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The Pharmaceutical Society of Korea (대한약학회)
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Biological Significance of Essential Fatty Acids/Prostanoids/Lipoxygenase-Derived Monohydroxy Fatty Acids in the Skin

  • Ziboh, Vincent-A. (Department of Dermatology, University of California Davis) ;
  • Cho, Yunhi (Department of Dermatology, University of California Davis) ;
  • Mani, Indu (Department of Dermatology, University of California Davis) ;
  • Xi, Side (Department of Dermatology, University of California Davis)
  • Published : 2002.12.01
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Abstract

The skin displays a highly active metabolism of polyunsaturated fatty acids (PUFA). Dietary deficiency of linoleic acid (LA), an 18-carbon (n-6) PUFA, results in characteristic scaly skin disorder and excessive epidermal water loss. Although arachidonic acid (AA), a 20-carbon (n6) PUFA, is metabolized via cyclooxygenase pathway into predominantly prostaglandin $E_2(PGE_2)$ and $PGF_{2{\alpha}}$, the metabolism of AA via the 15-lipoxygenase (15-LOX) pathway, which is very active in skin epidermis and catalyzes the transformation of M into predominantly 15S-hydroxyeicosatetraenoic acid (15S-HETE). Additionally, the 15-LOX also metabolizes the 18-carbon LA into 13S-hydroxyoctadecadienoic acid (13S-HODE), respectively. Interestingly, 15-LOX catalyzes the transformation of $dihomo-{\gamma}-linolenic$ acid (DGLA), derived from dietary gamma-linolenic acid, to 15S-hydroxyeicosatrienoic acid (15S-HETrE). These monohydroxy fatty acids are incorporated into the membrane inositol phospholipids which undergo hydrolytic cleavage to yield substituted-diacylglycerols such as 13S-HODE-DAG from 13S-HODE and 15S-HETrE-DAG from 15S-HETrE. These substituted-monohydroxy fatty acids seemingly exert anti-inflammatory/antiproliferative effects via the modulation of selective protein kinase C as well as on the upstream/down-stream nuclear MAP-kinase/AP-1/apoptotic signaling events.

Keywords

References

  1. Andel son, K. M., Seed, T., Vos, M., Mulshine, J., Meng, J., Alnlfai, W., Ou D., Harris, J. E., 5-Lipoxygenase inhibitors reduce PC-3 cell proliferation and initiate non-necrotic cell death. Prostate, 37, 161-173 (1998) https://doi.org/10.1002/(SICI)1097-0045(19981101)37:3<161::AID-PROS5>3.0.CO;2-D
  2. Aron, H., Uber den Nahwert (On the nutritional value). Biochem. Z., 92, 211-233 (1919)
  3. Baker D G., Krakauer, K. A, Tate, G. A, Laposata, M., Zurier, R. B., Suppression of human synovial cell proliferation by diholmo-y-Iinolenic acid. Arthritis Rheum., 32, 1273-1281 (1939) https://doi.org/10.1002/anr.1780321013
  4. Bauer F. W., van de Kerkhof, P. C. M., Maassen-De, Grood R. M., Epidermal hyperproliferation following the induction of mlcroa bcesses by leukotriene $B_{4}$. Br. J. Dermatol., 114, 409-412 (1986) https://doi.org/10.1111/j.1365-2133.1986.tb02843.x
  5. Berra, E., Diaz-Meco, M. T., Lozano, J., Frutos, S., Municio, M. M., Sanches, P., Sanz, L., Moscat, J., Evidence for a role of MEK and MAPK during signal transduction by protein kinase zeta. EMBO J., 14, 6157-6163 (1995)
  6. Brenner, R. R., The oxidative desaturation of unsaturated fatty acids in animals. Molec. Cell Biochem., 3, 41-52 (1974) https://doi.org/10.1007/BF01660076
  7. Brain, S., Camp, R, Dowd, P., Black, A. K., Greaves, M. W., The release of leukotriene $B_{4}$-like material in biologically active amounts from the lesional skin of patients with psoriasis. J. Invest. Dermatol., 83, 70-73 (1986) https://doi.org/10.1111/1523-1747.ep12261712
  8. Bowser, P. A, Nugteren, D. H., White, R. J., Houtsmuller, U. M. T., Prottey, C., Identification, isolation, and Characterization of epidermal lipids containing linoleic acid. Biochim. Biophys. Acta, 834, 419-428 (1985) https://doi.org/10.1016/0005-2760(85)90016-5
  9. Buckman, S. Y, Gresham, A, Hale, P., Hruza, G., Anast, J., Masferrer, J., Pentland, A. P., COX-2 expression is induced by UVB exposure in human skin: Implications for the development of skin cancer. Carcinogenesis, 19, 723-729 (1998) https://doi.org/10.1093/carcin/19.5.723
  10. Brash, A R, Baertschi, S. W., Ingram, C. D., Harris, T. M., On non-cyclooxygenase prostaglandin synthesis in the sea whip coral, Plexaura homonalla: an 8(R)-lipoxygenase pathway leads to formation of an alpha-keto and a Racemic prostanoid. J. Biol. Chem., 262, 15829-15839 (1987)
  11. Bundy, G. L., Nidy, E. G., Epps, D. E., Mizsak, S. A, Wnuk, R. J., Discovery of an arachidonic acid C-8 lipoxygenase in the gorgonian coral Pseudoplexaura porosa. J. Biol. Chem., 261, 747-751 (1986)
  12. Burr, G. O., Burr, M. M., A new deficiency disease produced by the rigid exclusion of fat from the diet. J. Biol. Cnem., 82, 345-356 (1929)
  13. Burr, G. O., Burr, M. M., On the nature of the fatty acids essential in nutrition. J. Biol. Chem., 86, 587-621 (1930)
  14. Burr, G. O., Brown, J. B., Kass, J. P., Lundberg, W. 0., Comparative curative values of unsaturated fatty acids in fat deficiency. Proc. Soc. Exp. Bioi. Med., 44, 242-245 (1940) https://doi.org/10.3181/00379727-44-11416
  15. Burrall, B. A., Wintraub, B. U., Goetz, E. J., Selective expression of 15-lipoxygenase activity by cultured human keratinocytes. Biochem. Biophys. Res. Commun., 133, 208-211 (1985) https://doi.org/10.1016/0006-291X(85)91862-5
  16. Camp, R. D., Mallet, A. L., Woollard, P. M., Brain, S. D., Black, A. K., Greaves MW. The identification of hydroxy fatty acids in psoriatic skin. Prostaglandins, 26, 431-447 (1983) https://doi.org/10.1016/0090-6980(83)90178-8
  17. Camp, R. D., Jones, R. R., Brain, S., Woollard, P. M., Greaves, M. W., Production of intraepidermal microabcesses by topical application of leukotriene $B_{4}$. J. Invest. Dermatol., 82, 202-204 (1984) https://doi.org/10.1111/1523-1747.ep12259945
  18. Chan, C. C., Duhamel, L., Ford-Hutchinson, A., Leukotriene $B_{4}$ and 12-hydroxyeicosatetraenoic acid stimulate epidermal proliferation in vivo in the guinea pig. J. Invest. Dermatol., 85, 333-334 (1985) https://doi.org/10.1111/1523-1747.ep12276933
  19. Chapkin, R. S., Ziboh, V. A., Inability of skin enzyme preparation to biosynthesize arachidonic acid from linoleic acid. Biochem. Biophys. Res. Comm., 124, 784-792 (1984) https://doi.org/10.1016/0006-291X(84)91026-X
  20. Chapkin, R. S., Ziboh, V. A., Marcelo, C. L., Voorhees, J. J., Metabolism of essential fatty acids by human epidermal preparations: Evidence of chain elongation. J. Lipid Res., 27, 945-954 (1986)
  21. Cho, Y., Ziboh, V. A., Incorporation of 13-hydroxyoctadecadienoic acid (13-HODE) into epidermal ceramides and phospholipids: phospholipase C-catalyzed release of novel 13-HODE-containing diacylglycerol. J. Lipid Res., 35, 255-262 (1994)
  22. Cho, Y., Ziboh, V. A., Expression of protein kinase C isozymes in guinea pig epidermis: Selective inhibition of PKC..$\beta$ activity by 13-hydroxyoctadecadienoic acid-containing diacylglycerol, J. Lipid Res., 35, 913-921 (1994)
  23. Cho, Y., Ziboh, V. A., Nutritional modulation of skin hyperproliferation in essential fatty acid-deficiency is associated with selective down-regulation of protein kinase C-$\beta$. J. Nuir., 125, 744-2750 (1995)
  24. Cho, Y., Ziboh, V. A., A novel 15-hydroxyeicosatrienoic acid substituted diacylglycerol (15-HETrE-DAG) selectively inhibits epidermal protein kinase C-$\beta$. Biochim. Biophys. Acta, 1349, 67-71 (1997) https://doi.org/10.1016/S0005-2760(97)00144-6
  25. Crofford, L., COX-1 and COX-2 tissue expression: implications and predictions. J. Rheumatol., 24(suppI49), 15-19 (1997)
  26. Cunningham, F. M., Woollard, P. M., Camp, R. D. R, Proinflammatory properties of unsaturated fatty acids and their monohydroxy metabolites. Prostaglandins, 30, 497-510 (1985) https://doi.org/10.1016/0090-6980(85)90122-4
  27. Czarnetski, B. M., Rosenbach, T., Chemotaxis of human neutrophils and eosinophils towards leukotriene $B_{4}$ and its 20-omega-oxidation products in vitro. Prostaglandins, 31, 851-858 (1986) https://doi.org/10.1016/0090-6980(86)90018-3
  28. Ding, X. Z., Iversen, P., Cluck, M. W., Knezetic, J. A., Adrian, T. E., Lipoxygenase inhibitors abolish proliferation of human pancreatic cancer cells. Biochem. Biophys. Res. Commun., 261, 218-223 (1999) https://doi.org/10.1006/bbrc.1999.1012
  29. Duell, E. A., Ellis, C. N., Voorhees, J. J., Determination of 5, 12 and 15-lipoxygenase products in keratomed biopsies of normal and psoriatic skin. J. Invest. Dermatol., 91, 446-450 (1988) https://doi.org/10.1111/1523-1747.ep12476562
  30. Elias, P. M., Brown, B. E., Fritsch, P., Goerke, J., Gray, G. M., White, R. J., Localization and composition of lipids in neonatal mouse stratum granulosum and stratum corneum. J. Invest. Dermatol., 73, 339-348 (1979) https://doi.org/10.1111/1523-1747.ep12550377
  31. Fogh, K., Sogaard, H., Herlin, T., Kragballe, K., Improvement of psoriasis vulgaris after intralesional injections of 15-hydroxy-eicosatetraenoic acid (15-HETE). J. Am. Acad. Dermatol., 18, 279-285 (1988) https://doi.org/10.1016/S0190-9622(88)70040-7
  32. Fujiwara, Y., Okayasu, T., Ishibashi, T., Imai, Y., Immunological evidence for the enzymatic difference of $\Delta^{6}$-desaturase from -$\Delta^{9}$-and $\Delta^{5}$-desaturase in rat liver microsomes. Biochem. Biophys. Res. Comm., 110, 36-41 (1983) https://doi.org/10.1016/0006-291X(83)91256-1
  33. Gierse, J. K., McDonald, J. J., Hauser, S. D., Rangwala, S. H., Koboldt, C. M., Seibert, K., A single amino acid difference between cyclooxygenase-1 (COX-1) and 2 (COX-2) reverses the selectivity of COX-2 specific inhibitors. J. Biol. Chem., 271, 15810-15814 (1996) https://doi.org/10.1074/jbc.271.26.15810
  34. Gschwendt, M., Furstenberger, G., Kittstein, W., Besemfelder, E., Hull, W. E., Hagedorn, H., Opferkuch, H. J., Marks, F., Generation of the arachidonic acid metabolite 8-HETE by extracts of mouse skin treated with phorbol ester in vivo; identification by 1H-n.m.r. and GC-MS spectroscopy. Carcinogenesis, 7, 449-455 (1986) https://doi.org/10.1093/carcin/7.3.449
  35. Hammerstrom, S., Hamberg, M., Samuelsson, B., Duell, E. A., Strawiski, M., Voorhees, J. J., Increased concentration of nonesterified arachidonic acid. 12L-hydroxy-5,8,10,14-eico-satetraenoic acid, prostaglandin $E {2}$ and prostaglandin $F {2}$ in epidermis of psoriasis. Proc. Natl. Acad. Sci. USA, 72, 5130-5134 (1975) https://doi.org/10.1073/pnas.72.12.5130
  36. Hansen, H. A., Jensen, B., Essential function of linoleic acid esterified in acylglucosylceramide and acylceramide in maintaining the epidermal water permeability barrier. Evidence from feeding studies with oleate, linoleate, arachidonate, columbinate, and a-linolenate. Biochim. Biophys. Acta, 834, 357-363 (1985) https://doi.org/10.1016/0005-2760(85)90009-8
  37. Herschman, H. R., Reddy, S. T., Xie, W., Function and regulation of prostaglandin synthase-2. Adv. Exp. Med. BioI., 62, 61-66 (1997)
  38. Holtzman, M. J., Turk, J., Pentland, A., A regiospecific monoxyqenase with novel stereopreference is the major pathway for arachidonic acid oxygenastion in isolated epidermal cells. J. Clin. Invest., 85, 1446-1453 (1989)
  39. Iversen L, Fogh K, Ziboh VA, Kristensen P, Schmedes A, Kragballe K. Leukotriene $B_{4}$ formation during human neutrophil keatinocyte interactions: evidence for transformation of leuhobiene $A {4}$ by putative keratinocyte leukotriene $A {4}$ hydrolase. J. Invest. Dermatol., 100: 293-298 (1993) https://doi.org/10.1111/1523-1747.ep12469865
  40. lversen, L., Kristensen, P, Gron, B., Ziboh, V. A, Kragballe, K., Human epidermis transforms exogenous leukotriene $A_{4}$ into peplide leukotrienes: possible role in transcellular metabolism. Arcn. Dermatol. Res., 286, 261-266 (1994) https://doi.org/10.1007/BF00387598
  41. Jisaka, IV., Kim, R. B., Boeglin, W. E., Nanney, L. B., Brash, A R, vlolecular cloning and functional expression of a phorbol ester-inducible 8S-lipoxygenase from mouse skin. J. BioI. Chem., 272, 24410-24416 (1997) https://doi.org/10.1074/jbc.272.39.24410
  42. Julin, L., Hammerstrom, S., Wheal reactions in human skin after injection of leukotriene $B_{4}$, $C_{4}$ , $D_{4}$ and $E_{4}$. Prost. Leuko. Med., 11, 381-383 (1983) https://doi.org/10.1016/0262-1746(83)90090-2
  43. Kliewer, S. A., Sundseth, S. S., Jones, S. A., Brown, P. J., Wisely G. B., Koble, C. S., Devchand, P., Wahli, W., Wilson, T. M., Fatty acids and eicosanoids regulate gene expression thro ugh direct interactions with peroxisome proliferator-acti-vated receptors $\alpha$ and $\gamma$. Proc. Natl. Acad. Sci. USA, 94, 4318-4323 (1997) https://doi.org/10.1073/pnas.94.9.4318
  44. Kragballe, L., Duell, E. A., Voorhees, J. J., Selective decrease of ' 5 -hydroxyeicosatetraenoic acid (15-HETE) formation in invclved psoriatic dermis. Arch. Dermatol., 122: 877-880 (1986) https://doi.org/10.1001/archderm.122.8.877
  45. KururnbaI, R. G., Stevens, A. M., Gierse, J. K., McDonald, J. J., Stegernan, R. A., Pak, J. Y., Gildehaus, D., Miyashiro, J. M., Perning, T. D., Seibert, K., Iskson, P. C., Stallings, W. C., Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature, 384, 644-648 (1996) https://doi.org/10.1038/384644a0
  46. Leong, J., Hughes-Fulford, M., Rakhin, N., et al., Cyclooxygenases in human and mouse skin and cultured human keratinecytes: association of COX-2 expression with human keratinccyte differentiation. Exp. Cell Res., 224, 79-87 (1996) https://doi.org/10.1006/excr.1996.0113
  47. Mane ,H., Uz, T, Sugaya K, Qu T. Putative role of neuronal 5-lipoxygenase in an aging brain. FASEB J., 14: 1464-1469, (2000) https://doi.org/10.1096/fj.14.10.1464
  48. Mani, I., Iversen, L., Ziboh, V. A., Evidence of nuclear PKC/MAP-kinase cascade in guinea pig model of epidermal hyperpro iferation. J. lnvest. Dermatol., 112, 42-48 (1999) https://doi.org/10.1046/j.1523-1747.1999.00480.x
  49. Marcel, Y. L., Christiansen, K., Holman, R. T., The preferred me abollc pathway from linoleic acid to arachidonic acid in vitro. Eiochim. Biophys. Acta, 164, 25-34 (1968) https://doi.org/10.1016/0005-2760(68)90067-2
  50. Mensing, H., Czarnetzki, B. M., Leukotriene $B_{4}$ induces in vitro flbroblast chemotaxis. J Invest. Dermatol., 82, 9-12 (1984) https://doi.org/10.1111/1523-1747.ep12258678
  51. Miller, C. C., McCreedy, C. A, Jones, A D., Ziboh, V. A, Oxidatve metabolism of dihomogammalinolenic acid by guinea pig epidermis. Evidence of generation of anti-inflammatory products. Prostaglandins, 35, 917-938 (1988) https://doi.org/10.1016/0090-6980(88)90116-5
  52. Miller, C. C., Ziboh, V. A, Gammalinolenic acid-enriched diet alters cutaneous eicosanoids. Biochem. Biophys. Res. Comm., 154, 967-974 (1988) https://doi.org/10.1016/0006-291X(88)90234-3
  53. Miller, C. C., Ziboh, V. A, Wong, T, Fletcher, M. P., Dietary sup- piementation with oils rich in (n-3) and (n-6) fatty acids influences in vivo levels of epidermal lipoxygenase products in guinea pigs. J Nutr., 120, 36-44 (1990) https://doi.org/10.1093/jn/120.1.36
  54. Miller, C. C., Tang, W, Ziboh, V. A, Fletcher, M. P, Dietary supplementation with ethyl ester concentrates of fish oil (n-3) and borage oil (n-6) polyunsaturated fatty acids induces epidermal generation of local putative anti-inflammatory metabolites. J. Invest. Dermatol., 96, 98-103 (1991) https://doi.org/10.1111/1523-1747.ep12515911
  55. Mohrhauer, H., Holman, R T, The effect of dose level of essential fatty acids upon fatty acid composition of the rat liver. J Lipid Res., 4, 151-159 (1963)
  56. Muller-Decker, K., Reinerth, G., Krieg, P., Zimmermann, R., Heise, H., Bayerl, C., Marks, S. F., Furstenberger, G., Prostaglandin- H-synthase isozyme expression in normal and neoplastic human skin. Int. J. Cancer, 82, 648-656 (1999) https://doi.org/10.1002/(SICI)1097-0215(19990827)82:5<648::AID-IJC6>3.0.CO;2-D
  57. Nishida, E., Gotoh, Y., The MAP kinase cascade is essential for diverse signal transduction pathways. Trends Biochem. Sci., 18, 128-131 (1993) https://doi.org/10.1016/0968-0004(93)90019-J
  58. Nugteren, D. H., Christ-Hazelhof, E., van der Beek, A., Houtsmuller, U. M. T., Metabolism of linoleic acid and other essential fatty acids in the epidermis of the rat. Biochim. Biophys. Acta, 834, 429-436 (1985) https://doi.org/10.1016/0005-2760(85)90017-7
  59. Quackenbush, F. W., Kummerow, F. A., Steen bock, H., The effectiveness of linoleic, arachidonic, and linolenic acids in reproduction and lactaction. J. Nutr., 24, 213-224 (1942) https://doi.org/10.1079/BJN19700022
  60. Ruzicka, T, Simmet, T, Peskar, B. A., Ring, J., Skin levels of arachidonic acid-derived inflammatory mediators and histamine in atopic dermatitis and psoriasis. J. Invest. Dermatol., 83, 70-73 (1984) https://doi.org/10.1111/1523-1747.ep12261712
  61. Saez, E., Rutberg, S. E., Mueller, E., Oppenheim, H., Smoluk, J., Yuspa, S. H., Spiegelman, B. M., C-fos is required for malignant progression of skin tumors. Cell, 82, 721-732 (1995) https://doi.org/10.1016/0092-8674(95)90469-7
  62. Salasche, S. J., Epidemiology of actinic keratoses and squamous cell carcinoma. J Am. Acad. Dermatol., 42, S4-S7 (2000) https://doi.org/10.1067/mjd.2000.103342
  63. Scholz, K., Furstenberger, G., Muller-Decker, K., et al., Differential expression of prostaglandin-H synthase isoenzymes in normal and activated keratinocytes in vivo and in vitro. Biochem. J., 309, 263-269 (1995) https://doi.org/10.1042/bj3090263
  64. Schuh, A. C., Keating, S. J., Montecarlo, F. S., Vogt, P. K., Breitman, M. L., Obligatory wounding requirement for tumorigenesis in vjun transgeneic mice. Nature, 346, 756-760 (1990) https://doi.org/10.1038/346756a0
  65. Smeyne, R. J., Vendrell, M., Hayward, M., Baker, S. J., Miao, G. G., Schilling, K., Robertson, L. M., Curran, T, Morgan, J. I,. Continuous c-fos expression precedes programmed cell death in vivo. Nature, 363, 166-169 (1993) https://doi.org/10.1038/363166a0
  66. Smith, C. J., Morrow, J. D., Roberts, L. J., et al., Differentiation of monocytoid THP-1 cells with phorbol ester induces expression of prostaglandin endoperoxide synthase-1 (COX-1). Biochem. Biophys. Res. Commun., 182, 787-793 (1993)
  67. Smith, W. L., DeWitt, D. L., Prostaglandin endoperoxide H synthases-1 and 2. Adv.lmmunol., 62, 167-215 (1996) https://doi.org/10.1016/S0065-2776(08)60430-7
  68. Soter, N. A., Lewis, R. A., Corey, E. J., Austen, K. F., Local effects of synthetic leukotrienes ($LTC_{4}$, $LTD_{4}$, $LTE_{4}$ and $LTB_{4}$) in human skin. J. lnvest. Dermatol., 80, 115-119 (1983) https://doi.org/10.1111/1523-1747.ep12531738
  69. Tate, G., Mandell, B. F., Laposata, M., Ohliger, D., Baker, D. G., Schumacher, H. R., Zurier, R. B., Suppression of acute and chronic inflammation of dietary dihomo-y-linolenic acid. J Rheumatol., 16, 1729-1736 (1989)
  70. Ternowitz, T., Herlin, T., Fogh, K., Human monocyte and polymorphonuclear leukocyte chemotaxic and chemokinetic responses to leukotriene $B_4$ and FMLP. Acta Pathol. Microbiol. Immunol. Scand., 95, 47-54 (1987)
  71. Turpeinen, O., Further studies on the unsaturated fatty acids essential in nutrition. J. Nutr., 15: 351-366 (1937)
  72. Vanderhoek, J. Y, Bryant, R. V., Bailey, J. M., Inhibition of leukotriene biosynthesis by the leukocytes product 15-hydroxy5,8,11,13-eicosatetraenoic acid. J. Biol. Chem., 225, 10064-10066 (1980)
  73. Wang, Q., Haynam, D. R., Hyde, D. M., Combs, A., B., Giri, S.N., Reduction of bleomycin-induced sequestration of neutrophils and vascular injury in hamster lungs by nitroglycerin. Inflammopharmacol., 1, 249-261 (1992) https://doi.org/10.1007/BF02735374
  74. Wertz, P. W., Cho, E. S., Downing, D. T, Effect of essential fatty acid deficiency on the epidermal sphingolipids of the rat. Biochim. Biophys. Acta, 753, 350-355 (1983) https://doi.org/10.1016/0005-2760(83)90058-9
  75. Wertz, P. W., Downing, D. T, Ceramides of pig epidermis: Structure determination. J. Lipid Res., 24, 759-765 (1983)
  76. Woollard, P. M., Stereochemical difference between 12-hydroxy- 5,8,1 0,14-eicosatetraenoic acid in platelets and psoriatic lesions. Biochem. Biophys. Res. Commun., 136, 169-176 (1986) https://doi.org/10.1016/0006-291X(86)90891-0
  77. Wright, S., Burton, J. L., Oral evening primrose-seed oil improves atopic eczema. Lancet, 1, 1120-1122 (1982)
  78. Xi, S., Ziboh, V. A., Suppression of proto-oncogene (AP-1) in a model of skin epidermal hyperproliferation is reversed by topical application of 13-octadecadienoic acid and 15-hydroxyeicosatrienoic acid. Prost. Leuko. Ess. Fatty Acids, 62, 13-19 (2000) https://doi.org/10.1054/plef.1999.0119
  79. Xi, S., Pham, H., Ziboh, V. A., 15-Hydroxyeicosatrienoic acid (15-HIETrE) suppresses epidermal hyperproliferation via the modulation of nuclear transcription factor (AP-1) and apoptosis. Arch. Dermatol. Res., 292, 397-403 (2000) https://doi.org/10.1007/s004030000139
  80. Xia, Z., Dickens, M., Raingeaud, J., Davis, R. J., Greenberg, M. E., Opposing effects of ERK and JNK-p38 MAP-kinase on apoptosis. Science, 270, 1326-1331 (1995) https://doi.org/10.1126/science.270.5240.1326
  81. Yardley, H. J., Summerly, R., Lipid composition and metabolism in normal and diseased epidermis. Pharmacol. Ther., 13, 357-383 (1981) https://doi.org/10.1016/0163-7258(81)90006-1
  82. Ziboh, V. A., Yun, M., Hyde DM, Giri SN. $\gamma$-linolenic acidcontaining diet attenuates bleomycin-induced lung fibrosis in hamsters. Lipids, 32, 759-767 (1997) https://doi.org/10.1007/s11745-997-0097-x