Decorin (DCN) Downregulation Activates Breast Stromal Fibroblasts and Promotes Their Pro-Carcinogenic Effects through the IL-6/STAT3/AUF1 Signaling.

Decorin (DCN), a member of the small leucine-rich proteoglycan gene family, is secreted from stromal fibroblasts with non-cell-autonomous anti-breast-cancer effects. Therefore, in the present study, we sought to elucidate the function of decorin in breast stromal fibroblasts (BSFs). We first showed DCN downregulation in active cancer-associated fibroblasts (CAFs) compared to their adjacent tumor counterpart fibroblasts at both the mRNA and protein levels. Interestingly, breast cancer cells and the recombinant IL-6 protein, both known to activate fibroblasts in vitro, downregulated DCN in BSFs. Moreover, specific DCN knockdown in breast fibroblasts modulated the expression/secretion of several CAF biomarkers and cancer-promoting proteins (α-SMA, FAP- α, SDF-1 and IL-6) and enhanced the invasion/proliferation abilities of these cells through activation of the STAT3/AUF1 signaling. Furthermore, DCN-deficient fibroblasts promoted the epithelial-to-mesenchymal transition and stemness processes in BC cells in a paracrine manner, which increased their resistance to cisplatin. These DCN-deficient fibroblasts also enhanced angiogenesis and orthotopic tumor growth in mice in a paracrine manner. On the other hand, ectopic expression of DCN in CAFs suppressed their active features and their paracrine pro-carcinogenic effects. Together, the present findings indicate that endogenous DCN suppresses the pro-carcinogenic and pro-metastatic effects of breast stromal fibroblasts.

Decorin suppresses tumor lymphangiogenesis: A mechanism to curtail cancer progression.

The complex interplay between malignant cells and the cellular and molecular components of the tumor stroma is a key aspect of cancer growth and development. These tumor-host interactions are often affected by soluble bioactive molecules such as proteoglycans. Decorin, an archetypical small leucine-rich proteoglycan primarily expressed by stromal cells, affects cancer growth in its soluble form by interacting with several receptor tyrosine kinases (RTK). Overall, decorin leads to a context-dependent and protracted cessation of oncogenic RTK activity by attenuating their ability to drive a prosurvival program and to sustain a proangiogenic network. Through an unbiased transcriptomic analysis using deep RNAseq, we identified that decorin down-regulated a cluster of tumor-associated genes involved in lymphatic vessel (LV) development when systemically delivered to mice harboring breast carcinoma allografts. We found that Lyve1 and Podoplanin, two established markers of LVs, were markedly suppressed at both the mRNA and protein levels, and this suppression correlated with a significant reduction in tumor LVs. We further identified that soluble decorin, but not its homologous proteoglycan biglycan, inhibited LV sprouting in an ex vivo 3D model of lymphangiogenesis. Mechanistically, we found that decorin interacted with vascular endothelial growth factor receptor 3 (VEGFR3), the main lymphatic RTK, and its activity was required for the decorin-mediated block of lymphangiogenesis. Finally, we identified that Lyve1 was in part degraded via decorin-evoked autophagy in a nutrient- and energy-independent manner. These findings implicate decorin as a biological factor with antilymphangiogenic activity and provide a potential therapeutic agent for curtailing breast cancer growth and metastasis.

The extracellular matrix differentially directs myoblast motility and differentiation in distinct forms of muscular dystrophy: Dystrophic matrices alter myoblast motility.

Extracellular matrix (ECM) pathologic remodeling underlies many disorders, including muscular dystrophy. Tissue decellularization removes cellular components while leaving behind ECM components. We generated "on-slide" decellularized tissue slices from genetically distinct dystrophic mouse models. The ECM of dystrophin- and sarcoglycan-deficient muscles had marked thrombospondin 4 deposition, while dysferlin-deficient muscle had excess decorin. Annexins A2 and A6 were present on all dystrophic decellularized ECMs, but annexin matrix deposition was excessive in dysferlin-deficient muscular dystrophy. Muscle-directed viral expression of annexin A6 resulted in annexin A6 in the ECM. C2C12 myoblasts seeded onto decellularized matrices displayed differential myoblast mobility and fusion. Dystrophin-deficient decellularized matrices inhibited myoblast mobility, while dysferlin-deficient decellularized matrices enhanced myoblast movement and differentiation. Myoblasts treated with recombinant annexin A6 increased mobility and fusion like that seen on dysferlin-deficient decellularized matrix and demonstrated upregulation of ECM and muscle cell differentiation genes. These findings demonstrate specific fibrotic signatures elicit effects on myoblast activity.

Effect of Vaginal Microecological Alterations on Female Pelvic Organ Prolapse.

INTRODUCTION AND HYPOTHESIS: The objective was to investigate the correlation between endogenous vaginal microecological alterations and female pelvic organ prolapse (POP). METHODS: Patients who underwent vaginal hysterectomy were retrospectively analyzed as the POP group (n = 30) and the non-POP group (n = 30). The vaginal microbial metabolites and enzyme levels were tested using the dry chemoenzymatic method. The mRNA and protein expression were tested using real-time quantitative PCR and immunohistochemistry. SPSS version 25.0 and GraphPad Prism 8.0 were performed for statistical analysis. RESULTS: Compared with the non-POP group, the vaginal pH, H2O2 positivity and leukocyte esterase positivity were higher in patients with POP (all p < 0.05). Further analysis showed that patients with pelvic organ prolapse quantification (POP-Q) stage IV had higher rates of vaginal pH, H2O2 positivity and leukocyte esterase positivity than those with POP-Q stage III. Additionally, the mRNA expression of decorin (DCN), transforming growth factor beta 1 (TGF-ß1), and matrix metalloproteinase-3 (MMP-3) in uterosacral ligament tissues were higher, whereas collagen I and III were lower. Similarly, the positive expression of MMP-3 in uterosacral ligament tissue was significantly upregulated in the POP group compared with the non-POP group (p = 0.035), whereas collagen I (p = 0.004) and collagen III (p = 0.019) in uterosacral ligament tissue were significantly downregulated in the POP group. Correlation analysis revealed that there was a significant correlation between vaginal microecology and collagen metabolism. In addition, MMP-3 correlated negatively with collagen I and collagen III (p = 0.002, r = -0.533; p = 0.002, r = -0.534 respectively), whereas collagen I correlated positively with collagen III (p = 0.001, r = 0.578). CONCLUSIONS: Vaginal microecological dysbiosis affects the occurrence of female POP, which could be considered a novel therapeutic option.

Long-Term Follow-Up of Pediatric Excimer Laser-Assisted Penetrating Keratoplasty for Congenital Stromal Corneal Dystrophy.

PURPOSE: The purpose of this study was to highlight characteristic clinical and microscopic findings and report the long-term follow-up of pediatric excimer laser-assisted penetrating keratoplasty (excimer-PKP) for congenital stromal corneal dystrophy (CSCD). METHODS: A 2-year-old Greek child presented with CSCD at our department. Clinical examination showed bilateral flake-like whitish corneal opacities affecting the entire corneal stroma up to the limbus. Genetic testing identified a mutation of the decorin gene (c.962delA). The variant was not present in the parents and represented a de novo mutation. The uncorrected visual acuity was 20/100 in both eyes. Excimer-PKP (8.0/8.1 mm) was performed on the right eye at the age of 2.5 years and on the left eye at the age of 3 years. Postoperatively, alternating occlusion treatment was performed. RESULTS: The light microscopic examination demonstrated a disorganized extracellular matrix of the corneal stroma characterized by a prominent irregular arrangement of stromal collagen lamellae with large interlamellar clefts containing ground substance, highlighted by periodic acid-Schiff- and Alcian blue-positive reaction detecting acid mucopolysaccharides. Electron microscopy showed disorganization and caliber variation of collagen lamellae and thin filaments within an electron-lucent ground substance. The postoperative course was unremarkable. Both grafts remained completely clear 14 years postoperatively. Corneal tomography showed moderate regular astigmatism with normal corneal thickness. The corrected distance visual acuity was 20/25 in both eyes. CONCLUSIONS: Excimer-PKP for CSCD might be associated with excellent long-term results and a good prognosis, particularly when the primary surgery is performed at a very young age. However, this requires close postoperative follow-up examinations by an experienced pediatric ophthalmologist to avoid severe amblyopia.

Tissue-targeted and localized AAV5-DCN and AAV5-PEDF combination gene therapy abrogates corneal fibrosis and concurrent neovascularization in rabbit eyes in vivo.

PURPOSE: Corneal fibrosis and neovascularization (CNV) after ocular trauma impairs vision. This study tested therapeutic potential of tissue-targeted adeno-associated virus5 (AAV5) mediated decorin (DCN) and pigment epithelium-derived factor (PEDF) combination genes in vivo. METHODS: Corneal fibrosis and CNV were induced in New Zealand White rabbits via chemical trauma. Gene therapy in stroma was delivered 30-min after chemical-trauma via topical AAV5-DCN and AAV5-PEDF application using a cloning cylinder. Clinical eye examinations and multimodal imaging in live rabbits were performed periodically and corneal tissues were collected 9-day and 15-day post euthanasia. Histological, cellular, and molecular and apoptosis assays were used for efficacy, tolerability, and mechanistic studies. RESULTS: The AAV5-DCN and AAV5-PEDF combination gene therapy significantly reduced corneal fibrosis (p < 0.01 or p < 0.001) and CNV (p < 0.001) in therapy-given (chemical-trauma and AAV5-DCN + AAV5-PEDF) rabbit eyes compared to the no-therapy given eyes (chemical-trauma and AAV5-naked vector). Histopathological analyses demonstrated significantly reduced fibrotic α-smooth muscle actin and endothelial lectin expression in therapy-given corneas compared to no-therapy corneas on day-9 (p < 0.001) and day-15 (p < 0.001). Further, therapy-given corneas showed significantly increased Fas-ligand mRNA levels (p < 0.001) and apoptotic cell death in neovessels (p < 0.001) compared to no-therapy corneas. AAV5 delivered 2.69 × 107 copies of DCN and 2.31 × 107 copies of PEDF genes per µg of DNA. AAV5 vector and delivered DCN and PEDF genes found tolerable to the rabbit eyes and caused no significant toxicity to the cornea. CONCLUSION: The combination AAV5-DCN and AAV5-PEDF topical gene therapy effectively reduces corneal fibrosis and CNV with high tolerability in vivo in rabbits. Additional studies are warranted.

Neonatal Achilles Tendon Microstructure is Negatively Impacted by Decorin and Biglycan Knockdown After Injury and During Development.

Interest in studying neonatal development and the improved healing response observed in neonates is increasing, with the goal of using this work to create better therapeutics for tendon injury. Decorin and biglycan are two small leucine-rich proteoglycans that play important roles in collagen fibrillogenesis to develop, maintain, and repair tendon structure. However, little is known about the roles of decorin and biglycan in early neonatal development and healing. The goal of this study was to determine the effects of decorin and biglycan knockdown on Achilles tendon structure and mechanics during neonatal development and recovery of these properties after injury of the neonatal tendon. We hypothesized that knockdown of decorin and biglycan would disrupt the neonatal tendon developmental process and produce tendons with impaired mechanical and structural properties. We found that knockdown of decorin and biglycan in an inducible, compound decorin/biglycan knockdown model, both during development and after injury, in neonatal mice produced tendons with reduced mechanical properties. Additionally, the collagen fibril microstructure resembled an immature tendon with a large population of small diameter fibrils and an absence of larger diameter fibrils. Overall, this study demonstrates the importance of decorin and biglycan in facilitating tendon growth and maturation during neonatal development.

A role for decorin in improving motor deficits after traumatic brain injury.

Traumatic brain injury (TBI) is the leading cause of death and disability due to injury worldwide. Extracellular matrix (ECM) remodeling is known to significantly contribute to TBI pathophysiology. Glycosaminoglycans, which are long-chain, variably sulfated polysaccharides abundant within the ECM, have previously been shown to be substantially altered after TBI. In this study, we sought to delineate the dynamics of glycosaminoglycan alterations after TBI and discover the precise biologic processes responsible for observed glycosaminoglycan changes after injury. We performed state-of-the art mass spectrometry on brain tissues isolated from mice after TBI or craniotomy-alone. We observed dynamic changes in glycosaminoglycans at Day 1 and 7 post-TBI, with heparan sulfate, chondroitin sulfate, and hyaluronan remaining significantly increased after a week vis-à-vis craniotomy-alone tissues. We did not observe appreciable changes in circulating glycosaminoglycans in mice after experimental TBI compared to craniotomy-alone nor in patients with TBI and severe polytrauma compared to control patients with mild injuries, suggesting increases in injury site glycosaminoglycans are driven by local synthesis. We subsequently performed an unbiased whole genome transcriptomics analysis on mouse brain tissues 7 days post-TBI and discovered a significant induction of hyaluronan synthase 2, glypican-3, and decorin. The functional role of decorin after injury was further examined through multimodal behavioral testing comparing wild-type and Dcn-/- mice. We discovered that genetic ablation of Dcn led to an overall negative effect of TBI on function, exacerbating motor impairments after TBI. Collectively, our results provide a spatiotemporal characterization of post-TBI glycosaminoglycan alterations in the brain ECM and support an important adaptive role for decorin upregulation after TBI.

Molecular cues for immune cells from small leucine-rich repeat proteoglycans in their extracellular matrix-associated and free forms.

In this review we highlight emerging immune regulatory functions of lumican, keratocan, fibromodulin, biglycan and decorin, which are members of the small leucine-rich proteoglycans (SLRP) of the extracellular matrix (ECM). These SLRPs have been studied extensively as collagen-fibril regulatory structural components of the skin, cornea, bone and cartilage in homeostasis. However, SLRPs released from a remodeling ECM, or synthesized by activated fibroblasts and immune cells contribute to an ECM-free pool in tissues and circulation, that may have a significant, but poorly understood foot print in inflammation and disease. Their molecular interactions and the signaling networks they influence also require investigations. Here we present studies on the leucine-rich repeat (LRR) motifs of SLRP core proteins, their evolutionary and functional relationships with other LRR pathogen recognition receptors, such as the toll-like receptors (TLRs) to bring some molecular clarity in the immune regulatory functions of SLRPs. We discuss molecular interactions of fragments and intact SLRPs, and how some of these interactions are likely modulated by glycosaminoglycan side chains. We integrate findings on molecular interactions of these SLRPs together with what is known about their presence in circulation and lymph nodes (LN), which are important sites of immune cell regulation. Recent bulk and single cell RNA sequencing studies have identified subsets of stromal reticular cells that express these SLRPs within LNs. An understanding of the cellular source, molecular interactions and signaling consequences will lead to a fundamental understanding of how SLRPs modulate immune responses, and to therapeutic tools based on these SLRPs in the future.

Histopathologic Changes in Congenital Corneal Stromal Dystrophy: Report of 4 Cases in 2 Families.

Corneal dystrophies are hereditary diseases affecting the corneal tissue; they are bilateral, symmetrical and unrelated to environmental or systemic conditions. Congenital corneal stromal dystrophy is a very rare autosomal dominant dystrophy that is caused by a mutation in the DCN gene that encodes decorin (a proteoglycan of the extracellular matrix). We herein report 4 cases of congenital stromal corneal dystrophy in 2 families, highlighting the previously undescribed histopathologic features, the possible differential diagnosis of this entity and the key role played by decorin staining in its diagnosis.

Bifidobacterium adolescentis induces Decorin+ macrophages via TLR2 to suppress colorectal carcinogenesis.

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.

The Role of Decorin in the Adhesion Process of Treponema Pallidum Subspecies Pallidum to Human Brain Microvascular Endothelial Cells.

Objective: This study aims to investigate the role of decorin in the adhesion process of Treponema pallidum subspecies pallidum (T. pallidum) to human brain microvascular endothelial cells. Methods: The study involved an in vitro experimental design. Western blot analysis was conducted to determine the protein expression level of decorin in the cells. The cells were divided into four groups: Tp group, inactivated Tp group, LPS group, and negative control group. The adhesion of T. pallidum to the cells was analyzed using darkfield microscopy counting and quantitative polymerase chain reaction (qPCR). The cells were divided into four groups based on different preprocessing treatments: control group, decorin group, DCN-siRNA group, and DCN-siRNA+decorin group. Changes in the F-actin of the cells were explored using confocal laser scanning microscopy. The cells were divided into the Tp group, Tp+decorin group, and control group. Results: Western blot analysis showed high expression of decorin in the Tp group and LPS group. Darkfield microscopy counting revealed a significantly higher number of T. pallidum adhered to a single cell in the decorin group compared to the control group. Conversely, the number of adhered T. pallidum was significantly lower in the DCN-siRNA group compared to the control group. qPCR results indicated a considerably higher T. pallidum load in the decorin group compared to the control group. In the Tp group, T. pallidum treatment induced the reorganization of F-actin, while the distribution of F-actin in the Tp+decorin group was comparable to that of the control group. Conclusions: Decorin enhances the adhesion of T. pallidum to human brain microvascular endothelial cells, suggesting that decorin may act as one of the receptors regulating the adhesion of T. pallidum to cells. Furthermore, T. pallidum treatment triggers the rearrangement of F-actin in cells, and decorin plays a protective role in this process.

[Effect of up-regulation of Decorin on expression of EGFR, C-Myc and p21 in nude mice with oral squamous cell carcinoma].

PURPOSE: To explore the effect of overexpression of DCN（decorin） gene on the expression of epidermal growth factor receptor (EGFR), cellular-myelocytomatosis viral oncogene (C-Myc) and cyclin dependent kinase inhibitor (p21)in tumor-bearing nude mice with oral squamous cell carcinoma（OSCC）. METHODS: The expression of DCN gene in human oral squamous cell carcinoma(HSC-3) was up-regulated by liposome transfection. Nude mice were used as the carrier of OSCC. H-E staining was used to determine the pathological grade of tumor-bearing tissues in each group. Immunohistochemistry was used to detect the expression of EGFR, C-Myc and p21 protein in tumor-bearing tissues of each group after DCN overexpression. RT-qPCR and Western blot were used to quantitatively detect the expression of EGFR, C-Myc and p21 in tumor-bearing tissues of each group after DCN overexpression, and to determine the effects of DCN overexpression on the expression of EGFR, C-Myc and p21 in tumor-bearing tissues of OSCC nude mice. SPSS 20.0 software package was used for statistical analysis. RESULTS: H-E staining showed that the animal model of OSCC was successfully constructed. The tumor-bearing tissues of nude mice in the plasmid group were significantly lighter than those in the empty vector group and non-transfected group(P＜0.05). IHC results showed that DCN, EGFR, C-Myc and p21 proteins were expressed in the tumor-bearing tissues of nude mice in each group, the expression of DCN,EGFR and C-Myc proteins in the plasmid group was significantly different from the other groups(P＜0.05).There was no significant differece in p21 protein expression in each group(P＞0.05). RT-qPCR and Western blot results showed that DCN, EGFR, C-Myc and p21 were expressed in diffrent degrees in tumor-bearing tissues of nude mice（P＜0.05）. CONCLUSIONS: DCN can inhibit the growth of tumor in OSCC nude mice. In tumor-bearing tissues of nude mice with OSCC, overexpression of DCN can down-regulate the expression of EGFR and C-Myc, and up-regulate the expression of p21.DCN may play an inhibitory role in the occurrence and development of OSCC.

HBx downregulated decorin and decorin-derived peptides inhibit the proliferation and tumorigenicity of hepatocellular carcinoma cells.

Hepatitis B virus (HBV) is one of the important risk factors in inducing the occurrence and development of liver cancer, while the mechanism has not been fully clarified. In this study, we found decorin (DCN) was significantly reduced in HBV transgenic cell line HepG2-4D14 compared to HepG2. The data from hepatocellular carcinoma (HCC) patients indicated that the level of DCN mRNA was significantly lower in tumor tissues than healthy control and positively correlated with the survival of HCC patients. We revealed that HBV HBx can inhibit the transcription of DCN by blocking p53 activity. Functional analysis demonstrated that overexpression of DCN substantially inhibits the proliferation of HCC cells, while knockdown of DCN enhances the proliferation of HCC cells. It is known that DCN could competitively bind to c-Met to inhibit HGF/c-Met signaling pathway to inhibit the development of HCC. Therefore, we screened the novel antitumor peptides derived from DCN based on the sequence of DCN and the complex structure of HGF/c-Met with virtual screening and identified a set of DCN-derived peptides (DCN-Ps) which may competitively bind to c-Met. We found that 5 of peptides can reduce the proliferation and migration of HepG2 cells significantly. Among them, DCN-P#3 can inhibit the growth of HCC cells both in vitro and in vivo. In conclusion, we discovered that HBV HBx downregulates the expression of DCN, which in turn promotes the proliferation of hepatocytes and the development of HCC. We identified DCN-derived antitumor peptides which provides the candidates for developing novel drugs against HCC.

The levels of peripheral blood TNF-α, Decorin and neutrophils MAPK1 mRNA levels of patients with preeclampsia and their clinical significance.

Objective: This study analyzed the levels of peripheral blood tumor necrosis factor-α (TNF-α), Decorin (DCN) and Mitogen-activated protein kinase 1 (MAPK1) mRNA in neutrophils of patients with preeclampsia and their correlations, in order to provide more thoughts on the diagnosis and treatment of clinical patients. Methods: 81 patients with preeclampsia who had regular prenatal checkups and delivered in our hospital from June 2020 to April 2022 were analyzed, including 26 patients with early-onset and 55 patients with late-onset, and 50 pregnant women with normal pregnancy who had prenatal checkups and delivered in our hospital during the same period were selected as the control group. Record the clinical data of patients, record the expression of peripheral blood TNF-α, DCN and neutrophils MAPK1 mRNA of patients with early-onset, late-onset and the control group, and record the correlation between DCN level, MAPK1 mRNA expression and TNF-α level of patients with preeclampsia. Results: The diastolic and systolic blood pressures were significantly higher in early-onset and late-onset patients, and the gestational week of delivery was significantly lower in early-onset and late-onset patients, respectively (p < .05); there was no statistically significant difference in the average age, BMI, average pregnancy time, and average births between the three groups (p > .05). The expressions of peripheral blood TNF-α, DCN, and neutrophils MAPK1 mRNA of the early-onset and late-onset groups were all higher than those in the control group (p < .05); and the expressions of TNF-α, DCN, and MAPK1 mRNA in the peripheral blood of the early-onset group were all higher than those in the late-onset group (p < .05); Pearson correlation analysis showed that DCN level and TNF-α level in patients with preeclampsia were positively correlated (r = 0.98639, p < .05); Neutrophils MAPK1 mRNA expression and TNF-α level were positively correlated (r = 0.9611, p < .05). Conclusion: TNF-α, DCN and neutrophils MAPK1 mRNA were all highly expressed in the peripheral blood of patients with pre-eclampsia and were more significantly elevated in patients with early-onset preeclampsia, and the expression levels of DCN and MAPK1 mRNA were positively correlated with TNF-α levels. It is possible that all three factors are involved in the pathogenesis of preeclampsia, and are expected to be used as indicators for early prediction and diagnosis.

Effect of transfected induced pluripotent stem cells with Decorin gene on control of lung remodeling in allergic asthma.

Asthma is a complex respiratory disease, which is controlled by genetic and environmental factors. Type 2-dominant immune response is responsible for asthma. Decorin (Dcn) and stem cells have modulatory effect on immune system and may control tissue remodeling and asthma pathophysiology. In this study, immunomodulatory effect of transduced induced pluripotent stem cells (iPSCs) with expression of Dcn gene on allergic asthma pathophysiology was evaluated. After transduction of iPSCs with Dcn gene, allergic asthma mice were treated with iPSCs and transduced iPSCs via intrabronchial. Then, airway hyperresponsiveness (AHR), levels of interleukin (IL)-4, IL-5, IL-13, IL-33, total IgE, leukotrienes (LTs) B4, C4, hydroxyproline (HP) content, and transforming growth factor-beta (TGF-ß) were measured. Also, lung histopathology study was done. AHR, levels of IL-4, IL-5, IL-13, IL-33, total IgE, LTs B4, C4, TGF-ß, HP content, mucus secretion, goblet cell hyperplasia, and eosinophilic inflammation were controlled by iPSCs and transduced iPSCs treatment. Therapeutic effect of iPSCs could control main allergic asthma symptoms and related pathophysiologic mechanisms and the effect can be increased when applied with Dcn expression gene.

Decorin improves human pancreatic ß-cell function and regulates ECM expression in vitro.

Transplantation of islets of Langerhans is a promising alternative treatment strategy in severe cases of type 1 diabetes mellitus; however, the success rate is limited by the survival rate of the cells post-transplantation. Restoration of the native pancreatic niche during transplantation potentially can help to improve cell viability and function. Here, we assessed for the first time the regulatory role of the small leucine-rich proteoglycan decorin (DCN) in insulin secretion in human ß-cells, and its impact on pancreatic extracellular matrix (ECM) protein expression in vitro. In depth analyses utilizing next-generation sequencing as well as Raman microspectroscopy and Raman imaging identified pathways related to glucose metabolism to be upregulated in DCN-treated cells, including oxidative phosphorylation within the mitochondria as well as proteins and lipids of the endoplasmic reticulum. We further showed the effectiveness of DCN in a transplantation setting by treating collagen type 1-encapsulated ß-cell-containing pseudo-islets with DCN. Taken together, in this study, we demonstrate the potential of DCN to improve the function of insulin-secreting ß-cells while reducing the expression of ECM proteins affiliated with fibrotic capsule formation, making DCN a highly promising therapeutic agent for islet transplantation.

Novel DCN Mutation in Armenian Family With Congenital Stromal Corneal Dystrophy.

PURPOSE: Congenital stromal corneal dystrophy (CSCD) is a rare congenital, dominantly inherited disorder characterized by diffuse stromal opacification associated with mutations in the decorin gene ( DCN ). As only 5 families with genetically confirmed CSCD have been reported, the identification of a novel pedigree provides the opportunity to better characterize the phenotype and genetic basis. METHODS: An Armenian family with individuals in 4 consecutive generations demonstrated clinical features consistent with CSCD. Consented individuals underwent slit lamp examination, optical coherence tomography, and confocal microscopy. Genomic DNA was collected from saliva and all coding and adjacent intronic regions of DCN were sequenced. In silico analysis was performed for identified mutation(s). Excised corneal tissue underwent light, electron microscopic, and immunohistochemical evaluation. RESULTS: Affected individuals demonstrated bilateral, diffuse, panstromal corneal opacification. Three of the 6 individuals diagnosed with CSCD underwent genetic analysis; all demonstrated a novel heterozygous frameshift deletion in exon 8 of DCN (p.His317Thrfs*11), predicted to cause a 33 amino acid truncation and to be damaging and disease causing by SIFT and MutationTaster. Light and electron microscopic examination of an excised cornea demonstrated increased corneal thickness, stromal scarring, keratocyte loss, and an irregularity of lamellar collagen spacing and fibril formation. Immunofluorescent examination demonstrated increased DCN immunostaining, predominantly in the widened interlamellar spaces. CONCLUSIONS: We report only the sixth pedigree with genetically confirmed CSCD, associated with a novel DCN frameshift mutation. The clinical evaluation, multimodal imaging, and histopathologic assessment in this family with CSCD broaden our understanding of this rare corneal disease.

Relationship of biglycan and decorin expression with clinicopathological features and prognosis in patients with oral squamous cell carcinoma.

OBJECTIVE: This study focused on investigating relation between biglycan (BGN) and decorin (DCN) expression and prognostic outcome for oral squamous cell carcinoma (OSCC) cases. MATERIAL AND METHODS: BGN and DCN mRNA and protein expression was detected by qRT-PCR and Western-blotting (WB) assays from 31 OSCC samples as well as healthy samples. This work harvested 101 paraffin-embedded OSCC together with 30 healthy samples, and conducted immunohistochemical (IHC) staining for assessing pathological changes. Association of DCN with BGN within OSCC was explored by Spearman's analysis. Survival rate was explored by Kaplan-Meier (KM) approach. Multivariate analysis was conducted by Cox regression. RESULTS: WB and qRT-PCR results showed BGN up-regulation (p < 0.001, p < 0.0001) whereas DCN down-regulation (p < 0.0001, p < 0.0001) with fresh OSCC tissues; the expression of BGN and DCN associated with the OSCC histopathological grade. IHC results suggested elevated BGN level (p < 0.0001) whereas DCN down-regulation (p < 0.0001) with paraffin embedded OSCC tissues. The expression of BGN and DCN associated with histopathologic grades and tumor stage of OSCC. The result of Spearman's analysis demonstrated significant association between the expression of BGN and DCN in OSCC. Survival analysis revealed that patients with higher BGN/lower DCN level showed poor overall survival (OS) as well as tumor-specific survival (TSS). Multivariate analysis proved that BGN and DCN independently predicted the prognosis of OS and TSS. CONCLUSION: BGN and DCN expression levels can be adopted for predicting OSCC prognostic outcome.