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      International Journal of Nanomedicine (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the application of nanotechnology in diagnostics, therapeutics, and drug delivery systems throughout the biomedical field. Sign up for email alerts here.

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      Effect of 5-aminolevulinic acid-based photodynamic therapy via reactive oxygen species in human cholangiocarcinoma cells

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          Abstract

          Cancer cells have been reported to exhibit an enhanced capacity for protoporphyrin IX (PpIX) synthesis facilitated by the administration of 5-aminolevulinic acid (ALA). We investigated the effect of ALA-based photodynamic therapy (PDT) on human cholangiocarcinoma cells (HuCC-T1). Since protoporphyrin IX (PpIX), a metabolite of ALA, can produce reactive oxygen species (ROS) under irradiation and then induce phototoxicity, ALA-based PDT is a promising candidate for the treatment of cholangiocarcinoma. When various concentrations of ALA (0.05–2 mM) were used to treat HuCC-T1 cells for 6 or 24 hours, the intracellular PpIX level increased according to the ALA concentration and treatment time. Furthermore, an increased amount of PpIX in HuCC-T1 cells induced increased production of ROS by irradiation, resulting in increased phototoxicity.

          Most cited references40

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          Laser and non-laser light sources for photodynamic therapy.

          Photodynamic therapy (PDT) is an anticancer combination therapy, which requires a photosensitiser, which tends to accumulate preferentially in the tumour, and light. Historically large, complex lasers have been used to carry out PDT treatment. Nowadays there is a wide range of coherent and non-coherent sources that can be used. This paper considers the important characteristics of light sources for PDT, including dye lasers pumped by argon or metal vapour lasers and frequency-doubled Nd:YAG lasers. Non-laser sources including tungsten filament, xenon arc, metal halide and fluorescent lamps are also discussed. New exciting developments such as LEDs and femtosecond lasers are also reviewed. The relative merits of laser and non-laser sources are critically examined.
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            5-Aminolevulinic acid-based photodynamic therapy. Clinical research and future challenges.

            Photodynamic therapy (PDT) for cancer patients has developed into an important new clinical treatment modality in the past 25-years. PDT involves administration of a tumor-localizing photosensitizer or photosensitizer prodrug (5-aminolevulinic acid [ALA], a precursor in the heme biosynthetic pathway) and the subsequent activation of the photosensitizer by light. Although several photosensitizers other than ALA-derived protoprophyrin IX (PpIX) have been used in clinical PDT, ALA-based PDT has been the most active area of clinical PDT research during the past 5 years. Studies have shown that a higher accumulation of ALA-derived PpIX in rapidly proliferating cells may provide a biologic rationale for clinical use of ALA-based PDT and diagnosis. However, no review updating the clinical data has appeared so far. A review of recently published data on clinical ALA-based PDT and diagnosis was conducted. Several individual studies in which patients with primary nonmelanoma cutaneous tumors received topical ALA-based PDT have reported promising results, including outstanding cosmetic results. However, the modality with present protocols does not in general, appear to be superior to conventional therapies with respect to initial complete response rates and long term recurrence rates, particularly in the treatment of nodular skin tumors. Topical ALA-PDT does have the following advantages over conventional treatments: it is noninvasive; it produces excellent cosmetic results; it is well tolerated by patients; it can be used to treat multiple superficial lesions in short treatment sessions; it can be applied to patients who refuse surgery or have pacemakers and bleeding tendency; it can be used to treat lesions in specific locations, such as the oral mucosa or the genital area; it can be used as a palliative treatment; and it can be applied repeatedly without cumulative toxicity. Topical ALA-PDT also has potential as a treatment for nonneoplastic skin diseases. Systemic administration of ALA does not seem to be severely toxic, but the advantage of using this approach for PDT of superficial lesions of internal hollow organs is still uncertain. The ALA-derived porphyrin fluorescence technique would be useful in the diagnosis of superficial lesions of internal hollow organs. Promising results of ALA-based clinical PDT and diagnosis have been obtained. The modality has advantages over conventional treatments. However, some improvements need to be made, such as optimization of parameters of ALA-based PDT and diagnosis; increased tumor selectivity of ALA-derived PpIX; better understanding of light distribution in tissue: improvement of light dosimetry procedure; and development of simpler, cheaper, and more efficient light delivery systems.
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              LRRK2 enhances oxidative stress-induced neurotoxicity via its kinase activity.

              LRRK2 is an autosomal dominant gene whose mutations cause familial Parkinson's disease (PD). The LRRK2 protein contains a functional kinase and a GTPase domain. PD phenotypes caused by LRRK2 mutations are similar to those of idiopathic PD, implying that LRRK2 is an important participant in PD pathogenesis. Of LRRK2's PD-specific mutations, the G2019S is the most frequently observed one. Its over-expression is known to increase kinase activity and neurotoxicity compared to wild type (WT) LRRK2. Here, using a simple colorimetric cell viability assay, we analyzed LRRK2's neurotoxicity in dopaminergic SN4741 cells following treatment with hydrogen peroxide. When WT, G2019S, or empty vector was expressed in SN4741 cells, cell death was modestly and significantly increased in the order of G2019S>WT>vector. When these transfected cells were treated with hydrogen peroxide to mimic oxidative stress, cellular neurotoxicity was enhanced in the same order (i.e. G2019S>WT>vector). Moreover, incubation of SN4741 cells with conditioned medium from cells expressing G2019S and subjected to hydrogen peroxide treatment exhibited 10-15% more cell death than conditioned medium from cells transfected with vector or WT, suggesting that G2019S-expressing cells secrete a factor(s) affecting viability of neighboring cells. The kinase domain was mapped to be responsible for oxidative stress-induced neurotoxicity. In addition, over-expression of WT and G2019S LRRK2 lead to a weak, but significant, increase in intracellular reactive oxygen species (ROS) in the order of G2019S>WT as measured by DCFH-DA assay in both the presence and absence of H(2)O(2) treatment. Furthermore, in G2019S-expressing cells, co-expression of the anti-oxidant protein DJ-1 or ERK inhibitor treatment restored survival rate to a level similar to that of cells transfected with control vector under H(2)O(2) treatment. Taken together, our data suggest that the LRRK2 kinase domain increases the generation of ROS and causes enhanced neurotoxicity under H(2)O(2) treatment, which can be at least partially rescued by DJ-1 or the ERK inhibitor. Copyright 2009 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Int J Nanomedicine
                International Journal of Nanomedicine
                Dove Medical Press
                1176-9114
                1178-2013
                2011
                2011
                30 June 2011
                : 6
                : 1357-1363
                Affiliations
                [1 ] National Research and Development Center for Hepatobiliary Cancer, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea
                [2 ] School of Medicine, Pusan National University, Yangsan, Republic of Korea
                Author notes
                Correspondence: DH Kang, 626-770 Beomeo-ri, Mulgeum-eup, Yangsan, Gyeongnam, Korea, Tel +9 82 55 360 3870, Fax +9 82 55 360 3879, Email sulsulpul@ 123456yahoo.co.kr

                The first two authors contributed equally to this work.

                Article
                ijn-6-1357
                10.2147/IJN.S21395
                3133526
                21760730
                1483f70a-9457-44d6-88f4-264be9773671
                © 2011 Kim et al, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                History
                Categories
                Original Research

                Molecular medicine
                ala-based photodynamic therapy,hucc-t1,protoporphyrin ix,ros
                Molecular medicine
                ala-based photodynamic therapy, hucc-t1, protoporphyrin ix, ros

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