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Theranostics 2022Recurrent pregnancy loss (RPL) is a distressing disorder that seriously affects the physical and psychological health of women. RPL is also a sentinel risk marker for...
Recurrent pregnancy loss (RPL) is a distressing disorder that seriously affects the physical and psychological health of women. RPL is also a sentinel risk marker for future obstetric complications and warrants in-depth investigation. Abnormal polarization and functions of decidual macrophages are associated with RPL; however, the underlying mechanisms remain poorly understood. Decorin expression, localization, and content in the decidua of women with normal pregnancy (NP) and those with RPL were measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blotting, immunofluorescence, and enzyme-linked immunosorbent assay. The profiles of decidual macrophage subsets were determined using flow cytometry and immunofluorescence in both groups. The correlation between decorin content and the proportion of decidual macrophage subsets in the decidua of early NP women was determined using Pearson analysis. The effects of decorin on the polarization and functions of macrophages were assessed in an model of Raw264.7 cells via flow cytometry, western blotting, and RT-qPCR. Moreover, the mitochondrial metabolism in Raw264.7 cells under decorin administration was measured via flow cytometry, western blotting, and immunofluorescence. Thirty-three pregnant mice were included in the model and underwent different treatments. The embryo abortion rate, macrophage phenotype in the spleen and uteri, and placental development were evaluated using flow cytometry and hematoxylin-eosin staining. Decorin, derived from decidual stromal cells, was highly expressed in the decidua of women with RPL. A positive correlation between decorin content and the proportion of M1-like macrophages was also observed in the decidua of early NP women. studies showed that decorin treatment inhibited macrophage polarization to M2-like subsets and boosted the inflammatory response, which was related to enhanced anaerobic glycolysis, increased mitochondrial membrane potential and intracellular reactive oxygen species levels, reduced mitochondrial mass, and activation of the myeloid differentiation primary response 88-nuclear factor-κB signaling pathway. Adoptive transfer of decorin-treated bone marrow-derived macrophages in pregnant C57BL/6 mice increased the embryo absorption, accompanied by impaired fetal vascularization. Decidual stromal cell-derived decorin can polarize decidual macrophages toward the M1 phenotype by regulating mitochondrial metabolism, resulting in the occurrence of RPL.
Topics: Animals; Female; Humans; Mice; Pregnancy; Abortion, Habitual; Decidua; Decorin; Macrophages; Mice, Inbred C57BL; Mitochondria; Placenta
PubMed: 36438479
DOI: 10.7150/thno.78467 -
International Journal of Molecular... May 2021Colorectal cancer (CRC) is one of the main causes of cancer death in the world. Post-translational modifications (PTMs) have been extensively studied in malignancies due... (Review)
Review
Colorectal cancer (CRC) is one of the main causes of cancer death in the world. Post-translational modifications (PTMs) have been extensively studied in malignancies due to its relevance in tumor pathogenesis and therapy. This review is focused on the dysregulation of glycosyltransferase expression in CRC and its impact in cell function and in several biological pathways associated with CRC pathogenesis, prognosis and therapeutic approaches. Glycan structures act as interface molecules between cells and their environment and in several cases facilitate molecule function. CRC tissue shows alterations in glycan structures decorating molecules, such as annexin-1, mucins, heat shock protein 90 (Hsp90), β1 integrin, carcinoembryonic antigen (CEA), epidermal growth factor receptor (EGFR), insulin-like growth factor-binding protein 3 (IGFBP3), transforming growth factor beta (TGF-β) receptors, Fas (CD95), PD-L1, decorin, sorbin and SH3 domain-containing protein 1 (SORBS1), CD147 and glycosphingolipids. All of these are described as key molecules in oncogenesis and metastasis. Therefore, glycosylation in CRC can affect cell migration, cell-cell adhesion, actin polymerization, mitosis, cell membrane repair, apoptosis, cell differentiation, stemness regulation, intestinal mucosal barrier integrity, immune system regulation, T cell polarization and gut microbiota composition; all such functions are associated with the prognosis and evolution of the disease. According to these findings, multiple strategies have been evaluated to alter oligosaccharide processing and to modify glycoconjugate structures in order to control CRC progression and prevent metastasis. Additionally, immunotherapy approaches have contemplated the use of neo-antigens, generated by altered glycosylation, as targets for tumor-specific T cells or engineered CAR (Chimeric antigen receptors) T cells.
Topics: Annexin A1; Colorectal Neoplasms; Decorin; ErbB Receptors; Gene Expression Regulation, Neoplastic; Glycosphingolipids; Glycosylation; Glycosyltransferases; Humans; Immunotherapy, Adoptive; Insulin-Like Growth Factor Binding Protein 3; Integrin beta1; Microfilament Proteins; Mucins; Neoplasm Proteins; Protein Processing, Post-Translational; fas Receptor
PubMed: 34070747
DOI: 10.3390/ijms22115822 -
Pharmacology & Therapeutics Jan 2021The transforming growth factor-beta (TGFβ) pathway is essential during embryo development and in maintaining normal homeostasis. During malignancy, the TGFβ pathway is... (Review)
Review
The transforming growth factor-beta (TGFβ) pathway is essential during embryo development and in maintaining normal homeostasis. During malignancy, the TGFβ pathway is co-opted by the tumor to increase fibrotic stroma, to promote epithelial to mesenchymal transition increasing metastasis and producing an immune-suppressed microenvironment which protects the tumor from recognition by the immune system. Compelling preclinical data demonstrate the therapeutic potential of blocking TGFβ function in cancer. However, the TGFβ pathway cannot be described as a driver of malignant disease. Two small molecule kinase inhibitors which block the serine-threonine kinase activity of TGFβRI on TGFβRII, a pan-TGFβ neutralizing antibody, a TGFβ trap, a TGFβ antisense agent, an antibody which stabilizes the latent complex of TGFβ and a fusion protein which neutralizes TGFβ and binds PD-L1 are in clinical development. The challenge is how to most effectively incorporate blocking TGFβ activity alone and in combination with other therapeutics to improve treatment outcome.
Topics: Animals; B7-H1 Antigen; Epithelial-Mesenchymal Transition; Humans; Neoplasms; Receptor, Transforming Growth Factor-beta Type I; Receptor, Transforming Growth Factor-beta Type II; Transforming Growth Factor beta; Tumor Microenvironment
PubMed: 32835827
DOI: 10.1016/j.pharmthera.2020.107666 -
Advanced Science (Weinheim,... Mar 2022Traumatic brain injury (TBI) is a risk factor for posttraumatic stress disorder (PTSD). Augmented fear is a defining characteristic of PTSD, and the amygdala is...
Single-Nucleus RNA Sequencing Reveals that Decorin Expression in the Amygdala Regulates Perineuronal Nets Expression and Fear Conditioning Response after Traumatic Brain Injury.
Traumatic brain injury (TBI) is a risk factor for posttraumatic stress disorder (PTSD). Augmented fear is a defining characteristic of PTSD, and the amygdala is considered the main brain region to process fear. The mechanism by which the amygdala is involved in fear conditioning after TBI is still unclear. Using single-nucleus RNA sequencing (snRNA-seq), transcriptional changes in cells in the amygdala after TBI are investigated. In total, 72 328 nuclei are obtained from the sham and TBI groups. 7 cell types, and analysis of differentially expressed genes (DEGs) reveals widespread transcriptional changes in each cell type after TBI are identified. In in vivo experiments, it is demonstrated that Decorin (Dcn) expression in the excitatory neurons of the amygdala significantly increased after TBI, and Dcn knockout in the amygdala mitigates TBI-associated fear conditioning. Of note, this effect is caused by a Dcn-mediated decrease in the expression of perineuronal nets (PNNs), which affect the glutamate-γ-aminobutyric acid balance in the amygdala. Finally, the results suggest that Dcn functions by interacting with collagen VI α3 (Col6a3). Consequently, the findings reveal transcriptional changes in different cell types of the amygdala after TBI and provide direct evidence that Dcn relieves fear conditioning by regulating PNNs.
Topics: Amygdala; Animals; Brain Injuries, Traumatic; Decorin; Fear; Mice; Sequence Analysis, RNA
PubMed: 35038242
DOI: 10.1002/advs.202104112 -
Journal of Experimental & Clinical... Jul 2023The interplay between gut microbiota and tumor microenvironment (TME) in the pathogenesis of colorectal cancer (CRC) is largely unknown. Here, we elucidated the...
BACKGROUND
The interplay between gut microbiota and tumor microenvironment (TME) in the pathogenesis of colorectal cancer (CRC) is largely unknown. Here, we elucidated the functional role of B. adolescentis and its possible mechanism on the manipulation of Decorin macrophages in colorectal cancer.
METHODS
The relative abundance of B. adolescentis in tumor or para-tumor tissue of CRC patients was analyzed. The role of B. adolescentis was explored in the CRC animal models. The single cell-RNA sequencing (scRNA-seq) was used to investigate the myeloid cells subsets in TME. The expression level of TLR2/YAP axis and its downstream Decorin in macrophages were tested by Western blot and qRT-PCR. Knockdown of Decorin in Raw264.7 was performed to investigate the effect of Decorin macrophages on subcutaneous tumor formation. Multi-immunofluorescence assay examined the number of Decorin macrophages on the CRC tissue.
RESULTS
We found that the abundance of B. adolescentis was significantly reduced in tumor tissue of CRC patients. Supplementation with B. adolescentis suppressed AOM/DSS-induced tumorigenesis in mice. ScRNA-seq and animal experiment revealed that B. adolescentis increased Decorin macrophages. Mechanically, Decorin was activated by TLR2/YAP axis in macrophages. The abundance of B. adolescentis was correlated with the number of Decorin macrophages and the expression level of TLR2 in tumor tissue of CRC patients.
CONCLUSIONS
These results highlight that B. adolescentis induced Decorin macrophages and provide a novel therapeutic target for probiotic-based modulation of immune microenvironment in CRC.
Topics: Animals; Mice; Bifidobacterium adolescentis; Decorin; Toll-Like Receptor 2; Carcinogenesis; Macrophages; Colorectal Neoplasms; Tumor Microenvironment
PubMed: 37464382
DOI: 10.1186/s13046-023-02746-6 -
Cells Dec 2022Decorin is an archetypal member of the small leucine-rich proteoglycan gene family and is involved in various biological functions and many signaling networks,... (Review)
Review
Decorin is an archetypal member of the small leucine-rich proteoglycan gene family and is involved in various biological functions and many signaling networks, interacting with extra-cellular matrix (ECM) components, growth factors, and receptor tyrosine kinases. Decorin also modulates the growth factors, cell proliferation, migration, and angiogenesis. It has been reported to be involved in many ischemic and fibrotic eye diseases, such as congenital stromal dystrophy of the cornea, anterior subcapsular fibrosis of the lens, proliferative vitreoretinopathy, et al. Furthermore, recent evidence supports its role in secondary posterior capsule opacification (PCO) after cataract surgery. The expression of decorin mRNA in lens epithelial cells in vitro was found to decrease upon transforming growth factor (TGF)-β-2 addition and increase upon fibroblast growth factor (FGF)-2 addition. Wound healing of the injured lens in mice transgenic for lens-specific human decorin was promoted by inhibiting myofibroblastic changes. Decorin may be associated with epithelial-mesenchymal transition and PCO development in the lens. Gene therapy and decorin administration have the potential to serve as excellent therapeutic approaches for modifying impaired wound healing, PCO, and other eye diseases related to fibrosis and angiogenesis. In this review, we present findings regarding the roles of decorin in the lens and ocular diseases.
Topics: Mice; Animals; Humans; Decorin; Lens, Crystalline; Capsule Opacification; Epithelial Cells; Fibrosis
PubMed: 36611867
DOI: 10.3390/cells12010074 -
Journal of Immunology Research 2022Decorin is an extracellular matrix protein that belongs to the family of small leucine-rich proteoglycans. As a matrix protein, the first discovered role of decorin is... (Review)
Review
Decorin is an extracellular matrix protein that belongs to the family of small leucine-rich proteoglycans. As a matrix protein, the first discovered role of decorin is participating in collagen fibril formation. Many other functions of decorin in various biological processes have been subsequently identified. Decorin is involved in an extensive signaling network and can interact with other extracellular matrix components, growth factors, receptor tyrosine kinases, and various proteases. Decorin has been shown to be involved in wound repair, cell cycle, angiogenesis, tumor metastasis, and autophagy. Recent evidence indicates that it also plays a role in immune regulation and inflammatory diseases. This review summarizes the characteristics of decorin in immune and inflammatory diseases, including inflammatory bowel disease (IBD), Sjögren's syndrome (SS), chronic obstructive pulmonary disease (COPD), IgA nephropathy, rheumatoid arthritis (RA), spondyloarthritis (SpA), osteoarthritis, multiple sclerosis (MS), idiopathic inflammatory myopathies (IIM), and systemic sclerosis (SSc) and discusses the potential role in these disorders.
Topics: Autoimmune Diseases; Decorin; Extracellular Matrix; Extracellular Matrix Proteins; Humans; Inflammation; Neovascularization, Pathologic; Proteoglycans
PubMed: 36033387
DOI: 10.1155/2022/1283383 -
Decorin: a potential therapeutic candidate for ligamentum flavum hypertrophy by antagonizing TGF-β1.Experimental & Molecular Medicine Jul 2023Ligamentum flavum hypertrophy (LFH) is the main physiological and pathological mechanism of lumbar spinal canal stenosis (LSCS). The specific mechanism for LFH has not...
Ligamentum flavum hypertrophy (LFH) is the main physiological and pathological mechanism of lumbar spinal canal stenosis (LSCS). The specific mechanism for LFH has not been completely clarified. In this study, bioinformatic analysis, human ligamentum flavum (LF) tissues collection and analysis, and in vitro and in vivo experiments were conducted to explore the effect of decorin (DCN) on LFH pathogenesis. Here, we found that TGF-β1, collagen I, collagen III, α-SMA and fibronectin were significantly upregulated in hypertrophic LF samples. The DCN protein expression in hypertrophic LF samples was higher than that in non-LFH samples, but the difference was not significant. DCN inhibited the expression of TGF-β1-induced fibrosis-associated proteins in human LF cells, including collagen I, collagen III, α-SMA, and fibronectin. ELISAs showed that TGF-β1 can upregulate PINP and PIIINP in the cell supernatant, and this effect was inhibited after DCN administration. Mechanistic studies revealed that DCN suppressed TGF-β1-induced fibrosis by blocking the TGF-β1/SMAD3 signaling pathway. In addition, DCN ameliorated mechanical stress-induced LFH in vivo. In summary, our findings indicated that DCN ameliorated mechanical stress-induced LFH by antagonizing the TGF-β1/SMAD3 signaling pathway in vitro and in vivo. These findings imply that DCN is a potential therapeutic candidate for ligamentum flavum hypertrophy.
Topics: Humans; Transforming Growth Factor beta1; Decorin; Fibronectins; Ligamentum Flavum; Collagen; Collagen Type I; Hypertrophy; Fibrosis
PubMed: 37394592
DOI: 10.1038/s12276-023-01023-y -
Cancers Feb 2022Proteoglycans are emerging as critical regulators of intracellular catabolism. This rise in prominence has transformed our basic understanding and alerted us to the... (Review)
Review
Proteoglycans are emerging as critical regulators of intracellular catabolism. This rise in prominence has transformed our basic understanding and alerted us to the existence of non-canonical pathways, independent of nutrient deprivation, that potently control the autophagy downstream of a cell surface receptor. As a member of the small leucine-rich proteoglycan gene family, decorin has single-handedly pioneered the connection between extracellular matrix signaling and autophagy regulation. Soluble decorin evokes protracted endothelial cell autophagy via Peg3 and breast carcinoma cell mitophagy via mitostatin by interacting with VEGFR2 or the MET receptor tyrosine kinase, respectively. In this paper, we give a mechanistic perspective of the vital factors underlying the nutrient-independent, SLRP-dependent programs utilized for autophagic and/or mitophagic progression in breast cancer. Future protein therapies based on decorin (or fellow proteoglycan members) will represent a quantum leap forward in transforming autophagic progression into a powerful tool to control intracellular cell catabolism from the outside.
PubMed: 35159071
DOI: 10.3390/cancers14030804 -
Frontiers in Oncology 2021The complex and adaptive nature of malignant neoplasm constitute a major challenge for the development of effective anti-oncogenic therapies. Emerging evidence has... (Review)
Review
The complex and adaptive nature of malignant neoplasm constitute a major challenge for the development of effective anti-oncogenic therapies. Emerging evidence has uncovered the pivotal functions exerted by the small leucine-rich proteoglycans, decorin and biglycan, in affecting tumor growth and progression. In their soluble forms, decorin and biglycan act as powerful signaling molecules. By receptor-mediated signal transduction, both proteoglycans modulate key processes vital for tumor initiation and progression, such as autophagy, inflammation, cell-cycle, apoptosis, and angiogenesis. Despite of their structural homology, these two proteoglycans interact with distinct cell surface receptors and thus modulate distinct signaling pathways that ultimately affect cancer development. In this review, we summarize growing evidence for the complex roles of decorin and biglycan signaling in tumor biology and address potential novel therapeutic implications.
PubMed: 34917515
DOI: 10.3389/fonc.2021.801801