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      Influence of caffeine and hyaluronic acid on collagen biosynthesis in human skin fibroblasts

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          The aim of this study was to evaluate the effect of caffeine on collagen biosynthesis in human skin fibroblasts and the influence of hyaluronic acid (HA) on this process.

          Materials and methods

          Collagen, [ 3H]-thymidine incorporation, and prolidase activity were measured in confluent human skin fibroblast cultures that had been treated with 1, 2, and 5 mM caffeine and with caffeine and 500 μg/mL HA. Western immunoblot analysis was performed to evaluate expression of β 1-integrin receptor, insulin-like growth factor receptor phospho-Akt protein and mitogen-activated protein kinase (phospho-extracellular signal-regulated kinase).


          Caffeine inhibited collagen biosynthesis in a dose-dependent manner. The mechanism of this process was found at the level of prolidase activity. Caffeine significantly inhibited the enzyme activity. The addition of HA had no effect on collagen biosynthesis or prolidase activity in fibroblasts incubated with caffeine. Caffeine also had an inhibitory effect on DNA biosynthesis. HA, however, did not have any significant effect on this process. The inhibition of the expression of β 1-integrin and insulin-like growth factor receptor in fibroblasts incubated with the caffeine indicates a possible mechanism of inhibition of collagen biosynthesis.


          Caffeine reduces collagen synthesis in human cultured skin fibroblasts. HA did not have any significant protective effect on this process. This is the first study to our knowledge that reports caffeine-induced inhibition of collagen synthesis in human skin fibroblasts.

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          Most cited references 17

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          The magic glue hyaluronan and its eraser hyaluronidase: a biological overview.

          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.
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            Molecular mechanisms of hepatic fibrogenesis.

            Liver fibrosis, a wound-healing response to a variety of chronic stimuli, is characterized by excessive deposition of extracellular matrix (ECM) proteins, of which type I collagen predominates. This alters the structure of the liver leading to organ dysfunction. The activated hepatic stellate cell (HSC) is primarily responsible for excess collagen deposition during liver fibrosis. Two important aspects are involved in mediating the fibrogenic response: first the HSC becomes directly fibrogenic by synthesizing ECM proteins; second, the activated HSC proliferates, effectively amplifying the fibrogenic response. Although the precise mechanisms responsible for HSC activation remain elusive, substantial insight is being gained into the molecular mechanisms responsible for ECM production and cell proliferation in the HSC. The activated HSC becomes responsive to both proliferative (platelet-derived growth factor) and fibrogenic (transforming growth factor-beta[TGF-beta]) cytokines. It is becoming clear that these cytokines activate both mitogen-activated protein kinase (MAPK) signaling, involving p38, and focal adhesion kinase-phosphatidylinositol 3-kinase-Akt-p70 S6 kinase (FAK-PI3K-Akt-p70(S6K)) signaling cascades. Together, these regulate the proliferative response, activating cell cycle progression as well as collagen gene expression. In addition, signaling by both TGF-beta, mediated by Smad proteins, and p38 MAPK influence collagen gene expression. Smad and p38 MAPK signaling have been found to independently and additively regulate alpha1(I) collagen gene expression by transcriptional activation while p38 MAPK, but not Smad signaling, increases alpha1(I) collagen mRNA stability, leading to increased synthesis and deposition of type I collagen. It is anticipated that by understanding the molecular mechanisms responsible for HSC proliferation and excess ECM production new therapeutic targets will be identified for the treatment of liver fibrosis.
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              Hyaluronan-dependent pericellular matrix.

              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.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                15 October 2014
                : 8
                : 1923-1928
                [1 ]Department of Esthetic Medicine, Faculty of Pharmacy, Medical University of Białystok, Białystok, Poland
                [2 ]Department of Medicinal Chemistry, Faculty of Pharmacy, Medical University of Białystok, Białystok, Poland
                Author notes
                Correspondence: Magdalena Donejko, Department of Esthetic Medicine, Faculty of Pharmacy, Medical University of Białystok, 3 Akademicka Street, 15-267 Białystok, Poland, Email donejko@ 123456gmail.com
                © 2014 Donejko et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                Pharmacology & Pharmaceutical medicine

                collagen, caffeine, hyaluronic acid, fibroblast


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