careful consideration when creating three-dimensional models of the BM.
PubMed: 38740324
DOI: 10.1016/j.exphem.2024.104233 -
Revista Da Associacao Medica Brasileira... 2024
Topics: Humans; Diabetes, Gestational; Pregnancy; Female; Plasminogen Activator Inhibitor 1; Vitronectin
PubMed: 38716956
DOI: 10.1590/1806-9282.20231607 -
Bioscience Reports May 2024During inflammation and situations of cellular stress protein disulfide isomerase (PDI) is released in the blood plasma from the platelet and endothelial cells to...
During inflammation and situations of cellular stress protein disulfide isomerase (PDI) is released in the blood plasma from the platelet and endothelial cells to influence thrombosis. The addition of exogenous PDI makes the environment pro-thrombotic by inducing disulfide bond formation in specific plasma protein targets like vitronectin, factor V, and factor XI. However, the mechanistic details of PDI interaction with its target remain largely unknown. A decrease in the coagulation time was detected in activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) on addition of the purified recombinant PDI (175 nM). The coagulation time can be controlled using an activator (quercetin penta sulfate, QPS) or an inhibitor (quercetin 3-rutinoside, Q3R) of PDI activity. Likewise, the PDI variants that increase the PDI activity (H399R) decrease, and the variant with low activity (C53A) increases the blood coagulation time. An SDS-PAGE and Western blot analysis showed that the PDI does not form a stable complex with either thrombin or antithrombin (ATIII) but it uses the ATIII-thrombin complex as a template to bind and maintain its activity. A complete inhibition of thrombin activity on the formation of ATIII-thrombin-PDI complex, and the complex-bound PDI-catalyzed disulfide bond formation of the target proteins may control the pro- and anti-thrombotic role of PDI.
Topics: Humans; Protein Disulfide-Isomerases; Thrombin; Blood Coagulation; Antithrombin III; Protein Binding; Antithrombins; Quercetin
PubMed: 38660763
DOI: 10.1042/BSR20231540 -
Medicine Apr 2024Chronic renal failure (CRF) causes a reduction in glomerular filtration rate and damage to renal parenchyma. Fushengong decoction (FSGD) showed improvement in renal... (Observational Study)
Observational Study
Chronic renal failure (CRF) causes a reduction in glomerular filtration rate and damage to renal parenchyma. Fushengong decoction (FSGD) showed improvement in renal function in CRF rats. This study aims to analyze the differentially expressed proteins in CRF patients treated with Western medicine alone or in combination with FSGD. Sixty patients with CRF recruited from Yongchuan Traditional Chinese Medicine Hospital affiliated to Chongqing Medical University were randomly assigned into control (treated with Western medicine alone) and observation groups (received additional FSGD treatment thrice daily for 8 weeks). The clinical efficacy and changes in serum Bun, serum creatinine, Cystatin C, and transforming growth factor beta 1 (TGF-β1) before and after treatment were observed. We employed isotope relative labeling absolute quantification labeling and liquid chromatography-mass spectrometry to identify differentially expressed proteins and carried out bioinformatics Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Patients in the observation group showed greater clinical improvement and lower levels of serum Bun, serum creatinine, Cyc-c, and TGF-β1 than the control group. We identified 32 differentially up-regulated and 52 down-regulated proteins in the observation group. These proteins are involved in the blood coagulation system, protein serine/threonine kinase activity, and TGF-β, which are closely related to the pathogenesis of CRF. Protein-protein-interaction network analysis indicated that candidate proteins fibronectin 1, fibrinogen alpha chain, vitronectin, and Serpin Family C Member 1 were in the key nodes. This study provided an experimental basis suggesting that FSGD combined with Western medicine could significantly improve renal function and renal fibrosis of CRF patients, which may be through the regulation of fibronectin 1, fibrinogen alpha chain, vitronectin, Serpin Family C Member 1, TGF-β, and the complement coagulation pathway (see Graphical abstract S1, Supplemental Digital Content, http://links.lww.com/MD/L947).
Topics: Animals; Humans; Rats; Creatinine; Extracellular Matrix Proteins; Fibrinogen; Fibronectins; Kidney Failure, Chronic; Renal Insufficiency, Chronic; Serpins; Transforming Growth Factor beta; Transforming Growth Factor beta1; Vitronectin
PubMed: 38608120
DOI: 10.1097/MD.0000000000037473 -
Biomaterials Jul 2024Cells assemble fibronectin, the major extracellular matrix (ECM) protein, into fibrillar matrices, which serve as 3D architectural scaffolds to provide, together with...
Cells assemble fibronectin, the major extracellular matrix (ECM) protein, into fibrillar matrices, which serve as 3D architectural scaffolds to provide, together with other ECM proteins tissue-specific environments. Although recent approaches enable to bioengineer 3D fibrillar fibronectin matrices in vitro, it remains elusive how fibronectin can be co-assembled with other ECM proteins into complex 3D fibrillar matrices that recapitulate tissue-specific compositions and cellular responses. Here, we introduce the engineering of fibrillar fibronectin-templated 3D matrices that can be complemented with other ECM proteins, including vitronectin, collagen, and laminin to resemble ECM architectures observed in vivo. For the co-assembly of different ECM proteins, we employed their innate fibrillogenic mechanisms including shear forces, pH-dependent electrostatic interactions, or specific binding domains. Through recapitulating various tissue-specific ECM compositions and morphologies, the large scale multi-composite 3D fibrillar ECM matrices can guide fibroblast adhesion, 3D fibroblast tissue formation, or tissue morphogenesis of epithelial cells. In other examples, we customize multi-composite 3D fibrillar matrices to support the growth of signal propagating neuronal networks and of human brain organoids. We envision that these 3D fibrillar ECM matrices can be tailored in scale and composition to modulate tissue-specific responses across various biological length scales and systems, and thus to advance manyfold studies of cell biological systems.
Topics: Fibronectins; Extracellular Matrix; Humans; Tissue Engineering; Fibroblasts; Animals; Tissue Scaffolds; Cell Adhesion; Mice; Organoids
PubMed: 38603826
DOI: 10.1016/j.biomaterials.2024.122560 -
BioRxiv : the Preprint Server For... Mar 2024Tissue barriers must be rapidly restored after injury to promote regeneration. However, the mechanism behind this process is unclear, particularly in cases where the...
Tissue barriers must be rapidly restored after injury to promote regeneration. However, the mechanism behind this process is unclear, particularly in cases where the underlying extracellular matrix is still compromised. Here, we report the discovery of matrimeres as constitutive nanoscale mediators of tissue integrity and function. We define matrimeres as non-vesicular nanoparticles secreted by cells, distinguished by a primary composition comprising at least one matrix protein and DNA molecules serving as scaffolds. Mesenchymal stromal cells assemble matrimeres from fibronectin and DNA within acidic intracellular compartments. Drawing inspiration from this biological process, we have achieved the successful reconstitution of matrimeres without cells. This was accomplished by using purified matrix proteins, including fibronectin and vitronectin, and DNA molecules under optimal acidic pH conditions, guided by the heparin-binding domain and phosphate backbone, respectively. Plasma fibronectin matrimeres circulate in the blood at homeostasis but exhibit a 10-fold decrease during systemic inflammatory injury . Exogenous matrimeres rapidly restore vascular integrity by actively reannealing endothelial cells post-injury and remain persistent in the host tissue matrix. The scalable production of matrimeres holds promise as a biologically inspired platform for regenerative nanomedicine.
PubMed: 38585943
DOI: 10.1101/2024.03.25.586585 -
Anatomy & Cell Biology Jun 2024Vitronectin (VN) is an extracellular matrix protein with a crucial role in regulating bone remodeling. In this study, we aimed to investigate the effect of VN deficiency...
Vitronectin (VN) is an extracellular matrix protein with a crucial role in regulating bone remodeling. In this study, we aimed to investigate the effect of VN deficiency in a mouse model of osteoporosis induced by ovariectomy (OVX). The findings revealed that the absence of VN led to an increase in the activity of tartrate-resistant acid phosphatase (TRAP), a marker for osteoclasts, in the plasma of OVX-operated mice. TRAP staining further demonstrated that VN deficiency resulted in a higher number of osteoclasts within the femurs of OVX-operated mice. X-ray micro-computed tomography analysis of the femurs in OVX-operated mice indicated that VN deficiency significantly suppressed the OVX-induced increase of marrow area and total volume of bone. Additionally, we assessed structural model index (SMI) and degree of anisotropy (DA) as indices of osteoporosis. The results showed that VN deficiency effectively attenuated the OVX-induced increase in SMI and DA among OVX-operated mice. In summary, our study demonstrates the vital role of VN in regulating osteoclastogenesis and bone remodeling in the mouse model of osteoporosis.
PubMed: 38575559
DOI: 10.5115/acb.23.251 -
Heliyon Mar 2024Ovarian cancer (OC) is deadly, and likely arises from the fallopian tube epithelium (FTE). Despite the association of OC with ovulation, OC typically presents in...
Ovarian cancer (OC) is deadly, and likely arises from the fallopian tube epithelium (FTE). Despite the association of OC with ovulation, OC typically presents in post-menopausal women who are no longer ovulating. The goal of this study was to understand how ovulation and aging interact to impact OC progression from the FTE. Follicular fluid released during ovulation induces DNA damage in the FTE, however, the role of aging on FTE exposure to follicular fluid is unexplored. Follicular fluid samples were collected from 14 women and its effects on FTE cells was assessed. Follicular fluid caused DNA damage and lipid oxidation in an age-dependent manner, but instead induced cell proliferation in a dose-dependent manner, independent of age in FTE cells. Follicular fluid regardless of age disrupted FTE spheroid formation and stimulated attachment and growth on ultra-low attachment plates. Proteomics analysis of the adhesion proteins in the follicular fluid samples identified vitronectin, a glycoprotein responsible for FTE cell attachment and spreading.
PubMed: 38501015
DOI: 10.1016/j.heliyon.2024.e27336