Skip to main content
Log in

DNA-aptamers raised against AGEs as a blocker of various aging-related disorders

  • Mini-Review
  • Published:
Glycoconjugate Journal Aims and scope Submit manuscript

Abstract

A non-enzymatic reaction between sugars or aldehydes and the amino groups of proteins, lipids and nucleic acids contributes to the aging of macromolecules, which could impair their structural integrity and function. This process begins with the conversion of reversible Schiff base adducts, and then to more stable, covalently-bound Amadori rearrangement products. Over a course of days to weeks, these early glycation products undergo further reactions, such as rearrangements and dehydration to become irreversibly crossed-linked, fluorescent protein derivatives termed advanced glycation end products (AGEs). The formation and accumulation of AGEs have been known to progress in a physiological aging process and at an accelerated rate under hyperglycemic, inflammatory and oxidative stress conditions. There is a growing body of evidence that AGEs and their receptor RAGE interaction play a role in the pathogenesis of various devastating disorders, including cardiovascular disease, Alzheimer’s disease, insulin resistance, osteoporosis and cancer growth and metastasis. Furthermore, diet has been recently recognized as a major environmental source of AGEs that could also elicit pro-inflammatory reactions, thereby being involved in organ damage in vivo. Therefore, inhibition of AGE formation and/or blockade of the interaction of AGEs with RAGE may be a novel therapeutic target for aging-related disorders. This article discusses a potential utility of DNA-aptamers raised against AGEs for preventing aging and/or diabetes-associated organ damage, especially focusing on diabetic microvascular complications, vascular remodeling, metabolic derangements, and melanoma growth and expansion in animal models.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Stevens V.J., Rouzer C.A., Monnier V.M., Cerami A.: Diabetic cataract formation: potential role of glycosylation of lens crystallins. Proc. Natl. Acad. Sci. U. S. A. 75, 2918–2922 (1978)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Monnier V.M.: Nonenzymatic glycosylation, the Maillard reaction and the aging process. J. Gerontol. 45, B105–B111 (1990)

    Article  CAS  PubMed  Google Scholar 

  3. Vlassara H., Bucala R.: Recent progress in advanced glycation and diabetic vascular disease: role of advanced glycation end product receptors. Diabetes Suppl. 3, S65–S66 (1996)

    Article  Google Scholar 

  4. Rahbar S.: Novel inhibitors of glycation and AGE formation. Cell Biochem. Biophys. 48, 147–157 (2007)

    Article  CAS  PubMed  Google Scholar 

  5. Bierhaus A., Hofmann M.A., Ziegler R., Nawroth P.P.: AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept. Cardiovasc. Res. 37, 586–600 (1998)

    Article  CAS  PubMed  Google Scholar 

  6. Schmidt A.M., Stern D.: Atherosclerosis and diabetes: the RAGE connection. Curr. Atheroscler. Rep. 2, 430–436 (2000)

    Article  CAS  PubMed  Google Scholar 

  7. Yamagishi S., Imaizumi T.: Diabetic vascular complications: pathophysiology, biochemical basis and potential therapeutic strategy. Curr. Pharm. Des. 11, 2279–2299 (2005)

    Article  CAS  PubMed  Google Scholar 

  8. Tan A.L., Forbes J.M., Cooper M.E.: AGE, RAGE, and ROS in diabetic nephropathy. Semin. Nephrol. 27, 130–143 (2007)

    Article  CAS  PubMed  Google Scholar 

  9. Takeuchi M., Yamagishi S.: Possible involvement of advanced glycation end-products (AGEs) in the pathogenesis of Alzheimer’s disease. Curr. Pharm. Des. 14, 973–978 (2008)

    Article  CAS  PubMed  Google Scholar 

  10. Yamagishi S.: Role of advanced glycation end products (AGEs) and receptor for AGEs (RAGE) in vascular damage in diabetes. Exp. Gerontol. 46, 217–224 (2011)

    Article  CAS  PubMed  Google Scholar 

  11. Yamagishi S.: Role of advanced glycation end products (AGEs) in osteoporosis in diabetes. Curr. Drug Targets. 12, 2096–2102 (2011)

    Article  CAS  PubMed  Google Scholar 

  12. Yamagishi S.: Potential clinical utility of advanced glycation end product cross-link breakers in age- and diabetes-associated disorders. Rejuvenation Res. 15, 564–572 (2012)

    Article  CAS  PubMed  Google Scholar 

  13. Yamagishi S., Matsui T., Fukami K.: Role of receptor for advanced glycation end products (RAGE) and its ligands in cancer risk. Rejuvenation Res. 18, 48–56 (2015)

    Article  CAS  PubMed  Google Scholar 

  14. Koulis C., Watson A.M., Gray S.P., Jandeleit-Dahm K.A.: Linking RAGE and Nox in diabetic micro- and macrovascular complications. Diabete Metab. 41, 272–281 (2015)

    Article  CAS  PubMed  Google Scholar 

  15. Yamagishi S., Matsui T.: Role of receptor for advanced glycation end products (RAGE) in liver disease. Eur. J. Med. Res. 20, 15 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  16. Stinghen, A.E., Massy, Z.A., Vlassara, H., Striker, G.E., Boullier, A.: Uremic Toxicity of Advanced Glycation End Products in CKD. J. Am. Soc. Nephrol. doi:10.1681/ASN.2014101047 (2015)

  17. Yamagishi S., Fukami K., Matsui T.: Evaluation of tissue accumulation levels of advanced glycation end products by skin autofluorescence: a novel marker of vascular complications in high-risk patients for cardiovascular disease. Int. J. Cardiol. 185, 263–268 (2015)

    Article  PubMed  Google Scholar 

  18. Vlassara H.: Advanced glycation in health and disease: role of the modern environment. Ann. NY. Acad. Sci. USA. 1043, 452–460 (2005)

    Article  CAS  Google Scholar 

  19. Yamagishi S., Ueda S., Okuda S.: Food-derived advanced glycation end products (AGEs): a novel therapeutic target for various disorders. Curr. Pharm. Des. 13, 2832–2836 (2007)

    Article  CAS  PubMed  Google Scholar 

  20. Luevano-Contreras C., Chapman-Novakofski K.: Dietary advanced glycation end products and aging. Nutrients. 2, 1247–1265 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Vlassara H., Striker G.E.: AGE restriction in diabetes mellitus: a paradigm shift. Nat. Rev. Endocrinol. 7, 526–539 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Han L., Li L., Li B., Zhao D., Li Y., Xu Z., Liu G.: Review of the characteristics of food-derived and endogenous ne-carboxymethyllysine. J. Food Prot. 76, 912–918 (2013)

    Article  CAS  PubMed  Google Scholar 

  23. Poulsen M.W., Hedegaard R.V., Andersen J.M., de Courten B., Bügel S., Nielsen J., Skibsted L.H., Dragsted L.O.: Advanced glycation endproducts in food and their effects on health. Food Chem. Toxicol. 60, 10–37 (2013)

    Article  CAS  PubMed  Google Scholar 

  24. Kellow N.J., Savige G.S.: Dietary advanced glycation end-product restriction for the attenuation of insulin resistance, oxidative stress and endothelial dysfunction: a systematic review. Eur. J. Clin. Nutr. 67, 239–248 (2013)

    Article  CAS  PubMed  Google Scholar 

  25. Yamagishi S., Matsui T.: Pathological role of dietary advanced glycation end products in cardiometabolic disorders and the therapeutic intervention. Nutrition. 32, 157–165 (2016)

    Article  CAS  PubMed  Google Scholar 

  26. Yamagishi S., Nakamura K., Matsui T., Inagaki Y., Takenaka K., Jinnouchi Y., Yoshida Y., Matsuura T., Narama I., Motomiya Y., Takeuchi M., Inoue H., Yoshimura A., Bucala R., Imaizumi T.: Pigment epithelium-derived factor inhibits advanced glycation end product-induced retinal vascular hyperpermeability by blocking reactive oxygen species-mediated vascular endothelial growth factor expression. J. Biol. Chem. 281, 20213–20220 (2006)

    Article  CAS  PubMed  Google Scholar 

  27. Bock L.C., Griffin L.C., Latham J.A., Vermaas E.H., Toole J.J.: Selection of single-stranded DNA molecules that bind and inhibit human thrombin. Nature. 355, 564–566 (1992)

    Article  CAS  PubMed  Google Scholar 

  28. Gragoudas E.S., Adamis A.P., Cunningham E.T., Feinsod M., Guyer D.R.: Group VISiONCT.: Pegaptanib for neovascular age-related macular degeneration. N. Engl. J. Med. 351, 2805–2816 (2004)

    Article  CAS  PubMed  Google Scholar 

  29. Jilma-Stohlawetz P., Gilbert J.C., Gorczyca M.E., Knöbl P., Jilma B.: A dose ranging phase I/II trial of the von Willebrand factor inhibiting aptamer ARC1779 in patients with congenital thrombotic thrombocytopenic purpura. Thromb. Haemost. 106, 539–547 (2011)

    Article  PubMed  Google Scholar 

  30. Markus H.S., McCollum C., Imray C., Goulder M.A., Gilbert J., King A.: The von Willebrand inhibitor ARC1779 reduces cerebral embolization after carotid endarterectomy: a randomized trial. Stroke. 42, 2149–2153 (2011)

    Article  CAS  PubMed  Google Scholar 

  31. Vavalle J.P., Cohen M.G.: The REG1 anticoagulation system: a novel actively controlled factor IX inhibitor using RNA aptamer technology for treatment of acute coronary syndrome. Futur. Cardiol. 8, 371–382 (2012)

    Article  CAS  Google Scholar 

  32. Osborne S.E., Matsumura I., Ellington A.D.: Aptamers as therapeutic and diagnostic reagents: problems and prospects. Curr. Opin. Chem. Biol. 1, 5–9 (1997)

    Article  CAS  PubMed  Google Scholar 

  33. Famulok M., Hartig J.S., Mayer G.: Functional aptamers and aptazymes in biotechnology, diagnostics, and therapy. Chem. Rev. 107, 3715–3743 (2007)

    Article  CAS  PubMed  Google Scholar 

  34. Keefe A.D., Pai S., Ellington A.: Aptamers as therapeutics. Nat. Rev. Drug Discov. 9, 537–550 (2010)

    Article  CAS  PubMed  Google Scholar 

  35. Yamagishi S., Nakamura K., Matsui T., Ueda S., Fukami K., Okuda S.: Agents that block advanced glycation end product (AGE)-RAGE (receptor for AGEs)-oxidative stress system: a novel therapeutic strategy for diabetic vascular complications. Expert Opin. Investig. Drugs. 17, 983–996 (2008)

    Article  CAS  PubMed  Google Scholar 

  36. Higashimoto Y., Yamagishi S., Nakamura K., Matsui T., Takeuchi M., Noguchi M., Inoue H.: In vitro selection of DNA aptamers that block toxic effects of AGE on cultured retinal pericytes. Microvasc. Res. 74, 65–69 (2007)

    Article  CAS  PubMed  Google Scholar 

  37. Yamagishi S., Kobayashi K., Yamamoto H.: Vascular pericytes not only regulate growth, but also preserve prostacyclin-producing ability and protect against lipid peroxide-induced injury of co-cultured endothelial cells. Biochem. Biophys. Res. Commun. 190, 418–425 (1993)

    Article  CAS  PubMed  Google Scholar 

  38. Kaida Y., Fukami K., Matsui T., Higashimoto Y., Nishino Y., Obara N., Nakayama Y., Ando R., Toyonaga M., Ueda S., Takeuchi M., Inoue H., Okuda S., Yamagishi S.: DNA aptamer raised against AGEs blocks the progression of experimental diabetic nephropathy. Diabetes. 62, 3241–3250 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bennett M.R., O’Sullivan M.: Mechanisms of angioplasty and stent restenosis: implications for design of rational therapy. Pharmacol. Ther. 91, 149–166 (2001)

    Article  CAS  PubMed  Google Scholar 

  40. Levizki A.: PDGF receptor kinase inhibitors for the treatment of restenosis. Cardiovasc. Res. 65, 581–586 (2005)

    Article  Google Scholar 

  41. Nakamura K., Yamagishi S., Matsui T., Yoshida T., Takenaka K., Jinnouchi Y., Yoshida Y., Ueda S., Adachi H., Imaizumi T.: Pigment epithelium-derived factor inhibits neointimal hyperplasia after vascular injury by blocking NADPH oxidase-mediated reactive oxygen species generation. Am. J. Pathol. 170, 2159–2170 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ojima A., Oda E., Higashimoto Y., Matsui T., Yamagishi S.: DNA aptamer raised against advanced glycation end products inhibits neointimal hyperplasia in balloon-injured rat carotid arteries. Int. J. Cardiol. 171, 443–446 (2014)

    Article  PubMed  Google Scholar 

  43. Soro-Paavonen A., Watson A.M., Li J., Paavonen K., Koitka A., Calkin A.C., Barit D., Coughlan M.T., Drew B.G., Lancaster G.I., Thomas M., Forbes J.M., Nawroth P.P., Bierhaus A., Cooper M.E., Jandeleit-Dahm K.A.: Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes. Diabetes. 57, 2461–2469 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yamamoto Y., Yamagishi S., Hsu C.C., Yamamoto H.: Advanced glycation endproducts-receptor interactions stimulate the growth of human pancreatic cancer cells through the induction of platelet-derived growth factor-B. Biochem. Biophys. Res. Commun. 222, 700–705 (1996)

    Article  CAS  PubMed  Google Scholar 

  45. Handa J.T., Reiser K.M., Matsunaga H., Hjelmeland L.M.: The advanced glycation endproduct pentosidine induces the expression of PDGF-B in human retinal pigment epithelial cells. Exp. Eye Res. 66, 411–419 (1998)

    Article  CAS  PubMed  Google Scholar 

  46. Yamagishi S., Matsu T.: Smooth muscle cell pathophysiology and advanced glycation end products (AGEs). Curr. Drug Targets. 11, 875–881 (2010)

    Article  CAS  PubMed  Google Scholar 

  47. Ojima A., Matsui T., Nakamura N., Higashimoto Y., Ueda S., Fukami K., Okuda S., Yamagishi S.: DNA aptamer raised against advanced glycation end products (AGEs) improves glycemic control and decreases adipocyte size in fructose-fed rats by suppressing AGE-RAGE axis. Horm. Metab. Res. 47, 253–258 (2015)

    CAS  PubMed  Google Scholar 

  48. Unoki H., Bujo H., Yamagishi S., Takeuchi M., Imaizumi T., Saito Y.: Advanced glycation end products attenuate cellular insulin sensitivity by increasing the generation of intracellular reactive oxygen species in adipocytes. Diabetes Res. Clin. Pract. 76, 236–244 (2007)

    Article  CAS  PubMed  Google Scholar 

  49. Unoki H., Yamagishi S.: Advanced glycation end products and insulin resistance. Curr. Pharm. Des. 14, 987–989 (2008)

    Article  CAS  PubMed  Google Scholar 

  50. Unoki-Kubota H., Yamagishi S., Takeuchi M., Bujo H., Saito Y.: Pyridoxamine, an inhibitor of advanced glycation end product (AGE) formation ameliorates insulin resistance in obese, type 2 diabetic mice. Protein Pept. Lett. 17, 1177–1181 (2010)

    Article  CAS  PubMed  Google Scholar 

  51. Maeda S., Matsui T., Takeuchi M., Yamagishi S.: Co-treatment with azelinidipine and olmesartan inhibits advanced glycation end products (AGEs) elicited down-regulation of adiponectin mRNA levels in cultured adipocytes partly via its anti-oxidative property. Int. J. Cardiol. 146, 264–266 (2011)

    Article  PubMed  Google Scholar 

  52. Maeda S., Matsui T., Takeuchi M., Yamagishi S.: Pigment epithelium-derived factor (PEDF) blocks advanced glycation end products (AGEs)-RAGE-induced suppression of adiponectin mRNA level in adipocytes by inhibiting NADPH oxidase-mediated oxidative stress generation. Int. J. Cardiol. 146, 408–410 (2010)

    Google Scholar 

  53. Stattin P., Bjor O., Ferrari P., Lukanova A., Lenner P., Lindahl B., Hallmans G., Kaaks R.: Prospective study of hyperglycemia and cancer risk. Diabetes Care. 30, 561–567 (2007)

    Article  PubMed  Google Scholar 

  54. Vigneri P., Frasca F., Sciacca L., Pandini G., Vigneri R.: Diabetes and cancer. Endocr. Relat. Cancer. 16, 1103–1123 (2009)

    Article  CAS  PubMed  Google Scholar 

  55. Emerging Risk Factors Collaboration, Seshasai S.R., Kaptoge S., Thompson A., Di Angelantonio E., Gao P., Sarwar N., Whincup P.H., Mukamal K.J., Gillum R.F., Holme I., Njølstad I., Fletcher A., Nilsson P., Lewington S., Collins R., Gudnason V., Thompson S.G., Sattar N., Selvin E., Hu F.B., Danesh J.: Diabetes mellitus, fasting glucose, and risk of cause-specific death. N. Engl. J. Med. 364, 829–841 (2011)

    Article  Google Scholar 

  56. Miki S., Kasayama S., Miki Y., Nakamura Y., Yamamoto M., Sato B., Kishimoto T.: Expression of receptors for advanced glycosylation end products on renal cell carcinoma cells in vitro. Biochem. Biophys. Res. Commun. 196, 984–989 (1993)

    Article  CAS  PubMed  Google Scholar 

  57. Abe R., Shimizu T., Sugawara H., Watanabe H., Nakamura H., Choei H., Sasaki N., Yamagishi S., Takeuchi M., Shimizu H.: Regulation of human melanoma growth and metastasis by AGE-AGE receptor interactions. J. Investig. Dermatol. 122, 461–467 (2004)

    Article  CAS  PubMed  Google Scholar 

  58. Takino J., Yamagishi S., Takeuchi M.: Cancer malignancy is enhanced by glyceraldehyde-derived advanced glycation end-products. J. Oncol. 2010(739852), (2010)

  59. Ishibashi Y., Matsui T., Takeuchi M., Yamagishi S.: Metformin inhibits advanced glycation end products (AGEs)-induced growth and VEGF expression in MCF-7 breast cancer cells by suppressing AGEs receptor expression via AMP-activated protein kinase. Horm. Metab. Res. 45, 387–390 (2013)

    CAS  PubMed  Google Scholar 

  60. Ojima A., Matsui T., Maeda S., Takeuchi M., Inoue H., Higashimoto Y., Yamagishi S.: DNA aptamer raised against advanced glycation end products inhibits melanoma growth in nude mice. Lab. Investig. 94, 422–429 (2014)

    Article  CAS  PubMed  Google Scholar 

  61. Yamagishi S., Abe R., Inagaki Y., Nakamura K., Sugawara H., Inokuma D., Nakamura H., Shimizu T., Takeuchi M., Yoshimura A., Bucala R., Shimizu H., Imaizumi T.: Minodronate, a newly developed nitrogen-containing bisphosphonate, suppresses melanoma growth and improves survival in nude mice by blocking vascular endothelial growth factor signaling. Am. J. Pathol. 165, 1865–1874 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Vicioso L., Gonzalez F.J., Alvarez M., Ribelles N., Molina M., Marquez A., Perez L., Matilla A., Alba E.: Elevated serum levels of vascular endothelial growth factor are associated with tumor-associated macrophages in primary breast cancer. Am. J. Clin. Pathol. 125, 111–118 (2006)

    Article  CAS  PubMed  Google Scholar 

  63. Higashimoto Y., Matsui T., Nishino Y., Taira J., Inoue H., Takeuchi M., Yamagishi S.: Blockade by phosphorothioate aptamers of advanced glycation end products-induced damage in cultured pericytes and endothelial cells. Microvasc. Res. 90, 64–70 (2013)

    Article  CAS  PubMed  Google Scholar 

  64. Maeda S., Matsui T., Ojima A., Suematsu M., Kaseda K., Higashimoto Y., Yamakawa R., Yamagishi S.: DNA aptamer raised against advanced glycation end products (AGEs) prevents abnormalities in electroretinogram of experimental diabetic retinopathy. Ophthalmic Res. 54, 175–180 (2015)

    Article  CAS  PubMed  Google Scholar 

  65. Segawa Y., Shirao Y., Yamagishi S., Higashide T., Kobayashi M., Katsuno K., Iyobe A., Harada H., Sato F., Miyata H., Asai H., Nishimura A., Takahira M., Souno T., Segawa Y., Maeda K., Shima K., Mizuno A., Yamamoto H., Kawasaki K.: Upregulation of retinal vascular endothelial growth factor mRNAs in spontaneously diabetic rats without ophthalmoscopic retinopathy. A possible participation of advanced glycation end products in the development of the early phase of diabetic retinopathy. Ophthalmic Res. 30, 333–339 (1998)

    Article  CAS  PubMed  Google Scholar 

  66. Fletcher E.L., Phipps J.A., Ward M.M., Puthussery T., Wilkinson-Berka J.L.: Neuronal and glial cell abnormality as predictors of progression of diabetic retinopathy. Curr. Pharm. Des. 13, 2699–2712 (2007)

    Article  CAS  PubMed  Google Scholar 

  67. Barile G.R., Pachydaki S.I., Tari S.R., Lee S.E., Donmoyer C.M., Ma W., Rong L.L., Buciarelli L.G., Wendt T., Hörig H., Hudson B.I., Qu W., Weinberg A.D., Yan S.F., Schmidt A.M.: The RAGE axis in early diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 46, 2916–2924 (2005)

    Article  PubMed  Google Scholar 

  68. Matsui T., Oda E., Higashimoto Y., Yamagishi S.: Glyceraldehyde-derived pyridinium (GLAP) evokes oxidative stress and inflammatory and thrombogenic reactions in endothelial cells via the interaction with RAGE. Cardiovasc. Diabetol. 14, 1 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  69. Usui T., Shimohira K., Watanabe H., Hayase F.: Detection and determination of glyceraldehyde-derived pyridinium-type advanced glycation end products in streptozotocin-induced diabetic rats. Biosci. Biotechnol. Biochem. 71, 442–448 (2007)

    Article  CAS  PubMed  Google Scholar 

  70. Huttunen H.J., Kuja-Panula J., Rauvala H.: Receptor for advanced glycation end products (RAGE) signaling induces CREB-dependent chromogranin expression during neuronal differentiation. J. Biol. Chem. 277, 38635–38646 (2002)

    Article  CAS  PubMed  Google Scholar 

  71. Sorci G., Riuzzi F., Arcuri C., Giambanco I., Donato R.: Amphoterin stimulates myogenesis and counteracts the antimyogenic factors basic fibroblast growth factor and S100B via RAGE binding. Mol. Cell. Biol. 24, 4880–4894 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported, in part, by Grants-in-Aid for Welfare and Scientific Research (C) (no. 22590904) (K.F) and Research (B) (no. 22390111) (S.Y) and from the Ministry of Education, Culture, Sports, Science and Technology of Japan. There is no conflict of interest in this paper.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sho-ichi Yamagishi.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yamagishi, Si., Taguchi, K. & Fukami, K. DNA-aptamers raised against AGEs as a blocker of various aging-related disorders. Glycoconj J 33, 683–690 (2016). https://doi.org/10.1007/s10719-016-9682-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10719-016-9682-2

Keywords

Navigation