Skip to main content
SpringerLink
Log in

Riparin B, a Synthetic Compound Analogue of Riparin, Inhibits the Systemic Inflammatory Response and Oxidative Stress in Mice

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

The aim of our study was to evaluate the anti-inflammatory, anti-nociceptive, and anti-oxidant action of Riparin B in vivo. We performed experiments in which we induced paw edema by carrageenan and other mediators, carrageenan-induced peritonitis and the level of myeloperoxidase (MPO) activity, pro-inflammatory cytokines (TNF-α and IL-1β), malondialdehyde (MDA) acid, and glutathione (GSH) from the peritoneal fluid. We also performed behavior tests such as acetic acid-induced writhing, formalin-induced linking, and the hot plate test. Among the doses tested of the Riparin B (1, 3, and 10 mg/kg), the dose of 10 mg/kg showed the strongest effect, and this dose was able to reduce the paw edema induced by carrageenan, dextran, histamine serotonin, bradykinin, 48/80, and PGE2. Similarly, the Riparin B in the same dose reduced cell migration and significantly decreased the nociception induced by formalin and acetic acid and reversed the parameters of the oxidative stress. Thus, we can infer that Riparin B exhibits anti-inflammatory, anti-nociceptive, and anti-oxidant actions in vivo.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

REFERENCES

  1. Calixto, J.B., M.F. Otuki, and A.R. Santos. 2003. Anti-inflammatory compounds of plant origin. Part I. Action on arachidonic acid pathway, nitric oxide and nuclear factor kappa B (NF-kappaB). Planta Medica 69(11): 973–983.

    Article  CAS  PubMed  Google Scholar 

  2. Soares, A.M., F.K. Ticli, S. Marcussi, M.V. Lourenço, A.H. Januário, S.V. Sampaio, J.R. Giglio, B. Lomonte, and P.S. Pereira. 2005. Medicinal plants with inhibitory properties against snake venoms. Current Medicinal Chemistry 12: 2625–2641.

    Article  CAS  PubMed  Google Scholar 

  3. Molinski, T.F., D.S. Dalisay, S.L. Lievens, and J.P. Saludes. 2009. Drug development from marine natural products. Nature Reviews Drug Discovery 8(1): 69–85.

    Article  CAS  PubMed  Google Scholar 

  4. Radjasa, O.K., Y.M. Vaske, G. Navarro, H.C. Vervoort, K. Tenney, R.G. Linington, and P. Crews. 2011. Highlights of marine invertebrate-derived biosynthetic products: Their biomedical potential and possible production by microbial associants. Bioorganic and Medicinal Chemistry 19(22): 6658–6674.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Nunes, G.B.L., P.R. Policarpo, L.M. Costa, T.G. Da Silva, C.G.G. Militão, C.A. Câmara, J.M. Barbosa Filho, S.J.C. Gutierrez, M.T. Islam, and R.M. De Freitas. 2014. In vitro antioxidant and cytotoxic activity of some synthetic riparin-derived compounds. Molecules 19(4): 4595–4607.

    Article  PubMed  Google Scholar 

  6. Essa, M.M., N. Braidy, W. Bridge, S. Subash, T. Manivasagam, R.K. Vijayan, S. Al-Adawi, and G.J. Guillemin. 2012. Review of natural products on Parkinson’s disease pathology. Journal of Aging Research & Clinical Practice 3(3): 127–136.

    Google Scholar 

  7. Araújo, F.L., C.T. Melo, N.F. Rocha, B.A. Moura, C.P. Leite, J.F. Amaral, J.M. Barbosa-Filho, S.J. Gutierrez, S.M. Vasconcelos, G.S. Viana, and F.C. de Sousa. 2009. Antinociceptive effects of (O-methyl)-N-benzoyl tyramine (riparin I) from Aniba riparia (Nees) Mez (Lauraceae) in mice. Naunyn-Schmiedeberg’s Archives of Pharmacology 380: 337–344.

  8. Carvalho, A.M.R., N.F.M. Rocha, L.F. Vasconcelos, E.R.V. Rios, M.L. Dias, M.I.G. Silva, M.M.F. Fonteles, J.M. Barbosa Filho, S.J.C. Gutierrez, and F.C.F. De Sousa. 2013. Evaluation of the anti-inflammatory activity of riparin II (O-methil-N-2-hidroxi-benzoyl tyramine) in animal models. Chemico-Biological Interactions 205: 165–172.

    Article  PubMed  Google Scholar 

  9. De Melo, C.T.V., A.P. Monteiro, C.P. Leite, F.L.O. De Araújo, V.T.M. Lima, J.M. Barbosa-Filho, M.M.F. Fonteles, S.M.M. Vasconcelos, G.S.B. Viana, and F.C.F. Sousa. 2006. Anxiolytic-like effects of (O-methyl)-N-2,6-dihydroxybenzoyl-tyramine (riparin III) from Aniba riparia (NEES) MEZ (Lauraceae) in mice. Biological and Pharmaceutical Bulletin 29: 451–454.

    Article  PubMed  Google Scholar 

  10. Geetha, T., P. Varalakshmi, and L.R. Mary. 1998. Effect of triterpenes from Crataeva nurvata stem bark on lipid peroxidation in adjuvant induced arthritis in rats. Pharmacological Research 37: 191–195.

    Article  CAS  PubMed  Google Scholar 

  11. Quignard, E.L.J., S.M. Nunomura, A.M. Pohlit, A.M. Alecrim, A.C.S. Pinto, C.N. Portela, L.C.P. Oliveira, L.C. Don, L.F. Rocha e Silva, and M.C. Henrique. 2004. Median lethal concentrations of amazonian plant extracts in the brine shrimp assay. Pharmaceutical Biology 42: 253–257.

    Article  Google Scholar 

  12. Marchand, F., M. Perretti, and S.B. McMahon. 2005. Role of the immune system in chronic pain. Nature Reviews Neuroscience 6: 521–532.

    Article  CAS  PubMed  Google Scholar 

  13. Nguemfo, E.L., T. Dimo, A.B.. Dongmo, A.G.B. Azebaze, K. Alaoui, A.E. Asongalem, Y. Cherrah, and P. Kamtchouing. 2009. Anti-oxidative and anti-inflammatory activities of some isolated constituents from the stem bark of Allanblackia monticola Staner L.C (Guttiferae). Inflammopharmacology 17: 37–41.

  14. Winter, C.A., E.A. Risley, and G.W. Nuss. 1962. Carrageenin-induced edema in hindpaw of the rat as an assay for anti-inflammatory drugs. Proceedings of the Society for Experimental Biology and Medicine 111: 544–547.

    Article  CAS  PubMed  Google Scholar 

  15. Lanhers, M.C., J. Fleurentin, P. Dorfman, F. Mortier, and J.M. Pelt. 1991. Analgesic, antipyretic and anti-inflammatory properties of Euphorbia hirta. Planta Medica 57: 225–231.

    Article  CAS  PubMed  Google Scholar 

  16. Collier, H.O.J., J.C. Dinneen, C.A. Johnson, and C. Schneider. 1968. The abdominal constriction response and its suppression by analgesic drugs in the mouse. British Journal of Pharmacology and Chemotherapy 32: 295–310.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Hunskaar, S., and K. Hole. 1987. The formalin test in mice: dissociation between inflammatory and non-inflammatory pain. Pain 30: 103–104.

    Article  CAS  PubMed  Google Scholar 

  18. Mihara, M., and M. Uchiyama. 1978. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Analytical Biochemistry 86: 271–278.

    Article  CAS  PubMed  Google Scholar 

  19. Nagy, L., M. Nagata, and S. Szabo. 2007. Protein and non-protein sulfhydryls and disulfides in gastric mucosa and liver after gastrotoxic chemicals and sucralfate: possible new targets of pharmacologic agents. World Journal of Gastroenterology 13(14): 2053–2060.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Josse, C., J.R. Boelaert, M. Best-Belpomme, and J. Piette. 2001. Importance of post-transcriptional regulation of chemokine genes by oxidative stress. Biochemical Journal 360: 321–333.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Cuzzocrea, S., D.P. Riley, A.P. Caputi, and D. Salvemini. 2001. Antioxidant therapy: a new pharmacological approach in shock, inflammation, and ischemia/reperfusion injury. Pharmacological Reviews 53: 135–159.

    CAS  PubMed  Google Scholar 

  22. Borghi, S.M., T.T. Carvalho, L. Staurengo-Ferrari, M.S.N. Hohmann, P. Pinge-Filho, R. Casagrande, and W.A. Verri Jr. 2013. Vitexin inhibits inflammatory pain in mice by targeting TRPV1, oxidative stress, and cytokines. Journal of Natural Products 76: 1141–1149.

    Article  CAS  PubMed  Google Scholar 

  23. Gutierrez, S.J.C. 2007. Síntese do bowdenol um dihidrobenzofuranoide isolado de bowdichia virgilioides e preparação de derivados da riparina isolada de aniba riparia com potencial atividade biológica. Doctorate Thesis, UFPB/CCS: João Pessoa, Brazil.

  24. Sherwood, E.R., and T. Toliver-Kinsky. 2004. Mechanisms of the inflammatory response. Best Practice & Research. Clinical Anaesthesiology 18: 385–405.

    Article  CAS  Google Scholar 

  25. Siddiqui, M.R., K. Tran, S.P. Reddy, and A.B... Malik. 2014. Reactive oxygen species in inflammation and tissue injury. Antioxidants & Redox Signaling 20(7): 1126–1167.

  26. Nathan, C. 2002. Points of control in inflammation. Nature 420: 846–852.

    Article  CAS  PubMed  Google Scholar 

  27. Xavier, S.M., C.O. Barbosa, D.O. Barros, R.F. Silva, A.A. Oliveira, and R.M. Freitas. 2007. Vitamin C antioxidant effects in hippocampus of adult Wistar rats after seizures and status epilepticus induced by pilocarpine. Neuroscience Letters 420: 76–79.

    Article  CAS  PubMed  Google Scholar 

  28. De Brito, T.V., R.S. Prudêncio, A.B... Sales, F. Vieira Jr., S.J. Candeira, Á.X. Franco, K.S. Aragão, R.A. Ribeiro, M.H.P. De Souza, L.S. Chaves, A.L. Freitas, J.V. Medeiros, and A.L.R. Barbosa. 2013. Anti-inflammatory effect of a sulphated polysaccharide fraction extracted from the red algae Hypnea musciformis via the suppression of neutrophil migration by the nitric oxide signalling pathway. Journal of Pharmacy and Pharmacology 65: 724–733.

  29. Dawson, J., A.D. Sedgwick, J.C. Edwards, and P. Lees. 1991. A comparative study of the cellular, exudative and histological responses to carrageenan, dextran and zymosan in the mouse. International Journal of Tissue Reactions 13(4): 171–185.

    CAS  PubMed  Google Scholar 

  30. Cragg, G.M., D.J. Newman, and K.M. Snader. 1997. Natural products in drug discovery and development. Journal of Natural Products 60: 52–60.

    Article  CAS  PubMed  Google Scholar 

  31. De Smet, P.A. 2007. The role of plant-derived drugs and herbal medicines in healthcare. Drugs 54: 801–840.

    Article  Google Scholar 

  32. Rowley, D.A., and E.P. Benditt. 1956. Serotonin and histamine as mediators of vascular injury produced by agents which damage mast cells in rats. Journal of Experimental Medicine 103: 399–415.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Kulkarni, S.K., A.K. Mehta, and J. Kunchandy. 1986. Anti-inflammatory actions of clonidine, guanfacine and B-HT 920 against various inflammagen-induced acute paw oedema in rats. Archives Internationales de Pharmacodynamie et de Thérapie 279(2): 324–334.

    CAS  PubMed  Google Scholar 

  34. Seibert, K., Y. Zhang, K. Leahy, S. Hauser, J. Masferrer, W. Perkins, L. Lee, and P. Isakson. 1994. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proceedings of the National Academy of Sciences 91: 12013–12017.

    Article  CAS  Google Scholar 

  35. Lago, J., A. Alfonso, M.R. Vieytes, and L.M. Botana. 2001. Ouabain-induced enhancement of rat mast cells response. Modulation by protein phosphorylation and intracellular pH. Cellular Signalling 13: 515–524.

    Article  CAS  PubMed  Google Scholar 

  36. Okazaki, T., V.S. Ilea, A. Okazaki, K. Wicher, R.E. Reisman, and C.E. Arbesman. 1976. Inhibition of antigen-induced histamine release by ouabain. Journal of Allergy and Clinical Immunology 57: 454–462.

    Article  CAS  PubMed  Google Scholar 

  37. Ennis, M., F.L. Pearce, and P.M. Weston. 1980. Some studies on the release of histamine from mast cells stimulated with polylysine. British Journal of Pharmacology 70: 329–334.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Senol, M., I.H. Ozerol, A.V. Patel, and D.P. Skoner. 2007. The effect of Na+-K+ ATPase inhibition by ouabain on histamine release from human cutaneous mast cells. Molecular and Cellular Biochemistry 294: 25–29.

    Article  CAS  PubMed  Google Scholar 

  39. Carvalho, J.C., J.R. Teixeira, P.J. Souza, J.K. Bastos, D. Dos Santos Filho, and S.J. Sarti. 1996. Preliminary studies of analgesic and anti-inflammatory properties of Caesalpinia ferrea crude extract. Journal of Ethnopharmacology 53: 175–178.

    Article  CAS  PubMed  Google Scholar 

  40. Ajuebor, M.N., A. Singh, and J.L. Wallace. 2000. Cyclooxygenase-2-derived prostaglandin D(2) is an early anti-inflammatory signal in experimental colitis. American Journal of Physiology. Gastrointestinal and Liver Physiology 279(1): 238–244.

    Google Scholar 

  41. Souza, G.E., F.Q. Cunha, R. Mello, and S.H. Ferreira. 1988. Neutrophil migration induced by inflammatory stimuli is reduced by macrophage depletion. Agents and Actions 24: 377–380.

    Article  CAS  PubMed  Google Scholar 

  42. Montanher, A.B..., S.M. Zucolotto, E.P. Schenkel, and T.S. Fröde. 2007. Evidence of anti-inflammatory effects of Passiflora edulis in an inflammation model. Journal of Ethnopharmacology 109: 281–288.

    Article  PubMed  Google Scholar 

  43. Chaves, L.S., L.A.D. Nicolau, R.O. Silva, F.C. Barros, A.L. Freitas, K.S. Aragão, R.A. Ribeiro, M.H.L.P. Souza, A.L.R. Barbosa, and J.V.R. Medeiros. 2013. Antiinflammatory and antinociceptive effects in mice of a sulfated polysaccharide fraction extracted from the marine red algae Gracilaria caudata. Immunopharmacology and Immunotoxicology 35: 93–100.

    Article  CAS  Google Scholar 

  44. Sutbeyaz, Y., B. Yakan, H. Ozdemir, M. Karasen, F. Doner, and I. Kufrevioglu. 1996. Effect of SC-41930, a potent selective leukotriene B4 receptor antagonist, in the guinea pig model of middle ear inflammation. Annals of Otology, Rhinology and Laryngology 105: 476–480.

    Article  CAS  Google Scholar 

  45. Cunha, T.M., W.A. Verri Jr., J.S. Silva, S. Poole, F.Q. Cunha, and S.H. Ferreira. 2005. A cascade of cytokines mediates mechanical inflammatory hypernociception in mice. Proceedings of the National academy of Sciences of the United States of America 102: 1755–1760.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Verri Jr., W.A., T.M. Cunha, C.A. Parada, S. Poole, F.Q. Cunha, and S.H. Ferreira. 2006. Hypernociceptive role of cytokines and chemokines: targets for analgesic drug development? Pharmacology and Therapeutics 112: 116–138.

    Article  CAS  PubMed  Google Scholar 

  47. Zarpelon, A.C., T.M. Cunha, J.C. Alves-Filho, L.G. Pinto, S.H. Ferreira, I.B. McInnes, D. Xu, F.Y. Liew, F.Q. Cunha, and W.A. Verri Jr. 2013. IL-33/ST2 signalling contributes to carrageenin-induced innate inflammation and inflammatory pain: role of cytokines, endothelin-1 and prostaglandin E2. British Journal of Pharmacology 169: 90–101.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Collier, H.O., L.C. Dinneen, C.A. Johnson, and C. Schneider. 1968. The abdominal constriction response and its suppression by analgesic drugs in the mouse. British Journal of Pharmacology 32(2): 295–310.

    CAS  Google Scholar 

  49. Duarte, I.D.G., M. Nakamura, and S.H. Ferreira. 1988. Participation of the sympathetic system in acetic acid-induced writhing in mice. Brazilian Journal of Medical and Biological Research 21: 341–343.

    CAS  PubMed  Google Scholar 

  50. Medzhitov, R. 2008. Origin and physiological roles of inflammation. Nature 454: 428–435.

    Article  CAS  PubMed  Google Scholar 

  51. Ikeda, Y., A. Ueno, H. Naraba, and S. Oh-ishi. 2001. Involvement of vanilloid receptor VR1 and prostanoids in the acid-induced writhing responses of mice. Life Science 69: 2911–2919.

    Article  CAS  Google Scholar 

  52. Dubuisson, D., and S.G. Dennis. 1977. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain 4: 161–174.

    Article  CAS  PubMed  Google Scholar 

  53. Eddy, N.B., and D. Leimbach. 1953. Synthetic analgesics. II. Dithienylbutenyl- and dithienylbutylamines. Journal of Pharmacology and Experimental Therapeutics 107: 385–393.

    CAS  PubMed  Google Scholar 

  54. Bhandare, A.M., A.D. Kshirsagar, N.S. Vyawahare, A.A. Hadambar, and V.S. Thorve. 2010. Potential analgesic, anti-inflammatory and antioxidant activities of hydroalcoholic extract of Areca catechu L. nut. Food and Chemical Toxicology 48: 3412–3417.

    Article  CAS  PubMed  Google Scholar 

  55. Zeashan, H., G. Amresh, C.V. Rao, and S. Singh. 2009. Antinociceptive activity of Amaranthus spinosus in experimental animals. Journal of Ethnopharmacology 122: 492–496.

    Article  PubMed  Google Scholar 

  56. Verri Jr., W.A., F.T.M.C. Vicentini, M.M. Baracat, S.R. Georgetti, R.D.R. Cardoso, T.M. Cunha, S.H. Ferreira, F.Q. Cunha, M.J.V. Fonseca, and R. Casagrande. 2012. Flavonoids as anti-inflammatory and analgesic drugs: mechanisms of action and perspectives in the development of pharmaceutical forms. Studies in Natural Products Chemistry 36: 297–322.

    Article  CAS  Google Scholar 

  57. Wang, Z.Q., F. Porreca, S. Cuzzocrea, K. Galen, R. Lightfoot, E. Masini, C. Muscol, V. Mollace, M. Ndengele, H. Ischiropoulos, and D. Salvemini. 2004. A newly identified role for superoxide in inflammatory pain. Journal of Pharmacology and Experimental Therapeutics 309: 869–878.

    Article  CAS  PubMed  Google Scholar 

  58. Kilpatrick, L.E., S. Sun, H. Li, T.C. Vary, and H.M. Korchak. 2010. Regulation of TNF-induced oxygen radical production in human neutrophils: role of delta-PKC. Journal of Leukocyte Biology 87: 153–164.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Feng, L., Y. Xia, G.E. Garcia, D. Hwang, and C.B. Wilson. 1995. Involvement of reactive oxygen intermediates in cyclooxygenase-2 expression induced by interleukin-1, tumor necrosis factor-alpha, and lipopolysaccharide. Journal of Clinical Investigation 95: 1669–1675.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Amirshahrokhi, K., S. Bohlooli, and M.M. Chinifroush. 2011. The effect of methylsulfonylmethane on the experimental colitis in the rat. Toxicology and Applied Pharmacology 253: 197–202.

    Article  CAS  PubMed  Google Scholar 

  61. Pacher, P., J.S. Beckman, and L. Liaudet. 2007. Nitric oxide and peroxynitrite in health and disease. Physiological Reviews 87: 315–424.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

ACKNOWLEDGMENTS

The authors gratefully acknowledge UFPI/CNPq and Research foundation for the state of Piauí—FAPEPI for fellowship support.

Conflict of interest

The authors declare that they have no competing interests.

Author information

Authors and Affiliations

  1. LAFFEX—Laboratory of Experimental Physiopharmacology, Biotechnology and Biodiversity Center Research (BIOTEC), Federal University of Piauí, Parnaíba, 64202-020, PI, Brazil

    Renata Fortes Santiago, Tarcisio Vieira de Brito, Jordana Maia Dias, Genilson José Dias Jr., José Simião da Cruz Jr., Jalles Arruda Batista, Jand-Venes R. Medeiros & André Luiz dos Reis Barbosa

  2. LAFICA—Laboratory of Pharmacology of Inflammation and Cancer, Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, 60430-270, CE, Brazil

    Renan Oliveira Silva, Marcellus H. L. P. Souza & Ronaldo de Albuquerque Ribeiro

  3. Laboratory for Research in Experimental Neurochemistry, Campus Ministro Petrônio Portella, Federal University of Piauí, Teresina, PI, 64049550, Brazil

    Rivelilson M. Freitas

  4. Laboratory Chemistry of Bioactive Natural and Synthetic Products, Federal University of Piauí, Teresina, PI, Brazil

    Stanley Juan Chavez Gutierrez

Authors
  1. Renata Fortes Santiago
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tarcisio Vieira de Brito
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jordana Maia Dias
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Genilson José Dias Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. José Simião da Cruz Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jalles Arruda Batista
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Renan Oliveira Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marcellus H. L. P. Souza
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ronaldo de Albuquerque Ribeiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Stanley Juan Chavez Gutierrez
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Rivelilson M. Freitas
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jand-Venes R. Medeiros
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. André Luiz dos Reis Barbosa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to André Luiz dos Reis Barbosa.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Santiago, R.F., de Brito, T.V., Dias, J.M. et al. Riparin B, a Synthetic Compound Analogue of Riparin, Inhibits the Systemic Inflammatory Response and Oxidative Stress in Mice. Inflammation 38, 2203–2215 (2015). https://doi.org/10.1007/s10753-015-0203-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-015-0203-4

KEY WORDS

Search

Navigation