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Biology of Reproduction Aug 2022Hyaluronan is a structural component of the expanded cumulus matrix, and hyaluronan synthase 2 is the major enzyme for the synthesis of hyaluronan in humans. Versican...
Hyaluronan is a structural component of the expanded cumulus matrix, and hyaluronan synthase 2 is the major enzyme for the synthesis of hyaluronan in humans. Versican cross-links the hyaluronan-rich matrix to cumulus cells and is critical for successful ovulation. Activin A is a critical intrafollicular regulator of ovarian function. Although activin A has been shown to promote cumulus matrix expansion in mice, the functional role of activin A in the regulation of cumulus expansion in the human ovary remains to be elucidated. Using primary and immortalized human granulosa-lutein cells as study models, we provide the first data showing that activin A increased the production of hyaluronan by upregulating the expression of hyaluronan synthase 2 in these cells. Additionally, activin A also promoted the expression of the hyaluronan-binding protein versican. Moreover, using inhibitor- and small interfering RNA-mediated inhibition approaches, we found that these stimulatory effects of activin A are most likely mediated through the type I receptor activin receptor-like kinase (ALK4)-mediated Sma- and Mad-related protein (SMAD2)/SMAD3-SMAD4 signaling pathway. Notably, the chromatin immunoprecipitation analyses demonstrated that SMAD4 could bind to human hyaluronan synthase 2 and VERSICAN promoters. The results obtained from this in vitro study suggest that locally produced activin A plays a functional role in the regulation of hyaluronan production and stabilization in human granulosa-lutein cells.
Topics: Activins; Cells, Cultured; Female; Granulosa Cells; Humans; Hyaluronan Synthases; Hyaluronic Acid; Versicans
PubMed: 35403677
DOI: 10.1093/biolre/ioac070 -
Military Medical Research Mar 2024Neutrophils are traditionally viewed as first responders but have a short onset of action in response to traumatic brain injury (TBI). However, the heterogeneity,...
BACKGROUND
Neutrophils are traditionally viewed as first responders but have a short onset of action in response to traumatic brain injury (TBI). However, the heterogeneity, multifunctionality, and time-dependent modulation of brain damage and outcome mediated by neutrophils after TBI remain poorly understood.
METHODS
Using the combined single-cell transcriptomics, metabolomics, and proteomics analysis from TBI patients and the TBI mouse model, we investigate a novel neutrophil phenotype and its associated effects on TBI outcome by neurological deficit scoring and behavioral tests. We also characterized the underlying mechanisms both in vitro and in vivo through molecular simulations, signaling detections, gene expression regulation assessments [including dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays], primary cultures or co-cultures of neutrophils and oligodendrocytes, intracellular iron, and lipid hydroperoxide concentration measurements, as well as forkhead box protein O1 (FOXO1) conditional knockout mice.
RESULTS
We identified that high expression of the FOXO1 protein was induced in neutrophils after TBI both in TBI patients and the TBI mouse model. Infiltration of these FOXO1 neutrophils in the brain was detected not only in the acute phase but also in the chronic phase post-TBI, aggravating acute brain inflammatory damage and promoting late TBI-induced depression. In the acute stage, FOXO1 upregulated cytoplasmic Versican (VCAN) to interact with the apoptosis regulator B-cell lymphoma-2 (BCL-2)-associated X protein (BAX), suppressing the mitochondrial translocation of BAX, which mediated the antiapoptotic effect companied with enhancing interleukin-6 (IL-6) production of FOXO1 neutrophils. In the chronic stage, the "FOXO1-transferrin receptor (TFRC)" mechanism contributes to FOXO1 neutrophil ferroptosis, disturbing the iron homeostasis of oligodendrocytes and inducing a reduction in myelin basic protein, which contributes to the progression of late depression after TBI.
CONCLUSIONS
FOXO1 neutrophils represent a novel neutrophil phenotype that emerges in response to acute and chronic TBI, which provides insight into the heterogeneity, reprogramming activity, and versatility of neutrophils in TBI.
Topics: Animals; Humans; Mice; bcl-2-Associated X Protein; Brain; Brain Injuries, Traumatic; Depression; Forkhead Box Protein O1; Iron; Neutrophils
PubMed: 38556884
DOI: 10.1186/s40779-024-00523-w -
Frontiers in Immunology 2020Chondroitin sulfate (CS), a type of glycosaminoglycan (GAG), is a linear acidic polysaccharide comprised of repeating disaccharides, modified with sulfate groups at... (Review)
Review
Chondroitin sulfate (CS), a type of glycosaminoglycan (GAG), is a linear acidic polysaccharide comprised of repeating disaccharides, modified with sulfate groups at various positions. Except for hyaluronan (HA), GAGs are covalently bound to core proteins, forming proteoglycans (PGs). With highly negative charges, GAGs interact with a variety of physiologically active molecules, including cytokines, chemokines, and growth factors, and control cell behavior during development and in the progression of diseases, including cancer, infections, and inflammation. Heparan sulfate (HS), another type of GAG, and HA are well reported as regulators for leukocyte migration at sites of inflammation. There have been many reports on the regulation of immune cell function by HS and HA; however, regulation of immune cells by CS has not yet been fully understood. This article focuses on the regulatory function of CS in antigen-presenting cells, including macrophages and dendritic cells, and refers to CSPGs, such as versican and biglycan, and the cell surface proteoglycan, syndecan.
Topics: Adaptive Immunity; Antigen-Presenting Cells; Biglycan; Carbohydrate Conformation; Carbohydrate Sequence; Chondroitin Sulfate Proteoglycans; Chondroitin Sulfates; Dendritic Cells; Humans; Hyaluronan Receptors; Immunity, Innate; Macrophages; Receptor-Like Protein Tyrosine Phosphatases, Class 2; Structure-Activity Relationship; Syndecans; Toll-Like Receptors; Versicans
PubMed: 32194548
DOI: 10.3389/fimmu.2020.00232 -
International Journal of Molecular... May 2021Corneal transparency relies on the precise arrangement and orientation of collagen fibrils, made of mostly Type I and V collagen fibrils and proteoglycans (PGs). PGs are...
Corneal transparency relies on the precise arrangement and orientation of collagen fibrils, made of mostly Type I and V collagen fibrils and proteoglycans (PGs). PGs are essential for correct collagen fibrillogenesis and maintaining corneal homeostasis. We investigated the spatial and temporal distribution of glycosaminoglycans (GAGs) and PGs after a chemical injury. The chemical composition of chondroitin sulfate (CS)/dermatan sulfate (DS) and heparan sulfate (HS) were characterized in mouse corneas 5 and 14 days after alkali burn (AB), and compared to uninjured corneas. The expression profile and corneal distribution of CS/DSPGs and keratan sulfate (KS) PGs were also analyzed. We found a significant overall increase in CS after AB, with an increase in sulfated forms of CS and a decrease in lesser sulfated forms of CS. Expression of the CSPGs biglycan and versican was increased after AB, while decorin expression was decreased. We also found an increase in KS expression 14 days after AB, with an increase in lumican and mimecan expression, and a decrease in keratocan expression. No significant changes in HS composition were noted after AB. Taken together, our study reveals significant changes in the composition of the extracellular matrix following a corneal chemical injury.
Topics: Alkalies; Animals; Biomarkers; Burns, Chemical; Corneal Diseases; Dermatan Sulfate; Disease Models, Animal; Extracellular Matrix; Eye Burns; Fluorescent Antibody Technique; Gene Expression; Glycosaminoglycans; Heparitin Sulfate; Keratan Sulfate; Mice; Proteoglycans
PubMed: 34071909
DOI: 10.3390/ijms22115708 -
Experimental Dermatology Sep 2022Vitiligo is a depigmentation disease which affects skin and hair follicles with a prevalence of 0.5%-1% worldwide. In this study, we aimed to investigate treatmental...
Vitiligo is a depigmentation disease which affects skin and hair follicles with a prevalence of 0.5%-1% worldwide. In this study, we aimed to investigate treatmental potential of dermis-derived cells in monobenzone (MBEH)-induced mouse vitiligo model with light and electron microscopy. MBEH (40%) cream was topically applied to C57BL/6 mice until depigmentation occured in vitiligo and experimental groups. In experimental groups, dermis-derived cells obtained from back skin biopsy samples before induction of vitiligo, were injected intradermally to vitiligo mice. On Days 3 and 15 after cell transplantation to experimental groups, skin biopsies were compared with biopsies of control and vitiligo groups. Dermis-derived cells obtained from back skin biopsy samples of experimental groups showed nestin and versican immunoreactivity. Melanin in hair follicles of control group was detected by histochemical stainings (Haematoxylin and eosin and Fontana-Masson) whereas sparse melanin granules were observed in hair follicles of vitiligo group. In experimental groups, there was an increase in the number of hair follicles with melanin compared with vitiligo group. We observed MART-1 immunoreactive cells mostly around the hair follicles in control group and within dermis in vitiligo group. Electron microscopic investigation showed presence of melanosomes in hair follicles of control group and lacking in vitiligo group. In experimental groups, both type of hair follicles were observed with electron microscope. Our data suggest that autologously transplanted dermis-derived cells may be effective in vitiligo treatment by contrubuting to melanin production.
Topics: Animals; Dermis; Disease Models, Animal; Hair Follicle; Hydroquinones; Hypopigmentation; Melanins; Mice; Mice, Inbred C57BL; Vitiligo
PubMed: 35538739
DOI: 10.1111/exd.14603 -
Reproductive Biomedicine Online Apr 2020What is the effect of quercetin and indole-3-carbinol (I3C) on extracellular matrix expression, cell migration and proliferation in human myometrial and uterine...
RESEARCH QUESTION
What is the effect of quercetin and indole-3-carbinol (I3C) on extracellular matrix expression, cell migration and proliferation in human myometrial and uterine leiomyoma cells.
DESIGN
Myometrial and leiomyoma cells were treated with quercetin or I3C at different concentrations (10 µg/ml; 50 µg/ml; 100 µg/ml; and 250 µg/ml) for 48 h to measure mRNA and protein expressions of extracellular matrix (collagen 1A1, fibronectin and versican), as well as cell migration and the proliferation rate.
RESULTS
Quercetin decreased mRNA levels of collagen 1A1 in myometrial (P < 0.0001) and leiomyoma cells (P < 0.0001). Quercetin reduced mRNA and protein levels of fibronectin in myometrial cells (P < 0.05) and fibronectin protein in leiomyoma cells (P < 0.05). I3C reduced collagen 1A1 mRNA levels in myometrial (P < 0.05) and leiomyoma cells at higher dose (P < 0.05). The protein levels of fibronectin were also reduced in both myometrial and leiomyoma cells with highest dose of I3C (P < 0.05), although mRNA levels were not affected in leiomyoma cells. Neither quercetin nor I3C treatment altered versican mRNA levels in both cell types. A significant reduction of the migration of both myometrial and leiomyoma cells in response to quercetin was observed (P < 0.05) and I3C (P < 0.05 for myometrial and P < 0.01 for leiomyoma cells) treatment. Both quercetin and I3C significantly reduced myometrial cell proliferation (P < 0.05).
CONCLUSIONS
The in-vitro anti-fibrotic, anti-migratory and anti-proliferative effects of quercetin and I3C form the scientific basis for developing new therapeutic, preventive agents, or both, for uterine leiomyomas.
Topics: Adult; Cell Movement; Cell Proliferation; Collagen Type I; Extracellular Matrix; Female; Fibronectins; Humans; Indoles; Leiomyoma; Middle Aged; Myometrium; Quercetin; Uterine Neoplasms; Uterus
PubMed: 32276890
DOI: 10.1016/j.rbmo.2020.01.006 -
Journal of Family Medicine and Primary... Aug 2023Versican is a chondroitin sulphate proteoglycan with raised expression at site of inflammation, and uterine fibroids are associated with local inflammation. Hence, this...
OBJECTIVE
Versican is a chondroitin sulphate proteoglycan with raised expression at site of inflammation, and uterine fibroids are associated with local inflammation. Hence, this study aimed to estimate serum Versican levels in pre-menopausal women with uterine fibroids to evaluate its diagnostic efficiency.
MATERIALS AND METHODS
This case-control study included forty uterine fibroid cases and 40 healthy controls. Cases clinically evaluated with USG findings, that is number, location of fibroid and volume calculated by prolate ellipse formula a × b × c × 0.523 (a - height, b - width, c - depth). Biochemical investigations, that is serum Versican levels, were estimated by ELISA with total cholesterol, HDLc and LDLc. Triglycerides by fully automated chemistry analysers. Serum biochemical parameters were compared and correlated with volume of fibroid. Area under receiver operating characteristic curve was calculated along with cut-off value to determine diagnostic potential of Versican, differentiating women with fibroids.
RESULTS
In the present study, patients with fibroids had decreased levels of serum Versican (79.43 ± 18.60) as compared to healthy controls (101.81 ± 28.24, < 0.001). There was a statistically significant negative correlation ( = - 0. 307, = 0.04) between serum Versican level and volume of fibroid. Area under ROC was 0.726 (95% CI: 0.616-0.836; = 0.001). The best cut-off value for serum Versican level was 96.90 ng/ml with 90% sensitivity and 48% specificity.
CONCLUSION
Serum Versican levels were found significantly lower in women with fibroid with a negative correlation with volume of fibroid uterus. Furthermore, extensive study would help in substantiating diagnostic potential of serum Versican in fibroid uterus patients.
PubMed: 37767449
DOI: 10.4103/jfmpc.jfmpc_320_23 -
PloS One 2021Versican is a large proteoglycan in the extracellular matrix. During embryonic stages, it plays a crucial role in the development of cartilage, heart, and dermis....
Versican is a large proteoglycan in the extracellular matrix. During embryonic stages, it plays a crucial role in the development of cartilage, heart, and dermis. Previously, we reported that Prx1-Vcan conditional knockout mice, lacking Vcan expression in mesenchymal condensation areas of the limb bud, show the impaired joint formation and delayed cartilage development. Here, we investigated their phenotype in adults and found that they develop swelling of the knee joint. Histologically, their newborn joint exhibited impaired formation of both anterior and posterior cruciate ligaments. Immunostaining revealed a decrease in scleraxis-positive cells in both articular cartilage and ligament of Prx1-Vcan knee joint, spotty patterns of type I collagen, and the presence of type II collagen concomitant with the absence of versican expression. These results suggest that versican expression during the perinatal period is required for cruciate ligaments' formation and that its depletion affects joint function in later ages.
Topics: Animals; Animals, Newborn; Anterior Cruciate Ligament; Basic Helix-Loop-Helix Transcription Factors; Cartilage, Articular; Chondrogenesis; Collagen Type I; Collagen Type II; Knee Joint; Mice; Mice, Knockout; Phenotype; Posterior Cruciate Ligament; Versicans
PubMed: 33886644
DOI: 10.1371/journal.pone.0250366 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Aug 2020To investigate the expression and clinical significant of VCAN and its related molecules in patients with MM.
OBJECTIVE
To investigate the expression and clinical significant of VCAN and its related molecules in patients with MM.
METHODS
Ficoll density gradient centrifugation method was used to speared the bone marrow mononuclear cell in 25 cases of MM before and after treatment, the relative mRNA expression of VCAN and their related molecules (FAK, FN, MK, and HAS) in bone marrow was detected by real-time quantitative PCR, and their protein expression was determined by Western bolt.
RESULTS
The expression of VCAN, FK and FN in the effective group after treatment was significantly lower than that before treatment (P<0.05), however, the expression of MK and HAS showed no statistically significantly different before and after treatment (P<0.05). The expression of VCAN of patients in non remission group was significantly higher than that in control group (P<0.05). The expression of FAK and FN of patients in no remission group was significant increased as compared with the patients in newly diagnosed group (P<0.05). The relative expression of VCAN mRNA in the patients at 3rd stage was significantly higher than those at the 1st stage (P<0.05) and control group but showed no significant difference to the patients at 2nd stage (P<0.05). The expression of VCAN and its related proteins (FAK, MK, FN) showed positively correlation in bone marrow mononuclear cells of MM patients (P<0.05). The correlation between VCAN and HAS was not statistically significant (r=0.259,P>0.05). Survival analysis showed that the relative expression of VCAN mRNA was associated with OS (P=0.049) and PFS (P=0.041) in MM patients.
CONCLUSION
VCAN and its related molecules are highly expressed in MM patients; VCAN may act as potential biomarker in the development of multiple myeloma.
Topics: Bone Marrow; Humans; Multiple Myeloma; RNA, Messenger; Versicans
PubMed: 32798403
DOI: 10.19746/j.cnki.issn.1009-2137.2020.04.024 -
Journal of Pharmaceutical Analysis Mar 2024Hyaluronan and proteoglycan link protein 1 (Hapln1) supports active cardiomyogenesis in zebrafish hearts, but its regulation in mammal cardiomyocytes is unclear. This...
Hyaluronan and proteoglycan link protein 1 (Hapln1) supports active cardiomyogenesis in zebrafish hearts, but its regulation in mammal cardiomyocytes is unclear. This study aimed to explore the potential regulation of Hapln1 in the dedifferentiation and proliferation of cardiomyocytes and its therapeutic value in myocardial infarction with human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) and an adult mouse model of myocardial infarction. HiPSC-CMs and adult mice with myocardial infarction were used as and models, respectively. Previous single-cell RNA sequencing data were retrieved for bioinformatic exploration. The results showed that recombinant human Hapln1 (rhHapln1) promotes the proliferation of hiPSC-CMs in a dose-dependent manner. As a physical binding protein of Hapln1, versican interacted with Nodal growth differentiation factor (NODAL) and growth differentiation factor 11 (GDF11). GDF11, but not NODAL, was expressed by hiPSC-CMs. GDF11 expression was unaffected by rhHapln1 treatment. However, this molecule was required for rhHapln1-mediated activation of the transforming growth factor (TGF)-β/Drosophila mothers against decapentaplegic protein (SMAD)2/3 signaling in hiPSC-CMs, which stimulates cell dedifferentiation and proliferation. Recombinant mouse Hapln1 (rmHapln1) could induce cardiac regeneration in the adult mouse model of myocardial infarction. In addition, rmHapln1 induced hiPSC-CM proliferation. In conclusion, Hapln1 can stimulate the dedifferentiation and proliferation of iPSC-derived cardiomyocytes by promoting versican-based GDF11 trapping and subsequent activation of the TGF-β/SMAD2/3 signaling pathway. Hapln1 might be an effective hiPSC-CM dedifferentiation and proliferation agent and a potential reagent for repairing damaged hearts.
PubMed: 38618242
DOI: 10.1016/j.jpha.2023.09.013