No full-text available
To read the full-text of this research,
you can request a copy directly from the author.
Hyaluronic acid and extracellular matrix: a primitive molecule?
Abstract
Hyaluronic acid, or hyaluronan, is a polymer made of the repetition of a unique disaccharidic unit, D-glucuronic acid and D-N-acetylglucosamine, that can reach a molecular mass of 10(7) daltons. This primitive polymer has emerged as a remarkable extracellular matrix component by its viscoelastic properties, its hygroscopic capacities and the diversity of cell processes it controls. Identified in all vertebrate tissues, more than 50% of acid hyaluronic of the organism is present in skin. Having no protein core, its synthesis is performed through a unique process, depending on enzymatic activity of hyaluronan synthases acting at the internal face of the plasmatic membrane and extruding the nascent polymer to the extracellular medium. This polymer constitutes a scaffold on which a large number of sulfated proteoglycans, up to one hundred, can be linked. These supramolecular structures of considerable size are able to entrap large amounts of water and ions to provide tissues with hydration and turgescence. Hyaluronic acid is recognized by cell membrane receptors, notably CD44 which is the best known. Interaction of hyaluronic acid with its receptors triggers several intracellular signaling pathways regulating proliferation, migration and differentiation. Cell response is largely influenced by the size of the polymer and by that of the fragments generated upon degradation by hyaluronidases or free radicals. Hyaluronic acid is metabolically very active, as, for example, its half-life in skin is less than one day. Detected in epidermis where it could play a role in the control of proliferation and differentiation of basal cells, it is however prominent in dermis in association with versican. The remarkable physicochemical properties of hyaluronic acid as well as the diversity of biological processes it controls largely surpass the primitive character of this polymer.
Copyright 2010 Elsevier Masson SAS. All rights reserved.
... Cell adhesion molecules (CAMs), a family of transmembrane proteins, are involved in cell-to-cell adhesion and in the interaction between cells and the extracellular matrix (ECM) [1,2]. CAMs are generally characterized by three conserved domains: an intracellular domain that interacts with the cytoskeleton, a transmembrane domain that crosses the lipid bilayers of the cell membrane, and an extracellular domain that interacts either with the same CAMs by homophilic binding or with the ECM by heterophilic binding [3,4]. The modulation of cell adhesion is a key issue in regenerative medicine [5]. ...
... Although it has been hypothesized that cells cannot survive in ectopic sites, recent data from athymic mouse models have shown that cells can survive for months in ectopic sites, such as the lung, spleen, and kidney, and that they can be followed with positron emission tomography (PET) [22]. Several research groups are striving to find new strategies to reduce the ectopic localization of cells, and HA, a natural biomatrix found in most of the organs, is one of the most investigated molecules in the field of hepatology because of its multiple interesting properties [4,9,21,[31][32][33][34][35][36]. ...
... For many years, the ECM was believed to have only mechanical properties; however, in the last decades, multiple studies have shown how the ECM plays a crucial and dynamic role in regulating cell homeostasis. Indeed, the HA matrix supports cell adhesion, growth, and differentiation, it regulates cell trafficking, and it affects various processes, such as development and organogenesis, inflammation, wound healing, and tissue remodeling [4]. ...
Cell adhesion is essential for survival, it plays important roles in physiological cell functions, and it is an innovative target in regenerative medicine. Among the molecular interactions and the pathways triggered during cell adhesion, the binding of cluster of differentiation 44 (CD44), a cell-surface glycoprotein involved in cell-cell interactions, to hyaluronic acid (HA), a major component of the extracellular matrix, is a crucial step. Cell therapy has emerged as a promising treatment for advanced liver diseases; however, so far, it has led to low cell engraftment and limited cell repopulation of the target tissue. Currently, different strategies are under investigation to improve cell grafting in the liver, including the use of organic and inorganic biomatrices that mimic the microenvironment of the extracellular matrix. Hyaluronans, major components of stem cell niches, are attractive candidates for coating stem cells since they improve viability, proliferation, and engraftment in damaged livers. In this review, we will discuss the new strategies that have been adopted to improve cell grafting and track cells after transplantation.
... H YALURONIC ACID (HA), or hyaluronan, is a natural carbohydrate linear polysaccharide; that is found in almost all living organisms. Its chemical structure is consisting of multiple disaccharides which are N-acetylglucosamine and D-glucuronic acid, linked via alternating b-1,4 and b-1,3 glycosidic bonds (1,2). HA, is a highly hydrophilic molecule, plays an important role in tissue hydrodynamics and contributes to the transport of water, it helps to maintain the hydration and elastoviscosity of tissues (2,3). ...
... Its chemical structure is consisting of multiple disaccharides which are N-acetylglucosamine and D-glucuronic acid, linked via alternating b-1,4 and b-1,3 glycosidic bonds (1,2). HA, is a highly hydrophilic molecule, plays an important role in tissue hydrodynamics and contributes to the transport of water, it helps to maintain the hydration and elastoviscosity of tissues (2,3). The remarkable viscoelastic and water holding property of HA, besides its biocompatibility, biodegradability, and non-immunogenicity, has increased its appeal in numerous medical and cosmetic applications (4)(5)(6)(7)(8)(9). ...
... It is reported that in human skin, the quantity of HA represents a third of the all amount of HA that exists in human body (4). Also believed that one-third of the whole human body quantity of HA is broken down and synthesized on a daily basis (2). However, human cells do not always produce HA efficiently lifelong. ...
Topical delivery of molecules into the human skin is one of the main issues in dermatology and cosmetology. Several techniques were developed to study molecules penetration into the human skin. Although widely accepted, the conventional methods such as Franz diffusion cells are unable to provide the accurate localization of actives in the skin layers. A different approach based on Raman spectroscopy has been proposed to follow-up the permeation of actives. It presents a high molecular specificity to distinguish exogenous molecules from skin constituents.
Raman micro-imaging was applied to monitor the skin penetration of hyaluronic acids (HA) of different molecular weights. The first step, was the spectral characterization of these HA. After, we have determined spectral features of HA by which they can be detected in the skin. In the second part, transverse skin sections were realized and spectral images were recorded.
Our results show a difference of skin permeation of the three HA. Indeed, HA with low molecular weight (20-300 kDa) passes through the stratum corneum in contrast of the impermeability of high molecular weight HA (1000-1400 kDa).
Raman spectroscopy represents an analytical, non-destructive, and dynamic method to evaluate the permeation of actives in the skin layers.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
... Hyaluronic Acid (HA) is a polysaccharide and an extracellular matrix key molecule. It plays an important role in maintaining tissue structure and vascularity [2,3]. HA has a wide range of activities including the stimulation of fibroblast anabolism, interfering with the intercellular communication and transport of nutritive elements between cells. ...
... The gel's residual volume was calculated using a tool integrated in the Philips IntelliSpace Portal 7.0 image post-processing software, which can display and measure volumetric data from 2D images. An extrapolation from 2D slices was carried out and the provided volumetric measurements were expressed in mm 3 (Figures 2 and 3). ...
Introduction: Hyaluronic Acid (HA) gels are a commonly used option for correcting facial volume loss. Over the past 2 years, we have been testing the clinical results of two HA gels, without lidocaine, made by the same manufacturer using the patented “Inter- Penetrating NetworkLike” (IPN-Like) cross-linking technology. The aim of this work was to evaluate if there is a difference in the tissue stability and associated clinical outcomes between these two gels. Material and methods: A 67 and 75 years old Caucasian women, from our private aesthetic center, agreed to be injected with the different HA volumiser gel, one in each of their temporal fossae. The Stylage® XL and XXL HA gels (LABORATOIRES VIVACY, Archamps, France) were used for this study. The gels have different concentrations and levels of cross-linking, but have the same indications for correcting facial volume loss resulting from the ageing process. Clinical outcomes included assessing the degree of pain experienced by participants during and after injection using a Visual Analog Scale (VAS). Aesthetic improvement was evaluated using the Merz Analogic Scale® (MAS)® and Global Aesthetic Improvement Scale (GAIS) scales completed by patients and independent experts at different pre-set time-points using photographs taken from the front, profile and three-quarter left and right angles. Moreover, Serial magnetic Resonance Imaging (MRI) scans were used to assess the tissue behavior of the gels immediately after injection and then 6 monthly for 2 years. Results: Both gels led to an improvement in the patients’ clinical outcomes. This improvement persisted over time. The MRI scans showed that, at Day 0, the injected gel was spherical in shape and became elongated by 6 months. This appearance did not change throughout the follow-up period. The scans showed little resorption at 24 months. Conclusion: Despite the relatively advanced age of the two patients and the small quantities of gel injected, the IPN-Like cross-linked hyaluronic acid volumiser gels had a satisfactory sustainable clinical effect as assessed by patients and experts. There was a slight advantage in favor of the gel with the lower HA concentration but higher level of cross-linking (Stylage® XXL). Given the observed persistent effect of the gels in our preliminary observation, it is now important to conduct a larger study with longer follow- up.
... Its metabolism is regulated by three hyaluronan synthase genes [34] and the various isoforms of degrading hyaluronidases [35] . In order to exert its functions, HA is recognized by cell surface receptors, notably CD44 and receptor for HA mediated motility (RHAMM) [36,37]. Interaction of this highly metabolically active molecule with its receptors has a triggering effect on several intracellular signaling pathways, which in turn regulate cell proliferation, migration and differentiation [37,38]. ...
... In order to exert its functions, HA is recognized by cell surface receptors, notably CD44 and receptor for HA mediated motility (RHAMM) [36,37]. Interaction of this highly metabolically active molecule with its receptors has a triggering effect on several intracellular signaling pathways, which in turn regulate cell proliferation, migration and differentiation [37,38]. It is also known that HA acts as an immune regulator and activates a wide range of inflammatory cells [33,38]. ...
Biomarkers are extremely important in the case of multisystemic diseases, such as lysosomal storage disorders (LSDs), which are often difficult to assess in clinical practice. Several studies demonstrated significant alterations in the expression of extracellular matrix (ECM) components in LSD patients, raising important questions in relation to their possible involvement in disease pathogenesis and providing evidence for their possible utility as disease biomarkers. This article provides an overview of the possible pathogenic correlations between LSDs and ECM. Data regarding the expression of these molecules are discussed. Finally, the possible implication of ECM components as therapeutic targets in this group of diseases along with the impact of the differential expression of these components in current LSD treatment will be critically addressed.
... При з'єднанні ГК з мономерами агрекану за наявності білка в хрящі формуються великі негативно заряжені агрегати, що поглинають воду та відповідають за пружно-еластичні властивості хряща, його стійкість до компресії. З віком молекулярна маса ГК у хрящі зменшується, при цьому її загальний вміст збільшується [10, 33,43]. ...
Протягом останнього десятиріччя застосування препаратів гіалуронової кислоти (ГК) набуває дедалі більшого значення у комплексному лікуванні дегенеративно-дистрофічних захворювань скронево-нижньощелепного суглоба. Актуальність зумовлена численними дослідженнями в галузі біології та фармакології щодо структури і дії ГК, її впливу на процеси репарації ушкодженої кістки та відновлення суглобового хряща, а також позитивними віддаленими результатами лікування даних хворих.
... 52 Hyaluronic acid is also easily modified and found in the extracellular matrix of skin, cartilage, and vitreous humors but is expensive and not able to be easily physically crosslinked. 53 DNA is an easily modified polymer that can be obtained from any living organism and can be designed for a wide range of applications with responses to different stimuli, however it is a very expensive polymer to use in this application where low cost is a major factor. 54 Chitin is a readily available polymer (being the second most abundant carbon polymer in nature) extracted from the exoskeletons of crustaceans and insects. ...
Aquaculture is a large part of the food production sector which is greatly expanding. One of the largest losses in aquaculture is due to pathogens. Current solutions for protecting farmed finfish from pathogens can be very expensive with variable efficiency. Current disease prevention strategies include vaccination. Types of vaccines include immersion vaccines, feed vaccines, and injectable vaccines. The most popular solution is oil-based injectable vaccines due to its protection. However, the oil-based adjuvant used in most of these formulations causes adverse reactions in the fish including reduced growth. These vaccines require multiple administrations throughout the fish’s lifetime causing unwanted handling stress and additional labor costs. Preliminary trials show that cellulose nanomaterials cause minimal adverse reactions when injected into salmon and does not significantly affect their growth. The goal of this research was to create an adjuvant from cellulose nanomaterials which would increase bacterin efficacy while avoiding harmful side effects. A prolonged release formulation was also desirable, obviating the need for multiple vaccinations. Additionally, hydrogels have been used for a wide variety of applications including drug delivery, making them an attractive aquatic vaccine adjuvant. Cellulose nanomaterials were decided as the polymer to make up the hydrogel matrix due to their biocompatibility, sustainability, high tunability, high abundance, low cost. The development of the hydrogel formulation, modifying the hydrogel for easier delivery into the salmon, measuring the diffusive properties of the hydrogel, and in vivo testing of the hydrogel for analysis of delivery methods and reactions to the formulation are described in this research.
... It plays an important role in maintaining tissue integrity and vascularization. 22,23 HA bio-implants are sterile, biodegradable, viscoelastic, isotonic, transparent injectable gels, which were approved by the Food and Drug Administration (FDA) in 1996 and have since been successfully used for volume loss correction in several medical disciplines. However, there is paucity of information on its use in the management of orofacial cleft anomalies. ...
Background:
Surgical treatment of cleft lip and palate is divided into primary and secondary procedures to restore physiological function and appearance of the face, mouth, and nose. Hyaluronic acid (HA) bio-implants have been successfully used for volume loss correction in several medical disciplines. However, there is paucity of information about its use in the management of facial clefting.
Objectives:
The aim of this report is to present the preliminary findings on the feasibility of using a cross-linked HA for aesthetic correction in previously surgical treated cleft lip and palate cases.
Methods:
The cross-linked HA STYLAGE L, XL, and XXL (LABORATOIRES VIVACY, Paris, France) were used in this case series. Multiple treatment sessions, 4-6 weeks apart, were performed if required.
Results:
A total of 15 patients had undergone the HA injections between May 2018 and December 2021. Of these, 13 had simultaneous correction of the nose, lip, and paranasal scar and the remaining 2 only the lip and scar. The procedures were uneventful and well tolerated by the patients. At follow-up, aesthetic improvement was observed in all patients. Moreover, patients reported overall satisfaction with the outcome of the procedures particularly because of its minimally invasive nature.
Conclusions:
Cross-linked HA is a feasible and promising complimentary option for aesthetic, and potentially functional, correction in cases of cleft lip and palate. Larger clinical trials are needed to validate these preliminary findings.
Level of evidence 4:
... Hyaluronic acid. Hyaluronic acid, or hyaluronan, in the skin extracellular matrix has viscoelastic and hygroscopic properties [108], and may be a suitable alternative to vaginal estrogens for the treatment of symptoms of vaginal atrophy in women with contraindications to HRT [109]. ...
The skin is an endocrine organ and a major target of hormones such as estrogens, androgens and cortisol. Besides vasomotor symptoms (VMS), skin and hair symptoms often receive less attention than other menopausal symptoms despite having a significant negative effect on quality of life. Skin and mucosal menopausal symptoms include dryness and pruritus, thinning and atrophy, wrinkles and sagging, poor wound healing and reduced vascularity, whereas skin premalignant and malignant lesions and skin aging signs are almost exclusively caused by environmental factors, especially solar radiation. Hair menopausal symptoms include reduced hair growth and density on the scalp (diffuse effluvium due to follicular rarefication and/or androgenetic alopecia of female pattern), altered hair quality and structure, and increased unwanted hair growth on facial areas. Hormone replacement therapy (HRT) is not indicated for skin and hair symptoms alone due to the risk-benefit balance, but wider potential benefits of HRT (beyond estrogen's effect on VMS, bone, breast, heart and blood vessels) to include skin, hair and mucosal benefits should be discussed with women so that they will be able to make the best possible informed decisions on how to prevent or manage their menopausal symptoms.
... VVMW is highly enriched in 15 minerals and has shown to strengthen the skin's natural defenses, such as restoring the physical skin barrier, and stimulating both antioxidant activity and innate immunity. (9)(10)(11)(12)(13) HA is a polysaccharide that belongs to the glycosaminoglycan family and consists of a basic unit of two sugars, glucuronic acid and N-acetyl-glucosamine. HA usually exists as a high molecular mass in the synovial fluid that surrounds joints, cartilage, and eye tissue, and has been shown to play an important role in skin repair.(14, 15) It has been demonstrated that M89 improves the clinical signs and symptoms associated with various facial dermatoses, including rosacea, and even those appearing postprocedure. ...
Background:
M89M (Mineral 89 mask, Laboratoires Vichy, France) containing 89% Vichy volcanic mineralizing water and hyaluronic acid, aims to strengthen and repair skin barrier.
Objectives:
to assess the efficacy, tolerance, patient satisfaction and quality of life (QOL) using M89M after laser procedures (LP).
Methods:
M89M was applied immediately post-LP for 10 minutes, then daily for 5 days and 2 to 3 times a week, up to 28 days on the faces of 51 women. Evaluations were performed immediately post-LP, immediately after M89M application at D0, D1, D5 and D28, and included criteria such as erythema and skin dryness. Subjects scored burning and warm sensations, itching, skin tightness and stinging. Skin hydration using a Corneometer, skin barrier integrity using a Tewameter, and erythema using a Chromameter were assessed. Local tolerance and adverse events were recorded. After 28 days, subjects answered a questionnaire regarding the M89M subjective cosmetic properties and QOL.
Results:
All subjects were in their mid-forties with a phototype of II, III or IV. M89M significantly (p<0.001) reduced the immediate cutaneous discomfort sensation and laser procedure-related symptoms (burning, warmth sensation, itching/stinging, skin tightness). Skin hydration, and erythema, assessed using instrumental measures, were also significantly improved immediately after mask application (p≤0.01). Subjects highly appreciated M89M and their quality of life improved after 28 days of use. Local tolerance was good to excellent in both studies.
Conclusion:
M89M is effective and safe immediately after esthetic procedures such as ablative and non-ablative lasers, and also improves the subject's quality of life.
... Interestingly, this alternative splicing is regulated by mitogenic or oncogenic signals [96]. Despite originally being considered a receptor for hyaluronic acid, it has been observed that the interaction of CD44 with different-sized HA oligosaccharides, which could represent a sign of cellular distress especially in malig-nancies [97], triggers intracellular signaling pathways [98] that lead to an increase in the expression of MMP-14, cleavage of CD44, and cell migration [99]. The cleavage of CD44 facilitates the detachment from HA in the extracellular matrix, and the ICD fragment liberated by the cleavage process is capable to induce the expression of new CD44 molecules on the cell membrane, thus facilitating the binding to other sites [100]. ...
CD44 is a transmembrane glycoprotein expressed in several healthy and tumor tissues. Modifications in its structure contribute differently to the activity of this molecule. One modification that has provoked interest is the consecutive cleavage of the CD44 extracellular ectodomain by enzymes that belong mainly to the family of metalloproteases. This process releases biologically active substrates, via alternative splice forms of CD44, that generate CD44v3 or v6 isoforms which participate in the transcriptional regulation of genes and proteins associated to signaling pathways involved in the development of cancer. These include the protooncogene tyrosine-protein kinase Src (c-Src)/signal transducer and activator of transcription 3 (STAT3), the epithelial growth factor receptor, the estrogen receptor, Wnt/βcatenin, or Hippo signaling pathways all of which are associated to cell proliferation, differentiation, or cancer progression. Whereas CD44 still remains as a very useful prognostic cell marker in different pathologies, the main topic is that the generation of CD44 intracellular fragments assists the regulation of transcriptional proteins involved in the cell cycle, cell metabolism, and most importantly, the regulation of some stem cell-associated markers.
1. Main Text
1.1. Structure and Function of CD44
CD44 is a cell surface adhesion molecule involved in cell-cell interactions, cell adhesion, and migration [1]. The main ligand of CD44 is hyaluronic acid (HA), a polysaccharide abundantly present in the extracellular matrix of mammals, yet it can bind to other components of the extracellular matrix and perform different functions depending on the structure of the protein it binds to [2, 3]. It is composed of a distal extracellular amino-terminal domain (ECD), a stem region, a transmembrane domain (TM), and an intracellular cytoplasmic carboxy-terminal domain (ICD) (Figure 1).
(a)
... To analyze differences between tumor cells cultured in 2D versus 3D in more detail, we first looked at stemness. CD44 functions as a receptor that binds to hyaluronic acid and other components of the ECM (Nusgens, 2010). It is widely recognized as a stem cell marker in solid tumors, acts as a co-receptor and regulates cell behavior by integrating external signals (Wang et al., 2018). ...
High attrition-rates entailed by drug testing in 2D cell culture and animal models stress the need for improved modeling of human tumor tissues. In previous studies our 3D models on a decellularized tissue matrix have shown better predictivity and higher chemoresistance. A single porcine intestine yields material for 150 3D models of breast, lung, colorectal cancer (CRC) or leukemia. The uniquely preserved structure of the basement membrane enables physiological anchorage of endothelial cells and epithelial-derived carcinoma cells. The matrix provides different niches for cell growth: on top as monolayer, in crypts as aggregates and within deeper layers. Dynamic culture in bioreactors enhances cell growth. Comparing gene expression between 2D and 3D cultures, we observed changes related to proliferation, apoptosis and stemness. For drug target predictions, we utilize tumor-specific sequencing data in our in silico model finding an additive effect of metformin and gefitinib treatment for lung cancer in silico, validated in vitro. To analyze mode-of-action, immune therapies such as trispecific T-cell engagers in leukemia, as well as toxicity on non-cancer cells, the model can be modularly enriched with human endothelial cells (hECs), immune cells and fibroblasts. Upon addition of hECs, transmigration of immune cells through the endothelial barrier can be investigated. In an allogenic CRC model we observe a lower basic apoptosis rate after applying PBMCs in 3D compared to 2D, which offers new options to mirror antigen-specific immunotherapies in vitro. In conclusion, we present modular human 3D tumor models with tissue-like features for preclinical testing to reduce animal experiments.
... 120 HA in its natural state is a perfect filler material, but has an extremely short half-life. [121][122][123][124][125][126][127][128] To retard natural turnover and enhance its lifespan, manufacturers have attempted to modify the chemistry of HA by crosslinking chains using different dispersants such as 1,4-butanediol diglyceryl ether. 129 Minimal modification of the material enabled manufacturers to produce HA products that can be welltolerated by the immune system, as well as are durable and nonreactive. ...
Nonsurgical rhinoplasty is one choice for cases in which open surgery may be harmful, the deformity is not indicated to correct with open surgery, or in patients who have phobia of general anesthesia or any type of surgery. Autologous fat injection or fillers are most common materials currently available in the market. In this article, we explain the indications, contraindications, methods, and complications of this treatment.
... Half-life of hyaluronic acid in skin is less than one day 34 Tamisami 51 and Longinotti 52 , both in small, anecdotal, prospective studies treated deep partial thickness and full thickness burns, both with good results with regard to speed of healing and graftibility. Neither of the studies showed long-term results [51][52][53] In a review article by Voigt and Driver 57 , burn wounds, surgical wounds, and ulcers (venous insufficiency, diabetes, neuropathic), treated with eHAM were analyzed. ...
The role of the dermis is essential for the proper orchestration of all phases of the normal wound healing process. Wounds with seriously damaged or even absent dermis consistently show seriously impaired wound healing and/or long-term complications such as hypertrophic scarring.
Replacing a damaged dermis requires a dermal matrix that is compatible with, or even stimulates, the process of wound healing. Hyaluronic acid (HA), in an esterified form is among the many matrices that are available. HA has been used in a number of indications, such as ulcers (i.e. diabetic foot ulcers, venous leg ulcers), trauma, including burns, and for the repair of contractures and hypertrophic scars.
The shorter healing time and the decrease of recurring hypertrophy demonstrate the efficiency of hyaluronic acid derived matrices. Biopsies, taken up to 12 months post-reconstruction show a neodermis that histologically is largely comparable to normal skin, which probably is a function of hyaluronic acid playing such a pivotal role in normal, unwounded skin, as well as in the process of healing.
... Hyaluronic acid, or hyaluronan, is a biological polymer made of the repetition of a unique disaccharidic unit, D-glucuronic acid and D-N-acetylglucosamine, that can reach a molecular mass of 10 million daltons [106]. Hyaluronan is an important connective tissue glycosaminoglycan and its increased biosynthesis is a common feature during tissue remodeling under physiological and pathological conditions [107]. ...
Gentisic Acid (GA) is an endogenously synthesized quinonoid phenolic acid in plants,
where it functions as an immune molecule against viral plant pathogens via modifying
microRNAs. In mammalians, GA is both consumed from exogenous sources (from fruits
and vegetables) and produced endogenously as an endogenous siderophore and as a
byproduct of tyrosine catabolism. Besides the edible plants, aspirin is also an important
source of GA, since its catabolism produces GA. Noteworthy, humans with variant alleles of
CYP2C9 which are incapable to produce GA during aspirin catabolism do not benefit from
aspirin in reduction of adenomas in the large bowel. In past, GA was succesfully used in the
treatment of rheumatological diseases in humans with high biosafety. GA has an affinity
to connective tissue proteins and a higher retention of exogenous GA was demonstrated
in humans with cancer. GA has both direct and indirect strong antioxidant effects as a free
radical scavenger molecule and as an agonist of NRF2 (Nuclear factor erythroid-derived
2-like 2), an important transcription factor which regulates synthesis of antioxidant
molecules. GA blocks cancer promotion in animal models in association with reduction of
free radical products and stimulating antioxidant molecules. GA also exerts prominent antiinflammatory
effects while stimulating elements of acquired immunity, lymphocytes; which
likely occur due to its strong efficacies to block cyclooxygenases, 12-lipoxygenase and
acting as a ligand of GPR35/CXCR8. GA also specifically inhibit protumorigenic signaling
of Fibroblast Growth Factor (FGF) and cyclin dependent kinase-1 (CDK1). Sulfonated
derivative of GA (2,5-dihydroxyphenylsulfonate, dobesilic acid) blocks subcutaneous
growth of C6 glioma; and GA also acts as an agonist of Vasoactive Intestinal Polypeptide
(VIP) pathway, which suppresses invasion of glioma cells in vitro. GA also inhibits OAT3/
SLC22A8, which involves efflux of chemotherapeutics from the brain which may help
to achieve therapeutic concentrations of anticancer agents in brain tumors. In future,
combined aspirin-GA preparates may be tested for potential activity in cancer prevention
and treatment.
... The hyaluronic acid (HA) is a large glycosaminoglycan, which serves as one of the important components of the extracellular matrix. Numerous functions have been ascribed to it, including immune activation, promotion of proliferation, migration, and intracellular signaling 25,26 . Its role as a mediator of MSC homing is particularly interesting as its production increases during inflammation and injury 27 . ...
A major challenge in regenerative medicine is to improve therapeutic cells’ delivery and targeting using an efficient and simple protocol. Mesenchymal stem cells (MSC) are currently employed for the treatment of inflammatory-based diseases, due to their powerful immunosoppressive potential. Here we report a simple and versatile method to transiently overexpress the hyaluronic acid (HA) receptor, CD44, on MSC membranes, to improve their homing potential towards an inflammatory site without affecting their behavior. The effect of HA-coatings on murine MSC was functionally determined both, in vitro and in vivo as a consequence of the transient CD44 overexpression induced by HA. Data obtained from the in vitro migration assay demonstrated a two-fold increase in the migratory potential of HA-treated MSC compared to untreated cells. In an LPS-induced inflamed ear murine model, HA-treated MSC demonstrated a significantly higher inflammatory targeting as observed at 72 hrs as compared to untreated cells. This increased accumulation for HA-treated MSC yielded a substantial reduction in inflammation as demonstrated by the decrease in the expression of pro-inflammatory markers and by the induction of a pro-regenerative environment.
... HA is a chief component of the extracellular matrix (ECM) of connective tissues, but it can be also found in the pericellular and intracellular matrix (Necas et al., 2008;Kaux et al., 2016). This polymer plays a main structural role in the formation of ECM due to its viscoelastic properties, hygroscopic capacities and the diversity of cell processes it controls (Nusgens, 2010;Gressner et al., 2010). HA keeps ECM and ECM components (e.g. ...
The common pathway leading to liver fibrosis and cirrhosis is growing deposition of extracellular matrix (ECM). It results from molecular and histological rearrangement of collagens, glycoproteins and hyaluronans. Hyaluronic acid is a chief component of the extracellular matrix of connective tissues and plays the main structural role in the formation of ECM. The most important organ involved in the synthesis of hyaluronic acid is the liver. In this paper the meaning of hyaluronic acid in the diagnostics of liver diseases is discussed. Here, we focus on the described changes of hyaluronic acid concentration in the pathological processes of the liver, including alcoholic and non-alcoholic liver diseases. The results of published clinical studies have shown its high diagnostic sensitivity, which probably enables its application in laboratory diagnosis.
... Hyaluronic acid (HA) or hyaluronan, a polymer of molecular mass up to 10 Daltons, is produced by synovial fibroblasts and is composed of repeating disaccharidic units of D-glucuronic acid and D-N-acetyl-glucosamine. HA is part of the normal cartilage matrix where it has a central role in ECM stabilization together with aggrecan interaction. Moreover, HA has hydrodynamic properties and performs fundamental functions in lubrication and osmotic stability (Nusgens 2010). In an experimentally induced OA, HA has a suppressive character in reducing chondrocyte apoptosis (Echigo et al. 2006). ...
Extra-cellular matrix (ECM) components are important and their stabilization is significant in maintaining normal healthy joint environment. In osteoarthritis (OA), ECM components are altered and indicate disease progression. The joint ECM is composed of proteoglycans (aggrecan, perlecan, inter α-trypsin inhibitor), glycoproteins (fibronectin, lubricin, COMP) and collagen types (most abundantly collagen type II) which represent structural and functional transformation during disease advancement. ECM investigation revealed significant biomarkers of OA that could be used as a diagnostic and therapeutic tool in different canine orthopedic diseases. This review deliberates our current findings of how the components of ECM change at the molecular level during disease progression in canine OA.
... HA is a free unbranched GAG composed of repeating disaccharides of N-acetyl-glucosamine and glucuronic acid units, synthesized in a unique manner by a family of hyaluronan synthases (HAS 1-3), degraded by hyaluronidases (HYAL 1 and 2) and exerts its biological effects by binding to families of cellular receptors, the hyaladherins (Antonio and Iozzo, 2001;Nikitovic et al., 2013b). HA is ubiquitously distributed in the ECM (Noble, 2002), and it is primarily produced by dermal fibroblasts and epidermal keratinocytes and to a smaller amount by other cell types including smooth muscle cells (Nusgens, 2010). A strict dependence on size is evident on HA biological roles as high molecular weight HA (HMWHA) (<1 Â106 kDa) is anti-angiogenic, anti-inflammatory and immunosuppressive (Stern et al., 2006;Kim et al., 2008). ...
... HA is distributed widely throughout connective, epithelial, and neural tissues [21]. HA has various physiological functions, from acting as the major component of extracellular matrix, cell migration and proliferation, and wound repair, to endogenous activation of immunity [21][22][23][24]. Recently, there has been more evidence suggesting that HA degradation products interact directly with toll-like receptors (TLRs) and activate downstream inflammatory signals [25][26][27]. ...
Background
Activation of hyaluronic acid (HA) and associated enzyme synthesis has been demonstrated in experimental stroke animal models. Our study aimed to investigate the plasma levels of HA in acute stroke patients and the associations between HA levels and functional outcome.
Methods
This was a multicenter case–control study. Acute stroke patients and age- and sex-matched non-stroke controls were recruited. Plasma levels of HA in acute stroke patients were determined at <48 hours and at 48 to 72 hours after stroke onset by standard ELISA. Favorable functional outcome was defined as modified Rankin scale ≤2 at 3 months after stroke.
Results
The study included 206 acute stroke patients, including 43 who had intracerebral hemorrhage and 163 who had ischemic stroke, and 159 controls. The plasma levels of HA in the acute stroke patients were significantly higher than those in the controls (219.7 ± 203.4 ng/ml for <48 hours and 343.1 ± 710.3 ng/ml for 48 to 72 hours versus 170.4 ± 127.9 ng/ml in the controls; both P < 0.05). For intracerebral hemorrhage patients, HA ≤500 ng/ml (<48 hours) was an independent favorable outcome predictor (P = 0.016). For ischemic stroke patients, an inverted U-shaped association between plasma HA (48 to 72 hours) and outcome was noted, indicating that ischemic stroke patients with too high or too low plasma HA levels tended to have an unfavorable outcome.
Conclusion
HA plasma level was elevated in patients with acute stroke, and can predict 3-month functional outcome, particularly for patients with intracerebral hemorrhage.
... The biological roles of HA are also dependent on its hydrophilic and hydrodynamic properties due to inherent negative charge, which allow it to retain water and play a structural role in tissue organization. HA is ubiquitously distributed in the ECM (Stern et al., 2006; Noble, 2002), and it is primarily produced by dermal fibroblasts and epidermal keratinocytes and to a smaller amount by other cell types including smooth muscle cells (Nusgens, 2010 ). The versatile, in vivo, molecular weight of HA allows wide range of activities. ...
... Among these endogenous molecules are heat shock proteins, uric acid, ATP and ECM components such as biglycan and low MW fragments of hyaluronic acid (HA) [15,16,17,18]. HA is a negatively charged glucosaminoglycan ubiquitously distributed in the ECM [19] and is primarily produced by dermal fibroblasts and epidermal keratinocytes and to a lesser extent by other cell types like smooth muscle cells [20]. Regarding its immune-modulatory effects, the size of HA plays an important role. ...
Allergic contact dermatitis (ACD) represents a severe health problem with increasing worldwide prevalence. It is a T cell-mediated skin disease induced by protein-reactive organic and inorganic chemicals. A key feature of contact allergens is their ability to trigger an innate immune response that leads to skin inflammation. Previous evidence from the mouse contact hypersensitivity (CHS) model suggests a role for endogenous activators of innate immune signaling. Here, we analyzed the role of contact sensitizer induced ROS production and concomitant changes in hyaluronic acid metabolism on CHS responses.
We analyzed in vitro and in vivo ROS production using fluorescent ROS detection reagents. HA fragmentation was determined by gel electrophoresis. The influence of blocking ROS production and HA degradation by antioxidants, hyaluronidase-inhibitor or p38 MAPK inhibitor was analyzed in the murine CHS model. Here, we demonstrate that organic contact sensitizers induce production of reactive oxygen species (ROS) and a concomitant breakdown of the extracellular matrix (ECM) component hyaluronic acid (HA) to pro-inflammatory low molecular weight fragments in the skin. Importantly, inhibition of either ROS-mediated or enzymatic HA breakdown prevents sensitization as well as elicitation of CHS.
These data identify an indirect mechanism of contact sensitizer induced innate inflammatory signaling involving the breakdown of the ECM and generation of endogenous danger signals. Our findings suggest a beneficial role for anti-oxidants and hyaluronidase inhibitors in prevention and treatment of ACD.
... Perlecan and versican were distributed throughout the integument of A. fulica. A similar pattern has been described for collagen type-I in other gastropods [49]. Our results showed that these PGs were localised in the extracellular matrix (ECM) of the subepidermal connective tissue. ...
Proteoglycans encompass a heterogeneous group of glycoconjugates where proteins are substituted with linear, highly negatively charged glycosaminoglycan chains. Sulphated glycosaminoglycans are ubiquitous to the animal kingdom of the Eukarya domain. Information on the distribution and characterisation of proteoglycans in invertebrate tissues is limited and restricted to a few species. By the use of multidimensional protein identification technology and immunohistochemistry, this study shows for the first time the presence and tissue localisation of different proteoglycans, such as perlecan, aggrecan, and heparan sulphate proteoglycan, amongst others, in organs of the gastropoda Achatina fulica. Through a proteomic analysis of Golgi proteins and immunohistochemistry of tissue sections, we detected the machinery involved in glycosaminoglycan biosynthesis, related to polymer formation (polymerases), as well as secondary modifications (sulphation and uronic acid epimerization). Therefore, this work not only identifies both the proteoglycan core proteins and glycosaminoglycan biosynthetic enzymes in invertebrates but also provides a novel method for the study of glycosaminoglycan and proteoglycan evolution.
... HA has been assigned various physiological functions due to its 206 viscoelastic properties, its hygroscopic capacities. Polymers are either anchored firmly in the plasma membrane or bound via 207 receptors(Nusgens, 2010). One third of HA is replaced daily in tissues in which a part of it is removed by the lymphatic ves-208 sels and/or degraded by lymphatic cells in the lymph nodes. ...
The main physiological function of the lymphatic vasculature is to maintain tissue fluid homeostasis. Lymphangiogenesis or de novo lymphatic formation is closely associated with tissue inflammation in adults (i.e. wound healing, allograft rejection, tumor metastasis). Until recently, research on lymphangiogenesis focused mainly on growth factor/growth factor-receptor pathways governing this process. One of the lymphatic vessel features is the incomplete or absence of basement membrane. This close association of endothelial cells with the underlying interstitial matrix suggests that cell-matrix interactions play an important role in lymphangiogenesis and lymphatic functions. However, the exploration of interaction between extracellular matrix (ECM) components and lymphatic endothelial cells is in its infancy. Herein, we describe ECM-cell and cell-cell interactions on lymphatic system function and their modification occurring in pathologies including cancer metastasis.
Hyaluronic acid (HA) is a glycosaminoglycan composed of D-glucuronic acid and N-acetylglucosamine with an up-to-several-million-Daltons chain-length responsible for the lubricating properties of the temporomandibular joint (TMJ) synovial fluid. Arthritis results in the predominance of HA degradation over synthesis leading to temporomandibular disorders (TMDs). TMD injection treatments are divided into HA supplementation and platelet-rich plasma (PRP) inflammation suppression. We questioned whether either approach lubricated the TMJ better and answered it in a two-arm equal-allocation trial with a non-concurrent active treatment control (two groups of 39 patients each). HA statistically significantly improved (p < 0.01) and PRP did not statistically significantly change (0.06 ≤ p ≤ 0.53) articular mobility compared to baselines in 128 TMJs. Statistically significant inter-group discrepancies were observed for abduction (MD = −4.05 mm; SE = 1.08; p = 0.00; d = −0.85) and protrusion (MD = −0.97 mm; SE = 0.43; p = 0.03; d = −0.51) but not for rightward (MD = −0.21; SE = 0.43; p = 0.63; d = −0.11) and leftward (MD = −0.30; SE = 0.42; p = 0.47; d = −0.16) movements. HA supplementation proved superior to PRP autografting in ad hoc TMJ lubrication and hence is more appropriate in hypomobile TMD cases of symptomatic treatment.
Wound healing can result in complex problems, and discovering an effective method to improve the healing process is essential. Polymeric biomaterials have structures similar to those identified in the extracellular matrix of the tissue to be regenerated and also avoid chronic inflammation , and immunological reactions. To obtain smart and effective dressings, bioactive agents, such as essential oils, are also used to promote a wide range of biological properties, which can accelerate the healing process. Therefore, we intend to explore advances in the potential for applying hybrid materials in wound healing. For this, fifty scientific articles dated from 2010 to 2023 were investigated using the Web of Science, Scopus, Science Direct, and PubMed databases. The principles of the healing process, use of polymers, type and properties of essential oils and processing techniques, and characteristics of dressings were identified. Thus, the plants Syzygium romanticum or Eugenia caryophyllata, Origanum vulgare, and Cinnamomum zeylanicum present prospects for application in clinical trials due to their proven effects on wound healing and reducing the incidence of inflammatory cells in the site of injury. The antimicrobial effect of essential oils is mainly due to polyphenols and terpenes such as eugenol, cinnamaldehyde, carvacrol, and thymol.
Currently, tissue engineering has been dedicated to the development of 3D structures through bioprinting techniques that aim to obtain personalized, dynamic, and complex hydrogel 3D structures. Among the different materials used for the fabrication of such structures, proteins and polysaccharides are the main biological compounds (biopolymers) selected for the bioink formulation. These biomaterials obtained from natural sources are commonly compatible with tissues and cells (biocompatibility), friendly with biological digestion processes (biodegradability), and provide specific macromolecular structural and mechanical properties (biomimicry). However, the rheological behaviors of these natural-based bioinks constitute the main challenge of the cell-laden printing process (bioprinting). For this reason, bioprinting usually requires chemical modifications and/or inter-macromolecular crosslinking. In this sense, a comprehensive analysis describing these biopolymers (natural proteins and polysaccharides)-based bioinks, their modifications, and their stimuli-responsive nature is performed. This manuscript is organized into three sections: (1) tissue engineering application, (2) crosslinking, and (3) bioprinting techniques, analyzing the current challenges and strengths of biopolymers in bioprinting. In conclusion, all hydrogels try to resemble extracellular matrix properties for bioprinted structures while maintaining good printability and stability during the printing process.
Background:
Hyaluronic acid is synthesised in plasma membranes and can be found in extracellular tissues. It has been suggested that the application of hyaluronic acid to chronic wounds may promote healing, and the mechanism may be due to its ability to maintain a moist wound environment which helps cell migration in the wound bed.
Objectives:
To evaluate the effects of hyaluronic acid (and its derivatives) on the healing of chronic wounds.
Search methods:
We used standard, extensive Cochrane search methods. The latest search date was February 2022.
Selection criteria:
We included randomised controlled trials that compared the effects of hyaluronic acid (as a dressing or topical agent) with other dressings on the healing of pressure, venous, arterial, or mixed-aetiology ulcers and foot ulcers in people with diabetes.
Data collection and analysis:
We used standard methodological procedures expected by Cochrane. We assessed the certainty of the evidence using the GRADE approach.
Main results:
We included 12 trials (13 articles) in a qualitative synthesis, and were able to combine data from four trials in a quantitative analysis. Overall, the included trials involved 1108 participants (mean age 69.60 years) presenting 178 pressure ulcers, 54 diabetic foot ulcers, and 896 leg ulcers. Sex was reported for 1022 participants (57.24% female). Pressure ulcers It is uncertain whether there is a difference in complete healing (risk ratio (RR) 1.17, 95% confidence interval (CI) 0.58 to 2.35); change in ulcer size (mean difference (MD) 25.60, 95% CI 6.18 to 45.02); or adverse events (none reported) between platelet-rich growth factor (PRGF) + hyaluronic acid and PRGF because the certainty of evidence is very low (1 trial, 65 participants). It is also uncertain whether there is a difference in complete healing between lysine hyaluronate and sodium hyaluronate because the certainty of evidence is very low (RR 2.50, 95% CI 0.71 to 8.83; 1 trial, 14 ulcers from 10 participants). Foot ulcers in people with diabetes It is uncertain whether there is a difference in time to complete healing between hyaluronic acid and lyophilised collagen because the certainty of evidence is very low (MD 16.60, 95% CI 7.95 to 25.25; 1 study, 20 participants). It is uncertain whether there is a difference in complete ulcer healing (RR 2.20, 95% CI 0.97 to 4.97; 1 study, 34 participants) or change in ulcer size (MD -0.80, 95% CI -3.58 to 1.98; 1 study, 25 participants) between hyaluronic acid and conventional dressings because the certainty of evidence is very low. Leg ulcers We are uncertain whether there is a difference in complete wound healing (RR 0.98, 95% CI 0.26 to 3.76), percentage of adverse events (RR 0.79, 95% CI 0.22 to 2.80), pain (MD 2.10, 95% CI -5.81 to 10.01), or change in ulcer size (RR 2.11, 95% CI 0.92 to 4.82) between hyaluronic acid + hydrocolloid and hydrocolloid because the certainty of evidence is very low (1 study, 125 participants). It is uncertain whether there is a difference in change in ulcer size between hyaluronic acid and hydrocolloid because the certainty of evidence is very low (RR 1.02, 95% CI 0.84 to 1.25; 1 study, 143 participants). We are uncertain whether there is a difference in complete wound healing between hyaluronic acid and paraffin gauze because the certainty of evidence is very low (RR 2.00, 95% CI 0.21 to 19.23; 1 study, 24 ulcers from 17 participants). When compared with neutral vehicle, hyaluronic acid probably improves complete ulcer healing (RR 2.11, 95% CI 1.46 to 3.07; 4 studies, 526 participants; moderate-certainty evidence); may slightly increase the reduction in pain from baseline (MD -8.55, 95% CI -14.77 to -2.34; 3 studies, 337 participants); and may slightly increase change in ulcer size, measured as mean reduction from baseline to 45 days (MD 30.44%, 95% CI 15.57 to 45.31; 2 studies, 190 participants). It is uncertain if hyaluronic acid alters incidence of infection when compared with neutral vehicle (RR 0.89, 95% CI 0.53 to 1.49; 3 studies, 425 participants). We are uncertain whether there is a difference in change in ulcer size (cm2) between hyaluronic acid and dextranomer because the certainty of evidence is very low (MD 5.80, 95% CI -10.0 to 21.60; 1 study, 50 participants). We downgraded the certainty of evidence due to risk of bias or imprecision, or both, for all of the above comparisons. No trial reported health-related quality of life or wound recurrence. Measurement of change in ulcer size was not homogeneous among studies, and missing data precluded further analysis for some comparisons.
Authors' conclusions:
There is currently insufficient evidence to determine the effectiveness of hyaluronic acid dressings in the healing of pressure ulcers or foot ulcers in people with diabetes. We found evidence that hyaluronic acid probably improves complete ulcer healing and may slightly decrease pain and increase change in ulcer size when compared with neutral vehicle. Future research into the effects of hyaluronic acid in the healing of chronic wounds should consider higher sample size and blinding to minimise bias and improve the quality of evidence.
Purpose
Exposure of the skin to ultraviolet radiation (UV) or ozone (O3) results in stressed skin, leading to the alteration of the skin physical barrier and defence functions. In this work, the preventive benefit of a dermocosmetic, M89PF, containing Vichy mineralising water, probiotic fractions, antioxidant vitamins and hyaluronic acid, in the alteration of skin physical barrier and skin defence functions after exposure to O3 and UV, alone or combined, was assessed.
Methods
Untreated and treated (M89PF) skin explants were exposed to O3, to UV rays or to O3+UV. Immunofluorescence was performed for skin barrier, oxidative stress, and inflammatory markers after one and four days of exposure to the pollutants.
Results
M89PF significantly (p≤0.05) prevented the decrease of the expression level of different skin barrier markers, and significantly (p≤0.05) prevented the induction of OxInflammatory markers and inflammasome components by UV, O3, or both combined.
Conclusion
M89PF prevents skin barrier damage, as well as oxidative stress and inflammatory markers induced by exposome factors, such as UV, O3, or both combined.
Background
Hyaluronic acid (HA) based gel fillers help correct facial volume deficits through their volumizing effect.
Objectives
This post-market clinical follow-up study was a single center prospective cohort study designed to evaluate the efficacy and safety of Stylage XL Lidocaine (Laboratoires VIVACY; Paris, France) for the augmentation and/or restoration of facial volume.
Methods
Healthy subjects between the ages of 30 and 65 years with a facial volume grade of 3–5 according to the facial volume loss scale (FVLS) were considered eligible. Participants were injected subcutaneously in the area of the cheekbones (essential area). If necessary, subjects were also injected in the chin, the temples and the facial oval (optional areas). Outcomes were assessed at 1, 3, 6, 12, and 18 months following the initial treatment. A touch-up was possible at 1 month following the initial injection. The primary endpoint was the variation in the mean FVLS scores at M6 compared to baseline as evaluated by an independent assessor.
Results
A total of 40 female subjects (mean age of 52.5 years) were recruited between November 2019 and July 2021. There was a significant improvement in the mean FVLS score at 6 months compared to baseline (2.3 (0.6) vs. 3.1 (0.6); p < 0.0001). Subjects were satisfied with the achieved aesthetic improvements and results were still observed at 12 and 18 months. Stylage XL Lidocaine also had a good safety profile and was well tolerated by the study cohort.
Conclusions
The results of the 18-month Beauty Volume study confirmed the efficacy and safety of the Stylage XL Lidocaine HA-based gel filler in the augmentation and/or restoration of facial volumes.
Synthesis, characterization, and macromolecular engineering of efficient drug delivery systems are important fields of research and also of practical importance in medicine and health care. In this sense, a wide variety of biomaterials have been applied for drug delivery purposes over years. Polymers are among biomaterials significantly considered in biomaterial development as drug delivery platforms. Natural polymers due to their biodegradability and biocompatibility have been particularly employed for this purpose. Polysaccharides are the main members of natural polymers, known as macromolecules composed of simple sugars with ever-increasing applications. However, polysaccharide utilization in the form of a virgin in drug delivery systems (DDSs) has been relatively cautious compared to synthetic polyesters because of the lack of interaction with biological media as well as their relatively poor mechanical properties. Therefore, functionalization of polysaccharides based on the knowledge of polymer chemistry, such as copolymerization with monomers of the same or different family, has been recognized as a promising strategy to boost their properties for advanced applications as DDS. Grafted polysaccharides and grafting polysaccharides have recently emerged as a promising strategy for designing efficient drug delivery platforms. Grafting has been widely considered for incorporating polysaccharides with other types of polymers and porous materials to make stimuli-responsive and targeted delivery systems for the treatment of various diseases, especially in cancer treatment. An overview of recent grafted polysaccharide-based DDSs has been presented in this chapter. The advantages and drawbacks of using grafted polysaccharides together with molecules used as grafting agents are the subjects the present chapter covers.
Hyaluronan (HA) plays crucial roles in the maintenance of high‐quality cartilage extracellular matrix. Several studies have reported the HA in synovial fluid in patients with osteoarthritis (OA), but few have described the changes of HA in articular cartilage of OA or idiopathic osteonecrosis of femoral head (ONFH). KIAA1199 was recently reported to have strong hyaluronidase activity. The aim of this study was to clarify the HA metabolism in OA and ONFH, particularly the involvement of KIAA1199. Immunohistochemical analysis of KIAA1199 and HA deposition was performed for human OA (n=10), ONFH (n=10), and control cartilage (n=7). The concentration and molecular weight of HA were determined by competitive HA ELISA and Chromatography, respectively. Regarding HA metabolism related molecules, HAS1, HAS2, HAS3, HYAL1, HYAL2, and KIAA1199 gene expression was assessed by RT‐PCR. Histological analysis showed the overexpression of KIAA1199 in OA cartilage, which was accompanied by decreased HABP staining compared with ONFH and control. Little KIAA1199 expression was observed in cartilage at the collapsed area of ONFH, which was accompanied by a slight decrease in HABP staining. The mRNA expression of HAS2 and KIAA1199 was up‐regulated in OA cartilage, while the mRNA expression of genes related to HA catabolism in ONFH cartilage showed mostly a downward trend. The MW of HA in OA cartilage increased while that in ONFH cartilage decreased. HA metabolism in ONFH is suggested to be generally indolent, and is activated in OA including high expression of KIAA1199. Interestingly, MW of HA in OA cartilage was not reduced. This article is protected by copyright. All rights reserved.
In skin, although the extracellular matrix (ECM) is highly developed in dermis and hypodermis, discrete intercellular spaces between cells of the living epidermal layers are also filled with ECM components. Herein, we review knowledge about structure, localization and role of epidermal hyaluronan (HA), a key ECM molecule. HA is a non-sulfated glycosaminoglycan non-covalently bound to proteins or lipids. Components of the basal lamina maintain some segregation between the epidermis and the underlying dermis, and all epidermal HA is locally synthesized and degraded. Functions of HA in keratinocyte proliferation and differentiation are still controversial. However, through interactions with partners, such as the TSG-6 protein, HA is involved in the formation, organization and stabilization of the epidermal ECM. In addition, epidermal HA is involved in the formation of an efficient epidermal barrier made of cornified keratinocytes. In atopic dermatitis (AD) with profuse alterations of the epidermal barrier, HA is produced in larger amounts by keratinocytes than in normal skin. Epidermal HA inside AD lesional skin is located in enlarged intercellular spaces, likely as the result of disease-related modifications of HA metabolism.
Background
Vulvo-vaginal atrophy (VVA) is one of the common consequences of estrogen deficiency especially after the menopause. Several studies have assessed the effects of Hyaluronic acid (HA) on physical and sexual symptoms associated with VVA with promising results. However, most of these studies have focused on subjective assessment of symptom response to topically administered preparations. Nonetheless, HA is an endogenous molecule and it is logical that its effects are best realized if injected in the superficial epithelial layers. Desirial® is the first crosslinked HA that is administered by injection in the vaginal mucosa. The aim of this study was to explore the effect of multipoint vaginal intra-mucosal injections of specific cross-linked hyaluronic acid (DESIRIAL®, Laboratoires VIVACY) on several clinical and patient reported core outcomes.
Methods
A cohort bi-centric pilot study. The chosen outcomes included change in vaginal mucosa thickness, biological markers for collagen formation, vaginal flora, vaginal pH, vaginal health index, vulvo-vaginal atrophy symptoms and sexual function 8 weeks post Desirial® injection. Patients’ satisfaction was also assessed using the patient global impression of improvement (PGI-I) scale.
Results
A total of 20 participants were recruited between 19/06/2017 and 05/07/2018. At the end of the study, there was no difference in the median total thickness of the vaginal mucosa or in procollagen I, III or Ki67 fluorescence. However, there was a statistically significant increase in COL1A1 and COL3A1 gene expression ( p = 0.0002 and p = 0.0010 respectively). There was also a significant reduction in reported dyspareunia, vaginal dryness, vulvar pruritus, vaginal chafing and significant improvement in all female sexual function index dimensions. Based on PGI-I, 19 patients (95%) reported varying degrees of improvement where, 4 (20%) felt slightly better; 7 (35%) better and 8 (40%) much better.
Conclusions
Multi-point vaginal intra-mucosal injections, of Desirial® (a crosslinked HA) was significantly associated with the expression of CoL1A1 and CoL3A1 suggesting stimulation of collagen formation. Furthermore, there was a significant reduction in VVA symptomatology and a significant improvement in patient satisfaction and sexual function scores. However, there was no demonstrable change in the total vaginal mucosal thickness.
Study registration ID-RCB: 2016-A00124-47, Protocol code number: LOCAL/2016/PM-001.
Objective
Our study aimed to find potential biomarkers for drug resistance in liver cancer cells using metabolomics and further to evaluate the potential of psoralen-loaded polymer lipid nanoparticles (PSO-PLNs) to reverse the resistance of cells to doxorubicin.
Methods
We used LC-MS-based non-targeted metabolomics, also known as global metabolite profiling, to screen in serum and urine of mice engrafted with a liver cancer cell line sensitive (HepG2/S) or resistant to doxorubicin (HepG2/ADR) for differentially regulated metabolites. We subsequently quantified the abundance of these metabolites in serum and the urine of mice. The mice were engrafted with HepG2 cells resistant against doxorubicin and were treated with I) doxorubicin, II) a combination of doxorubicin and psoralen and III) a combination of doxorubicin and psoralen packed in polymer lipid nanoparticles.
Results
Metabolites found to be differentially present in urine of mice engrafted with resistant HepG2 cells were: hippuric acid, hyaluronic acid, pantothenic acid, and betaine; retinoic acid and α-linolenic acid were found to be reduced in serum samples of mice with HepG2 cells resistant to doxorubicin. The targeted analysis showed that the degree of regression of metabolic markers in groups differed: treatment group 2 had stronger degree of regression than treatment group 1 and the negative control group had the smallest, which indicates that the PSO-PLNs have superior properties compared with other treaments.
Conclusion
Psoralen reverses drug resistance of liver cancer cells and its efficacy can be increased by encapsulation in polymer lipid nanoparticles.
Introduction
Minéral 89 (M89), comprised of 89% Vichy mineralizing water and hyaluronic acid, has been formulated to help strengthen and restore skin barrier.
Aim
Assess tolerance and efficacy of M89 in post‐aesthetic procedures and dry skin‐related facial dermatoses.
Method
Adults post‐aesthetic procedure or presenting with inflammatory dermatoses (47 subjects; mean age 40.9 ± 13.2 years; any Fitzpatrick or skin phototype), applied M89 for 4 weeks, once or twice daily, as an adjuvant treatment. Information on clinical signs and subject‐reported symptoms, skin characteristics, tolerance, and subject and investigator satisfaction were collected.
Results
Following 4 weeks of M89 use, significant decreases with complete resolution of erythema (27.6%), desquamation (29.8%), irritation (32%), and skin dehydration (35.8%), as compared to baseline signs and symptoms, were observed. Overall grading improvements for erythema (84.8%; p < 0.001), desquamation (91.7%; %; p < 0.003), irritation (91.7%; %; p < 0.015), and skin hydration (46.2%; p < 0.015) were noted. There was no significant improvement in papules and pustules.
Evaluation of subjective signs demonstrated significant decreases in skin sensations such as burning (‐73%; p < 0.0001), itching (‐71%; p < 0.0001), stinging‐tingling (‐66.7%; p < 0.0001), as well as in skin dryness (‐60%; p < 0.0001). M89 texture was rated very pleasant by 90% of patients. Investigators assessed M89 tolerance to be either good or very good (93%), and satisfactory or highly satisfactory impact on patient’s skin (91.5%).
Conclusion
M89 is a highly tolerable adjuvant treatment that significantly improved clinical signs and symptoms related to a compromised skin barrier in various facial dermatoses and post‐aesthetic procedures.
Diabetic wound (DW) healing is a major clinical challenge due to multifactorial complications leading to prolonged inflammation. Electrospun nanofibrous (NF) membranes, due to special structural features, are promising biomaterials capable to promote DW healing through the delivery of active agents in a controlled manner. Herein, we report a multifunctional composite NF membrane loaded with ZnO nanoparticles (NP) and oregano essential oil (OEO), employing a new loading strategy, capable to sustainedly co-deliver bioactive agents. Physicochemical characterization revealed the successful fabrication of loaded nanofibers with strong in vitro anti-bacterial and anti-oxidant activities. Furthermore, in vivo wound healing confirmed the potential of bioactive NF membranes in epithelialization and granulation tissue formation. The angiogenesis was greatly prompted by the bioactive NF membranes through expression of vascular endothelial growth factor (VEGF). Moreover, the proposed NF membrane successfully terminated the inflammatory cycle by downregulating the pro-inflammatory cytokines interleukin −6 (IL-6) and matrix metalloproteinases-9 (MMP-9). In vitro and in vivo studies revealed the proposed NF membrane is a promising dressing material for the healing of DW.
Background:. The first phase of this study showed that ART FILLER Universal filler (AFU; FILORGA Laboratories) and ART FILLER Fine lines (AFFL) were non-inferior to JUVÉDERM Ultra 3 (Allergan) and FIRST LINES PureSense (Teoxane), respectively. The clinical benefits of AFU and AFFL on nasolabial folds and crow’s feet persisted until at least Day 180. This article reports results from an open-label extension phase that assessed the tolerability and efficacy of AFU and AFFL for up to 18 months based on clinical evaluation and ultrasound high-frequency imaging.
Methods:. Eligible subjects were enrolled at D180 and assessed on D270, D360, and D540. The primary outcome measured was local tolerability. Secondary outcomes measured included: proportion of subjects in whom the severity of nasolabial folds and crow’s feet remained at least 1 point below the baseline measurement (Lemperle scale); general safety; Global Aesthetic Improvement Scale scores by subjects and investigators; wrinkle volumes; and skin thickness by high-frequency ultrasound.
Results:. Adverse events were consistent with the product information and the initial study. No serious adverse events were recorded. In exploratory analyses, wrinkle correction with AFU and AFFL is sustained for at least 18 months: 48.4% and 98.3% of subjects respectively still showed at least a 1-point decrease in the mean Lemperle score compared with the baseline. The benefits were sustained irrespective of whether subjects received additional injections. Modifications in wrinkle volume and skin thickness at D540 were statistically significant compared with the baseline.
Conclusion:. AFU and AFFL were well tolerated and, in exploratory analyses, showed a sustained efficacy for at least 18 months.
Objective
This study assessed the efficacy and tolerability of M89 in patients with rosacea associated with erythema and sensitive skin.
Methods
Intra-individual study in a split-face design comparing after 30 days M89 twice daily and usual skin care in 20 adult subjects with rosacea and sensitive skin. M89 contains 89% Vichy volcanic mineralizing water (VVMW) and 0.4% hyaluronic acid. It is hypoallergenic and contains no perfume and this convenes in rosacea. Contained minerals reinforce the natural defences of the skin in restoring the natural skin barrier, stimulating antioxidant activity and reducing inflammation, commonly observed in subjects with rosacea. Clinical evaluations included assessment of erythema, desquamation, papules and pustules, skin tightness, dryness, burning sensation, itching, stinging and stinging test as well as local tolerability. Instrumental evaluations included skin hydration and TEWL. Subject satisfaction was assessed at Days 15 and 30. Demodex density was assessed at Day 30.
Results
A significant superiority of M89 over the standard skin care was observed for erythema, skin tightness and dryness (all P≤0.05) as early as Day 15, the skin stinging test was significantly in favour of M89 (P<0.05 at Day 15 and P<0.01 at Day 30) and for skin hydration (P<0.0001) at Day 15 and 30 with no difference in mean Demodex density between M89 and usual skin care after 30 days. Tolerance was excellent and subject satisfaction very high.
Conclusion
Study results concerning M89 are encouraging for its use either alone or as an adjuvant daily skin care to topical medication in patients with persistent centrofacial erythema of rosacea with no more than 3 papules and pustules.
Introduction:
M89, containing 89% of Vichy mineralizing water and hyaluronic acid, has been developed to reinforce the skin barrier and to improve skin quality.
Aim:
To assess efficacy and tolerability of M89.
Method:
Observational survey of subjects with facial dermatoses or after esthetic procedures. M89 served as adjunct to conventional therapy. Clinician assessments of erythema, desquamation, irritation and patient-reported dryness, burning, itching, and stinging/tingling were conducted at baseline and 4 weeks. At 1 week and 4 weeks, patient assessed tolerance and satisfaction with M89.
Results:
A total of 1630 subjects participated; 92.5% were females. Mean age was 41.1 ± 11.3 years. Dermatological indications accounted for 32.5%, procedures for 67.5%. At 4 weeks, in subjects with dermatoses, erythema had resolved or improved in 68.0%, desquamation in 83.4%, and irritation in 93.3%. Dryness, burning, itching, and stinging/tingling scores had decreased by 63.8%, 81.8%, 70.9%, and 85.2%, respectively (all P ≤ .0001); 75.7% considered that their skin was sufficiently hydrated. In the procedure group, erythema had resolved or improved in 72.5%, desquamation in 75.2%, and irritation in 88.1%. Dryness, burning, itching, and stinging/tingling scores had decreased by 62.1%, 78.8%, 70.0%, and 84.2%, respectively (all P ≤ .0001); 74.1% considered that their skin was sufficiently hydrated. Almost all subjects reported soothed skin and satisfaction with product texture. Subject and investigator satisfaction was very high.
Conclusion:
M89 significantly improves skin signs and symptoms after 4 weeks of continued use with no tolerance issues in subjects with dermatological indications. Moreover, subjects who have had recently undergone esthetic procedures M89 allowed a satisfying skin recovery.
Background
The skin exposome refers to the constellation of external exposures that contribute to cutaneous aging, including solar radiation, air pollution, tobacco smoke, unbalanced nutrition, and cosmetic products. This review explores the skin exposome and the role of a combination hyaluronic acid and mineralized thermal water product used to restore and maintain optimal skin barrier function.
Method
An expert panel of 7 dermatologists who treat clinical signs of facial aging convened for a one‐day meeting to discuss the results of a literature review on the skin exposome and the role of M89, a mineralized thermal water and hyaluronic acid‐based gel, to improve the quality of facial skin. Evidence coupled with expert opinion and experience of the panel was used to address clinical challenges in the treatment of photo‐aging, and the use of M89.
Results
Solar radiation (ultraviolet radiation, visible light, and infrared radiation), air pollution, tobacco smoke, nutrition, and miscellaneous factors, including stress, sleep deprivation, and temperature, may potentiate skin aging by triggering molecular processes that damage skin structure. M89 was developed to maintain and restore skin and contains ingredients to aid physical, hydric, antioxidant, and antimicrobial skin barrier function.
Conclusions
Increasing knowledge of the exposome and microenvironment contributing to skin aging may support a better understanding of measures to support the skin. The initial results of in vitro and clinical studies of M89 show its potential to improve skin barrier function.
Background:
Due to significant limitations to the access to orthotropic liver transplantation, cell therapies for liver diseases have gained large interest worldwide.
Scope of review:
To revise current literature dealing with cell therapy for liver diseases. We discussed the advantages and pitfalls of the different cell sources tested so far in clinical trials and the rationale underlying the potential benefits of transplantation of human biliary tree stem cells (hBTSCs).
Major conclusions:
Transplantation of adult hepatocytes showed transient benefits but requires immune-suppression that is a major pitfall in patients with advanced liver diseases. Mesenchymal stem cells and hematopoietic stem cells transplanted into patients with liver diseases are not able to replace resident hepatocytes but, rather they target autoimmune or inflammatory processes into the liver. Stem cells isolated from fetal or adult liver have been recently proposed as an alternative cell sources for advanced liver cirrhosis and metabolic liver disease. We demonstrated the presence of multipotent cells expressing a variety of endodermal stem cell markers in (peri)-biliary glands of bile ducts in fetal or adult human tissues, and in crypts of gallbladder epithelium. In the first cirrhotic patients treated in our center with biliary tree stem cell therapy we registered no adverse event but significant benefits.
General significance:
The biliary tree stem cell could represent the ideal cell source for the cell therapy of liver diseases. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
Hydrogels are hydrophilic, three-dimensional hydrophilic polymeric networks, capable of absorbing large quantities of water and biological fluids and simulating biological tissue when swollen. Hydrogels are frequently explored for use in numerous biological and biomedical applications. The chemical process of hydrogel synthesis is accomplished using one of two primary methods: single-step processes, involving the polymerization and simultaneous crosslinking of multifunctional monomers or multi-phase processes involving the chemical production of polymer molecules, and subsequent reticulation using crosslinking agents. Hydrogels are characterized by the nature of their constituent polymers, making them synthetic, natural or hybrid. Their polymeric crosslinking structure defines their physical or chemical nature, while their polymeric composition, indicates whether they are homopolymeric, copolymeric of multipolymeric. The use of natural polymers in hydrogel synthesis is advantageous in biomedical applications due to their biocompatibilility, biodegradability and non-toxicity, whereas synthetic polymers are hydrophobic, possessing strong covalent bonds within their matrix, which allow for more durability and mechanical strength. All the classifying properties of hydrogels affect their applicability and types of areas in which they can be incorporated. In this paper, we critically detail the most common natural and synthetic hydrogel formulations, their designs and their most significant and current biomedical applications.
This is the protocol for a review and there is no abstract. The objectives are as follows: To evaluate the effects of hyaluronic acid (and its derivatives such as sodium hyaluronate) on the healing of chronic wounds.
Introduction:
Painful bladder syndrome/interstitial cystitis (PBS/IC) pathogenesis is not fully known, but evidence shows that glycosaminoglycans (GAG) of bladder urothelium can participate in its genesis. The loss of these compounds facilitates the contact of urine compounds with deeper portions of bladder wall triggering an inflammatory process. We investigated GAG in urine and tissue of PBS/IC and pure stress urinary incontinence (SUI) patients to better understand its metabolism.
Materials and methods:
Tissue and urine of 11 patients with PBS/IC according to NIDDK criteria were compared to 11 SUI patients. Tissue samples were analyzed by histological, immunohistochemistry and immunofluorescence methods. Statistical analysis were performed using t Student test and Anova, considering significant when p < 0.05.
Results:
PBS/IC patients had lower concentration of GAG in urine when compared to SUI (respectively 0.45 ± 0.11 x 0.62 ± 0.13 mg/mg creatinine, p < 0.05). However, there was no reduction of the content of GAG in the urothelium of both groups. Immunofluorescence showed that PBS/IC patients had a stronger staining of TGF-beta, decorin (a proteoglycan of chondroitin/dermatan sulfate), fibronectin and hyaluronic acid.
Conclusion:
the results suggest that GAG may be related to the ongoing process of inflammation and remodeling of the dysfunctional urothelium that is present in the PBS/IC.
Dermal filling has rapidly become one of the most common procedures performed by clinicians worldwide. The vast majority of treatments are successful and patient satisfaction is high. However, complications, both mild and severe, have been reported and result from injection of many different types of dermal fillers. In this Continuing Medical Education review article, the author describes common technical errors, the signs and symptoms of both common and rare complications, and management of sequelae in clear, easily adaptable treatment algorithms.
Hyaluronan (hyaluronic acid) is a naturally occurring polysaccharide of a linear repeating disaccharide unit consisting of β-(1→4)-linked D-glucopyranuronic acid and β-(1→3)-linked 2-acetamido-2-deoxy-D-glucopyranose, which is present in extracellular matrices, the synovial fluid of joints, and scaffolding that comprises cartilage.
In its mechanism of synthesis, its size, and its physico-chemical properties, hyaluronan is unique amongst other glycosaminoglycans. The network-forming, viscoelastic and its charge characteristics are important to many biochemical properties of living tissues. It is an important pericellular and cell surface constituent; its interaction with other macromolecules such as proteins, participates in regulating cell behavior during numerous morphogenic, restorative, and pathological processes in the body. The knowledge of HA in diseases such as various forms of cancers, arthritis and osteoporosis has led to new impetus in research and development in the preparation of biomaterials for surgical implants and drug conjugates for targeted delivery.
A concise and focused review on hyaluronan is timely. This review will cover the following important aspects of hyaluronan: (i) biological functions and synthesis in nature; (ii) current industrial production and potential biosynthetic processes of hyaluronan; (iii) chemical modifications of hyaluronan leading to products of commercial significance; and (iv) and the global market position and manufacturers of hyaluronan.
Cellular function and adaptive behavior is often driven by signals generated in response to the local tissue microenvironment. Cell surface receptors that detect changes in extracellular matrix composition and modifications to extracellular matrix components, are ideally positioned to provide highly responsive sensors of changes in the microenvironment and mediate changes in cellular function required to maintain tissue integrity. Receptors can act as “on/off” switches, but ligand/receptor complexes that provide “rheostatic” control may be more sensitive, provide a more rapid mechanism of control and allow for fine-tuning of cellular responses to the microenvironment. Herein, we review evidence that transitions in the physiochemical properties of the extracellular glycosaminoglycan hyaluronan and in the function of its major receptor, CD44, differentially regulate ERK and Rac signal transduction pathways to provide critical rheostatic control of mesenchymal cell proliferation.
Hyaluronan has been implicated in biological processes such as cell adhesion, migration and proliferation. Traditionally, it was thought to be associated with the extracellular matrix, but, hyaluronan may also have unimagined roles inside the cell. Investigation of hyaluronan synthesis and degradation, the identification of new receptors and binding proteins, and the elucidation of hyaluronan-dependent signaling pathways are providing novel insights into the true biological functions of this fascinating molecule.
Hyaluronan is a multifunctional glycosaminoglycan that forms the structural basis of the pericellular matrix. Hyaluronan is extruded directly through the plasma membrane by one of three hyaluronan synthases and anchored to the cell surface by the synthase or cell surface receptors such as CD44 or RHAMM. Aggregating proteoglycans and other hyaluronan-binding proteins, contribute to the material and biological properties of the matrix and regulate cell and tissue function. The pericellular matrix plays multiple complex roles in cell adhesion/de-adhesion, and cell shape changes associated with proliferation and locomotion. Time-lapse studies show that pericellular matrix formation facilitates cell detachment and mitotic cell rounding. Hyaluronan crosslinking occurs through various proteins, such as tenascin, TSG-6, inter-alpha-trypsin inhibitor, pentraxin and TSP-1. This creates higher order levels of structured hyaluronan that may regulate inflammation and other biological processes. Microvillous or filopodial membrane protrusions are created by active hyaluronan synthesis, and form the scaffold of hyaluronan coats in certain cells. The importance of the pericellular matrix in cellular mechanotransduction and the response to mechanical strain are also discussed.
The high-molecular-mass polysaccharide hyaluronan is abundant in the extracellular space between adjacent keratinocytes throughout the vital part of epidermis. It has a rapid turnover, and its content is subject to large fluctuations due to physiological and environmental conditions, with the strongest effects mediated by EGFR signaling. Using an elegant organotypic culture system, Monslow et al. (2009, this issue) demonstrate that heparin-binding (HB)-EGF released from its membrane anchor is the major ligand of EGFR in injured epidermis, accounting for the autocrine and paracrine activation of hyaluronan synthesis by the keratinocytes in the neighborhood, thus facilitating the epidermal wound-healing response.
The lymphatic system is best known for draining interstitial fluid from the tissues and returning it to the blood circulation. However, the lymphatic system also provides the means for immune surveillance in the immune system, acting as conduits that convey soluble antigens and antigen-presenting cells from the tissues to the lymph nodes, where primary lymphocyte responses are generated. One macromolecule that potentially unites these two functions is the large extracellular matrix glycosaminoglycan hyaluronan (HA), a chemically simple copolymer of GlcNAc and GlcUA that fulfills a diversity of functions from danger signal to adhesive substratum, depending upon chain length and particular interaction with its many different binding proteins and a small but important group of receptors. The two most abundant of these receptors are CD44, which is expressed on leukocytes that traffic through the lymphatics, and LYVE-1, which is expressed almost exclusively on lymphatic endothelium. Curiously, much of the HA within the tissues is turned over and degraded in lymph nodes, by a poorly understood process that occurs in the medullary sinuses. Indeed there are several mysterious aspects to HA in the lymphatics. Here we cover some of these by reviewing recent findings in the biology of lymphatic endothelial cells and their possible roles in HA homeostasis together with fresh insights into the complex and enigmatic nature of LYVE-1, its regulation of HA binding by sialylation and self-association, and its potential function in leukocyte trafficking.
Hyaluronan (hyaluronic acid) is a high-molecular-mass polysaccharide found in the extracellular matrix, especially of soft connective tissues. It is synthesized in the plasma membrane of fibroblasts and other cells by addition of sugars to the reducing end of the polymer, whereas the nonreducing end protrudes into the pericellular space. The polysaccharide is catabolized locally or carried by lymph to lymph nodes or the general circulation, from where it is cleared by the endothelial cells of the liver sinusoids. The overall turnover rate is surprisingly rapid for a connective tissue matrix component (t1/2 0.5 to a few days). Hyaluronan has been assigned various physiological functions in the intercellular matrix, e.g., in water and plasma protein homeostasis. Hyaluronan production increases in proliferating cells and the polymer may play a role in mitosis. Extensive hyaluronidase-sensitive coats have been identified around mesenchymal cells. They are either anchored firmly in the plasma membrane or bound via hyaluronan-specific binding proteins (receptors). Such receptors have now been identified on many different cells, e.g., the lymphocyte homing receptor CD 44. Interaction between a hyaluronan receptor and extracellular polysaccharide has been connected with locomotion and cell migration. Hyaluronan seems to play an important role during development and differentiation and has other cell regulatory activities. Hyaluronan has also been recognized in clinical medicine. A concentrated solution of hyaluronan (10 mg/ml) has, through its tissue protective and rheological properties, become a device in ophthalmic surgery. Analysis of serum hyaluronan is promising in the diagnosis of liver disease and various inflammatory conditions, e.g., rheumatoid arthritis. Interstitial edema caused by accumulation of hyaluronan may cause dysfunction in various organs.
Hyaluronan is a straight chain, glycosaminoglycan polymer of the extracellular matrix composed of repeating units of the disaccharide [-D-glucuronic acid-beta1,3-N-acetyl-D-glucosamine-beta1,4-]n. Hyaluronan is synthesized in mammals by at least three synthases with products of varying chain lengths. It has an extraordinary high rate of turnover with polymers being funneled through three catabolic pathways. At the cellular level, it is degraded progressively by a series of enzymatic reactions that generate polymers of decreasing sizes. Despite their exceedingly simple primary structure, hyaluronan fragments have extraordinarily wide-ranging and often opposing biological functions. There are large hyaluronan polymers that are space-filling, anti-angiogenic, immunosuppressive, and that impede differentiation, possibly by suppressing cell-cell interactions, or ligand access to cell surface receptors. Hyaluronan chains, which can reach 2 x 10(4) kDa in size, are involved in ovulation, embryogenesis, protection of epithelial layer integrity, wound repair, and regeneration. Smaller polysaccharide fragments are inflammatory, immuno-stimulatory and angiogenic. They can also compete with larger hyaluronan polymers for receptors. Low-molecular-size polymers appear to function as endogenous "danger signals", while even smaller fragments can ameliorate these effects. Tetrasaccharides, for example, are anti-apoptotic and inducers of heat shock proteins. Various fragments trigger different signal transduction pathways. Particular hyaluronan polysaccharides are also generated by malignant cells in order to co-opt normal cellular functions. How the small hyaluronan fragments are generated is unknown, nor is it established whether the enzymes of hyaluronan synthesis and degradation are involved in maintaining proper polymer sizes and concentration. The vast range of activities of hyaluronan polymers is reviewed here, in order to determine if patterns can be detected that would provide insight into their production and regulation.
Hyaluronan (HA) is a multifunctional high molecular weight polysaccharide found throughout the animal kingdom, especially in the extracellular matrix (ECM) of soft connective tissues. HA is thought to participate in many biological processes, and its level is markedly elevated during embryogenesis, cell migration, wound healing, malignant transformation, and tissue turnover. The enzymes that degrade HA, hyaluronidases (HAases) are expressed both in prokaryotes and eukaryotes. These enzymes are known to be involved in physiological and pathological processes ranging from fertilization to aging. Hyaluronidase-mediated degradation of HA increases the permeability of connective tissues and decreases the viscosity of body fluids and is also involved in bacterial pathogenesis, the spread of toxins and venoms, acrosomal reaction/ovum fertilization, and cancer progression. Furthermore, these enzymes may promote direct contact between pathogens and the host cell surfaces. Depolymerization of HA also adversely affects the role of ECM and impairs its activity as a reservoir of growth factors, cytokines and various enzymes involved in signal transduction. Inhibition of HA degradation therefore may be crucial in reducing disease progression and spread of venom/toxins and bacterial pathogens. Hyaluronidase inhibitors are potent, ubiquitous regulating agents that are involved in maintaining the balance between the anabolism and catabolism of HA. Hyaluronidase inhibitors could also serve as contraceptives and anti-tumor agents and possibly have antibacterial and anti-venom/toxin activities. Additionally, these molecules can be used as pharmacological tools to study the physiological and pathophysiological role of HA and hyaluronidases.
Hyaluronan is a major macromolecular polysaccharide component of the extra-cellular matrix that confers structural frameworks for cells. Despite its relatively simple chemical composition, hyaluronan mediates many other important functional aspects including signalling activity during embryonic morphogenesis, cellular regeneration and wound healing. Abnormalities in hyaluronan metabolism have been implicated in many diseases, such as inflammatory disorders, cardiovascular diseases and cancer. To date, it has become increasingly clear that hyaluronan production in vertebrates is tightly regulated by three hyaluronan synthases and that hyaluronan catabolism is regulated by an enzymatic degradation reaction involving several hyaluronidases. Together, these discoveries have provided key insights into the physiological roles of hyaluronan and a deeper understanding of the mechanisms underlying altered hyaluronan turnover in diseases. The central aim of this review article is therefore to highlight the multiple roles of hyaluronan in physiological and pathological states via its complex turnover regulation.
Hyaluronan is a glycosaminoglycan polymer prominent in embryogenesis and in tissues undergoing repair. It is responsible for the water content of skin, where half the hyaluronan of the body is present. As in other tissues, it undergoes rapid turnover. Its biology is vastly different between dermis and epidermis. Levels do not diminish with age but instead become increasingly associated with tissues and resistant to extraction in vitro. Hyaluronan-binding proteins are involved, most of which remain unidentified. Hyaluronan size is critical for its various functions. High molecular size reflects intact tissues and antiangiogenic and immunosuppressive state, whereas smaller polymers are distress signals and potent inducers of inflammation and angiogenesis.