Connective Tissue Extracellular Matrix Research Articles

Mechanisms of ammonotelism, epithelium damage, cellular apoptosis, and proliferation in gill of Litopenaeus vannamei under NH4Cl exposure.

Excessive ammonia-N in coastal environment and aquaculture threatens the health of marine organisms. To explore the mechanism of gill damage induced by ammonia-N, transcriptome of Litopenaeus vannamei 's gill was carried out under 20 mg/L NH4Cl for 0, 6, and 48 h. K-means clustering analysis suggested that ammonia excretion and metabolism-related genes were elevated. GO and KEGG enrichment analysis suggested that glycosyltransferase activity and amino acid metabolism were affected by ammonia. Moreover, histological observation via three staining methods gave clues on the changes of gill after ammonia-N exposure. Increased mucus, hemocyte infiltration, and lifting of the lamellar epithelium suggested that gill epithelium was suffering damage under ammonia-N stress. Meanwhile, the composition of extracellular matrix (ECM) in connective tissue changed. Based on the findings of transcriptomic and histological analysis, we further investigated the molecular mechanism of gill damage under multiple concentrations of NH4Cl (0, 2, 10, 20 mg/L) for multiple timepoints (0, 3, 6, 12, 24, 48, 72 h). First, ammonia excretion was elevated via ion channel, transporter, and exocytosis pathways, but hemolymph ammonia still kept ata high level under 20 mg/L NH4Cl exposure. Second, we focused on glycosaminoglycan metabolism which was related to the dynamics of ECM. It turned out that the degradation and biosynthesis of chondroitin sulfate (CS) were elevated, suggesting that the structure of CS might be destructed under ammonia-N stress and CS played an important role in maintaining gill structure. It was enlightening that the destructions occurred in extracellular regions were vital to gill damage. Third, ammonia-N stress induced a series of cellular responses including enhanced apoptosis, active inflammation, and inhibited proliferation which were closely linked and jointly led to the impairment of gill. Our results provided some insights into the physiological changes induced by ammonia-N and enriched the understandings of gill damage under environmental stress.

DEVELOPMENT OF PATHOLOGICAL CHANGES IN THE ORAL CAVITY ORGANS OF ANIMALS UNDER CONDITIONS OF POLYNEUROPATHIES OF DIFFERENT GENESIS

The aim of our research is to study the effect of polyneuropathy of different genesis on the development of pathological changes in the large salivary glands and periodontal tissues of animals. Methods. The study was conducted on 62 laboratory rats of both sexes. Toxic polyneuropathy was induced by paclitaxel injection, experimental type 1 diabetes mellitus was modeled by streptozocin injection, and alcoholic polyneuropathy was induced by chronic administration of increasing concentrations of ethanol. The development of polyneuropathy was confirmed by a change in the the pain sensitivity threshold (PST) using the Randall-Selitto tensoalgometric method. In the homogenate of oral cavity organs, total proteolytic and total antitryptic activity, catalase activity, content of TBARS, average mass molecules, oxidatively modified proteins, fucose and glycosaminoglycans (GAG), and amylase activity were determined. The level of total, protein-bound and non-protein sulfhydryl groups, activity of superoxide dismutase, glutathione peroxidase, glutathione transferase, glutathione reductase; content of reduced and oxidized glutathione, diene conjugates and Schiff bases were determined in blood serum. Results. We established the increasing of PST in animals that were simulated neuropathies of different genesis. All three types of polyneuropathies are accompanied by the development of carbonyl-oxidative stress in the soft tissues of the periodontium and large salivary glands of rats, which is evidenced by a probable increase in the content of oxidatively modified proteins and the content of TBARS, as well as average mass molecules compared to these indicators in intact animals . Under the conditions of modeling all three polyneuropathies, the protein-synthetic activity in the large salivary glands is suppressed, as evidenced by a decrease in the activity of α-amylase. Under conditions of experimental diabetic and toxic neuropathy in the salivary glands of animals, changes in the proteinase-inhibitor balance of the compensatory type are observed. We found that polyneuropathies of different genesis cause increased catabolism of biopolymers of the extracellular matrix of the periodontal connective tissue of rats, which confirms the increase in the content of GAG and fucose compared to these indicators in control animals. Conclusions. Under conditions of diabetic, toxic and alcoholic neuropathy, the amylolytic activity of the large salivary glands of animals is suppressed, the balance of the pro- and antioxidant system changes. When modeling peripheral polyneuropathy in animals by administration of paclitaxel, streptozocin, and ethanol, the development of periodontal syndrome is observed, the leading pathogenetic mechanisms of which are increased catabolism of connective tissue glycoconjugates and the development of oxidative stress and proteinase-inhibitor imbalance.

Histoarchitecture of stromal collagen fibers in gastrointestinal hollow organs of mice after a 30-day space flight

The digestive organs are highly sensitive to the influence of orbital flight factors and can limit the professional activities of crew members aboard the International Space Station. Connective tissue, as a system-forming matrix of the integrative-buffer metabolic environment, is of particular relevance in space biomedicine, ensuring the functioning of internal organs under an altered gravitational stimulus. However, the adaptive mechanisms of the fibrous extracellular matrix of the gastric and intestinal connective tissue have not been fully investigated under prolonged microgravity weightlessness. Using histochemical techniques, we experimentally studied the state of collagen fibers in the specific tissue microenvironment of the gastric and intestinal membranes in C57BL/6 N mice after a 30-day space flight, subsequent 7-day ground readaptation, and in animals of the relevant control groups. The 30-day stay of laboratory animals aboard the Bion-M 1 biosatellite resulted in a reduction in the fibrous extracellular matrix of connective tissue in the studied digestive organs, excepting the gastric lamina propria. Increased fibrillogenesis was revealed in the gastrointestinal mucous membranes of animals 7 days after biosatellite landing compared with the parameters of animals in the space flight group. During the experiment with ground simulated orbital flight conditions, changes in collagen fibers were not significant compared to the vivarium control group. Thus, the results obtained evidence gravisensitivity of the fibrous extracellular matrix of the intraorgan connective tissue. This fact also highlights the necessity to further improve gastrointestinal tract-related preventive measures for astronauts during orbital flight.

Analysis of differential expression of genes of structural and regulatory proteins of connective tissue as factors associated with the vaginal prolapse

The article presents data on the differential expression of genes of structural and regulatory proteins of connective tissue (COLIA1, fibronectin, elastin, TGF-β1, LOX) in women with pelvic organ prolapse and stigmas of undifferentiated connective tissue dysplasia (UCTD) compared to patients with prolapse but without UCTD stigmas.
 Research objectives: analysis of the prognostic significance of differential expression of structural and regulatory genes of connective tissue proteins COLIA1, fibronectin, elastin, TGF-β1, LOX as factors associated with the vaginal prolapse among Ukrainian women.
 Materials and methods. Vaginal tissue samples were taken from 18 patients at the menopausal age with vaginal prolapse III, IV degree, which required surgical correction during vaginal hysterectomy and/or plastic surgery of vaginal walls. The main group included 11 patients with clinical and anamnestic UCTD stigmas, the comparison group included 7 women without it. Gene expression analysis of structural and regulatory proteins of the extracellular matrix of connective tissue was performed using real-time quantitative polymerase chain reaction. The relative number of transcripts of the studied genes was normalized by the expression level of the GAPDH gene. The data were calculated using the 2–ΔΔCt method.
 Results. There was decrease in gene expression of the main structural proteins of the extracellular matrix of the connective tissue: COLIA1 (t=-1.7; p=0.044), fibronectin (t=1.66; p=0.047), elastin (t=-1.75, p=0,04), gene of the regulatory protein LOX (t=-1.8, p=0.035) and no statistically significant difference in the TGF-β1 gene in patients with pelvic organ prolapse and clinical and anamnestic UCTD stigmas.
 Conclusions. Statistically significant lower expression of the genes of the main structural proteins of the extracellular matrix of the connective tissue and the gene of the regulatory protein LOX in patients with pelvic organ prolapse and clinical and anamnestic UCTD stigmas is evidence of the importance of genetically determined pathological remodeling of the connective tissue in the etiology of genital prolapse.

Hyaluronic Acid-Extraction Methods, Sources and Applications.

In this review, a compilation of articles in databases on the extraction methods and applications of hyaluronic acid (HA) was carried out. HA is a highly hydrated component of different tissues, including connective, epithelial, and neural. It is an anionic, linear glycosaminoglycan (GAG) primarily found in the native extracellular matrix (ECM) of soft connective tissues. Included in the review were studies on the extraction methods (chemical, enzymatical, combined) of HA, describing advantages and disadvantages as well as news methods of extraction. The applications of HA in food are addressed, including oral supplementation, biomaterials, medical research, and pharmaceutical and cosmetic industry applications. Subsequently, we included a section related to the structure and penetration routes of the skin, with emphasis on the benefits of systems for transdermal drug delivery nanocarriers as promoters of percutaneous absorption. Finally, the future trends on the applications of HA were included. This final section contains the effects before, during, and after the application of HA-based products.

P076 Beyond articular cartilage: a systematic review of the extracellular matrix in other components of the osteoarthritic joint

Abstract Background/Aims Traditionally viewed from the perspective of cartilage degeneration, osteoarthritis is increasingly seen as a disease of global joint dysfunction. Connective tissue extracellular matrix (ECM) is a crucial determinant of joint mechanobiology, providing cells with scaffolding, topographical cues, and a reservoir of soluble factors. While ECM dysregulation has been extensively studied in osteoarthritic cartilage, it remains poorly defined in other joint tissues. Here, we systematically review the composition, architecture, and remodelling of non-cartilage soft joint tissue ECM in human osteoarthritis and animal disease models. Methods A systematic search strategy was run through the MEDLINE, EMBASE and Scopus databases on 30 October 2020 and repeated on 1 October 2021. The search criteria included disease nomenclature, relevant tissues, as well as structural ECM components and architectural features. All papers were independently screened by two reviewers on the Covidence platform according to predefined eligibility criteria. Relevant clinical, demographic, and biological data were extracted from included studies, which were assessed for bias using the OHAT Risk of Bias Rating Tool for Human and Animal Studies. Results 148 of 8,156 identified studies met all eligibility criteria. 113 papers evaluated human osteoarthritis; of 35 animal studies, the most frequently used models involved surgical joint destabilisation in small mammals. ECM was best defined in menisci, ligaments, and synovium; fewer papers assessed skeletal muscles, tendons, and fat pads. Compared to the healthy joint, osteoarthritis is associated with qualitative and quantitative alterations in structural ECM components, most notably collagens and proteoglycans. In recent years, whole proteome sequencing has been employed to address these changes systematically. The mechanical properties of ECM change significantly in osteoarthritis in response to post-translational modifications, extensive calcification, and the marked loss of matrix organisation across the joint. Notably, some aspects of ECM remodelling in these tissues appear to precede discernible cartilage dysregulation. Similar ECM dysregulation is also observed in animal models, although inter-model variability in arthritogenic precipitant and the range of reported outcomes make comparisons difficult. Many studies are limited by significant bias, notably in the infrequent reporting of investigator blinding, and in the poor demographic matching of osteoarthritic and control patients. Encouragingly, the quality of methodology reporting and use of age-matched control populations have improved in recent years. Conclusion Current data provide compelling evidence of whole joint ECM changes in osteoarthritis and importantly suggest that these changes occur early in the disease process. How ECM dysfunction affects the behaviour of tissue-resident cells remains less well understood. Our work will support the design of disease-relevant biomaterials used to model osteoarthritis in vitro, helping to address this issue, by more accurately recreating the extracellular environment. Furthermore, the development of imaging modalities sensitive to connective tissue ECM changes warrants investigation from both diagnostic and prognostic perspectives. Disclosure J.Y. Mimpen: None. I.G.A. Raza: None. S.J.B. Snelling: None.

The Remodeling of Dermal Collagen Fibrous Structures in Mice under Zero Gravity: The Role of Mast Cells.

Mechanisms of adaptive rearrangements of the fibrous extracellular matrix of connective tissues under microgravity practically remain unexplored, despite the most essential functions of the stroma existing to ensure the physiological activity of internal organs. Here we analyzed the biomaterial (the skin dermis) of C57BL/6J mice from the Rodent Research-4 experiment after a long stay in space flight. The biomaterial was fixed onboard the International Space Station. It was found that weightlessness resulted in a relative increase in type III collagen-rich fibers compared to other fibrous collagens in the skin. The number of mast cells in the skin did not change, but their secretory activity increased. At the same time, co-localization of mast cells with fibroblasts, as well as impregnated fibers, was reduced. Potential molecular-cellular causes of changes in the activity of fibrillogenesis under zero-gravity conditions and the slowdown of the polymerization of tropocollagen molecules into supramolecular fibrous structures, as well as a relative decrease in the number of fibrous structures with a predominant content of type-I collagen, are discussed. The data obtained evidence of the different sensitivity levels of the fibrous and cellular components of a specific tissue microenvironment of the skin to zero-gravity conditions. The obtained data should be taken into account in the systematic planning of long-term space missions in order to improve the prevention of undesirable effects of weightlessness.

Новые маркеры генитального пролапса

Pelvic organ prolapse (POP) is a very considerable problem not only due to its high prevalence, but also because of the significant decrease in the quality of life of women suffering from this disease. Given the high prevalence, pelvic floor disorders requiring plastic surgery are becoming an economic problem for public health. In recent decades, techniques for the treatment of pelvic floor dysfunction (PFD) have evolved rapidly. However, the pathophysiology of this disease is still poorly understood, which may be the reason for inadequate, untimely, and sometimes ineffective treatment of POP. One of the important findings when analyzing the results of morphological and morphometric studies of the levator ani muscle in PFD and clinical forms of POP became the detection of significant fibrous degradation of the pelvic floor muscular compartment in all the examined samples. Objective. To search for promising biomarkers of muscular and connective tissue remodeling and the interaction of the muscular and fascial compartments of the pelvic floor to predict pelvic organ prolapse. According to the literature, we found at least three candidate markers for assessing the condition of the muscular-fascial compartment of the pelvic floor: tenascin C, hyaluronic acid (HA), and myofibroblasts (MFB). Tenascin C is a non-structural component of the extracellular matrix of both muscular and connective tissue. Its role in the regulation of inflammation pathways has been discovered in recent studies, but in our study, this protein is of interest as a marker of tissue remodeling in case of tissue damage. Hyaluronic acid is one of the most abundant glycosaminoglycans in the connective tissue of vertebrates. HA is ubiquitous in fascial tissue, but its content is particularly high in loose connective tissue and between muscles and deep fascia. In the fascia, HA is not only a key structural component of the extracellular matrix, but also a functional one. The qualitative and quantitative analysis of HA content in pelvic floor fasciae is likely to help more accurately assess the tissue state, identify the nature of myofascial interaction during the formation of the hernia gate and may be the key to determining the treatment tactics for the initial signs of PFD. Myofibroblasts are connective tissue cells that represent an intermediate link between fibroblasts and smooth muscle cells. Their main task is to increase the basal tone and rigidity of the fascia and ensure proper muscular-skeletal dynamics. Normally, this tension is not enough for significant changes in musculature biomechanics, but persistent “hypertonicity” of the fascia quite quickly led to the formation of pathological contractures, which limited the motor activity of the underlying muscles. Thus, it can be assumed that myofibroblasts participate in the process of healing and remodeling of the fascial compartment. And the search for MFB in biopsy specimens of the levator ani muscle in patients with PFD can shed light on connective tissue dysplasia as the most controversial component of POP development. Conclusion. To date, the problem of pelvic organ prolapse remains unresolved in modern gynecology. When studying the literature, it became evident that determining the biochemical and biomechanical properties of the myofascial complex of the pelvic floor is necessary to gain a comprehensive picture of the disease. Although the significance of markers in predicting pelvic organ prolapse has not yet been investigated, we express optimistic expectations to find an ideal biomarker of the rate of PFD and POP development, improving knowledge about the pathogenesis of the disease. Key words: biomarkers, hyaluronic acid, myofibroblasts, pelvic organ prolapse, connective tissue, tenascin C

Tumor Suppressive Role of the PRELP Gene in Ovarian Clear Cell Carcinoma.

Ovarian clear cell carcinoma (OCCC) has a poor prognosis, and its therapeutic strategy has not been established. PRELP is a leucine-rich repeat protein in the extracellular matrix of connective tissues. Although PRELP anchors the basement membrane to the connective tissue and is absent in most epithelial cancers, much remains unknown regarding its function as a regulator of ligand-mediated signaling pathways. Here, we obtained sets of differentially expressed genes by PRELP expression using OCCC cell lines. We found that more than 1000 genes were significantly altered by PRELP expression, particularly affecting the expression of a group of genes involved in the PI3K-AKT signaling pathway. Furthermore, we revealed the loss of active histone marks on the loci of the PRELP gene in patients with OCCC and how its forced expression inhibited cell proliferation. These findings suggest that PRELP is not only a molecule anchored in connective tissues but is also a signaling molecule acting in a tumor-suppressive manner. It can serve as the basis for early detection and novel therapeutic approaches for OCCC toward precision medicine.

A Systematic Review of the Evidence of Hematopoietic Stem Cell Differentiation to Fibroblasts.

Fibroblasts have an important role in the maintenance of the extracellular matrix of connective tissues by producing and remodelling extracellular matrix proteins. They are indispensable for physiological processes, and as such also associate with many pathological conditions. In recent years, a number of studies have identified donor-derived fibroblasts in various tissues of bone marrow transplant recipients, while others could not replicate these findings. In this systematic review, we provide an overview of the current literature regarding the differentiation of hematopoietic stem cells into fibroblasts in various tissues. PubMed, Embase, and Web of Science (Core Collection) were systematically searched for original articles concerning fibroblast origin after hematopoietic stem cell transplantation in collaboration with a medical information specialist. Our search found 5421 studies, of which 151 were analysed for full-text analysis by two authors independently, resulting in the inclusion of 104 studies. Only studies in animals and humans, in which at least one marker was used for fibroblast identification, were included. The results were described per organ of fibroblast engraftment. We show that nearly all mouse and human organs show evidence of fibroblasts of hematopoietic stem cell transfer origin. Despite significant heterogeneity in the included studies, most demonstrate a significant presence of fibroblasts of hematopoietic lineage in non-hematopoietic tissues. This presence appears to increase after the occurrence of tissue damage.

Matrix Metalloproteinases in Pathogenesis of Ventilation Disorders of the Respiratory System in Patients with Chronic Pulmonary Tuberculosis

The imbalance in matrix metalloproteinase (MMP)/inhibitors system leads to degradation of extracellular matrix of connective tissue and pathological remodeling forming the morphological basis for respiratory dysfunction.The objective: to study the relationship between parameters of MMP/inhibitors system in blood and parameters of ventilation and gas exchange disorders in patients with chronic pulmonary tuberculosis (PTB).Subjects and Methods. Patients with the verified diagnosis of tuberculoma (n = 45) and fibrous-cavernous pulmonary tuberculosis (n = 85) were examined. All patients underwent computed tomography of the chest and assessment of respiratory function. Serum concentrations of MMP-1, -3, -8, -9 and their inhibitors TIMP-1 and α2-macroglobulin (MG) were tested by ELISA (R&D Systems, Minneapolis, MN, USA). Statistica 7.0 and an ANCOVA model were used for statistical analysis which considered the diagnosis and smoking status as factors, and the respiratory function parameters were considered as covariates.Results. In pulmonary tuberculosis patients, the concentrations of MMP-9 and MMP-8 in the blood correlated with extension of lung parenchyma lesions when compared to tuberculomas and fibro-cavernous tuberculosis, MMP-9 and TIMP-1 with changes in lung volumes (R2 = 0.60 and 0.80; p = 0.001), and MMP-8 correlated with functional disorders of gas exchange (R2 = 0.60 and 0.80; p = 0.001). Changes in MMP-1, MMP-3, and α2-MG (R2 = 0.60 and 0.80; p = 0.45) did not correlate with extension of lung parenchymal lesions and decreased lung function.

Research advances on the application of natural and recombinant collagen in wound repair

Collagen is a macromolecular protein constituting the extracellular matrix of animal connective tissue, which has been widely used and developed in fields of biomedicine, tissue engineering, food, and cosmetics. Due to its advantages such as abundant sources and good biocompatibility, low immunogenicity, and degradability, collagen can be used as a dressing or tissue engineering scaffold for wound repair. According to the source of materials, collagen can be divided into natural collagen and recombinant collagen. Natural collagen is mainly extracted directly from mammals and fish; recombinant collagen is obtained based on genetic engineering technology, and its sources include recombinant expression systems of microorganisms, animals, and plants. This paper summarizes the sources of collagen, and the roles, advantages, and disadvantages of different sources of collagen in wound repair, the particularity and superiority of collagen combined with three-dimensional printing technology in wound repair, the impact of market norms of China's collagen industry on the field of wound repair, and explains the precautions for the development of collagen-related products, aiming to provide new ideas for selecting a suitable source of collagen for wound repair.

Engineering collagenous analogs of connective tissue extracellular matrix.

Connective tissue extracellular matrix (ECM) consists of an interwoven network of contiguous collagen fibers that regulate cell activity, direct biological function, and guide tissue homeostasis throughout life. Recently, ECM analogs have emerged as a unique ex vivo culture platform for studying healthy and diseased tissues and in the latter, enabling the screening for and development of therapeutic regimen. Since these tissue models can mitigate the concern that observations from animal models do not always translate clinically, the design and production of a collagenous ECM analogue with relevant chemistry and nano- to micro-scale architecture remains a frontier challenge in the field. Therefore, the objectives of this study are two-fold— first, to apply green electrospinning approaches to the fabrication of an ECM analog with nanoscale mimicry and second, to systematically optimize collagen crosslinking in order to produce a stable, collagen-like substrate with continuous fibrous architecture that supports human cell culture and phenotypic expression. Specifically, the “green” electrospinning solvent acetic acid was evaluated for biofabrication of gelatin-based meshes, followed by the optimization of glutaraldehyde (GTA) crosslinking under controlled ambient conditions. These efforts led to the production of a collagen-like mesh with nano- and micro-scale cues, fibrous continuity with little batch-to-batch variability, and proven stability in both dry and wet conditions. Moreover, the as-fabricated mesh architecture and native chemistry were preserved with augmented mechanical properties. These meshes supported the in vitro expansion of stem cells and the production of a mineralized matrix by human osteoblast-like cells. Collectively these findings demonstrate the potential of green fabrication in the production of a collagen-like ECM analog with physiological relevance. Future studies will explore the potential of this high-fidelity platform for elucidating cell-matrix interactions and their relevance in connective tissue healing.

Role of Hyaluronic acid in various diseases with special emphasis on Periodontal inflammation - A review

Hyaluronic acid is a naturally occurring polysaccharide of extracellular matrix of connective tissues, synovial fluid, and other body tissues. It has an important role in regulating interactions intra and extracellularly between different growth factors, in addition to regulating osmotic pressure, maintaining tissue volume and lubrication.Periodontitis is an multifactorial inflammatory disease that affects teeth supporting structures which results in teeth loss. It is considered a wide world cause of teeth loss in adults. In addition to its local effect, teeth loss, it can have systemic impacts on many systemic organs. Although its main cause is bacteria, exaggerated host response and risk factors such as smoking, diabetes mellitus, HIV/AIDS, family history, and certain medications increase the disease progress.Hence teeth supporting structures are connective tissues and hyaluronic acid is a main component of connective tissues, a correlation of both in health and disease is explained in this article

The role of elastin on the mechanical properties of the anterior leaflet in porcine tricuspid valves.

Elastin is present in the extracellular matrix (ECM) of connective tissues, and its mechanical properties are well documented. In Marfan syndrome, however, the inability to properly code for the protein fibrillin-1 prematurely leads to the degradation and loss of elastin fiber integrity in the ECM. In this study, the role of elastin in the ECM of the anterior leaflet of the tricuspid valve was investigated by examining the biomechanical behavior of porcine leaflets before and after the application of the enzyme elastase. Five loading protocols were applied to the leaflet specimens in two groups (elastase-treated and control samples). The mechanical response following elastase application yielded a significantly stiffer material in both the radial and circumferential directions. At a physiological level of stress (85 kPa), the elastase group had an average strain of 26.21% and 6.32% in the radial and circumferential directions, respectively, at baseline prior to elastase application. Following elastase treatment, the average strain was 5.28% and 0.97% in the radial and circumferential directions, respectively. No statistically significant change was found in the control group following sham treatment with phosphate-buffered saline (PBS). Two-photon microscopy images confirmed that after the removal of elastin, the collagen fibers displayed a loss of undulation. With a significant reduction in radial compliance, the ability to withstand physiological loads may be compromised. As such, an extracellular matrix that is structurally deficient in elastin may hinder normal tricuspid valve function.

CAH-X Syndrome: Genetic and Clinical Profile.

The term CAH-X was coined to describe a subset of patients with 21-hydroxylase deficiency displaying a phenotype compatible with the hypermobility type of Ehlers Danlos syndrome. The genetic defect is due to the monoallelic presence of a CYP21A2 deletion extending into the gene encoding tenascin X (TNXB), a connective tissue extracellular matrix protein. The result is a chimeric TNXA/TNXB gene causing tenascin-X haploinsufficiency. The prevalence of CAH-X was estimated to be around 14-15% in large cohorts of patients with 21-hydroxylase deficiency. However, population studies are still scarce and the clinical picture of the syndrome has yet to be fully defined. In this review, we discuss the current knowledge regarding the genetic and clinical profile of the CAH-X syndrome.

Chondroitin Sulfate Enhances Proliferation and Migration via Inducing β-Catenin and Intracellular ROS as Well as Suppressing Metalloproteinases through Akt/NF-κB Pathway Inhibition in Human Chondrocytes.

Chondroitin sulfate (CS) is found in humans' cartilage, bone, cornea, skin, and arterial wall. It consists of the foundation substance in the extracellular matrix (ECM) of connective tissue. The oral supplement form of CS is clinically used in treating osteoarthritis (OA). Cell migration was observed by the transwell assay. The EMT, Akt/IKK/IκB pathways, TIMPs, collagen and MMPs in cell lysate were determined by Western blotting. The expression of MMP activity was determined by gelatin zymography. The production of reactive oxygen species (ROS) was determined by using a fluorescence spectrophotometer. In the current report, we demonstrated that CS can increase the cell proliferation and migration of chon-001 chondrocytes. Treatment with CS induced the epithelial-mesenchymal transition and increased the expression of type II collagen and TIMP-1/TIMP2 and inhibited the expressions and activities of metalloproteinase-9 (MMP-9) and metalloproteinase-2 (MMP-2). The phosphorylation of Akt, IκB kinase (IKK), IκB and p65 was decreased by CS. CS treatment resulted in β-catenin production and XAV939, a β-catenin inhibitor, and inhibited the cell proliferation by CS treatment. In addition, also significantly induced intracellular ROS generation. Treatment with antioxidant propyl gallate blocked cell migration induced by CS. We demonstrated that CS induced cell proliferation and migration of chondrocytes by inducing β-catenin and enhancing ROS production. Moreover, our studies demonstrated that CS can increase the activity of chondrocytes and help patients with osteoarthritis to restore cartilage function.

English

Available therapeutic interventions for managing preterm labour have not been consistently successful due to controversies related to its etiology. Multiple mechanisms, including inflammation play a significant role in the pathogenesis of preterm labour. The connective tissue extracellular matrix of the amniochorion contains collagen fibres that maintain the tensile strength of the amniochorion, resisting mechanical stress and preventing rejection of the fetal allograft. Expression of pro-inflammatory mediators in the amniochorion triggers production of prostaglandins in the uterus and enzymatic degradation of the resilient extracellular matrix of the fetal membranes by matrix metalloproteinases leading to uterine contractions and cervical remodelling resulting in preterm labour. This review   appraises the pathophysiological mechanisms of pro-inflammatory mediators in spontaneous preterm labour and their associations with multi-factorial etiological pathways. The physiological pathways and biological mechanisms of uterine activity during pregnancy and parturition are also discussed. Finally, the review provides an overview of the biological basis of common therapeutic agents for treating preterm labour. In this review, keywords related to pathophysiological mechanisms of maternal pro-inflammatory mediators in preterm labour and clinical management were used in the literature search from the PubMed and Google Scholar databases. The snowball sampling methodology was further employed to obtain a comprehensive literature search. Key words: Preterm labour, pro-inflammatory mediators, pathophysiology.

Identification of biomarkers and regulatory networks for cartilage damage patients.

The aim of this study was to mine cartilage damage and regeneration-related biomarkers and identify the gene regulatory networks of cartilage damage. A gene expression data set (GSE129147) containing damaged and control samples collected from the knee of the same patients was employed. R package limma was used to identify differentially expressed genes (DEGs), and clusterProfiler was performed for the GO and KEGG functional enrichment analysis. Cytoscape plug-ins of CytoHubba and MCODE were applied to investigate protein-protein interaction (PPI) network, modules, and hub genes. We identified 422 DEGs that were involved in skeletal system development, bone development, ossification, mesenchyme development, mesenchymal cell differentiation, connective tissue development, osteoblast differentiation, and extracellular matrix. We dug out 30 hub genes, identified three PPI modules, and constructed a miRNA regulatory network for DEGs. The miRNAs of the DEGs were predicted by miRNet, and the miRNA-mRNA network displayed some important miRNAs such as miR-335-5p, miR-92a-3p, and miR-98-5p. Collectively, these results have the potential to clarify the mechanism of cartilage damage and to assist us in discovering the damage and repair-related biomarkers.

Cancer-associated fibroblasts and their role in tumor progression.

The stromal elements of a malignant tumor can promote cancer progression and metastasis. The structure of the tumor stroma includes connective tissue elements, blood vessels, nerves, and extracellular matrix (ECM). Some of the cellular elements of the tumor stroma are cancer-associated f ibroblasts (CAFs). The origin and function of CAFs have been actively studied over the past thirty years. CAFs produce collagen, the main scaffold protein of the extracellular matrix. Collagen in the tumor stroma stimulates f ibrosis, enhances the rigidity of tumor tissue, and disrupts the transmission of proliferation and differentiation signaling pathways. CAFs control tumor angiogenesis, cell motility, tumor immunogenic properties, and the development of resistance to chemo- and immunotherapy. As a result of metabolic adaptation of rapidly growing tumor tissue to the nutrients and oxygen deprivation, the main type of energy production in cells changes from oxidative phosphorylation to anaerobic glycolysis. These changes lead to sequential molecular alterations, including the induction of specif ied transcriptional factors that result in the CAFs activation. The molecular phenotype of activated CAFs is similar to f ibroblasts activated during inf lammation. In activated CAFs, alpha-smooth muscle actin (α-SMA) is synthetized de novo and various proteases and f ibronectin are produced. Since CAFs are found in all types of carcinomas, these cells are potential targets for the development of new approaches for anticancer therapy. Some CAFs originate from resident f ibroblasts of the organs invaded by the tumor, while others originate from epithelial tumor cells, which are undergoing an epithelial-mesenchymal transition (EMT). To date, many molecular and metabolic inducers of the EMT have been discovered including the transforming growth factor-beta (TGF-β), hypoxia, and inf lammation. This review classif ies modern concepts of molecular markers of CAFs, their functional features, and discusses the stages of epithelial- mesenchymal transition, and the potential of CAFs as a target for antitumor therapy