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Overproduction of Hyaluronan in the Tumor Stroma
Published in Róza Ádány, Tumor Matrix Biology, 2017
Warren Knudson, Cheryl B. Knudson
Evidence suggests that the enzyme responsible for hyaluronan synthesis, hyaluronan synthase, is turned over relatively rapidly,111 and its activity modulated by phosphorylation.111,112 The latter includes activation by pp60src in Rous sarcoma virus-transformed chick embryo fibroblasts.112 Since the hyaluronan synthase can be regulated at the level of protein synthesis as well as phosphorylation,113 it is not surprising that several agents such as hormones, growth factors, activated receptors, various environmental factors, etc., have the capacity to activate or inhibit hyaluronan synthesis (for a list of agents see Laurent and Fraser114). Nevertheless, two signal transduction pathways seem to predominate in the regulation of the hyaluronan synthase. Activators of calcium-dependent kinases such as protein kinase C stimulate synthesis of hyaluronan in human mesothelial cells and induced depletion of protein kinase C inhibits stimulation by PDGF-BB in these cells.113 Others have shown that activators of cAMP and adenylate cyclase, particularly prostaglandins, also stimulate hyaluronan synthesis.97,115,116 In addition, hyaluronan synthesis is closely coupled to cell division.117–119 How hyaluronan is specifically regulated in tumors is unknown and may represent responses to a complex mixture of signals from a variety of cellular sources.
Cervical insufficiency
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
Sonia S. Hassan, Roberto Romero, Francesca Gotsch, Lorraine Nikita, Tinnakorn Chaiworapongsa
Word et al. have proposed that early in pregnancy, tensile strength of the softened cervix is maintained by increasing collagen synthesis and cervical growth (6). Collagens type I and III confer tensile strength. During cervical ripening, the cervix becomes thin and pliable, and the collagen concentrations are decreased. This decrease is due to a relative increase in hydrophilic glycosaminoglycans and non-collagenous proteins. The increased expression of aquaporin water channels leads to tissue hydration; this, in turn, disperses collagen fibers and increases collagen solubility and its susceptibility to endogenous proteases. The primary glycosaminoglycan involved is decorin, which protects collagen fibers; however, later in gestation, decorin decreases and hyaluronan increases. The latter can weaken the interaction between collagen and fibronectin, contributing to collagen dispersal (6). Hyaluronan has been found in human endocervical mucous (32). Mahendroo’s laboratory has demonstrated that, in mice, the hyaluronan content of the cervix is increased with advancing gestational age along with the expression of the enzyme hyaluronan synthase 2 (28). Low–molecular weight hyaluronan can bind CD44 and activate macrophages to produce chemokines that attract inflammatory cells (33). Thus, the current understanding is that once collagen is solubilized, an inflammatory cascade is initiated. Studies in humans are necessary to determine the biochemistry of these processes. Strong evidence suggests that a suspension of progesterone action can lead to cervical ripening (34,35).
Application of hyaluronic acid as carriers in drug delivery
Published in Drug Delivery, 2018
Gangliang Huang, Hualiang Huang
The first gene delivery application of hyaluronic acid was that hyaluronic acid-adipic acid dihydrazide (ADH) hydrogels were used to protect DNA from enzyme degradation and for sustained release of DNA (Shoham et al., 2013). In addition, Yun et al. also prepared hyaluronic acid microparticles colloid in a similar way, and the DNA was incorporated into the gel network for delivery (Yun et al., 2004). These methods of gene delivery using hydrogel have been widely used, especially in tissue engineering. Hyaluronic acid hydrogel was used as warehouse system to control gene delivery in tissue regeneration. In keeping with the same concept, Chun et al. developed a photocross-linked pluronic hydrogel to encapsulate a plasmid DNA (Chun et al., 2005). Hyaluronic acid films and a gene delivery system encoding hyaluronan synthase two have also been developed as the prevention of postoperative peritoneal adhesion membrane barrier membranes with good effect. According to the report, even after the hyaluronic acid membrane was degraded, the release of hyaluronic acid could also be spread by infected neighboring cells to reduce peritoneal adhesion (Kim et al., 2005). Fan et al. first linked the PEI and dexamethasone (Dex), and then made a double-targeted ternary complex hyaluronic acid/PEI-Dex/DNA having a nucleo-shell structure with hyaluronic acid and DNA. The ternary complex showed low toxicity and high transfection efficiency in the tumor cells B16–F10. The intracellular localization showed that hyaluronic acid/PEI-Dex/DNA could promote cellular uptake and DNA nuclear translocation. In vivo experiments show that the hyaluronic acid/PEI-Dex/DNA ternary complex had obvious anti-inflammatory activity and tumor growth inhibition in tumor-bearing mice (Fan et al., 2013). Therefore, as a nonviral vector of gene drugs, hyaluronic acid could be targeted to tumor cells through CD44 receptor-mediated endocytosis, and better play the antitumor effect of gene drugs.
Glucosamine for the Treatment of Osteoarthritis: The Time Has Come for Higher-Dose Trials
Published in Journal of Dietary Supplements, 2019
Mark F. McCarty, James H. O'Keefe, James J. DiNicolantonio
Intravenous glucosamine might also have potential for aiding wound healing. As compared to healing in adult or juvenile animals, fetal wounds are known to heal more rapidly, and without scarring (Adzick and Longaker, 1992; Lorenz et al., 1995; Dostal and Gamelli, 1993; Estes et al., 1993; Alaish et al., 1994; Shepard et al., 1996; Sawai et al., 1997; Samuels and Tan, 1999; Nyman et al., 2013). This effect is at least partially attributable to high production of hyaluronic acid by fetal fibroblasts during the wound-healing process. This hyaluronic acid aids efficient healing by promoting the migration and proliferation of mesenchymal and epithelial cells. A recent review and meta-analysis of controlled clinical trials concluded that topical preparations of hyaluronic acid (or derivative thereof) do indeed aid wound healing (Voigt and Driver, 2012). The addition of exogenous glucosamine to mesenchymal cell cultures, in concentrations of at least 250 µM, can markedly enhance their production of hyaluronic acid, by up to several-fold (Uitterlinden et al., 2008; Vigetti et al., 2012; Igarashi et al., 2011; Rilla et al., 2013). This reflects the fact that UDP-N-acetylglucosamine is the rate-limiting substrate for hyaluronic acid synthesis, as well as the fact that O-GlcNAcylation of type 2 hyaluronan synthase protects it from proteasomal degradation (Vigetti et al., 2012). In 1966, Michael Carlozzi and Domenic Iezonni were issued a U.S. patent (#3,232,836) entitled “Facilitating healing of body surface wounds by intravenous administration of N-acetylglucosamine, glucosamine, or pharmaceutically acceptable acid salts of glucosamine.” These surgeons described a regimen of administering glucosamine or N-acetylglucosamine, intravenously and later orally, to surgical patients. They recommended 100–200 g of glucosamine per day intravenously for four days, followed by 20 g per day orally for five days. In their patent, they summarized the clinical course of six surgical patients treated with this regimen who, in their judgment, had shown “a remarkable improvement in healing time”; the wounds of some of these patients had been refractory to healing following surgery. The patients were also said to “show a sense of well-being,” and their protein balance remained positive after surgery. Although the doses recommended may seem extreme, they may indeed be necessary if a large increase in wound hyaluronic acid production is to be achieved. Unfortunately, Carlozzi and Iezonni's observations do not appear to have been published in the formal medical literature, and the patent's licensee, Pfizer, did not choose to pursue it.
Hyalocyte functions and immunology
Published in Expert Review of Ophthalmology, 2022
Stefaniya K Boneva, Julian Wolf, Peter Wieghofer, J Sebag, Clemens AK Lange
The human vitreous body consists of 98% water and 2% structural proteins (primarily collagen and hyaluronan), as well as components of the extracellular matrix (ECM), such as chondroitin sulfate [30] (Figure 3). As early as the 19th century it was assumed by Schoeler (1848) and Virchow (1852), and later by Szirmai and Balazs (1958) that hyalocytes take part in the anabolism of vitreous, most probably via the production of hyaluronan [31,32]. Consistent with this hypothesis, Boneva and colleagues, who studied the RNA expression profile of hyalocytes in people aged about 70 years, found that several ECM components, including COL5A1 and COL9A2, are abundantly expressed in vitreous hyalocytes, suggesting that hyalocytes synthesize structural proteins in the vitreous body during aging [8]. Balazs had previously described that the total vitreous collagen concentration in patients aged 70–90 years was significantly increased compared to ages 15–20 years (0.1 mg/mL versus 0.05 mg/mL). While this increase in collagen concentration was explained by an age-related decrease in the volume of the vitreous gel and a simultaneously stable total collagen amount during aging [10], it is feasible that collagen synthesis by hyalocytes contributes to the increased collagen content in senescent vitreous. This notion is supported by the identification of a collagen precursor, the type II procollagen, in the adult vitreous [33]. Contrary to the general assumption that hyalocytes contribute to hyaluronan synthesis and despite the fact that hyalocytes are located in the region with the highest hyaluronan concentration in the vitreous [10], Boneva and colleagues found a relatively low expression of the key factors for hyaluronan production in hyalocytes, namely hyaluronan synthase 1–3 (Table 1), suggesting that, at least in adults, hyaluronan is not produced by hyalocytes [8]. However, it is presently unclear if hyalocytes produce hyaluronan during development of the secondary vitreous and thereby contribute to vitreous formation. Therefore, further studies focusing on the molecular biology of fetal hyalocytes and their differences from adult hyalocytes are needed to clarify the precise role of hyalocytes in vitreous anabolism during embryonic development. The data from Boneva and colleagues further indicate that aged hyalocytes strongly express versican [8], which, in addition to collagen type IX, is the second chondroitin sulfate proteoglycan in the vitreous body forming complexes with hyaluronan, fibulin-1, and fibulin-2, thus playing a critical role in maintaining the molecular morphology of vitreous [34].