Protein-fatty acid complexes: Biochemistry, biophysics and function

FEBS Journal

Volumn 280, Issue 8, 2013, Pages 1733-1749

  Brinkmann, Christel R ^a,c   Thiel, Steffen ^a   Otzen, Daniel E ^b  

^a AARHUS UNIVERSITY   (Denmark)

^b AARHUS UNIVERSITY   (Denmark)

^c AARHUS UNIVERSITY HOSPITAL   (Denmark)

Author keywords

lactalbumin; BAMLET; cancer cells; cell death; cytotoxicity; denaturation; fatty acid; HAMLET; human lactalbumin made lethal to tumour cells; oleic acid

Indexed keywords

ALPHA LACTALBUMIN; ANTIBIOTIC AGENT; BOVINE ALPHA LACTALBUMIN MADE LETHAL TO TUMOR CELL; CYTOTOXIC AGENT; FATTY ACID; HUMAN ALPHA LACTALBUMIN MADE LETHAL TO TUMOR CELL; LIPOPROTEIN; LIPOPROTEIN COMPLEX OF EQUINE LYSOZYME WITH OLEIC ACID; MILK PROTEIN; OLEIC ACID; PLACEBO; PROTEIN MAL; UNCLASSIFIED DRUG;

BIOCHEMISTRY; BIOPHYSICS; BLADDER CANCER; CANCER CELL; COMPLEX FORMATION; DRUG CYTOTOXICITY; DRUG POTENTIATION; GLIOBLASTOMA; HUMAN; IMMUNE RESPONSE; INFLAMMATION; LIPID MEMBRANE; NONHUMAN; PRIORITY JOURNAL; PROTEIN FOLDING; PROTEIN FUNCTION; PROTEIN LIPID INTERACTION; REVIEW; SIGNAL TRANSDUCTION; SKIN PAPILLOMA;

ANIMALS; FATTY ACIDS; HUMANS; LACTALBUMIN; OLEIC ACID; OLEIC ACIDS; PROTEIN FOLDING; PROTEINS;

EID: 84876280933     PISSN: 1742464X     EISSN: 17424658     Source Type: Journal    
DOI: 10.1111/febs.12204     Document Type: Review

References (114)

1. Håkansson A, Zhivotovsky B, Orrenius S, Sabharwal H, &, Svanborg C, (1995) Apoptosis induced by a human milk protein. Proc Natl Acad Sci USA 92, 8064-8068.
2. Svensson M, Håkansson A, Mossberg AK, Linse S, &, Svanborg C, (2000) Conversion of alpha-lactalbumin to a protein inducing apoptosis. Proc Natl Acad Sci USA 97, 4221-4226.
3. Håkansson A, Svensson M, Mossberg AK, Sabharwal H, Linse S, Lazou I, Lönnerdal B, &, Svanborg C, (2000) A folding variant of alpha-lactalbumin with bactericidal activity against Streptococcus pneumoniae. Mol Microbiol 35, 589-600.
4. Mossberg AK, Hun Mok K, Morozova-Roche LA, &, Svanborg C, (2010) Structure and function of human alpha-lactalbumin made lethal to tumor cells (HAMLET)-type complexes. FEBS J 277, 4614-4625.
5. Knyazeva EL, Grishchenko VM, Fadeev RS, Akatov VS, Permyakov SE, &, Permyakov EA, (2008) Who Is Mr HAMLET? Interaction of human alpha-lactalbumin with monomeric oleic acid. Biochemistry 47, 13127-13137.
6. Liskova K, Kelly AL, O'Brien N, &, Brodkorb A, (2010) Effect of denaturation of alpha-lactalbumin on the formation of BAMLET (bovine alpha-lactalbumin made lethal to tumor cells). J Agric Food Chem 58, 4421-4427.
7. Pettersson-Kastberg J, Mossberg AK, Trulsson M, Yong YJ, Min S, Lim Y, O'Brien JE, Svanborg C, &, Mok KH, (2009) alpha-Lactalbumin, engineered to be nonnative and inactive, kills tumor cells when in complex with oleic acid: a new biological function resulting from partial unfolding. J Mol Biol 394, 994-1010.
8. Tolin S, De Franceschi G, Spolaore B, Frare E, Canton M, Polverino de Laureto P, &, Fontana A, (2010) The oleic acid complexes of proteolytic fragments of alpha-lactalbumin display apoptotic activity. FEBS J 277, 163-173.
9. Wilhelm K, Darinskas A, Noppe W, Duchardt E, Mok KH, Vukojevic V, Schleucher J, &, Morozova-Roche LA, (2009) Protein oligomerization induced by oleic acid at the solid-liquid interface-equine lysozyme cytotoxic complexes. FEBS J 276, 3975-3989.
10. Pettersson J, Mossberg AK, &, Svanborg C, (2006) alpha-Lactalbumin species variation HAMLET formation, and tumor cell death. Biochem Biophys Res Commun 345, 260-270.
11. Brinkmann CR, Heegaard CW, Petersen TE, Jensenius JC, &, Thiel S, (2011) The toxicity of bovine α-lactalbumin made lethal to tumor cells is highly dependent of oleic acid and induces killing in cancer cell lines and non-cancer derived primary cells. FEBS J 278, 1955-1967.
12. Permyakov SE, Knyazeva EL, Khasanova LM, Fadeev RS, Zhadan AP, Roche-Hakansson H, Hakansson AP, Akatov VS, &, Permyakov EA, (2012) Oleic Acid is a Key Cytotoxic Component of HAMLET-like Complexes. Biol Chem 393, 85-92.
13. Nielsen SB, Wilhelm K, Vad B, Schleucher J, Morozova-Roche LA, &, Otzen D, (2010) The interaction of equine lysozyme: oleic acid complexes with lipid membranes suggests a cargo off-loading mechanism. J Mol Biol 398, 351-361.
14. Heine WE, Klein PD, &, Reeds PJ, (1991) The importance of alpha-lactalbumin in infant nutrition. J Nutr 121, 277-283.
15. Acharya KR, Ren JS, Stuart DI, Phillips DC, &, Fenna RE, (1991) Crystal structure of human alpha-lactalbumin at 1.7 A resolution. J Mol Biol 221, 571-581.
16. Permyakov EA, &, Berliner LJ, (2000) α-Lactalbumin: structure and function. FEBS Lett 473, 269-274.
17. Kuwajima K, (1977) A folding model of a-lactalbumin deduced from three-state denaturation mechanism. J Mol Biol 114, 241-258.
18. Pfeil W, (1987) Is thermally denatured protein unfolded? The example of lactalbumin. Biochim Biophys Acta 911, 114-116.
19. Ikeguchi M, Kuwajima K, Mitani M, &, Sugai S, (1986) Evidence for identity between the equilibrium unfolding intermediate and a transient folding intermediate: a comparative study of the folding reactions of alpha-lactalbumin and lysozyme. Biochemistry 25, 6965-6972.
20. Peng ZY, &, Kim PS, (1994) A protein dissection study of a molten globule. Biochemistry 33, 2136-2141.
21. Kuwajima K, (1996) The molten globule state of alpha-lactalbumin. FASEB J 10, 102-109.
22. Halskau O, Underhaug J, Frøystein NA, &, Martinez A, (2005) Conformational flexibility of alpha-lactalbumin related to its membrane binding capacity. J Mol Biol 349, 1072-1086.
23. Chaudhuri D, Narayan M, &, Berliner LJ, (2004) Conformation-dependent interaction of alpha-lactalbumin with model and biological membranes: a spin-label ESR study. Prot J 23, 95-101.
24. Otzen DE, Sehgal P, &, Westh P, (2009) α-lactalbumin is unfolded by all classes of detergents but with different mechanisms. J Colloid Interface Sci 329, 273-283.
25. Hanssens I, Houthuys C, Herreman W, &, van Cauwelaert FH, (1980) Interaction of alpha-lactalbumin with dimyristoyl phosphatidylcholine vesicles. I. A microcalorimetric and fluorescence study. Biochim Biophys Acta 602, 539-557.
26. Kim J, &, Kim H, (1986) Fusion of Phospholipid Vesicles Induced by a-Lactalbumin at Acidic pH. Biochemistry 25, 7867-7874.
27. Kuwajima K, (1989) The molten globule state as a clue for understanding the folding and cooperativity of globular-protein structure. Proteins 6, 87-103.
28. De Laureto PP, Frare E, Gittardo R, &, Fontana A, (2002) Molten globule of bovine alpha-lactalbumin at neutral pH induced by heat, trifluoroethanol, and oleic acid: a comparative analysis by circular dichroism spectroscopy and limited proteolysis. Proteins 49, 385-397.
29. Permyakov SE, Pershikova IV, Zhadan AP, Goers J, Bakunts AG, Uversky VN, Berliner LJ, &, Permyakov EA, (2005) Conversion of human alpha-lactalbumin to an apo-like state in the complexes with basic poly-amino acids: toward understanding of the molecular mechanism of antitumor action of HAMLET. J Proteome Res 4, 564-569.
30. Malmendal A, Underhaug J, Otzen DE, &, Nielsen NC, (2010) Fast mapping of global protein folding states by multivariate NMR: a GPS for proteins. PLoS ONE 5, e10262.
31. Svensson M, Sabharwal H, Håkansson A, Mossberg A-K, Lipniunas P, Leffler H, Svanborg C, &, Linse S, (1999) Molecular characterization of alpha-lactalbumin folding variants that induce apoptosis in tumor cells. J Biol Chem 274, 6388-6396.
32. Svensson M, Fast J, Mossberg AK, Düringer C, Gustafsson L, Hallgren O, Brooks CL, Berliner L, Linse S, &, Svanborg C, (2003) Alpha-lactalbumin unfolding is not sufficient to cause apoptosis, but is required for the conversion to HAMLET (human alpha-lactalbumin made lethal to tumor cells). Protein Sci 12, 2794-2804.
33. Fast J, Mossberg A-K, Svanborg C, &, Linse S, (2005) Stability of HAMLET-a kinetically trapped alpha-lactalbumin oleic acid complex. Prot Sci 14, 329-340.
34. Casbarra A, Birolo L, Infusini G, Dal Piaz F, Svensson M, Pucci P, Svanborg C, &, Marino G, (2004) Conformational analysis of HAMLET, the folding variant of human alpha-lactalbumin associated with apoptosis. Protein Sci 13, 1322-1330.
35. Spolaore B, Pinato O, Canton M, Zambonin M, De Laureto PP, &, Fontana A, (2010) a-lactalbumin forms with oleic acid a high molecular weight complex displaying cytotoxic activity. Biochemistry 49, 8658-8667.
36. Xie Y, Min S, Harte NP, Kirk H, O'Brien JE, Voorheis HP, Svanborg C, &, Hun Mok K, (2012) Electrostatic interactions play an essential role in the binding of oleic acid with alpha-lactalbumin in the HAMLET-like complex: A study using charge-specific chemical modifications. Proteins 81, 1-17.
37. Brinkmann CR, Thiel S, Larsen MK, Petersen TE, Jensenius JC, &, Heegaard CW, (2011) Preparation and comparison of cytotoxic complexes formed between oleic acid and either bovine or human α-lactalbumin. J Dairy Sci 94, 2159-2170.
38. Fast J, Mossberg AK, Nilsson H, Svanborg C, Akke M, &, Linse S, (2005) Compact oleic acid in HAMLET. FEBS Lett 579, 6095-6100.
39. Kamijima T, Ohmura A, Sato T, Akimoto K, Itabashi M, Mizuguchi M, Kamiya M, Kikukawa T, Aizawa T, Takahashi M, et al,. (2008) Heat-treatment method for producing fatty acid-bound alpha-lactalbumin that induces tumor cell death. Biochem Biophys Res Comm 376, 211-214.
40. Mercer N, Ramakrishnan B, Boeggeman E, &, Qasba PK, (2011) Applications of site-specific labeling to study HAMLET, a tumoricidal complex of alpha-lactalbumin and oleic acid. PLoS ONE 6, e26093.
41. Zhang M, Yang F Jr, Yang F, Chen J, Zheng CY, &, Liang Y, (2009) Cytotoxic aggregates of alpha-lactalbumin induced by unsaturated fatty acid induce apoptosis in tumor cells. Chem Biol Interact 180, 131-142.
42. Permyakov SE, Knyazeva EL, Leonteva MV, Fadeev RS, Chekanov AV, Zhadan AP, Hakansson AP, Akatov VS, &, Permyakov EA, (2011) A novel method for preparation of HAMLET-like protein complexes. Biochimie 93, 1495-1501.
43. Lišková K, Auty MAE, Chaurin V, Min S, Mok Hun K, O'Brien N, Kelly AL, &, Brodkorb A, (2011) Cytotoxic complexes of sodium oleate with β-lactoglobulin. Eur J Lipid Sci Technol 113, 1207-1218.
44. Brinkmann CR, Brodkorb A, Thiel S, &, Kehoe JJ, (2012) The cytotoxicity of fatty acid/α-lactalbumin complexes depends on the amount and type of fatty acid, doi: 10.1002/ejlt.201200165.
45. Pettersson J, (2007) Structure-Function Analysis of HAMLET-Human Alpha Lactalbumin Made Lethal to Tumor Cells. Lund University, Lund.
46. Pettersson-Kastberg J, Aits S, Gustafsson L, Mossberg A, Storm P, Trulsson M, Persson F, Hun Mok K, &, Svanborg C, (2008) Can misfolded proteins be beneficial? The HAMLET case. Ann Med 41, 162-176.
47. Svensson M, Mossberg AK, Pettersson J, Linse S, &, Svanborg C, (2003) Lipids as cofactors in protein folding: stereo-specific lipid-protein interactions are required to form HAMLET (human alpha-lactalbumin made lethal to tumor cells). Protein Sci 12, 2805-2814.
48. Baumann A, Gjerde AU, Ying M, Svanborg C, Holmsen H, Glomm WR, Martinez A, &, Halskau O, (2012) HAMLET forms annular oligomers when deposited with phospholipid monolayers. J Mol Biol 418, 90-102.
49. Kim YJ, Nakatomi R, Akagi T, Hashikawa T, &, Takahashi R, (2005) Unsaturated fatty acids induce cytotoxic aggregate formation of amyotrophic lateral sclerosis-linked superoxide dismutase 1 mutants. J Biol Chem 280, 21515-21521.
50. Sharon R, Goldberg MS, Bar-Josef I, Betensky RA, Shen J, &, Selkoe DJ, (2001) alpha-Synuclein occurs in lipid-rich high molecular weight complexes, binds fatty acids, and shows homology to the fatty acid-binding proteins. Proc Natl Acad Sci USA 98, 9110-9115.
51. Sharon R, Bar-Joseph I, Frosch MP, Walsh DM, Hamilton JA, &, Selkoe DJ, (2003) The formation of highly soluble oligomers of alpha-synuclein is regulated by fatty acids and enhanced in Parkinson's disease. Neuron 37, 583-595.
52. Gamblin TC, King ME, Kuret J, Berry RW, &, Binder LI, (2000) Oxidative regulation of fatty acid-induced tau polymerization. Biochemistry 39, 14203-14210.
53. Andersen KK, Oliveira CLP, Larsen KL, Poulsen FM, Callisen TH, Westh P, Pedersen JS, &, Otzen DE, (2009) The role of decorated SDS micelles in sub-cmc protein denaturation and association. J Mol Biol 391, 207-226.
54. Giehm L, Oliveira CLP, Christiansen G, Pedersen JS, &, Otzen DE, (2010) SDS-induced fibrillation of α-synuclein: an alternative fibrillation pathway. J Mol Biol 401, 115-133.
55. Otzen DE, (2010) Amyloid formation in surfactants and alcohols: membrane mimetics or structural switchers? Curr Protein Pept Sci 11, 355-371.
56. Dobson CM, (1999) Protein misfolding, evolution and disease. Trends Biochem Sci 24, 329-332.
57. Permyakov SE, Knyazeva EL, Khasanova LM, Fadeev RS, Zhadan AP, Roche-Hakansson H, Hakansson AP, Akatov VS, &, Permyakov EA, (2012) Oleic acid is a key cytotoxic component of HAMLET-like complexes. Biol Chem 393, 85-92.
58. Konuma T, Sakurai K, &, Goto Y, (2007) Promiscuous binding of ligands by beta-lactoglobulin involves hydrophobic interactions and plasticity. J Mol Biol 368, 209-218.
59. Hansted JG, Wejse PL, Bertelsen H, &, Otzen DE, (2011) Effect of protein-surfactant interactions on aggregation of β-lactoglobulin. Biochim Biophys Acta 1814, 713-723.
60. Svanborg C, Agerstam H, Aronson A, Bjerkvig R, Düringer C, Fischer W, Gustafsson L, Hallgren O, Leijonhuvud I, Linse S, et al,. (2003) HAMLET kills tumor cells by an apoptosis-like mechanism-cellular, molecular, and therapeutic aspects. Adv Cancer Res 88, 1-29.
61. Hallgren O, Gustafsson L, Irjala H, Selivanova G, Orrenius S, &, Svanborg C, (2006) HAMLET triggers apoptosis but tumor cell death is independent of caspases, Bcl-2 and p53. Apoptosis 11, 221-233.
62. Gustafsson L, Leijonhufvud I, Aronsson A, Mossberg AK, &, Svanborg C, (2004) Treatment of skin papillomas with topical alpha-lactalbumin-oleic acid. N Engl J Med 350, 2663-2672.
63. Fischer W, Gustafsson L, Mossberg AK, Gronli J, Mork S, Bjerkvig R, &, Svanborg C, (2004) Human alpha-lactalbumin made lethal to tumor cells (HAMLET) kills human glioblastoma cells in brain xenografts by an apoptosis-like mechanism and prolongs survival. Cancer Res 64, 2105-2112.
64. Düringer C, Hamiche A, Gustafsson L, Kimura H, &, Svanborg C, (2003) HAMLET interacts with histones and chromatin in tumor cell nuclei. J Biol Chem 278, 42131-42135.
65. Mossberg AK, Wullt B, Gustafsson L, Månsson W, Ljunggren E, &, Svanborg C, (2007) Bladder cancers respond to intravesical instillation of HAMLET (human alpha-lactalbumin made lethal to tumor cells). Int J Cancer 121, 1352-1359.
66. Gustafsson L, Hallgren O, Mossberg AK, Pettersson J, Fischer W, Aronsson A, &, Svanborg C, (2005) HAMLET kills tumor cells by apoptosis: structure, cellular mechanisms, and therapy. J Nutr 135, 1299-1303.
67. Baltzer A, Svanborg C, &, Jaggi R, (2004) Apoptotic cell death in the lactating mammary gland is enhanced by a folding variant of alpha-lactalbumin. Cell Mol Life Sci 61, 1221-1228.
68. Brinkmann CR, (2011) Cytotoxic Activity of a Bovine Alpha-Lactalbumin: Oleic Acid Complex. Aarhus University, Aarhus.
69. Hakansson AP, Roche-Hakansson H, Mossberg AK, &, Svanborg C, (2011) Apoptosis-like death in bacteria induced by HAMLET, a human milk lipid-protein complex. PLoS ONE 6, e17717.
70. Marks LR, Clementi EA, &, Hakansson AP, (2012) the human milk protein-lipid complex HAMLET sensitizes bacterial pathogens to traditional antimicrobial agents. PLoS ONE 7, e43514.
71. Gibbs S, (2006) Breakthrough in the treatment of warts? Arch Dermatol 142, 767-768.
72. Mossberg AK, Hou Y, Svensson M, Holmqvist B, &, Svanborg C, (2010) HAMLET treatment delays bladder cancer development. J Urol 183, 1590-1597.
73. Min S, Meehan J, Sullivan LM, Harte NP, Xie Y, Davey GP, Svanborg C, Brodkorb A, &, Mok KH, (2012) Alternatively folded proteins with unexpected beneficial functions. Biochem Soc Trans 40, 746-751.
74. Gustafsson L, Aits S, Onnerfjord P, Trulsson M, Storm P, &, Svanborg C, (2009) Changes in proteasome structure and function caused by HAMLET in tumor cells. PLoS ONE 4, e5229.
75. Vukojevic V, Bowen AM, Wilhelm K, Ming Y, Ce Z, Schleucher J, Hore PJ, Terenius L, &, Morozova-Roche LA, (2010) Lipoprotein complex of equine lysozyme with oleic acid (ELOA) interactions with the plasma membrane of live cells. Langmuir 26, 14782-14787.
76. Svensson M, Düringer C, Hallgren O, Mossberg AK, Håkansson A, Linse S, &, Svanborg C, (2002) Hamlet-a complex from human milk that induces apoptosis in tumor cells but spares healthy cells. Adv Exp Med Biol 503, 125-132.
77. Köhler C, Gogvadze V, Håkansson A, Svanborg C, Orrenius S, &, Zhivotovsky B, (2001) A folding variant of human alpha-lactalbumin induces mitochondrial permeability transition in isolated mitochondria. Eur J Biochem 268, 186-191.
78. Aits S, Gustafsson L, Hallgren O, Brest P, Gustafsson M, Trulsson M, Mossberg AK, Simon HU, Mograbi B, &, Svanborg C, (2009) HAMLET (human alpha-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death. Int J Cancer 124, 1008-1019.
79. Trulsson M, Yu H, Gisselsson L, Chao Y, Urbano A, Aits S, Mossberg AK, &, Svanborg C, (2011) HAMLET binding to alpha-actinin facilitates tumor cell detachment. PLoS ONE 6, e17179.
80. Rammer P, Groth-Pedersen L, Kirkegaard T, Daugaard M, Rytter A, Szyniarowski P, Hoyer-Hansen M, Povlsen LK, Nylandsted J, Larsen JE, et al,. (2010) BAMLET activates a lysosomal cell death program in cancer cells. Mol Cancer Ther 9, 24-32.
81. Cawthern KM, Permyakov E, &, Berliner LJ, (1996) Membrane-bound states of alpha-lactalbumin: implications for the protein stability and conformation. Protein Sci 5, 1394-1405.
82. Berliner LJ, &, Koga K, (1987) Alpha-lactalbumin binding to membranes: evidence for a partially buried protein. Biochemistry 26, 3006-3009.
83. Mossberg AK, Puchades M, Halskau O, Baumann A, Lanekoff I, Chao Y, Martinez A, Svanborg C, &, Karlsson R, (2010) HAMLET interacts with lipid membranes and perturbs their structure and integrity. PLoS ONE 5, e9384.
84. Zherelova OM, Kataev AA, Grishchenko VM, Knyazeva EL, Permyakov SE, &, Permyakov EA, (2009) Interaction of antitumor alpha-lactalbumin-oleic acid complexes with artificial and natural membranes. J Bioenerg Biomembr 41, 229-237.
85. Pocovi C, Conesa C, Barbana C, Perez MD, Calvo M, &, Sanchez L, (2009) Comparison of the activity of human and bovine milk on two cell lines. J Dairy Res 76, 308-316.
86. Permyakov SE, Pershikova IV, Khokhlova TI, Uversky VN, &, Permyakov EA, (2004) No need to be HAMLET or BAMLET to interact with histones: binding of monomeric alpha-lactalbumin to histones and basic poly-amino acids. Biochemistry 43, 5575-5582.
87. Thompson MP, Farrell HM, Mohanam S, Liu S, Kidwell WR, Bansal MP, Cook RG, Medina D, Kotts CE, &, Bano M, (1992) Identification of human-milk alpha-lactalbumin as a cell-growth inhibitor. Protoplasma 167, 134-144.
88. Sternhagen LG, &, Allen JC, (2001) Growth rates of a human colon adenocarcinoma cell line are regulated by the milk protein alpha-lactalbumin. Adv Exp Med Biol 501, 115-120.
89. Ganjam LS, Thornton WH Jr, Marshall RT, &, MacDonald RS, (1997) Antiproliferative effects of yogurt fractions obtained by membrane dialysis on cultured mammalian intestinal cells. J Dairy Sci 80, 2325-2329.
90. Lin IC, Su SL, &, Kuo CD, (2008) Induction of cell death in RAW 264.7 cells by alpha-lactalbumin. Food Chem Toxicol 46, 842-853.
91. Xu M, Sugiura Y, Nagaoka S, &, Kanamaru Y, (2005) IEC-6 intestinal cell death induced by bovine milk alpha-lactalbumin. Biosci Biotechnol Biochem 69, 1082-1089.
92. Xu M, Sugiura Y, Nagaoka S, &, Kanamaru Y, (2005) Involvement of SDS-stable higher M(r) forms of bovine normal milk alpha-lactalbumin in inducing intestinal IEC-6 cell death. Biosci Biotechnol Biochem 69, 1189-1192.
93. Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J, Taddei N, Ramponi G, Dobson CM, &, Stefani M, (2002) Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 416, 507-511.
94. Chiti F, &, Dobson CM, (2006) Protein misfolding, functional amyloid, and human disease. Ann Rev Biochem 75, 333-366.
95. Lin IC, &, Kuo CD, (2010) Pro-inflammatory effects of commercial alpha-lactalbumin on RAW 264.7 macrophages is due to endotoxin contamination. Food Chem Toxicol 48, 2642-2649.
96. Calder PC, (1996) Sir David Cuthbertson Medal Lecture. Immunomodulatory and anti-inflammatory effects of n-3 polyunsaturated fatty acids. Proc Nutr Soc 55, 737-774.
97. Zhu Y, Schwarz S, Ahlemeyer B, Grzeschik S, Klumpp S, &, Krieglstein J, (2005) Oleic acid causes apoptosis and dephosphorylates Bad. Neurochem Int 46, 127-135.
98. Martins de Lima T, Cury-Boaventura MF, Giannocco G, Nunes MT, &, Curi R, (2006) Comparative toxicity of fatty acids on a macrophage cell line (J774). Clin Sci 111, 307-317.
99. Dymkowska D, Szczepanowska J, Wieckowski MR, &, Wojtczak L, (2006) Short-term and long-term effects of fatty acids in rat hepatoma AS-30D cells: the way to apoptosis. Biochim Biophys Acta 1763, 152-163.
100. Finstad HS, Myhrstad MC, Heimli H, Lomo J, Blomhoff HK, Kolset SO, &, Drevon CA, (1998) Multiplication and death-type of leukemia cell lines exposed to very long-chain polyunsaturated fatty acids. Leukemia 12, 921-929.
101. Cury-Boaventura MF, Gorjao R, de Lima TM, Newsholme P, &, Curi R, (2006) Comparative toxicity of oleic and linoleic acid on human lymphocytes. Life Sci 78, 1448-1456.
102. Cury-Boaventura MF, Pompeia C, &, Curi R, (2004) Comparative toxicity of oleic acid and linoleic acid on Jurkat cells. Clin Nutr 23, 721-732.
103. Andrade LN, de Lima TM, Curi R, &, Castrucci AM, (2005) Toxicity of fatty acids on murine and human melanoma cell lines. Toxicol In Vitro 19, 553-560.
104. Penzo D, Tagliapietra C, Colonna R, Petronilli V, &, Bernardi P, (2002) Effects of fatty acids on mitochondria: implications for cell death. Biochim Biophys Acta 1555, 160-165.
105. Oyanagi E, Yano H, Kato Y, Fujita H, Utsumi K, &, Sasaki J, (2008) L-Carnitine suppresses oleic acid-induced membrane permeability transition of mitochondria. Cell Biochem Funct 26, 778-786.
106. Healy DA, Watson RW, &, Newsholme P, (2003) Polyunsaturated and monounsaturated fatty acids increase neutral lipid accumulation, caspase activation and apoptosis in a neutrophil-like, differentiated HL-60 cell line. Clin Sci (Lond) 104, 171-179.
107. Anel A, Richieri GV, &, Kleinfeld AM, (1993) Membrane partition of fatty acids and inhibition of T cell function. Biochemistry 32, 530-536.
108. Azevedo-Martins AK, Monteiro AP, Lima CL, Lenzen S, &, Curi R, (2006) Fatty acid-induced toxicity and neutral lipid accumulation in insulin-producing RINm5F cells. Toxicol In Vitro 20, 1106-1113.
109. Lux CA, Koschinski A, Dersch K, Husmann M, &, Bhakdi S, (2009) Hypersusceptibility of neutrophil granulocytes towards lethal action of free fatty acids contained in enzyme-modified atherogenic low density lipoprotein. Atherosclerosis 207, 116-122.
110. Meyer RK, Schindler H, &, Burger MM, (1982) alpha-Actinin interacts specifically with model membranes containing glycerides and fatty acids. Proc Natl Acad Sci USA 79, 4280-4284.
111. Hamel FG, (2009) Preliminary report: inhibition of cellular proteasome activity by free fatty acids. Metabolism 58, 1047-1049.
112. Speert DP, Wannamaker LW, Gray ED, &, Clawson CC, (1979) Bactericidal effect of oleic acid on group A streptococci: mechanism of action. Infect Immun 26, 1202-1210.
113. Stenz L, Francois P, Fischer A, Huyghe A, Tangomo M, Hernandez D, Cassat J, Linder P, &, Schrenzel J, (2008) Impact of oleic acid (cis-9-octadecenoic acid) on bacterial viability and biofilm production in Staphylococcus aureus. FEMS Microbiol Lett 287, 149-155.
114. Huang CM, Chen CH, Pornpattananangkul D, Zhang L, Chan M, Hsieh MF, &, Zhang L, (2011) Eradication of drug resistant Staphylococcus aureus by liposomal oleic acids. Biomaterials 32, 214-221.