Alkannins and Shikonins: A new class of wound healing agents

Current Medicinal Chemistry

Volumn 15, Issue 30, 2008, Pages 3248-3267

  Papageorgiou, Vas P ^a   Assimopoulou, A N ^a   Ballis, A C ^a  

^a ARISTOTLE UNIVERSITY OF THESSALONIKI   (Greece)

Author keywords

Alkannin; Anti inflammatory activity; Antibacterial activity; Leprosy; Leprotic ulcer; Natural products; Quinones; Shikonin; Ulcers; Wound healing

Indexed keywords

ACETYLALKANNIN; ACETYLSHIKONIN; ALKANNAN; ALKANNIN; ANGELYLALKANNIN; ANGELYLSHIKONIN; ANHYDROALKANNIN; ANTIOXIDANT; BETA ACETOIXYSOVALERYLALKANNIN; BETA BETA DIMETHYLACRYLALKANNIN; BETA BETA DIMETHYLACRYLSHIKONIN; BETA HYDROXYISOVALERYLALKANNIN; CHEMOKINE RECEPTOR ANTAGONIST; CORTISONE; CYCLOOXYGENASE 2 INHIBITOR; DEOXYALKANNIN; DEOXYALKANNIN DEOXYSHIKONIN; EPOULODERM; FUSIDIC ACID; HELIXDERM; HISTOPLASTIN RED; ISOBUTYLALKANNIN; ISOBUTYLSHIKONIN; LEUKOTRIENE RECEPTOR BLOCKING AGENT; MDS 004; POVIDONE IODINE; SHIKONIN; SHIKONIN DERIVATIVE; TERACRYLALKANNIN; TERACRYLSHIKONIN; TUMOR NECROSIS FACTOR ALPHA INHIBITOR; UNCLASSIFIED DRUG; WOUND HEALING PROMOTING AGENT; NAPHTHOQUINONE;

ANALGESIC ACTIVITY; ANGIOGENESIS; ANTIBACTERIAL ACTIVITY; ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; ANTIVIRAL ACTIVITY; ARTHRITIS; BIOLOGICAL ACTIVITY; BURN; CELL PROLIFERATION; CLINICAL TRIAL; DRUG EFFICACY; DRUG ISOLATION; DRUG MECHANISM; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TARGETING; HUMAN; INFLAMMATORY DISEASE; LEG ULCER; NONHUMAN; PHYTOCHEMISTRY; PLANT ROOT; REVIEW; SKIN INFLAMMATION; SKIN INJURY; SKIN ULCER; WOUND; WOUND HEALING; ANIMAL; CHEMICAL MODEL; CHEMICAL STRUCTURE; CHEMISTRY; COMPUTER SIMULATION; DRUG EFFECT; STEREOISOMERISM;

ANIMALS; COMPUTER SIMULATION; HUMANS; MODELS, CHEMICAL; MOLECULAR STRUCTURE; NAPHTHOQUINONES; STEREOISOMERISM; WOUND HEALING;

EID: 61549085024     PISSN: 09298673     EISSN: None     Source Type: Journal    
DOI: 10.2174/092986708786848532     Document Type: Review

References (153)

1. Papageorgiou, V.P. Naturally Occurring Isohexenylnaphthazarin Pigments: A New Class of Drugs. Planta Medica, 1980, 38, 193-203.
2. Papageorgiou, V.P.; Assimopoulou, A.N.; Couladouros, E.A.; Hepworth, D.; Nicolaou, K.C. Chemistry and Biology of Alkannins, Shikonins and Related Naphthazarin Natural Products. Angew. Chem. Int. Ed., 1999, 38, 270-301.
3. Papageorgiou, V.P.; Assimopoulou, A.N.; Samanidou, V.F.; Papadoyannis, I. Recent advances in chemistry, biology and biotechnology of alkannins and shikonins. Curr. Org. Chem., 2006, 10, 2123-2142.
4. Brockmann, H. Die Konstitution des Alkannins, Shikonins und Alkannans. Justus Liebigs Ann. Chem., 1936, 521, 1-47.
5. Thomson, R.H. Naturally Occurring Quinones, 2nd ed., Academic Press: New York, 1971, pp 248.
6. Thomson, R.H. Naturally Occurring Quinones III, Recent Advances, Chapman & Hall, 1987, pp 219.
7. Weigle, P. Ancient Dyes for Modern Weavers, Watson-Guptil: New York, 1974, pp 50.
8. Translations of the works of Hippocrates by Francis Adams can be found in the Internet Classics Archive. For the use of alkanet, see http://webatomics.com/Classics/Hippocrates/ulcers.10.10.html.
9. Theophrastus, Enquiry into Plants and Minor works on Odours and Weather Signs, Vol. 2 (Translation by A. Hort), Harvard University Press: Cambridge, Massachusetts, 1949, pp 113.
10. Max Wellman (Ed.), P. Dioscorides in De Materia Medica, Vol. IV.23, Berloni Apud Weidmannos: Berlin, 1958, pp 187.
11. Gunther, R.T. The Greek Herbal of Dioscorides, Vol. IV, Hafner: New York, 1968, pp 421.
12. Hyatt, R.; Feldman, R. Chinese Herbal Medicine: Ancient Art and Modern Science, Schocken Books: New York, 1978, pp 17.
13. Read, B. E. Chinese Medicinal Plants from the Pen Ts'ao Kang Mu (AD 1596), 3rd ed., Peking Natural History Bulletin: Peking, 1936, pp 38.
14. Papageorgiou, V.P. Study on the chemical structure of the components of Alkanna tinctoria Tausch. Readership, School of Engineering, Aristotle University of Thessaloniki, Greece, 1976.
15. Papageorgiou, V.P. Wound healing properties of naphthaquinone pigments from Alkanna tinctoria. Experientia, 1978, 34, 1499-1500.
16. Papageorgiou, V.P. A Composition for the Treatment of Skin Conditions and Damage and Process for the preparation thereof. British Patent GB 1574397, January 9, 1978.
17. Curtin, M.E. Harvesting profitable products from plant tissue culture. Biotechnology, 1983, 1, 649-657.
18. Papageorgiou, V.P.; Assimopoulou, A.N.; Samanidou, V.F.; Papadoyannis, I. Analytical methods for the determination of alkannins and shikonins. Curr. Org. Chem., 2006, 10, 583-622.
19. Stadelmann, W.K.; Digenis, A.G.; Tobin, G.R. Physiology and healing dynamics of chronic cutaneous wounds. Am. J. Surg., 1998, 176 (Suppl. 2A), 26S-38S.
20. Valencia, I.C.; Falabella, A.; Kirsner, R.S.; Eaglstein, W.H. Chronic venous insufficiency and venous leg ulceration. J. Am. Acad. Dermatol., 2001, 44, 401-421.
21. Lazarus, G.S.; Cooper, D.M.; Knighton, D.R.; Margolis, D.J.; Pecoraro, R.E.; Rodeheaver, G.; Robson, M.C. Definitions and guidelines for assessment of wounds and evaluation of healing. Arch. Dermatol., 1994, 130, 489-493.
22. Jeffcoate, W.J.; Harding, K.G. Diabetic foot ulcers. Lancet, 2003, 361, 1545-1551.
23. Petrie, N.C.; Yao F.; Eriksson, E. Gene therapy in wound healing. Surg. Clin. North Am., 2003, 83, 194-199.
24. Frykberg, R.G.; Armstrong, D.G.; Giurini, J.; Frykberg, R.G.; Edwards, A; Kravette, M; Kravitz, S.; Ross, C.; Stavosky, J.; Stuck, R.; Vanore, J. Diabetic foot disorders: A clinical practice guideline. American College of Foot and Ankle Surgeons. J. Foot Ankle Surg., 2000, 39(Suppl), S1-60.
25. Harding, K.G.; Morris, H.L.; Patel, G.K. Healing chronic wounds. Br. Med. J., 2002, 324, 160-163.
26. Steed, D.L. Foundations of good ulcer care. Am. J. Surg., 1998, 176 (Suppl A), 20S-25S.
27. Henry, G.; Garner, W.L. Inflammatory mediators in wound healing. Surg. Clin. North Am., 2003, 83, 483-507.
28. Furie, B.; Furie, B.C. Thrombus formation in vivo. J. Clin. Invest., 2005, 115, 3355-3362.
29. Eming, S.A.; Smola, H.; Krieg, T. Treatment of chronic wounds: State of the art and future concepts. Cells Tissues Organs, 2002, 172, 105-117.
30. Douglass, J. Wound bed preparation: A systematic approach to chronic wounds. Br. J. Community Nurs., 2003, 8(Suppl.), S26-34.
31. Williams, J.Z.; Barbul, A. Nutrition and wound healing. Surg. Clin. N. Am., 2003, 83, 571-596.
32. Stadelmann, W.K.; Digenis, A.G.; Tobin, G.R. Impediments to wound healing. Am. J. Surg., 1998, 176 (Suppl 2A), 39S-47S.
33. Mustoe, T. Understanding chronic wounds: A unifying hypothesis on their pathogenesis and implications for therapy. Am. J. Surg., 2004, 187, 65S-70S.
34. Papageorgiou, V.P. Study on the structure of the components of Alkanna tinctoria. Chim. Chron., New Series, 1978, 7, 45-54.
35. Papageorgiou, V.P.; Winkler A.; Sagredos, A.N.; Digenis, G.A. Studies on the relationship of structure to antimicrobial properties of naphthaquinones and other constituents of Alkanna tinctoria. Planta Med., 1979, 35, 56-60.
36. Papageorgiou, V.P.; Mellidis, A.S.; Sagredos, A.N. Study on the antibiotic fraction of Alkanna tinctoria Tausch. Chim. Chron., New Series, 1980, 9, 57-63.
37. Papageorgiou, V.P.; Digenis, G.A. Isolation of two alkannin esters from Alkanna tinctoria. Planta Med., 1980, 39, 81-84.
38. Papageorgiou, V.P. A new pigment of Alkanna tinctoria having naphthaquinone structure. Planta Med., 1977, 31, 390-394.
39. Brokalakis, J.; Kyriakos, J; Sakkis, D; Koumantaki, E; Toska, N.; Stratigos, J.; Kapetanakis, J. Treatment of leg ulcers with HISTOPLASTIN RED®, Archives of "A. Sygros" Hospital, Vol II, Athens, 1979, pp 108.
40. Katsarou, A.; Koumantaki, E.; Athanasiou, T.; Tasoulas, A.; Papageorgiou, M.; Stratigos, I. Healing Action of HELIXDERM®, 2nd Congress of the European Academy of Dermatology and Venerology, Athens, Greece, Oct 1991.
41. Karkanias, G.; Alexandropoulos, N.; Haritopoulos, N. Treatment of fissure-in-ano with HELIXDERM® ointment, 45th Panhellenic Medical Conference, Athens, Greece, November 1991, Book of abstracts, pp 61.
42. Hengge, U.R.; Ruzicka, T.; Schwartz, R.A.; Cork, M.J. Adverse effects of topical glucocorticosteroids. J. Am. Acad. Dermatol., 2006, 54, 1-15.
43. Heiss, F. Die Bestimmung des kontakt-wachstums-index, eine neue methode zur prufung von wasserunloslichen bakteriostaten, Reichstoffe Aromen Korperpflegemittel, 1973, 4, 103.
44. Michaelides, C.; Striglis, C.; Panayiotou, P.; Ioannovich, J. The therapeutic action of Alkanna root extract in the conservative treatment of partial-thickness burn injuries, 5th Mediterranean Burns Club, Athens, Greece, November 1991.
45. Michaelides, C.; Striglis, C.; Panayiotou, P.; Ioannovich, J. The therapeutic action of Alkanna root extract in the conservative treatment of partial-thickness burn injuries, Ann. Medit. Burns Club, Vol VI, March 1993, pp 24-25.
46. Huang, K.F.; Hsu, Y.C.; Lin, C.N.; Tzeng, J.I.; Chen, Y.W.; Wang, J.J. Shiunko promotes epithelization of wounded skin. Am. J. Chinese Med., 2004, 32, 389-396.
47. Tebbe, B.; Aryee-Boi, J.; Orfanos, C.E. Alkanna tinctoria - ein Phytotherapeutikum zur Ulcera-cruris-Therapie, Allergologie, 1998, 21, 390.
48. Wu, L.; Xia, Y.P.; Roth, S.I.; Gruskin, E.; Mustoe, T.A. Transforming growth factor-beta1 fails to stimulate wound healing and impairs its signal transduction in an aged ischemic ulcer model: Importance of oxygen and age. Am. J. Pathol., 1999, 154, 301-309.
49. Bonomo, S.R.; Davidson, J.D.; Tyrone, J.W.; Lin, X.; Mustoe, T.A. Enhancement of wound healing by hyperbaric oxygen and transforming growth factor beta3 in a new chronic wound model in aged rabbits. Arch. Surg., 2000, 135, 1148-1153.
50. Castana, O.; Prokopakis, E.S.Z.; Alexakis, D. The application of an ancient treatment of pressure sores in our days. Poster presented at 10e Conference Nationale des Plaies et Cicatrisations, Paris, France, 15-17/1/2006
51. Papageorgiou, V.P. Structure of the waxes substances of the plant Alkanna tinctoria Tausch. Chem. Chron., 1977, 6, 365-374.
52. Hayashi, M. Pharmacological studies of Shikon and Tooki. (1) Pharmacological effects of the water and ether extracts. Nippon Yakurigaku Zassh, 1977, 73, 177-191.
53. Hayashi, M. Pharmacological studies of Shikon and Tooki. (2) Pharmacological effects of the pigment components, Shikonin and acetylshikonin. Nippon Yakurigaku Zasshi 1977, 73, 193-203.
54. Hayashi, M. Pharmacological studies of Shikon and Tooki. (3) Effect of topical application of the ether extracts and Shiunko on inflammatory reactions. Nippon Yakurigaku Zasshi 1977, 73, 205-214.
55. Ozaki, Y.; Ohno, A.; Abe, K.I.; Saito, Y.; Satake, M. Comparative study on the accelerative effect of "koushikon" and "nanshikon" and their constituents on proliferation of granuloma tissue in rats. Biol. Pharm. Bull., 1993, 16, 683-685.
56. Ozaki, Y.; Ohno, A.; Saito, Y.; Satake, M. Accelerative effect of shikonin, alkannin and acetylshikonin on the proliferation of granulation tissue in rats. Biol. Pharm. Bull., 1994, 17, 1075-1077.
57. Ozaki, Y.; Xing, L.; Satake, M. Accelerative effect of "nanshikon" and its constituents on the proliferation of granulation tissue in rats. Biol. Pharm. Bull., 1996, 19, 233-236.
58. Tanaka, S.; Tajima, M.; Tsukada, M.; Tabata, M. A comparative study on anti-inflammatory activities of the enantiomers, shikonin and alkannin. J. Nat. Prod., 1986, 49, 466-469.
59. Seto, Y.; Motoyoshi, S.; Nakamura, H.; Imuta, J.; Ishitoku, T.; Isayama, S. Effect of shikonin and its derivatives, pentaacetylated shikonin (MDS-004) on granuloma formation and delayed-type allergy in experimental animals. Yakugaku Zassh, 1992, 112, 259-271.
60. Lin, Z.-B.; Chai, B.-L.; Wang, P.; Guo, Q.-X.; Lu, F.-S.; Xiang, G.-Q. Studies on the anti-inflammatory effect of chemical principle of Zi-Cao Arnebia euchroma (Royle) Johnst.]. Pei-ching I Hsueh Yuan Hsueh Pao, 1980, 12, 101-106.
61. Lin, Z.-B.; Wang, P.; Ruan, Y.; Guo, Q.-X. Anti-inflammatory effect of beta, beta-dimethylacrylshikonin. Acta Pharmacol. Sin. 1980, 1, 60-63.
62. Singh, B.; Sharma, M.K.; Meghwal, P.R.; Sahu, P.M.; Singh, S. Anti-inflammatory activity of shikonin derivatives from Arnebia hispidissima. Phytomedicine, 2003, 10, 375-380.
63. Singh, B.; Sahu, P.M.; Jain, S.C.; Singh, S. Estimation of naphthaquinones from Arnebia hispidissima (Lehm.) DC. In vivo and in vitro. I. Anti-inflammatory screening. Phytother. Res., 2004, 18, 154-159.
64. Tsioli, V.; Karayannopoulou, M.; Loukopoulos, P.; Anagnostou, T.; Kaldrymidou, E. Evaluation of the effect of Alkanna tinctoria extracts on wound healing in the dog. Proceeding of the European Veterinary Conference Voorjaarsdagen, Amsterdam, The Netherlands, 2008, pp 259.
65. Bhakuni, D.S.; Dhar, M.L.; Dhar, M.M.; Dhawn, B.N.; Mehrotra, B.N. Screening of Indian plants for biological activity. II. Indian J. Exp. Biol., 1969, 7, 250-262.
66. Kyogoku, K.; Terayama, H.; Tachi, Y.; Suzuki, T.; Komatsu, M. Constituents of Shikon. II. Comparison of contents, constituents, and antibacterial effect of fat soluble fraction between Nanshikon and Koshikon Shoyakugaku Zasshi, 1973, 27, 24-31.
67. Tanaka, Y.; Odani, T. Pharmacodynamic study on Shiunko. I. Antibacterial effect of Shiunko. Yakugaku Zasshi, 1972, 92, 525-530.
68. Kyogoku, K.; Terayama, H.; Tachi, Y.; Suzuki, T.; Komatsu, M. Constituents of shikon. II. Comparison of contents, constituents, and antibacterial effect of fat soluble fraction between nanshikon and koshikon. Shoyakugaku Zasshi, 1973, 27, 31-36.
69. Tanaka, Y.; Odani, T.; Kanaya, T. Pharmacodynamic study of Shiunko. II. Extractive condition of Shikon in making Shiunko. Shoyakugaku Zasshi, 1974, 28, 173-178.
70. Tabata, M.; Mizukami, H.; Naoe, S.; Konoshima, M. Antimicrobial activity of Lithospermum erythrorhizon callus cultures. Yakugaku Zasshi, 1975, 95, 1376-1379.
71. Shukla, Y.N.; Tandon, J.S.; Bhakuni, D.S.; Dhar, M.M. Chemical constituents of the antibiotic fraction of Arnebia nobilis. Experientia, 1969, 25, 357-358.
72. Shukla, Y.N.; Tandon, J.S.; Bhakuni, D.S.; Dhar, M.M. Naphthaquinones of Arnebia nobilis. Phytochem., 1971, 10, 1909-1915.
73. Fujii, N.; Yamashita, Y.; Arima, Y.; Nagashima, M.; Nakano, H. Induction of topoisomerase II-mediated DNA cleavage by the plant naphthoquinones plumbagin and shikonin. Antimicrob. Agents Chemother., 1992, 36, 2589-2594.
74. Tabata, M.; Tsukada, M.; Fukui, H. Antimicrobial activity of quinone derivatives from Echium lycopsis callus cultures. Planta Med., 1982, 44, 234-236.
75. Liu, M.; Ohuchi, T.; Ieiri, T.; Ohe, M.; Matsuzaki, S. Shikonin has potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Dokkyo J. Med. Sci., 1996, 23, 63-69.
76. Shen, C.C.; Syu, W.J.; Li, S.Y.; Lin, C.H.; Lee, G.H.; Sun, C.M. Antimicrobial activities of naphthazarins from Arnebia euchroma. J. Nat. Prod., 2002, 65, 1857-1862.
77. Sekine, T.; Kojima, K.; Sasaki, S.; Matsumoto, T.; Yamamoto, T.; Maitani, Y.; Nagai, T. Evaluation of antibacterial effect of shikonin ointment against methicillin-resistant Staphylococcus aureus. S.T.P. Pharma Sci., 1998, 8, 255-259.
78. Ozgen, U.; Houghton, P.J.; Ogundipe, Y.; Coskun, M. Antioxidant and antimicrobial activities of Onosma argentatum and Rubia peregrine. Fitoterapia, 2003, 74, 682-685.
79. Rajbhandari, M.; Schoepke, Th.; Mentel, R.; Lindequist, U. Anti-bacterial and antiviral naphthazarins from Maharanga bicolour. Pharmazie, 2007, 62, 633-635.
80. Naz, S.; Ahmad, S.; Ajaz Rasool, S.; Asad Sayeed, S.; Siddiqi, R. Antibacterial activity directed isolation of compounds from Onosma hispidum. Microbiol. Res., 2006, 161, 43-48.
81. Kuo, H.M.; Hsia, T.C.; Chuang, Y.C.; Lu, H.F.; Lin, S.Y.; Chung, J.G. Shikonin inhibits the growth and N-acetylation of 2-aminofluorene in Helicobacter pylori from ulcer patients. Anticancer Res., 2004, 24, 1587-1592.
82. Karyagina, T.B.; Arzumanyan, V.G.; Timchenko, T.V.; Bairamashvili, D.I. Antimicrobial activity of shikonin preparations. Pharmaceut. Chem. J., 2001, 35, 435-436.
83. Sasaki, K.; Yoshizaki, F.; Abe, H. The anti-Candida activity of Shikon Yakugaku Zasshi, 2000, 120, 587-589.
84. Wahab, S.; Tandon, R.N.; Jacob, Z.; Chandra, B.; Srivastava, O.P. Comparative in vitro and in vivo effect of lactones and arnebins on Trichophyton mentagrophytes and Candida albicans. Indian J. Med. Res., 1982, 76S, 77-82.
85. Sasaki, K.; Abe, H.; Yoshizaki, F. In vitro antifungal activity of naphthoquinone derivatives.Biol. Pharm. Bull., 2002, 25, 669-670.
86. Meazza, G.; Dayan, F.E.; Wedge, D.E. Activity of quinones on Colletotrichum species. J. Agric. Food Chem., 2003, 51, 3824-3828.
87. Li, C.; Fukishi, Y.; Kawabata, J.; Tahara, S.; Mizutani, J.; Uyeda, I. Antiviral and antifungal activities of some naphthoquinones isolated from the roots of Lithospermum erythrorhizon. Nippon Noyaku Gakkaishi, 1998, 23, 54-57.
88. Shcerbanovskii, L.R.; Nilov, G.I.; Rabinovich, Z.D.; Gorina, V.A. Plant naphthoquinones as inhibitors of yeasts as well as lactic acid and acetic acid bacteria. Rast. Resur., 1972, 8, 112-115.
89. Sherbanivs'kii, L.P. Presence of the shikonin in some species of the family Boraginaceae and its effect on lactic acid bacteria. Ukr. Bot. Zh. 1971, 28, 504-508.
90. Shcherbanivs'kii, L.R.; Luks, Iu A.; Kapelev, I.G. Study of the antimicrobial effect of higher plants on lactic acid bacteria. Mikrobiol. Zh. (Kiev), 1975, 37, 629-634.
91. Shcherbanovskii, L.R. Study of the antimicrobial activity of higher plants with respect to yeasts and lactic acid bacteria. Fitontsidy: Rol Biogeotsenozakh, Znach. Med. Mater. Soveshch. (Kiev, USSR) 1979, 121-126.
92. Rubinchik, M.A. Antiamoebic properties of shikonin. Abstr. Pap. Mater. Vses. Konf. Issled. Lek. Rast. Perspekt. Ikh Isol'z Proivod. Lek. Prep. (Bittsa, USSR) 1970, pp 236-237.
93. Greenberg, E.P.; Banin, E. In Control of Biofilm Infections by Signal Manipulation, Balaban N., Ed.; Springer: New York, 2007; Vol. 2, pp 141-156.
94. Bjarnsholt, T.; Kirketerp-Møller, K.; Jensen, P.Ø.; Madsen, K.G.; Phipps, R.; Krogfelt, K.; Høiby, N.; Givskov, M. Why chronic wounds will not heal: A novel hypothesis. Wound Repair and Regeneration, 2008, 16, 2-10.
95. Sekine, T.; Masumizu, T.; Maitani, Y.; Takayama, K.; Kohno, M.; Nagai, T. Effect of Shikonin and Alkannin on hydroxyl radical generation system concerned with iron ion. Yakugaku Zasshi, 1998, 118, 609-615.
96. Gao, D.; Kakuma, M.; Oka, S.; Sugino, K.; Sakurai, H. Reaction of beta-alkannin (shikonin) with reactive oxygen species: Detection of beta-alkannin free radicals. Bioorg. Med. Chem., 2000, 8, 2561-2569.
97. Sekine, T.; Masumizu, T.; Maitani, Y.; Nagai, T. Evaluation of superoxide anion radical scavenging activity of shikonin by electron spin resonance. Int. J. Pharm., 1998, 174, 133-139.
98. Chen, X.; Yang, L.; Zhang, N.; Turpin, J.A.; Buckheit, R.W.; Osterling, C.; Oppenheim, J.J.; Howard, O.M. Shikonin, a component of chinese herbal medicine, inhibits chemokine receptor function and suppresses human immunodeficiency virus type 1. Antimicrob. Agents and Chemother., 2003, 47, 2810-2816.
99. Dannenberg, A.J.; Subbaramaiah, K. Treatment of HPV caused diseases. U.S. Patent 2002 0164385, November 7, 2002.
100. Zhuravlev, J.U.N.; Fedoreev, S.A.; Bulgakov, V.P.; Muzarok, T.I.; Beresneva, N.V.; Golovko, E.I. Anti-inflammatory and antibacterial agent "Maslo shikoninovoe". Patent RU2141840, November 27, 1999.
101. Kundakovic, T.; Fokialakis, N.; Dobric, S.; Pratsinis, H.; Kletsas, D.; Kovacevic, N.; Chinou, I. Evaluation of the anti-inflammatory and cytotoxic activities of naphthazarine derivatives from Onosma leptantha. Phytomedicine, 2006, 13, 290-294.
102. Omkar, M.; Jeeja, T.; Chhaya, G. Evaluation of Anti-inflammatory activity of Nyctanthes arbor-tristis and Onosma echioides. Pharmacognosy Magazine, 2006, 2, 258-260.
103. Locksley, R.M.; Killeen, N.; Lenardo, M.J. The TNF and TNF receptor superfamilies: Integrating mammalian biology. Cell, 2001, 104, 487-501.
104. Chiu, S.C.; Yang, N.S. Inhibition of tumor necrosis factor-alpha through selective blockade of Pre-mRNA splicing by shikonin. Mol. Pharmacol., 2007, 71, 1640-1645.
105. Feldmann, M.; Maini, R.N. Anti-TNF alpha therapy of rheumatoid arthritis: What have we learned? Annu Rev. Immunol., 2001, 19, 163-196.
106. Palladino, M.A.; Bahjat, F.R.; Theodorakis, E.A.; Moldawer, L.L. Anti-TNF-alpha therapies: The next generation. Nat. Rev. Drug Discover., 2003, 2, 736-746.
107. Scottelius, A.J.; Moldawer, L.L.; Dinarello, C.A.; Asaduallah, K.; Sterry, W.; Edwards, C.K. 3rd. Biology of tumor necrosis factor-alpha-implications for psoriasis. Exp. Dermatol., 2004, 13, 193-222.
108. Elliot, M.J.; Maini, R.N.; Feldmann, M.; Long-Fox, A.; Charles, P.; Katasikis, P.; Brennan, F.M.; Bijl, H.; Ghrayeb, J.; Woody, J.N. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum., 2008, 58(Suppl), S92-S101.
109. Subbaramaiah, K.; Bulic, P.; Lin Y.; Dannenberg, A.J.; Pasco, D.S. Development and use of a gene promoter-based screen to identify novel inhibitors of cyclooxygenase-2 transcription. J. Biomol. Screening, 2001, 6, 101-110.
110. Staniforth, V.; Wang, S.Y.; Shyur, L.F.; Yang, N.S. Shikonins, phytocompounds from Lithospermum erythrorhizon, inhibit the transcriptional activation of human Tumor Necrosis Factor {alpha} promoter in vivo. J. Biol. Chem., 2004, 279, 5877-5885.
111. Staniforth, V.; Chiu, L.T.; Yang, N.S. Transcriptional Repression by Shikonin Involves Inactivation of TATA Box-binding Protein In Vivo. Poster, Biochemical Society Annual Symposium, BioScience, Glasgow. 18-22 July, 2004.
112. 4 biosynthesis, Yaoxe Xuebao, 1994, 29, 161-165.
113. Futagami, A.; Ishizaki, M.; Fukuda, Y.; Kawana, S.; Yamanaka, N. Wound healing involves induction of cyclooxygenase-2 expression in rat skin. Lab Invest., 2002, 82, 1503-1513.
114. Wilgus, T.A.; Vodovotz, Y.; Vittadini, E.; Clubbs, E.A.; Oberyszyn, T.M.; Reduction of scar formation in full-thickness wounds with topical celecoxib treatment. Wound Repair Regen., 2003, 11, 25-34.
115. Lim, E.S.; Rhee, Y.H.; Park, M.K.; Shim, B.S.; Ahn, K.S.; Kang, H.; Yoo, H.S.; Kim, S.H. DMNQ S-64 induces apoptosis via caspase activation and cyclooxygenase-2 inhibition in human nonsmall lung cancer cells. Ann. N. Y. Acad. Sci., 2007, 1095, 7-18.
116. Carlson, M.L.; Wilson, E.T.; Prescott, S.M. Regulation of COX-2 transcription in a colon cancer cell line by Pontin52/TIP49a. Molecular Cancer, 2003, 2, 42-46.
117. Wang, S.C.; Lien, H.C.; Xia, W.; Chen, I.F.; Lo, H.W.; Wang, Z.; Ali-Seyed, M.; Lee, D.F.; Bartholomeusz, G.; Ou-Yang, F.; Giri, D.K.; Hung, M.C. Binding at and transactivation of COX-2 promoter by nuclear tyrosine kinase receptor ErbB2. Cancer Cell, 2004, 6, 251-261.
118. Telliez, A.; Furman, C.; Pommery, N.; He nichart, J.P. Mechanisms leading to COX-2 expression and COX-2 induced tumorigenesis: Topical therapeutic strategies targeting COX-2 expression and activity. Anti-Cancer Agents in Medicinal Chemistry, 2006, 6, 187-208.
119. Chen, X.; Oppenheim, J.; Howard, O.M. Shikonin, a component of antiinflammatory Chinese herbal medicine, selectively blocks chemokine binding to CC chemokine receptor-1. Int. Immunopharmacol., 2001, 1, 229-236.
120. Chen, X.; Yang, L.; Oppenheim, J.J.; Howard, O.M.Z. Cellular pharmacology studies of shikonin derivatives. Phytother. Res., 2002, 16, 199-209.
121. Donlon, T.A.; Krensky, A.M.; Wallace, M.R.; Collins, F.S.; Lovett, M.; Clayberger, C. Localization of a human T-cell-specific gene, RANTES (D17S136E), to chromosome 17q11.2-q12. Genomics, 1990, 6, 548-553.
122. Maghazachi, A.A.; Al-Aoukaty, A.; Schall, T.J. CC chemokines induce the generation of killer cells from CD56+ cells. Eur. J. Immunol. 1996, 26, 315-319.
123. Schall, T.; Bacon, K.; Camp, R.D.; Kaspari, J.W.; Goeddel, D.V. Human macrophage inflammatory protein alpha (MIP-1 alpha) and MIP-1 beta chemokines attract distinct populations of lymphocytes. J. Exp. Med., 1993, 177, 1821-1826.
124. Taub, D.D.; Conlon, K.; Lloyd, A.R.; Oppenheim, J.J.; Kelvin, D.J. Preferential migration of activated CD4+ and CD8+ T cells in response to MIP-1 alpha and MIP-1 beta. Science, 1993, 260, 355-358.
125. Maghazachi, A.A.; al-Aoukaty, A.; Schall, T.J. C-C chemokines induce the chemotaxis of NK and IL-2-activated NK cells. Role for G proteins. J. Immunol., 1994, 153, 4969-4977.
126. Fahey 3rd, T.J.; Tracey, K.J.; Tekamp-Olson, P.; Cousens, L.S.; Jones, W.G.; Shires, G.T.; Cerami, A.; Sherry, B. Macrophage inflammatory protein 1 modulates macrophage function. J. Immunol., 1992, 148, 2764-2769.
127. Rot, A.; Krieger, M.; Brunner, T.; Bischoff, S.C.; Schall, T.J.; Dahinden, C.A. RANTES and macrophage inflammatory protein 1 alpha induce the migration and activation of normal human eosinophil granulocytes. J. Exp. Med., 1992, 176, 1489-1495.
128. Kourounakis, A.P.; Assimopoulou, A.N.; Papageorgiou, V.P.; Gavalas, A.; Kourounakis, P.N. Alkannin and Shikonin: Effect on free radical processes and on inflammation. A preliminary pharmacochemical investigation. Arch. Pharm. Pharm. Med. Chem., 2002, 335, 262-266.
129. Klebanoff, S.J. In Inflammation, Basic Principles and Clinical Correlates, Gallin, J.I.; Snyderman, R., Ed.; Lippincott Williams & Wilkins: Philadelphia, 1999; pp. 721-768.
130. Leto, T.L. In Inflammation, Basic Principles and Clinical Correlates, Gallin, J.I.; Snyderman, R., Ed.; Lippincott Williams & Wilkins: Philadelphia, 1999; pp. 769-786.
131. Yamamoto, S. "Enzymatic" lipid peroxidation: Reactions of mammalian lipoxygenases. Free Radic. Biol. Med., 1991, 10, 149-159.
132. Landino, L.; Crews, B.; Timmons, M.; Morrow, J.D.; Marnett, L.J. Peroxynitrite, the coupling product of nitric oxide and superoxide, activates prostaglandin biosynthesis. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 15069-15074.
133. Sahnoun, Z.; Jamoussi, K.; Zeghal, K.M. Free radicals and antioxidants: physiology, human pathology and therapeutic aspects. Therapie, 1998, 53, 315-339.
134. Juranek, I.; Suzuki, H.; Yamamoto, S. Affinities of various mammalian arachidonate lipoxygenases and cyclooxygenases for molecular oxygen as substrate. Biochim. Biophys. Acta, 1999, 1436, 509-518.
135. Juranek, I.; Rekalov, V. Oxygenation of arachidonic acid under hypoxic conditions: Some methodological aspects and possible biological relevance. Biologia, Bratislava, 2000, 55 (Suppl.), 49-53.
136. Juranek, I.; Bauer, V.; Donnerer, J.; Lembeck, F.; Peskar, B.A. Severe hypoxia inhibits prostaglandin I2 biosynthesis and vasodilatory responses Induced by ionophore A23187 in the isolated rabbit ear. Pharmacology, 2002, 66, 199-205.
137. Assimopoulou, A.N.; Boskou, D.; Papageorgiou, V.P. Antioxidant activities of alkannin, shikonin and Alkanna tinctoria root extracts in oil substrates. Food Chem., 2004, 87, 433-438.
138. Assimopoulou, A.N.; Papageorgiou, V.P. Radical scavenging activity of Alkanna tinctoria root extracts and their main constituents, hydroxynaphthoquinones. Phytother. Res., 2005, 19, 141-147.
139. Nishizawa, M.; Kohno, M.; Nishimura, M.; Kitagawa, A.; Niwano, Y. Presence of peroxyradicals in cigarette smoke and the scavenging effect of shikonin, a naphthoquinone pigment. Chem. Pharm. Bull. (Tokyo), 2005, 53, 796-799.
140. Han, J.; Weng, X.; Kaishun, B. Antioxidants from a Chinese medicinal herb - Lithospermum erythrorhizon. Food Chem., 2008, 106, 2-10.
141. Kabe, Y.; Ando, K.; Hirao, S.; Yoshida, M.; Handa, H. Redox regulation of NF-κB activation: Distinct redox regulation between the cytoplasm and the nucleus. Antioxid. Redox Signal., 2005, 7, 395-403.
142. Pantano, C.; Reynaert, N.L.; van der Vliet, A.; Janssen-Heininger, Y.M. Redox-sensitive kinases of the nuclear factor-κB signaling pathway. Antioxid. Redox Signal., 2006, 8, 1791-1806.
143. Min, R.; Tong, J.; Wenjun, Y.; Wenhu, D.; Xiaojian, Z.; Jiacai, H.; Jian, Z.; Wantao, C.; Chenping, Z. Growth inhibition and induction of apoptosis in human oral squamous cell carcinoma Tca-8113 cell lines by shikonin was partly through the inactivation of NF-κ-B pathway. Phytother. Res., 2008, 22, 407-415.
144. Chung, H.S.; Kang, M.; Cho, C.; Park, S.; Kim, H.; Yoon, Y.S.; Kang, J.; Shin, M.K.; Hong, M.C.; Bae, H. Inhibition of lipopoly-saccharide and interferon-gamma-induced expression of inducible nitric oxide synthase and tumor necrosis factor-alpha by Lithospermi radix in mouse peritoneal macrophages. J. Ethnopharmacol., 2005, 102, 412-417.
145. Choi, W.H.; Hong, S.S.; Lee, S.A.; Han, X.H.; Lee, K.S.; Lee, M.K.; Hwang, B.Y.; Ro, J.S. Monoamine oxidase inhibitory naphthoquinones from the roots of Lithospermum erythrorhizon. Arch. Pharm. Res., 2005, 28, 400-404.
146. Kang, J.J.; Lee, P.J.; Chen, Y.J.; Lee, C.C.; Li, C.H.; Cheng, H.W.; Cheng, Y.W. Naphthazarin and methylnaphthazarin cause vascular dysfunction by impairment of endothelium-derived nitric oxide and increased superoxide anion generation. Toxicol. In Vitro, 2006, 20, 43-51.
147. Sakaguchi, I.; Tsujimura, M.; Ikeda, N.; Minamino, M.; Kato, Y.; Watabe, K.; Yano, I.; Kaneda, K. Granulomatous tissue formation of shikon and shikonin by air pouch method. Biol. Pharm. Bull., 2001, 24, 650-655.
148. Sidhu, G.S; Singh, A.K.; Banaudha, K.K.; Gaddipati, J.P.; Patnaik, G.K.; Maheshwari, R.K. Arnebin-1 accelerates normal and hydrocortisone-induced impaired wound healing. J. Invest. Dermatol., 1999, 113, 773-781.
149. Mani, H.; Sidhu, G.S.; Singh, A.K.; Gaddipati, J.; Banaudha, K.K.; Raj, K.; Maheshwari, R.K. Enhancement of wound healing by Shikonin analogue 93/637 in normal and impaired healing. Skin Pharmacol. Physiol., 2004, 17, 49-56.
150. Pei, X.W.; Wang, K.Z.; Song, J.H.; Wang, Q.; Shi, Z.B.; Gao, D.F. Arnebia root oil promotes histological change and up-regulates bFGF and it's mRNA expression in the raw surface of the rabbits. Zhongguo Zhong Yao Za Zhi, 2006, 31, 336-339.
151. Pei, X.W.; Wang, K.Z.; Dang, X.Q.; Song, J.H.; Shi, Z.B.; Gao, D.F. Arnebia root oil promotes wound healing and expression of basic fibroblast growth factor on the wound surface in rabbits. Zhong Xi Yi Jie He Xue Bao., 2006, 4(1), 52-55.
152. Ozgen, U.; Ikbal, M.; Hacimuftuoglu, A.; Houghton, P.J.; Gocer, F.; Dogan, H.; Coskun, M. Fibroblast growth stimulation by extracts and compounds of Onosma argentatum roots. J. Ethnopharmacol., 2006, 104, 100-103.
153. Lu, P.J..; Yang, C.; Lin, C.N.; Li, C.F.; Chu, C.C..; Wang, J.J..; Chen, J.Y. Shiunko and acetylshikonin promote reepithelialization, angiogenesis, and granulation tissue formation in wounded skin. Am. J. Chin. Med., 2008, 36, 115-123.