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      Anti-Wrinkle Effect of Magnesium Lithospermate B from Salvia miltiorrhiza BUNGE: Inhibition of MMPs via NF-kB Signaling


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          Skin is in direct contact with the environment and therefore undergoes aging as a consequence of environmentally induce damage. Wrinkle formation is a striking feature of intrinsic and photo-induced skin aging, which are both associated with oxidative stress and inflammatory response. The present study was undertaken to identify the mechanisms responsible for the anti-wrinkle effects of MLB, and thus, we investigated whether magnesium lithospermate B (MLB) from Salvia miltiorrhiza BUNGE associated with wrinkle formation caused by intrinsic and extrinsic skin aging using Sprague-Dawley rats aged 5 and 20 months and ultraviolet B (UVB)-irradiated human skin fibroblasts cells, respectively. The results obtained showed that the oral administration of MLB significantly upregulated the level of type I procollagen and downregulated the activities and expressions of matrix-metalloproteinases (MMPs) in rat skin. In fibroblasts, MLB suppressed the transactivation of nuclear factor-kB (NF-kB) and activator protein 1(AP-1), which are the two transcription factors responsible for MMP expression, by suppressing oxidative stress and the mitogen activated protein kinase (MAPK) pathway. Our results show that the antioxidant effect of MLB is due to the direct scavenging of reactive oxygen species (ROS) and its inhibitory effects on NF-kB-dependent inflammation genes, such as, cyclooxygenase-2 and inducible nitric oxide synthase. MLB was found to reverse both age- and UVB-related reductions in skin procollagen levels by suppressing the expressions and activities of NF-kB and AP-1-dependent MMPs by modulating ROS generation and the MAPK signaling pathway. We suggest that MLB potentially has anti-wrinkle and anti-skin aging effects.

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          Most cited references 16

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          UV-light-induced signal cascades and skin aging.

           L Rittié (2002)
          UV irradiation acts as a broad activator of cell surface growth factor and cytokine receptors. This ligand-independent receptor activation induces multiple downstream signaling pathways that regulate expression of multiple genes. These signaling pathways converge to stimulate transcription factor AP-1. Among genes whose expression is regulated by AP-1 are several matrix-metalloproteinase (MMP) family members and type I procollagen. UV-enhanced matrix degradation is accompanied with decreased collagen production mediated not only by activation of AP-1, but also by inhibition of transforming growth factor (TGF)-beta signaling. Several alterations to skin connective tissue that occur during aging are mediated by mechanisms that are similar to those that occur in response to UV irradiation. Thus, skin aging is associated with increased AP-1 activity, increased MMP expression, impaired TGF-beta signaling, enhanced collagen degradation, and decreased collagen synthesis. Knowledge gained from examining molecular responses of human skin to UV irradiation provides not only a framework for understanding mechanisms involved in skin aging, but also may help in development of new clinical strategies to impede chronological and UV-induced skin aging.
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            Inflammation, gene mutation and photoimmunosuppression in response to UVR-induced oxidative damage contributes to photocarcinogenesis.

             G Halliday (2005)
            Ultraviolet (UV) radiation causes inflammation, gene mutation and immunosuppression in the skin. These biological changes are responsible for photocarcinogenesis. UV radiation in sunlight is divided into two wavebands, UVB and UVA, both of which contribute to these biological changes, and therefore probably to skin cancer in humans and animal models. Oxidative damage caused by UV contributes to inflammation, gene mutation and immunosuppression. This article reviews evidence for the hypothesis that UV oxidative damage to these processes contributes to photocarcinogenesis. UVA makes a larger impact on oxidative stress in the skin than UVB by inducing reactive oxygen and nitrogen species which damage DNA, protein and lipids and which also lead to NAD+ depletion, and therefore energy loss from the cell. Lipid peroxidation induces prostaglandin production that in association with UV-induced nitric oxide production causes inflammation. Inflammation drives benign human solar keratosis (SK) to undergo malignant conversion into squamous cell carcinoma (SCC) probably because the inflammatory cells produce reactive oxygen species, thus increasing oxidative damage to DNA and the immune system. Reactive oxygen or nitrogen appears to cause the increase in mutational burden as SK progress into SCC in humans. UVA is particularly important in causing immunosuppression in both humans and mice, and UV lipid peroxidation induced prostaglandin production and UV activation of nitric oxide synthase is important mediators of this event. Other immunosuppressive events are likely to be initiated by UV oxidative stress. Antioxidants have also been shown to reduce photocarcinogenesis. While most of this evidence comes from studies in mice, there is supporting evidence in humans that UV-induced oxidative damage contributes to inflammation, gene mutation and immunosuppression. Available evidence implicates oxidative damage as an important contributor to sunlight-induced carcinogenesis in humans.
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              Ultraviolet-B irradiation and matrix metalloproteinases: from induction via signaling to initial events.

              Effects of sunlight have fascinated researchers for decades because nearly every living thing on earth is likely to be exposed to sunlight and the ultraviolet (UV) fraction of it. In addition to detrimental long-term effects such as immunosuppression and skin cancer, premature aging of the skin (photoaging) is a well-documented consequence of exposure to UVA and UVB. Photoaged skin is biochemically characterized by an overgrowth of abnormal elastic fibers in the dermis and by a dramatic decrease of distinct collagen types. Ultraviolet irradiation induces delayed UV-responsive genes, among them matrix metalloproteinases, which degrade macromolecules of the extracellular matrix, a hallmark in carcinogenesis and aging. We are interested in UVB-triggered initial events and in subsequent signaling resulting in enhanced expression of two major members of the matrix metalloproteinase family, the interstitial collagenase (MMP-1) and stromelysin-1 (MMP-3), in human dermal fibroblasts. Especially, these skin cells play a central role in connective tissue breakdown in photoaging and as stromal cells in tumor invasion and metastasis by means of their capability to produce matrix metalloproteinases. In this review, we will focus on UVB-triggered induction of matrix metalloproteinases, the so far identified components of the UVB-modulated signal transduction pathway(s), and the UVB irradiation-associated generation of reactive oxygen species (ROS). Finally, a potentially novel aspect in UVB irradiation-mediated expression of interstitial collagenase and stromelysin-1-namely, the involvement of reactive nitrogen species (RNS)-is discussed.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                6 August 2014
                : 9
                : 8
                [1 ]Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Busan, Republic of Korea
                [2 ]Graduate School of Science and Engineering for Research, University of Toyama, Toyama, Japan
                [3 ]Faculty of Pharmaceutical Sciences, Nagasaki University, Nagasaki, Japan
                [4 ]DrSkin, Busan, Republic of Korea
                IDI, Istituto Dermopatico dell'Immacolata, Italy
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: YRJ HYC. Performed the experiments: YRJ SRK HJA DHK EKL. Analyzed the data: YRJ HYC NDK JNP. Contributed reagents/materials/analysis tools: YRJ TT TY. Wrote the paper: YRJ HYC.


                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 9
                This work was carried out with the support of "Cooperative Research Program for Agriculture Science & Technology Development (Project No. PJ006522132013)" Rural Development Administration, Republic of Korea. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2009-0083538). The authors also take this opportunity to thank the Aging Tissue Bank (Busan, Korea) for supplying research materials. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Biology and life sciences
                Agricultural Biotechnology
                Agricultural Production
                Chemical Biology
                Cell biology
                Signal transduction
                Cell signaling
                Signaling cascades
                MAPK signaling cascades
                Cellular Types
                Molecular Cell Biology
                Developmental Biology
                Medicine and Health Sciences
                Clinical Medicine
                Photodermatology and Skin Aging
                Drug Research and Development
                Physical Sciences
                Applied Chemistry
                Chemical Physics
                Chemical Reactions
                Research and Analysis Methods
                Model Organisms
                Animal Models



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