Welcome to JOURNAL OF SICHUAN UNIVERSITY (MEDICAL SCIENCE EDITION)
Volume 51 Issue 6
Nov.  2020
Turn off MathJax
Article Contents
ZHU Cheng-guang, REN Biao, CHENG Lei, et al. Effects of Artemisinin and Its Derivatives on Oral Microbes[J]. JOURNAL OF SICHUAN UNIVERSITY (MEDICAL SCIENCE EDITION), 2020, 51(6): 760-766. doi: 10.12182/20201160502
Citation: ZHU Cheng-guang, REN Biao, CHENG Lei, et al. Effects of Artemisinin and Its Derivatives on Oral Microbes[J]. JOURNAL OF SICHUAN UNIVERSITY (MEDICAL SCIENCE EDITION), 2020, 51(6): 760-766. doi: 10.12182/20201160502

Effects of Artemisinin and Its Derivatives on Oral Microbes

doi: 10.12182/20201160502
More Information
  • Corresponding author: E-mail: zhouxd@scu.edu.cn
  • Received Date: 2020-07-06
  • Rev Recd Date: 2020-10-11
  • Publish Date: 2020-11-20
  • The oral environment provides suitable conditions for the colonization of various microorganisms. However, the oral microbials could be the initial factors of some kinds of oral infectious diseases, therefore the treatment against oral microbial pathogens has become an effective strategy. Artemisinin, a kind of sesquiterpene lactone extracted from Traditional Chinese Medicine Artemisia annua L, is the first-line therapy to treat tertian malaria, subtertian malaria and anti-chloroquine malaria for its high efficiency and low toxicity. In recent years, artemisinin and its derivatives have also been proven to be effective against bacteria, fungi, viruses, parasites, and tumors, some of which are closely related to oral diseases. In this review, we summarize the potential effects of artemisinin and its derivatives on oral microorganism by analyzing previous research and latest progress to provide the evidence for further improvement, and look forward to the new research directions. Further studies are needed to improve existing technologies and standards to clarify the effects of artemisinin and its derivatives on microorganisms with controversial effects, to expand the detection of microorganisms associated with oral infectious diseases, and to clarify the interaction with existing antifungal agents in the field of antifungal diseases. In addition, in the study of anti-oral infectious diseases, artemisinin and its derivatives’ administration scheme, potential drug interactions, toxic and side effects and other aspects are necessary conditions for further research, which is also a new direction of research. With the maturity of the production process, the improvement of relevant research and the potential demand for the treatment of oral infectious diseases, artemisinin and its derivatives have a broad prospect in the field of oral microorganisms, and provide a new opportunity for the research and development of oral drugs.
  • loading
  • [1]
    VERMA D, GARG P K, DUBEY A K. Insights into the human oral microbiome. Arch Microbiol,2018,200(4): 525–540. doi: 10.1007/s00203-018-1505-3
    [2]
    MOSADDAD S A, TAHMASEBI E, YAZDANIAN A, et al. Oral microbial biofilms: an update. Eur J Clin Microbiol Infect Dis,2019,38(11): 2005–2019. doi: 10.1007/s10096-019-03641-9
    [3]
    何金枝, 徐欣, 周学东. 口腔微生物与全身健康研究进展. 微生物与感染,2017,12(3): 139–145. doi: 10.3969/j.issn.1673-6184.2017.03.003
    [4]
    GARCIA S S, BLACKLEDGE M S, MICHALEK S, et al. Targeting of Streptococcus mutans biofilms by a novel small molecule prevents dental caries and preserves the oral microbiome. J Dent Res,2017,96(7): 807–814. doi: 10.1177/0022034517698096
    [5]
    LEE L W, LEE Y L, HSIAO S H, et al. Bacteria in the apical root canals of teeth with apical periodontitis. J Formos Med Assoc,2017,116(6): 448–456. doi: 10.1016/j.jfma.2016.08.010
    [6]
    TORRES P J, THOMPSON J, MCLEAN J S, et al. Discovery of a novel periodontal disease-associated bacterium. Microb Ecol,2019,77(1): 267–276. doi: 10.1007/s00248-018-1200-6
    [7]
    LEWIS M, WILLIAMS D W. Diagnosis and management of oral candidosis. Br Dent J,2017,223(9): 675–681. doi: 10.1038/sj.bdj.2017.886
    [8]
    NAGLIK J R, KONIG A, HUBE B, et al. Candida albicans-epithelial interactions and induction of mucosal innate immunity. Curr Opin Microbiol,2017,40: 104–112. doi: 10.1016/j.mib.2017.10.030
    [9]
    JIA G, ZHI A, LAI P, et al. The oral microbiota—a mechanistic role for systemic diseases. Br Dent J,2018,224(6): 447–455. doi: 10.1038/sj.bdj.2018.217
    [10]
    NAZIR M A. Prevalence of periodontal disease, its association with systemic diseases and prevention. Int J Health Sci,2017,11(2): 72–80.
    [11]
    于德鑫, 刘乃仲, 何帅, 等. 青蒿素的合成与应用研究综述. 山东化工,2019,20: 86–87. doi: 10.3969/j.issn.1008-021X.2019.19.036
    [12]
    王令兆, 吴洪达, 王读福, 等. 双氢青蒿素合成工艺探. 山东化工,2017,7: 62–65. doi: 10.3969/j.issn.1008-021X.2017.01.020
    [13]
    屠呦呦. 青蒿素的药理学研究//张文虎, 贾维娜. 青蒿及青蒿素类药物. 北京: 化学工业出版社, 2009: 164-173.
    [14]
    WHITE N J. Qinghaosu (artemisinin): the price of success. Science,2008,320(5874): 330–334. doi: 10.1126/science.1155165
    [15]
    青蒿素结构研究协作组. 一种新型的倍半萜内酯—青蒿素. 科技导报,2015,20: 125.
    [16]
    王宇彤, 邵钰柔, 陈利娜, 等. 青蒿素抗疟作用机制研究进展. 世界科学技术-中医药现代化,2018,20(8): 1357–1363.
    [17]
    MESHNICK S R. Artemisinin: mechanisms of action, resistance and toxicity. Int J Parasitol,2002,32(13): 1655–1660. doi: 10.1016/S0020-7519(02)00194-7
    [18]
    CUI L, SU X. Discovery, mechanisms of action and combination therapy of artemisinin. Expert Rev Anti Infect Ther,2009,7(8): 999–1013. doi: 10.1586/eri.09.68
    [19]
    TU Y. The discovery of artemisinin (Qinghaosu) and gifts from Chinese Medicine. Nat Med,2011,17(10): 1217–1220. doi: 10.1038/nm.2471
    [20]
    WATTS G. Nobel awarded to discoverers of ivermectin and artemisinin. BMJ,2015,351: h5352[2020-06-15]. https://doi.org/10.1136/bmj.h5352.
    [21]
    SHEN B. A new golden age of natural products drug discovery. Cell,2015,163(6): 1297–1300. doi: 10.1016/j.cell.2015.11.031
    [22]
    黄梅, 沈建英, 杜成成, 等. 青蒿素及其衍生物的抗菌活性初步研究. 中国中药杂志,2019,9: 1946–1952.
    [23]
    于朋涛, 李之拓, 王鹏飞, 等. 青蒿素及其衍生物抗肿瘤作用的研究进展. 肿瘤药学,2019,4: 534–539. doi: 10.3969/j.issn.2095-1264.2019.04.02
    [24]
    蒋为薇, 钱妍. 青蒿素类药物的抗炎免疫作用机制及其安全性研究进展. 免疫学杂志,2019,35(7): 630–636.
    [25]
    HO W E, PEH H Y, CHAN T K, et al. Artemisinins: pharmacological actions beyond anti-malarial. Pharmacol Ther,2014,142(1): 126–139. doi: 10.1016/j.pharmthera.2013.12.001
    [26]
    SLEZAKOVA S, RUDA-KUCEROVA J. Anticancer activity of artemisinin and its derivatives. Anticancer Res,2017,37(11): 5995–6003.
    [27]
    APPALASAMY S, LO K Y, CH'NG S J, et al. Antimicrobial activity of artemisinin and precursor derived from in vitro plantlets of Artemisia annua L. Biomed Res Int,2014,2014: 215872[2020-06-15]. http://dx.doi.org/10.1155/2014/215872.
    [28]
    DAS S, CZUNI L, BALO V, et al. Cytotoxic action of artemisinin and scopoletin on planktonic forms and on biofilms of Candida Species. Molecules, 2020, 25(3):476[2020-06-15]. https://doi.org/10.3390/molecules25030476.
    [29]
    KRISHNAN K, CHEN T, PASTER B J. A practical guide to the oral microbiome and its relation to health and disease. Oral Diseases,2017,23(3): 276–286. doi: 10.1111/odi.12509
    [30]
    WANG Y, REN B, ZHOU X, et al. Growth and adherence of Staphylococcus aureus were enhanced through the PGE2 produced by the activated COX-2/PGE2 pathway of infected oral epithelial cells. PloS One, 2017, 12(5): e0177166[2020-06-15]. https://doi.org/10.1371/journal.pone.0177166.
    [31]
    杨文宾, 李春洁, 李龙江, 等. 口腔颌面部肿瘤患者术后感染细菌及耐药性分析. 上海口腔医学,2015,24(5): 584–588.
    [32]
    CHEN Y, LAI L, ZHANG H, et al. Effect of artesunate supplementation on bacterial translocation and dysbiosis of gut microbiota in rats with liver cirrhosis. World J Gastroenterol,2016,22(10): 2949–2959. doi: 10.3748/wjg.v22.i10.2949
    [33]
    SLADE D, GALAL A M, GUL W, et al. Antiprotozoal, anticancer and antimicrobial activities of dihydroartemisinin acetal dimers and monomers. Bioorg Med Chem,2009,17(23): 7949–7957. doi: 10.1016/j.bmc.2009.10.019
    [34]
    LOHR G D, HOLLABAUGH B, WATERS P, et al. Methicillin-resistant Staphylococcus aureus and antibiotic use in septorhinoplasty: case report and review of literature. Oral Surg Oral Med Oral Pathol Oral Radiol, 2017, 123(6): e177-e181[2020-05-09]. https://doi.org/10.1016/j.oooo.2017.01.002.
    [35]
    李萍, 龚正涛. 口腔颌面部间隙感染病原及菌株耐药性特征. 中国病原生物学杂志,2018,13(11): 1280–1283.
    [36]
    VELLAPPALLY S, DIVAKAR D D, AL KHERAIF A A, et al. Occurrence of vancomycin-resistant Staphylococcus aureus in the oral cavity of patients with dental caries. Acta Microbiol Immunol Hung,2017,64(3): 343–351. doi: 10.1556/030.64.2017.033
    [37]
    GOSWAMI S, BHAKUNI R S, CHINNIAH A, et al. Anti Helicobacter pylori potential of artemisinin and its derivatives. Antimicrob Agents Chemother,2012,56(9): 4594–4607. doi: 10.1128/AAC.00407-12
    [38]
    LIN L, MAO X, SUN Y, et al. Antibacterial mechanism of artemisinin/beta-cyclodextrins against methicillin-resistant Staphylococcus aureus (MRSA). Microb Pathog,2018,118: 66–73. doi: 10.1016/j.micpath.2018.03.014
    [39]
    LI B, LI J, PAN X, et al. Artesunate protects sepsis model mice challenged with Staphylococcus aureus by decreasing TNF-alpha release via inhibition TLR2 and Nod2 mRNA expressions and transcription factor NF-kappaB activation. Int Immunopharmacol,2010,10(3): 344–350. doi: 10.1016/j.intimp.2009.12.006
    [40]
    JIANG W, LI B, ZHENG X, et al. Artesunate has its enhancement on antibacterial activity of beta-lactams via increasing the antibiotic accumulation within methicillin-resistant Staphylococcus aureus (MRSA). J Antibiot (Tokyo),2013,66(6): 339–345. doi: 10.1038/ja.2013.22
    [41]
    VILLAFUERTE K R V, MARTINEZ C J H, DANTAS F T, et al. The impact of chemotherapeutic treatment on the oral microbiota of patients with cancer: a systematic review. Oral Surg Oral Med Oral Pathol Oral Radiol,2018,125(6): 552–566. doi: 10.1016/j.oooo.2018.02.008
    [42]
    赵晨. 产超广谱β-内酰胺酶大肠埃希菌和肺炎克雷伯菌的检测和耐药性分析. 全科口腔医学电子杂志,2019,6(24): 198[2020-06-15].http://d.wanfangdata.com.cn/periodical/qkkqyxdzzz201924137.
    [43]
    WANG J, ZHOU H, ZHENG J, et al. The antimalarial artemisinin synergizes with antibiotics to protect against lethal live Escherichia coli challenge by decreasing proinflammatory cytokine release. Antimicrob Agents Chemother,2006,50(7): 2420–2427. doi: 10.1128/AAC.01066-05
    [44]
    LI B, ZHANG R, LI J, et al. Antimalarial artesunate protects sepsis model mice against heat-killed Escherichia coli challenge by decreasing TLR4, TLR9 mRNA expressions and transcription factor NF-kappa B activation. Int Immunopharmacol,2008,8(3): 379–389. doi: 10.1016/j.intimp.2007.10.024
    [45]
    LI B, YAO Q, PAN X, et al. Artesunate enhances the antibacterial effect of {beta}-lactam antibiotics against Escherichia coli by increasing antibiotic accumulation via inhibition of the multidrug efflux pump system AcrAB-TolC. J Antimicrob Chemother,2011,66(4): 769–777. doi: 10.1093/jac/dkr017
    [46]
    WU C, LIU J, PAN X, et al. Design, synthesis and evaluation of the antibacterial enhancement activities of amino dihydroartemisinin derivatives. Molecules,2013,18(6): 6866–6882. doi: 10.3390/molecules18066866
    [47]
    SONG Y, QIN R, PAN X, et al. Design of new antibacterial enhancers based on AcrB's structure and the evaluation of their antibacterial enhancement activity. Int J Mol Sci,2016,17(11): 1934. doi: 10.3390/ijms17111934
    [48]
    陈颖颖. 口腔内幽门螺杆菌的研究进展. 大医生,2019,4(2): 8–11.
    [49]
    朱志雾, 晏桂萍. 口腔幽门螺杆菌与胃幽门螺杆菌感染关系的研究进展. 系统医学,2017,2(12): 7–9.
    [50]
    SISTO F, SCALTRITO M M, MASIA C, et al. In vitro activity of artemisone and artemisinin derivatives against extracellular and intracellular Helicobacter pylori. Int J Antimicrob Agents,2016,48(1): 101–105. doi: 10.1016/j.ijantimicag.2016.03.018
    [51]
    IVANESCU B, MIRON A, CORCIOVA A. Sesquiterpene lactones from Artemisia Genus: biological activities and methods of analysis. J Anal Methods Chem, 2015, 2015: 247685[2020-06-15]. https://doi.org/10.1155/2015/247685.
    [52]
    KIM W S, CHOI W J, LEE S, et al. Anti-inflammatory, antioxidant and antimicrobial effects of artemisinin extracts from Artemisia annua L. Korean J Physiol Pharmacol,2015,19(1): 21–27.
    [53]
    SINGH A, VERMA R, MURARI A, et al. Oral candidiasis: an overview. J Oral Maxillofac Pathol,2014,18(S1): S81–85.
    [54]
    HU L, HE C, ZHAO C, et al. Characterization of oral candidiasis and the Candida species profile in patients with oral mucosal diseases. Microb Pathog, 2019, 134: 103575[2020-06-15]. https://doi.org/10.1016/j.micpath.2019.103575.
    [55]
    PEREIRA D, SENEVIRATNE C J, KOGA-ITO C Y, et al. Is the oral fungal pathogen Candida albicans a cariogen? Oral Dis,2018,24(4): 518–526. doi: 10.1111/odi.12691
    [56]
    XIAO J, GRIER A, FAUSTOFERRI R C, et al. Association between oral Candida and Bacteriome in Children with severe ECC. J Dent Res,2018,97(13): 1468–1476. doi: 10.1177/0022034518790941
    [57]
    GOMES C C, GUIMARAES L S, PINTO L C C, et al. Investigations of the prevalence and virulence of Candida albicans in periodontal and endodontic lesions in diabetic and normoglycemic patients. J Appl Oral Sci,2017,25(3): 274–281. doi: 10.1590/1678-7757-2016-0432
    [58]
    REX J H, COOPER C R, Jr, MERZ W G, et al. Detection of amphotericin B-resistant Candida isolates in a broth-based system. Antimicrob Agents Chemother,1995,39(4): 906–909. doi: 10.1128/AAC.39.4.906
    [59]
    GALAL A M, ROSS S A, JACOB M, et al. Antifungal activity of artemisinin derivatives. J Nat Prod,2005,68(8): 1274–1276. doi: 10.1021/np050074u
    [60]
    KOLACZKOWSKI M, KOLACZKOWSKA A, STERMITZ F R. Modulation of the antifungal activity of new medicinal plant extracts active on Candida glabrata by the major transporters and regulators of the pleiotropic drug-resistance network in Saccharomyces cerevisiae. Microb Drug Resist,2009,15(1): 11–17. doi: 10.1089/mdr.2009.0854
    [61]
    KANEKO Y, FUKAZAWA H, OHNO H, et al. Combinatory effect of fluconazole and FDA-approved drugs against Candida albicans. J Infect Chemother,2013,19(6): 1141–1145. doi: 10.1007/s10156-013-0639-0
    [62]
    DE CREMER K, LANCKACKER E, COOLS T L, et al. Artemisinins, new miconazole potentiators resulting in increased activity against Candida albicans biofilms. Antimicrob Agents Chemother,2015,59(1): 421–426. doi: 10.1128/AAC.04229-14
    [63]
    BHATTACHARYA A, MISHRA L C, BHASIN V K. In vitro activity of artemisinin in combination with clotrimazole or heat-treated amphotericin B against Plasmodium falciparum. Am J Trop Med Hyg,2008,78(5): 721–728. doi: 10.4269/ajtmh.2008.78.721
    [64]
    白丽, 申元英, 王晶, 等. 健康人群口腔酵母菌的分离及菌种分布. 中国微生态学杂志,2005,17(2): 111–112.
    [65]
    陈文颖. HIV/AIDS患者口腔真菌定植状况及药敏研究. 昆明: 昆明医学院, 2011.
    [66]
    MOORE C M, HOEY E M, TRUDGETT A, et al. Artemisinins act through at least two targets in a yeast model. FEMS Yeast Res,2011,11(2): 233–237. doi: 10.1111/j.1567-1364.2010.00706.x
    [67]
    PULCINI S, STAINES H M, PITTMAN J K, et al. Expression in yeast links field polymorphisms in PfATP6 to in vitro artemisinin resistance and identifies new inhibitor classes. J Infect Dis,2013,208(3): 468–478. doi: 10.1093/infdis/jit171
    [68]
    LI W, MO W, SHEN D, et al. Yeast model uncovers dual roles of mitochondria in action of artemisinin. PLoS Genet,2005,1(3): e36[2020-06-15]. https://doi.org/10.1371/journal.pgen.0010036. doi: 10.1371/journal.pgen.0010036
    [69]
    MAGRI A, DI ROSA M C, TOMASELLO M F, et al. Overexpression of human SOD1 in VDAC1-less yeast restores mitochondrial functionality modulating beta-barrel outer membrane protein genes. Biochim Biophys Acta,2016,1857(6): 789–798. doi: 10.1016/j.bbabio.2016.03.003
    [70]
    SUN C, ZHOU B. The molecular and cellular action properties of artemisinins: what has yeast told us? Microb Cell,2016,3(5): 196–205. doi: 10.15698/mic2016.05.498
    [71]
    SUN C, ZHOU B. The antimalarial drug artemisinin induces an additional, Sod1-supressible anti-mitochondrial action in yeast. Biochim Biophys Acta Mol Cell Res,2017,1864(7): 1285–1294. doi: 10.1016/j.bbamcr.2017.04.014
    [72]
    JENSEN A N, CHINDAUDOMSATE W, THITIANANPAKORN K, et al. Improper protein trafficking contributes to artemisinin sensitivity in cells lacking the KDAC Rpd3p. FEBS Lett,2014,588(21): 4018–4025. doi: 10.1016/j.febslet.2014.09.021
    [73]
    BAO X, WIEHE R, DOMMISCH H, et al. Entamoeba gingivalis causes oral inflammation and tissue destruction. J Dent Res,2020,99(5): 561–567. doi: 10.1177/0022034520901738
    [74]
    BONNER M, FRESNO M, GIRONÈS N, et al. Reassessing the role of Entamoeba gingivalis in periodontitis. Front Cell Infect Microbiol,2018,8: 379. doi: 10.3389/fcimb.2018.00379
    [75]
    HASSAN S, MADKOUR G, HENIN R, et al. Is Entamoeba Gingivalis a risk factor for periodontal diseases? A case-control study. Perio J,2019,3(1): 18–28. doi: 10.26810/perioj.2019.a3
    [76]
    COOKE D W, LALLINGER G J, DURACK D T. In vitro sensitivity of Naegleria fowleri to qinghaosu and dihydroqinghaosu. J Parasitol,1987,73(2): 411–413. doi: 10.2307/3282098
    [77]
    DENG Y, RAN W, MAN S, et al. Artemether exhibits amoebicidal activity against Acanthamoeba castellanii through inhibition of the serine biosynthesis pathway. Antimicrob Agents Chemother,2015,59(8): 4680–4688. doi: 10.1128/AAC.04758-14
    [78]
    BENABDELKADER S, ANDREANI J, GILLET A, et al. Specific clones of Trichomonas tenax are associated with periodontitis. PLoS One, 2019, 14(3): e0213338[2020-05-14]. https://doi.org/10.1371/journal.pone.0213338.
    [79]
    FANULI M, VIGANÒ L, CASU C. Trichosoma tenax and Entamoeba gingivalis: pathogenic role of protozoic species in chronic periodontal disease development. J Hum Virol Retrovirol,2018,6(3): 81–84.
    [80]
    SEO M Y, RYU J S, SATO A, et al. Potential of synthetic endoperoxides against Trichomonas vaginalis in vitro. Parasitol Int,2017,66(5): 619–621. doi: 10.1016/j.parint.2017.05.008
    [81]
    汤自豪, 周小鸥, 高兴政. 双氢青蒿素对体外培养阴道毛滴虫作用的电镜观察. 中国寄生虫学与寄生虫病杂志,2007,25(1): 41–44. doi: 10.3969/j.issn.1000-7423.2007.01.009
    [82]
    马凤霞. 口腔单纯性疱疹患者的诊疗分析. 世界最新医学信息文摘,2016,16(73): 70, 72.
    [83]
    郑直, 颜世果. 疱疹病毒与牙周炎的关系. 国际口腔医学杂志,2018,45(2): 224–227.
    [84]
    许鹏, 陈传俊. 原发性三叉神经痛与单纯疱疹病毒感染的相关性研究进展. 国际口腔医学杂志,2016,43(2): 220–222.
    [85]
    LIU X, CAO J, HUANG G, et al. Biological activities of artemisinin derivatives beyond Malaria. Curr Top Med Chem,2019,19(3): 205–222. doi: 10.2174/1568026619666190122144217
    [86]
    CANIVET C, MENASRIA R, RHEAUME C, et al. Valacyclovir combined with artesunate or rapamycin improves the outcome of herpes simplex virus encephalitis in mice compared to antiviral therapy alone. Antiviral Res,2015,123: 105–113. doi: 10.1016/j.antiviral.2015.09.007
    [87]
    ROY S, HE R, KAPOOR A, et al. Inhibition of human cytomegalovirus replication by artemisinins: effects mediated through cell cycle modulation. Antimicrob Agents Chemother,2015,59(7): 3870–3879. doi: 10.1128/AAC.00262-15
    [88]
    MILBRADT J, AUEROCHS S, KORN K, et al. Sensitivity of human herpesvirus 6 and other human herpesviruses to the broad-spectrum anti-infective drug artesunate. J Clin Virol,2009,46(1): 24–28. doi: 10.1016/j.jcv.2009.05.017
    [89]
    AUEROCHS S, KORN K, MARSCHALL M. A reporter system for Epstein-Barr virus (EBV) lytic replication: anti-EBV activity of the broad anti-herpesviral drug artesunate. J Virol Methods,2011,173(2): 334–339. doi: 10.1016/j.jviromet.2011.03.005
    [90]
    PADDON C J, WESTFALL P J, PITERA D J, et al. High-level semi-synthetic production of the potent antimalarial artemisinin. Nature,2013,496(7446): 528–532. doi: 10.1038/nature12051
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索
    Article views (2081) PDF downloads(37) Cited by()
    Proportional views
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return