Component Of Extracellular Matrices Research Articles

Effect of sodium hyaluronate added to topical corticosteroids in chronic rhinosinusitis with nasal polyposis.

Available medical treatments for chronic rhinosinusitis (CRS) with nasal polyposis (CRSwNP) comprise systemic and topical therapies. Although topical corticosteroids are effective in the treatment of CRS, they are not completely devoid of adverse effects. Thus, care has to be taken when long-term treatments are prescribed. There is recent evidence that sodium hyaluronate (SH), the major component of many extracellular matrices, promotes tissue healing, including activation and moderation of the inflammatory responses, cell proliferation, migration, and angiogenesis. The aim of the study was to evaluate clinical outcomes and quality of life in two groups of patients with CRSwNP treated with topical corticosteroids alone or in combination with 9 mg of high-molecular-weight SH. The impact of treatments was determined by using nasal endoscopy and validated quality of life questionnaires (Short Form-36, 22-item Sino-Nasal Outcome Test, visual analog scale [VAS]). Eighty subjects who had CRS with grade IV nasal polyposis: 40 diagnosed with allergic rhinitis (AR) and 40 with non-allergic-eosinophilic rhinitis (NARES) based on skin-prick test and nasal cytology results, were divided in two groups. Group I comprised 40 subjects (20 AR and 20 NARES), who received mometasone furoate plus SH; group II comprised 40 subjects (20 AR and 20 NARES), who received mometasone furoate plus saline solution alone. All the patients were followed up for 3 months. At baseline, no statistically significant differences were observed between the groups and the VAS score showed a moderate-to-severe degree of disease. After treatments, Lund and Kennedy, Short Form-36, 22-item Sino-Nasal Outcome Test, and VAS scores were statistically significant in both groups but slightly in favor of the group I and in the subjects with allergic CRSwNP. Analysis of our data indicated that an SH supplement to standard corticosteroid seems to play an important role in improving the severity of symptoms, the endoscopic appearance, and discomfort associated with CRSwNP. This effect seems to be strongest in patients with allergic CRSwNP.

CHARACTERIZATION OF COLLAGEN (IV) MRNA IN CELL LINES OF BREAST CANCER

Breast cancer incidence rate has increased in the 5 recent years with 14% increases in mortality. The structural change in the collagen chain has led to alterations in the cancer cells. Various biological processes, such as differentiation or gene expression, are regulated through extracelullar matrix (ECM)[1]. The restructuring of the collagenous architecture in the hypoxic microenvironment may influence the invasive growth of the cancer cells. With the increased stress within the cell, the invasion of cancer cells into the ECM was triggered. This cell lines model would enable the exploration of the relationship between the extracellular matrices component and the tumor proliferation. The aim of this study is to characterize the collagen (IV) mRNA expression in the breast cancer cell. Breast cancer (MCF7) cell lines were cultured and harvested upon confluent. The RNA was extracted from the cell lines and then the cDNA were synthesized. The collagen (IV) mRNA levels in breast cancer cell lines were measured using real time PCR and GAPDH was used as an internal control. The level of COL4A2 (IV) mRNA expression was higher compared with COL4A1 (IV) mRNA. The level of COL4A5 (IV) mRNA was reduced significantly in breast cancer cells lines. Overall, the expression of COL4A1-A6 (IV) was reduced. The reduced amount of collagen (IV) in breast cancer cell lines suggested that the collagen was restructured and this has triggered the tumor invasion into the ECM.

Keratan sulfate exacerbates experimental autoimmune encephalomyelitis

Proteoglycans (PGs) are the components of extracellular matrices in the central nervous system (CNS). Keratan sulfate (KS) is a glycosaminoglycan that is included in the KSPG that acts as an inhibitory factor in nerve regeneration after CNS injury. To investigate the role of KS in immune diseases, we induced experimental autoimmune encephalomyelitis (EAE) in mice that were deficient in the N-acetylglucosamine (GlcNAc)-6-O-sulfotransferase 1 (GlcNAc6ST1) gene (KS-KO). KS-KO mice developed less severe EAE and showed repressed recall response in the induction phase. Furthermore, GlcNAc6ST1 might have roles in the passage of the pathogenic lymphocytes through the blood-brain barrier via adhesion molecules. Thus, modulation of KS may become a treatment for neuroimmunological diseases.

Lectins as probes for assessing the accessibility of N-linked glycans in relation to the conformational changes of fibronectin.

Fibronectin, a ≈ 450-kDa protein with 4-9% (w/w) glycosylation, is a key component of extracellular matrices and has a high conformational lability regarding its functions. However, the accessibility and the role of glycosylated moieties associated with the conformational changes of fibronectin are poorly understood. Using lectins as probes, we developed an approach comprising dynamic light scattering, turbidimetry measurements, and isothermal titration calorimetry to assess the accessibility of glycosylated moieties of fibronectin undergoing thermal-induced conformational changes. Among a set of 14 lectins, fibronectin mainly reacted with mannose-binding lectins, specifically concanavalin A. When temperature was raised from 25 to 50 °C, fibronectin underwent progressive unfolding, but the conformation of concanavalin A was unaffected. Dynamic light scattering, turbidimetry measurements, and isothermal titration calorimetry showed increased concanavalin A binding to fibronectin during progressive thermal-induced unfolding of the protein core. Such data suggest that mannosylated residues are progressively exposed as fibronectin unfolds. Because oligosaccharide moieties can be differently exposed to cells, and the cell's responses could be modified physiologically or pathologically, modulation of fibronectin sugar chains could be relevant to its biological functions. Thus, lectins might be useful tools to probe the glycosylation accessibility accompanying changes in protein core folding, for which a better understanding would be of value for biological and biomedical research.

Interactions between Hyaluronan and Its Receptors (CD44, RHAMM) Regulate the Activities of Inflammation and Cancer.

The glycosaminoglycan hyaluronan (HA), a major component of extracellular matrices, and cell surface receptors of HA have been proposed to have pivotal roles in cell proliferation, migration, and invasion, which are necessary for inflammation and cancer progression. CD44 and receptor for HA-mediated motility (RHAMM) are the two main HA-receptors whose biological functions in human and murine inflammations and tumor cells have been investigated comprehensively. HA was initially considered to be only an inert component of connective tissues, but is now known as a “dynamic” molecule with a constant turnover in many tissues through rapid metabolism that involves HA molecules of various sizes: high molecular weight HA (HMW HA), low molecular weight HA, and oligosaccharides. The intracellular signaling pathways initiated by HA interactions with CD44 and RHAMM that lead to inflammatory and tumorigenic responses are complex. Interestingly, these molecules have dual functions in inflammations and tumorigenesis. For example, the presence of CD44 is involved in initiation of arthritis, while the absence of CD44 by genetic deletion in an arthritis mouse model increases rather than decreases disease severity. Similar dual functions of CD44 exist in initiation and progression of cancer. RHAMM overexpression is most commonly linked to cancer progression, whereas loss of RHAMM is associated with malignant peripheral nerve sheath tumor growth. HA may similarly perform dual functions. An abundance of HMW HA can promote malignant cell proliferation and development of cancer, whereas antagonists to HA-CD44 signaling inhibit tumor cell growth in vitro and in vivo by interfering with HMW HA-CD44 interaction. This review describes the roles of HA interactions with CD44 and RHAMM in inflammatory responses and tumor development/progression, and how therapeutic strategies that block these key inflammatory/tumorigenic processes may be developed in rodent and human diseases.

Cancer microenvironment and inflammation: role of hyaluronan.

The role of inflammation in the development of cancer was described as early as the nineteenth century. Abundant evidence supports the preposition that various cancers are triggered by infection and chronic inflammatory disease whereas, evading immune destruction has been proposed as one of the new “hallmarks of cancer.” Changes of the tumor microenvironment have been closely correlated to cancer-mediated inflammation. Hyaluronan (HA), an important extracellular matrices component, has become recognized as an active participant in inflammatory, angiogenic, fibrotic, and cancer promoting processes. This review discusses how HA and specific HA-binding proteins participate in and regulate cancer-related inflammatory processes.

Utilization of Glycosaminoglycans/Proteoglycans as Carriers for Targeted Therapy Delivery.

The outcome of patients with cancer has improved significantly in the past decade with the incorporation of drugs targeting cell surface adhesive receptors, receptor tyrosine kinases, and modulation of several molecules of extracellular matrices (ECMs), the complex composite of collagens, glycoproteins, proteoglycans, and glycosaminoglycans that dictates tissue architecture. Cancer tissue invasive processes progress by various oncogenic strategies, including interfering with ECM molecules and their interactions with invasive cells. In this review, we describe how the ECM components, proteoglycans and glycosaminoglycans, influence tumor cell signaling. In particular this review describes how the glycosaminoglycan hyaluronan (HA) and its major receptor CD44 impact invasive behavior of tumor cells, and provides useful insight when designing new therapeutic strategies in the treatment of cancer.

Fibronectin expression in the intervertebral disc of monkey.

Fibronectin, a large dimeric plasma glycoprotein found only in vertebrates, is a core component of several extracellular matrices. Integrin receptors regulate different cell activities. Fibronectin expression patterns in intervertebral disc have not been extensively studied. The aim of this study was to evaluate the distribution of fibronectin in the different regions of the intervertebral disc, and in intervertebral discs of different levels of monkeys. Spines of nine 3-4 year-old cynomolgus monkeys (Macaca fascicularis) were studied. From every spine, 5 vertebral motion segments were sectioned (C5-C6, T3-T4, T9-T10, L2-L3, L4-L5) producing forty-five vertebral motion segments. These were bisected in the sagittal plane. Immunohistochemical studies were performed using specific antibodies to detect fibronectin. A positive immunoreaction for fibronectin was found in the endplates, in the peripheral annulus fibrosus, and in the longitudinal ligaments. There was no fibronectin immunoreactivity in the nucleus pulposus and in the central annular region close to the nucleus pulposus. There were no differences in immunoreactivity to fibronectin among discs of different levels and discs of different monkeys. Fibronectin may exert a role in the organization of the extracellular matrix of the intervertebral discs. Identifying the structural features of the intervertebral disc extracellular matrix may help to understand the mechanisms of intervertebral disc pathology.

Tracking developmentally regulated post-synthetic processing of homogalacturonan and chitin using reciprocal oligosaccharide probes.

Polysaccharides are major components of extracellular matrices and are often extensively modified post-synthetically to suit local requirements and developmental programmes. However, our current understanding of the spatiotemporal dynamics and functional significance of these modifications is limited by a lack of suitable molecular tools. Here, we report the development of a novel non-immunological approach for producing highly selective reciprocal oligosaccharide-based probes for chitosan (the product of chitin deacetylation) and for demethylesterified homogalacturonan. Specific reciprocal binding is mediated by the unique stereochemical arrangement of oppositely charged amino and carboxy groups. Conjugation of oligosaccharides to fluorophores or gold nanoparticles enables direct and rapid imaging of homogalacturonan and chitosan with unprecedented precision in diverse plant, fungal and animal systems. We demonstrated their potential for providing new biological insights by using them to study homogalacturonan processing during Arabidopsis thaliana root cap development and by analyzing sites of chitosan deposition in fungal cell walls and arthropod exoskeletons.

CB-01 * TARGETING COLLAGEN REGULATION IN GLIOBLASTOMA MULTIFORME

Extracellular matrices (ECM) are quintessential complex structures that provide cells and tissues of functional support for cell adhesion and migration, cell-to-cell communication and differentiation. Collagens are fibrillar proteins that constitute the major component of ECM and have key structural roles. Intracellular maturation of collagen precursors, prior to secretion, is dependent on the hydroxylation of collagen proline residues. This reaction is mediated by collagen prolyl 4-hydroxylases (P3H and P4H families' enzymes) in the presence of α-ketoglutarate, oxygen, Fe2+ and ascorbate. It is already known that ECM and collagen prolyl-hydroxylases are important players in cancer migration and invasion, but little has been explored in brain tumours and hypoxia. We have focused our investigations on glioblastoma multiforme (GBM) using two independent and specific inhibitors of collagen prolyl-hydroxylases: Ethyl 3,4-dihydroxybenzoate (EDHB), an α-ketoglutarate competitor, and 3,4-Dehydro-DL-proline (L-Proline analogue). The presence of these inhibitors showed a dramatic reduction in cell proliferation in a panel of established GBM cell lines. Similar results were obtained in primary cell lines from GBM tumours and melanoma brain metastasis. The mechanisms behind these effects are independent of apoptosis and we are currently exploring the role of autophagy and cell cycle arrest as possible other mechanisms. Surprisingly, even in low oxygen concentration (1%) there was a significant reduction in proliferation. Collagen regulation and its role in cell proliferation in both normoxic and hypoxic conditions will be discussed as a potential new therapeutic strategy for GBMs.

P52 * TARGETING COLLAGEN REGULATION IN GLIOBLASTOMA MULTIFORME

INTRODUCTION: Extracellular matrices (ECM) are quintessential complex structures that provide cells and tissues with functional support for adhesion, migration, cell-to-cell communication and differentiation. Collagens are fibrillar proteins that constitute the major component of ECM and have a key structural role. Intracellular maturation of collagen precursors, prior to secretion, is dependent on the hydroxylation of the collagen proline residues which is mediated by the prolyl 4-hydroxylases (P4H) family of enzymes. Although, ECM and collagen prolyl-hydroxylases have been shown to be important players in cancer migration and invasion, little is known of their role in brain tumours. METHOD: To examine the role of P4H enzymes in the biology of GBM we profiled their expression in a panel of GBM cell lines a variety of techniques including RT-PCR, western blotting and MSP. For functional studies we assesed the effects of two independent inhibitors of P4H on the growth of these lines using proliferation and apoptotic assays (SRB and Annexin V respectively). RESULTS: Pharmacological inhibition of collagen prolyl-hydroxylases dramatically reduced the proliferation of a panel of GBM cell lines. This reduction was independent of apoptosis. CONCLUSION: Our preliminary results show that collagen biosynthesis plays an important role in the growth of GBM and therefore could be a potential therapeutic strategy that needs further investigation.

Adipose tissue: A valuable resource of biomaterials for soft tissue engineering

Extracellular matrices (ECMs), isolated through decellularization of mammalian tissues, have been successfully used in a variety of tissue engineering and regenerative medicine applications. The composition and spatial structure of ECMs provide not only specific instructive cues for the growth, migration, and differentiation of various cells in vitro, but afford ideal substrates for in vivo tissue reconstruction. Adipose tissue, which is the most prevalent and expendable tissue in the body and can be harvested in large quantities with minimal morbidity, has received much attention as a rich source of ECMs. Recent studies have designed different processes to isolate intact ECMs from adipose tissue and have fabricated various three-dimensional (3-D) tissue engineering scaffolds such as microparticles, powders, sponges, sheets, and hydrogels for use in regenerative medicine, particularly for patients requiring soft tissue regeneration. Indeed, because of the abundance of ECM components within adipose tissue, combined with the relative ease of large tissue harvesting, adipose tissue is a valuable resource in tissue regeneration therapy, encompassing autotransplantation, allotransplantation, and xenotransplantion. We briefly review extraction and decellularization techniques of ECMs from adipose tissue, biological characterization and fabrication of ECM-based tissue engineering scaffolds, and their use in soft tissue engineering.

Involvement of a membrane potassium channel in heparan sulphate-induced activation of macrophages

Increasing evidence has demonstrated that Toll-like receptor 4 (TLR4) -mediated systemic inflammatory response syndrome accompanied by multiple organ failure, is one of the most common causes of death in patients with severe acute pancreatitis. Recent reports have revealed that heparan sulphate (HS) proteoglycan, a component of extracellular matrices, potentiates the activation of intracellular pro-inflammatory responses via TLR4, contributing to the aggravation of acute pancreatitis. However, little is known about the participants in the HS/TLR4-mediated inflammatory cascades. Our previous work provided a clue that a membrane potassium channel (MaxiK) is responsible for HS-induced production of inflammatory cytokines. Therefore, in this report we attempted to reveal the roles of MaxiK in the activation of macrophages stimulated by HS. Our results showed that incubation of RAW264.7 cells with HS up-regulated MaxiK and TLR4 expression levels. HS could also activate MaxiK channels to promote the efflux of potassium ions from cells, as measured by the elevated activity of caspase-1, whereas this was significantly abolished by treatment with paxilline, a specific blocker of the MaxiK channel. Moreover, it was found that paxilline substantially inhibited HS-induced activation of several different transcription factors in macrophages, including nuclear factor-κB, p38 and interferon regulatory factor-3, followed by decreased production of tumour necrosis factor-α and interferon-β. Taken together, our investigation provides evidence that the HS/TLR4-mediated intracellular inflammatory cascade depends on the activation of MaxiK, which may offer an important opportunity for a new approach in therapeutic strategies of severe acute pancreatitis.

Notice of Retraction

Cellular fibronectin (cFN) is one of the main components of tissue extracellular matrices and is involved in multiple physiologic and pathologic processes such as embryogenesis, wound healing, inflammation and tumor progression. The function of fibronectin in regulating normal cell adhesion and migration is well documented, but its function in cancer progression is only partially unraveled. We have reported previously that fibronectin stimulates the proliferation and survival of non-small lung carcinoma cells through upregulation of pro-oncogenic signals related to cyclooxygenase-2/phosphatidylinositol-3-kinase/protein kinase B (COX-2/PI3-K/AKT)/mammalian target of rapamycin triggered by activation of the integrin α5β1. Here, we extend these studies by showing that fibronectin promotes epithelial-mesenchymal transition (EMT) in lung cancer cells. We found that cFN, but not plasma fibronectin or type 1 collagen, induces lung carcinoma cell scattering in vitro, promotes cell migration and invasion of Matrigel and stimulates the expression of the mesenchymal marker α-smooth muscle actin while decreasing the expression of the epithelial marker E-cadherin through PI3-K and Erk pathways. Interestingly, the extra domain A (EDA) within cFN was found to be crucial for this process, as confirmed by testing cells overexpressing EDA or cells exposed to EDA-containing matrices. We found that the integrin α9, but not α5, mediated cFN-induced EMT as silencing integrin α9 neutralized cFN-induced EMT. Overall, our findings show that the EDA domain within cFN induces EMT in lung carcinoma cells through integrin α9-mediated activation of PI3-K and Erk.

ROS-major mediators of extracellular matrix remodeling during tumor progression

Extracellular matrices (ECMs) represent a complex network of proteins, proteoglycans and glycosaminoglycans (GAGs), composed of independent structural domains, ultimately constituting the cell microenvironment. As a highly organized, insoluble suprastructure, the ECM can, in a spatially patterned and regulated manner, integrate and deliver multiple complex signals to cells that affect their behavior. During the progression of carcinogenesis, tumor cells, through a continually changing interface, remodel and simultaneously interact with the components of ECM, as well as with surrounding stromal cells. Within this complex network of ECM components affecting tumor progression, reactive oxygen species/reactive nitrogen species (ROS/RNS) play a wide emerging role. In this minireview we will focus on the ROS-dependent modulations of tumor ECM and how this in turn affects the insidious pathways of tumor progression and dissemination.

Defective Initiation of Glycosaminoglycan Synthesis due to B3GALT6 Mutations Causes a Pleiotropic Ehlers-Danlos-Syndrome-like Connective Tissue Disorder

Proteoglycans are important components of cell plasma membranes and extracellular matrices of connective tissues. They consist of glycosaminoglycan chains attached to a core protein via a tetrasaccharide linkage, whereby the addition of the third residue is catalyzed by galactosyltransferase II (β3GalT6), encoded by B3GALT6. Homozygosity mapping and candidate gene sequence analysis in three independent families, presenting a severe autosomal-recessive connective tissue disorder characterized by skin fragility, delayed wound healing, joint hyperlaxity and contractures, muscle hypotonia, intellectual disability, and a spondyloepimetaphyseal dysplasia with bone fragility and severe kyphoscoliosis, identified biallelic B3GALT6 mutations, including homozygous missense mutations in family 1 (c.619G>C [p.Asp207His]) and family 3 (c.649G>A [p.Gly217Ser]) and compound heterozygous mutations in family 2 (c.323_344del [p.Ala108Glyfs(∗)163], c.619G>C [p.Asp207His]). The phenotype overlaps with several recessive Ehlers-Danlos variants and spondyloepimetaphyseal dysplasia with joint hyperlaxity. Affected individuals' fibroblasts exhibited a large decrease in ability to prime glycosaminoglycan synthesis together with impaired glycanation of the small chondroitin/dermatan sulfate proteoglycan decorin, confirming β3GalT6 loss of function. Dermal electron microcopy disclosed abnormalities in collagen fibril organization, in line with the important regulatory role of decorin in this process. A strong reduction in heparan sulfate level was also observed, indicating that β3GalT6 deficiency alters synthesis of both main types of glycosaminoglycans. In vitro wound healing assay revealed a significant delay in fibroblasts from two index individuals, pointing to a role for glycosaminoglycan defect in impaired wound repair in vivo. Our study emphasizes a crucial role for β3GalT6 in multiple major developmental and pathophysiological processes.

Collagen-like Triple Helical Peptides: Applications in Drug Development and Regenerative Medicine

Collagen family proteins are the predominant components of extracellular matrices existing in all multicellular animals. They provide mechanical strength to tissues, and maintain structural integrity of organs. Also, collagens regulate various biological events, including cell attachment, migration, tissue regeneration and animal development. The specific functions of collagens are generally elicited by interactions of collagen-binding molecules (membrane receptors, soluble factors and other matrix components) with certain amino acid sequences displayed on the collagen triple helices. To date, numbers of functional sequences have been identified from the triple helical domains. Collagen is also acknowledged as one of useful biomaterials in regenerative medicine and tissue engineering. In this review, I summarize challenges made for the development of safer and highly-functional collagen surrogates by means of self-assembly of synthetic collagen-like peptides. I also describe other possible applications of collagen-like peptides in drug delivery focusing on the particular biophysical properties of the triple helical structure.

Effects of Sodium Hyaluronate in Children with Recurrent Upper Respiratory Tract Infections: Results of a Randomised Controlled Study

Hyaluronic acid is a major component of many extracellular matrices that plays a role in the regulation of vasomotor tone and mucous gland secretion, and in the modulation of the inflammatory process in upper and lower airways. This pilot study was aimed at evaluating the effects of nasal washes with 9 mg nebulised sodium hyaluronate given for 15 days per month over 3 months in 75 paediatric patients with recurrent upper respiratory tract infections (URTI). Eligible patients were randomized to treatment with nasal washes containing 9 mg sodium hyaluronate plus saline solution or saline alone, according to an open-label, parallel group design, with blind observer assessment. Ciliary motility, which was assessed based on a 0-3 point rating scale (0 = absent, 1 = less than 5 minutes, 2 = greater than or equal to 5 and ≤ 10 minutes, 3 = greater than 10 minutes) was the primary study endpoint. The secondary efficacy variables included cytological (presence of neutrophils, eosinophils and mast cells), microbiological (presence of bacteria and mycetes), endoscopical (presence of adenoid hypertrophy and biofilm) and clinical (presence of rhinitis, post-nasal drip, nasal dyspnoea) parameters. The two treatment groups (mean age 7.5 years, 53percent of males) were comparable for baseline data, except a higher mean age in the control group than in the treated group. Treatment with 9 mg sodium hyaluronate was associated with significantly greater improvements (p less than 0.001 between groups) in primary outcome ciliary motility [odds ratio (OR) 13.61; 95 percent CI 4.51-41.00 in the univariate regression analysis that examined the probability of improvement]. Treatment with 9 mg sodium hyaluronate was also significantly superior to saline alone in adenoid hypertrophy (p less than 0.001; OR 14.72; 95 percent CI 4.74-45.68), presence of bacteria (p = 0.026; OR 2.95; 95 percent CI 1.15-7.55), neutrophils (p = 0.002; OR 4.51; 95 percent CI 1.75-11.62), rhinitis (p = 0.040; OR 10.47; 95 percent CI 3.10-35.31), nasal dyspnoea (p = 0.047; OR 3.80; 95 percent CI 1.09-13.19) and biofilm (p = 0.049; OR 9.90; 95 percent CI 2.61-37.47). Advantages of 9 mg of sodium hyaluronate over control on post-nasal drip and presence of mycetes (although evident) did not reach the level of statistical significance. The superiority of the treated group over saline alone was confirmed in a multivariate logistic regression analysis that took into account age as confounding factor. The number of days of absence from school was significantly lower in the 9 mg sodium hyaluronate group compared to controls (p less than 0.001 between groups). A 3-month intermittent treatment with 9 mg sodium hyaluronate with nasal washes plus saline solution was associated with significant improvements in ciliary motility and in cytological, microbiological, endoscopic and clinical outcomes compared to saline, in children with recurrent URTI.

Hyaluronan Plus Saline Nasal Washes in the Treatment of Rhino-Sinusal Symptoms in Patients Undergoing Functional Endoscopic Sinus Surgery for Rhino-Sinusal Remodeling

Hyaluronic acid is a major component of many extracellular matrices and plays a central role in the homeostasis of physiology in upper and lower airways. When topically administered following endoscopic sinus surgery, hyaluronic acid may be effective in functional recovery and in the prevention of recurrence of chronic rhinosinusistis. This pilot study was aimed at evaluating the effects of nebulised 9 mg of sodium hyaluronate given for 15 days per months over 3 months in 46 patients aged greater than 4 years who underwent functional endoscopic sinus surgery (FESS) for rhino-sinusal remodelling. Eligible patients were randomized to receive nebulised 9 mg sodium hyaluronate nasal washes plus saline solution or 5 ml saline alone (23 patients in each group), according to an open-label, parallel group design, with blind observer assessment. Treatment was administered by means of a nasal ampoule that allows nebulisation of particles with a median aerodynamic diameter greater than 10 micron, i.e. suitable for upper respiratory airways deposition. The efficacy variables included clinical (presence of nasal dyspnoea), endoscopical (ostium of paranasal sinuses, oedema, respiratory patency, synechiae, and appearance of nasal mucosa) and cytological (ciliary motility and presence of neutrophils, eosinophils, mast cells, bacteria, mycetes and bio film) measures. At the end of the study, patients expressed an opinion on the overall tolerability of treatment. The two treatment groups were comparable at baseline. Treatment with 9 mg of sodium hyaluronate was associated with significantly greater improvements compared to controls in nasal dyspnoea (p less than 0.001), presence of mycetes (p = 0.044), ciliary motility (p less than 0.001) and abnormalities in nasal secretions. A univariate logistic model, in which the odd ratio (OR) indicates the probability of success in the 9 mg sodium hyaluronate group compared to the control group, showed that the highest OR was observed for presence of nasal dyspnoea (OR = 21.36; 95 percent CI: 1.07 to 426.56), normal mucosa at endoscopy (OR: 9.62; 95 percent CI: 1.82 to 50.89), ciliary motility (OR: 7.27; 95 percent CI: 1.68 to 31.42) and presence of bio film (OR: 4.41; 95 percent CI: 1.26 to 15.40). Treatment with 9 mg sodium hyaluronate plus saline was well tolerated. A 3-month intermittent treatment with 9 mg sodium hyaluronate plus saline solution nasal washes following FESS for rhino-sinusal remodelling was associated with significant improvements in nasal dyspnoea, appearance of nasal mucosa at endoscopy and ciliary motility compared to saline alone.

Impacts of fullerene derivatives on regulating the structure and assembly of collagen molecules

During cancer development, the fibrous layers surrounding the tumor surface get thin and stiff which facilitates the tumor metastasis. After the treatment of metallofullerene derivatives Gd@C82(OH)22, the fibrous layers become thicker and softer, the metastasis of tumor is then largely suppressed. The effect of Gd@C82(OH)22 was found to be related to their direct interaction with collagen and the resulting impact on the structure of collagen fibrils, the major component of extracellular matrices. In this work we study the interaction of Gd@C82(OH)22 with collagen by molecular dynamics simulations. We find that Gd@C82(OH)22 can enhance the rigidity of the native structure of collagen molecules and promote the formation of an oligomer or a microfibril. The interaction with Gd@C82(OH)22 may regulate further the assembly of collagen fibrils and change the biophysical properties of collagen. The control run with fullerene derivatives C60(OH)24 also indicates that C60(OH)24 can influence the structure and assembly of collagen molecules as well, but to a lesser degree. Both fullerene derivatives can form hydrogen bonds with multiple collagen molecules acting as a "fullerenol-mediated bridge" that enhance the interaction within or among collagen molecules. Compared to C60(OH)24, the interaction of Gd@C82(OH)22 with collagen is stronger, resulting in particular biomedical effects for regulating the biophysical properties of collagen fibrils.