Multiplicity of effects and health benefits of resveratrol

Medicina (Lithuania)

Volumn 52, Issue 3, 2016, Pages 148-155

  Kuršvietienė, Lolita ^a   Stanevičienė, Inga ^a   Mongirdienė, Aušra ^a,b   Bernatonienė, Jurga ^a  

^a LITHUANIAN UNIVERSITY OF HEALTH SCIENCES   (Lithuania)

^b LITHUANIAN UNIVERSITY OF HEALTH SCIENCES   (Lithuania)

Author keywords

Anticancer; Antioxidant; Radicals; Resveratrol

Indexed keywords

ANTIDIABETIC AGENT; ANTINEOPLASTIC AGENT; ANTIOXIDANT; ANTITHROMBOCYTIC AGENT; GLUCOSE BLOOD LEVEL; RESVERATROL; STILBENE DERIVATIVE;

ANALYSIS; ANIMAL; ARACHIS; CHEMISTRY; DRUG EFFECTS; FRUIT; GLUCOSE BLOOD LEVEL; HUMAN; WINE;

ANIMALS; ANTINEOPLASTIC AGENTS, PHYTOGENIC; ANTIOXIDANTS; ARACHIS; BLOOD GLUCOSE; FRUIT; HUMANS; HYPOGLYCEMIC AGENTS; PLATELET AGGREGATION INHIBITORS; STILBENES; WINE;

EID: 84964607627     PISSN: 1010660X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.medici.2016.03.003     Document Type: Review

References (94)

1. [1] Sak, K., Everaus, H., Role of flavonoids in future anticancer therapy by eliminating the cancer stem cells. Curr Stem Cell Res Ther 10:3 (2015), 271–282.
2. [2] Xie, Y., Yang, W., Tang, F., Chen, X., Ren, L., Antibacterial activities of flavonoids: structure–activity relationship and mechanism. Curr Med Chem 22:1 (2015), 132–149.
3. [3] Aggarwal, B.B., Bhardwaj, A., Aggarwal, R.S., Seeram, N.P., Shishodia, S., Takada, Y., Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res 24:5A (2004), 2783–2840.
4. [4] Pervaiz, S., Resveratrol: from grapevines to mammalian biology. FASEB J 17 (2003), 1975–1985.
5. [5] Hu, Y., Wang, S., Wu, X., Zhang, J., Chen, R., Chen, M., et al. Chinese herbal medicine-derived compounds for cancer therapy: a focus on hepatocellular carcinoma. J Ethnopharmacol 149:3 (2013), 601–612.
6. [6] Mukherjee, S., Dudley, J.I., Das, D.K., Dose-dependency of resveratrol in providing health benefits. Dose Response 8:4 (2010), 478–500.
7. [7] Signorelli, P., Ghidoni, R., Resveratrol as an anticancer nutrient: molecular basis, and promises. J Nutr Biochem 16:8 (2005), 449–466.
8. [8] Regev-Shoshani, G., Shoseyov, O., Bilkis, I., Kerem, Z., Glycosylation of resveratrol protects it from enzymic oxidation. Biochem J 374:Pt 1 (2003), 157–163.
9. [9] Krasnow, M.N., Murphy, T.M., Polyphenol glucosylating activity in cell suspensions of grape (Vitis vinifera). J Agric Food Chem 52:11 (2004), 3467–3472.
10. [10] la Porte, C., Voduc, N., Zhang, G., Seguin, I., Tardiff, D., Singhal, N., et al. Steady-state pharmacokinetics and tolerability of trans-resveratrol 2000 mg twice daily with food, quercetin and alcohol (ethanol) in healthy human subjects. Clin Pharmacokinet 49:7 (2010), 449–454.
11. [11] Wong, R.H., Howe, P.R., Buckley, J.D., Coates, A.M., Kunz, I., Berry, N.M., Acute resveratrol supplementation improves flow-mediated dilatation in overweight/obese individuals with mildly elevated blood pressure. Nutr Metab Cardiovasc Dis 21:11 (2011), 851–856.
12. [12] Almeida, L., Vaz-da-Silva, M., Falcão, A., Soares, E., Costa, R., Loureiro, A.I., et al. Pharmacokinetic and safety profile of trans-resveratrol in a rising multiple-dose study in healthy volunteers. Mol Nutr Food Res 53:Suppl. 1 (2009), S7–S15.
13. [13] Patel, K.R., Scott, E., Brown, V.A., Gescher, A.J., Steward, W.P., Brown, K., Clinical trials of resveratrol. Ann N Y Acad Sci 1215 (2011), 161–169.
14. [14] Zamora-Ros, R., Urpí-Sardà, M., Lamuela-Raventós, R.M., Estruch, R., Vázquez-Agell, M., Serrano-Martínez, M., et al. Diagnostic performance of urinary resveratrol metabolites as a biomarker of moderate wine consumption. Clin Chem 52:7 (2006), 1373–1380.
15. [15] Chow, H.H., Garland, L.L., Hsu, C.H., Vining, D.R., Chew, W.M., Miller, J.A., et al. Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study. Cancer Prev Res (Phila) 3:9 (2010), 1168–1175.
16. [16] Tomé-Carneiro, J., Gonzálvez, M., Larrosa, M., Yáñez-Gascón, M.J., García-Almagro, F.J., Ruiz-Ros, J.A., et al. One-year consumption of a grape nutraceutical containing resveratrol improves the inflammatory and fibrinolytic status of patients in primary prevention of cardiovascular disease. Am J Cardiol 110:3 (2012), 356–363.
17. [17] Gambini, J., Inglés, M., Olaso, G., Lopez-Grueso, R., Bonet-Costa, V., Gimeno-Mallench, L., et al. Properties of resveratrol: in vitro and in vivo studies about metabolism, bioavailability, and biological effects in animal models and humans. Oxid Med Cell Longev, 2015, 2015, 837042.
18. [18] Jannin, B., Menzel, M., Berlot, J.P., Delmas, D., Lançon, A., Latruffe, N., Transport of resveratrol, a cancer chemopreventive agent, to cellular targets: plasmatic protein binding and cell uptake. Biochem Pharmacol 68:6 (2004), 1113–1118 [review].
19. [19] Walle, T., Hsieh, F., DeLegge, M.H., Oatis, J.E. Jr., Walle, U.K., High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos 32:12 (2004), 1377–1382.
20. [20] Kaldas, M.I., Walle, U.K., Walle, T., Resveratrol transport and metabolism by human intestinal Caco-2 cells. J Pharm Pharmacol 55:3 (2003), 307–312.
21. [21] Vitrac, X., Desmoulière, A., Brouillaud, B., Krisa, S., Deffieux, G., Barthe, N., et al. Distribution of [14C]-trans-resveratrol, a cancer chemopreventive polyphenol, in mouse tissues after oral administration. Life Sci 72:20 (2003), 2219–2233.
22. [22] Boocock, D.J., Faust, G.E., Patel, K.R., Schinas, A.M., Brown, V.A., Ducharme, M.P., et al. Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent. Cancer Epidemiol Biomarkers Prev 16:6 (2007), 1246–1252.
23. [23] Goldberg, D.M., Yan, J., Soleas, G.J., Absorption of three wine-related polyphenols in three different matrices by healthy subjects. Clin Biochem 36:1 (2003), 79–87.
24. [24] Ortuño, J.E., Kontaxakis, G., Rubio, J.L., Guerra, P., Santos, A., Efficient methodologies for system matrix modelling in iterative image reconstruction for rotating high-resolution PET. Phys Med Biol 55:7 (2010), 1833–1861.
25. [25] Pirola, L., Frojdo, S., Resveratrol: one molecule, many targets. IUBMB Life 60:5 (2008), 323–332.
26. [26] Hung, L.M., Chen, J.K., Huang, S.S., Lee, R.S., Su, M.J., Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes. Cardiovasc Res 47:3 (2000), 549–555.
27. [27] Kirk, R.I., Deitch, J.A., Wu, J.M., Lerea, K.M., Resveratrol decreases early signaling events in washed platelets but has little effect on platelet in whole blood. Blood Cells Mol Dis 26:2 (2000), 144–150.
28. [28] Valdecantos, M.P., Pérez-Matute, P., Quintero, P., Martínez, J.A., Vitamin C, resveratrol and lipoic acid actions on isolated rat liver mitochondria: all antioxidants but different. Redox Rep 15:5 (2010), 207–216.
29. [29] de la Lastra, C.A., Villegas, I., Resveratrol as an antioxidant and pro-oxidant agent: mechanisms and clinical implications. Biochem Soc Trans 35:Pt 5 (2007), 1156–1160.
30. [30] Sadi, G., Bozan, D., Yildiz, H.B., Redox regulation of antioxidant enzymes: post-translational modulation of catalase and glutathione peroxidase activity by resveratrol in diabetic rat liver. Mol Cell Biochem 393:1–2 (2014), 111–122.
31. [31] Vanamala, J., Reddivari, L., Radhakrishnan, S., Tarver, C., Resveratrol suppresses IGF-1 induced human colon cancer cell proliferation and elevates apoptosis via suppression of IGF-1R/Wnt and activation of p53 signaling pathways. BMC Cancer, 10, 2010, 238.
32. [32] Cucciolla, V., Borriello, A., Oliva, A., Galletti, P., Zappia, V., Della Ragione, F., Resveratrol: from basic science to the clinic. Cell Cycle 6:20 (2007), 2495–2510.
33. [33] Sun, A.Y., Wang, Q., Simonyi, A., Sun, G.Y., Resveratrol as a therapeutic agent for neurodegenerative diseases. Mol Neurobiol 41:2–3 (2010), 375–383.
34. [34] Alberdi, G., Rodríguez, V.M., Miranda, J., Macarulla, M.T., Arias, N., Andrés-Lacueva, C., et al. Changes in white adipose tissue metabolism induced by resveratrol in rats. Nutr Metab (Lond), 8(1), 2011, 29.
35. [35] Lasa, A., Schweiger, M., Kotzbeck, P., Churruca, I., Simon, E., Zechner, R., et al. Resveratrol regulates lipolysis via adipose triglyceride lipase. J Nutr Biochem 23:4 (2012), 379–384.
36. [36] Su, J.L., Yang, C.Y., Zhao, M., Kuo, M.L., Yen, M.L., Forkhead proteins are critical for bone morphogenetic protein-2 regulation and anti-tumor activity of resveratrol. J Biol Chem 282:27 (2007), 19385–19398.
37. [37] Dudley, J., Das, S., Mukherjee, S., Das, D.K., Resveratrol, a unique phytoalexin present in red wine, delivers either survival signal or death signal to the ischemic myocardium depending on dose. J Nutr Biochem 20:6 (2009), 443–452.
38. [38] Ahmad, K.A., Clement, M.V., Pervaiz, S., Pro-oxidant activity of low doses of resveratrol inhibits hydrogen peroxide-induced apoptosis. Ann N Y Acad Sci 1010 (2003), 365–373.
39. [39] Ferry-Dumazet, H., Garnier, O., Mamani-Matsuda, M., Vercauteren, J., Belloc, F., Billiard, C., et al. Resveratrol inhibits the growth and induces the apoptosis of both normal and leukemic hematopoietic cells. Carcinogenesis 23:8 (2002), 1327–1333.
40. [40] Lee, K.W., Lee, H.J., The roles of polyphenols in cancer chemoprevention. Biofactors 26:2 (2006), 105–121.
41. [41] Ozgová, S., Hermánek, J., Gut, I., Different antioxidant effects of polyphenols on lipid peroxidation and hydroxyl radicals in the NADPH-, Fe-ascorbate- and Fe-microsomal systems. Biochem Pharmacol 66:7 (2003), 1127–1137.
42. [42] Stojanovic, S., Sprinz, H., Brede, O., Efficiency and mechanism of the antioxidant action of trans-resveratrol and its analogues in the radical liposome oxidation. Arch Biochem Biophys 391:1 (2001), 79–89.
43. [43] Bradamante, S., Barenghi, L., Villa, A., Cardiovascular protective effects of resveratrol. Cardiovasc Drug Rev 22:3 (2004), 169–188.
44. [44] Acquaviva, R., Russo, A., Campisi, A., Sorrenti, V., Giacomo, C., Barcellona, M.L., et al. Antioxidant activity and protective effect on DNA cleavage of resveratrol. J Food Sci 67:1 (2002), 137–141.
45. [45] Wu, D., Cederbaum, A.I., Alcohol, oxidative stress, and free radical damage. Alcohol Res Health 27:4 (2003), 277–284 [review].
46. [46] Losa, G.A., Resveratrol modulates apoptosis and oxidation in human blood mononuclear cells. Eur J Clin Invest 33:9 (2003), 818–823.
47. [47] Leonard, S.S., Xia, C., Jiang, B.H., Stinefelt, B., Klandorf, H., Harris, G.K., et al. Resveratrol scavenges reactive oxygen species and effects radical-induced cellular responses. Biochem Biophys Res Commun 309:4 (2003), 1017–1026.
48. [48] Martinez, J., Moreno, J.J., Effect of resveratrol, a natural polyphenolic compound, on reactive oxygen species and prostaglandin production. Biochem Pharmacol 59:7 (2000), 865–870.
49. [49] Goswami, S.K., Das, D.K., Resveratrol and chemoprevention. Cancer Lett 284:1 (2009), 1–6.
50. [50] Olas, B., Wachowicz, B., Bald, E., Głowacki, R., The protective effects of resveratrol against changes in blood platelet thiols induced by platinum compounds. J Physiol Pharmacol 55:2 (2004), 467–476.
51. [51] Yen, G.C., Duh, P.D., Lin, C.W., Effects of resveratrol and 4-hexylresorcinol on hydrogen peroxide-induced oxidative DNA damage in human lymphocytes. Free Radic Res 37:5 (2003), 509–514.
52. [52] Chung-man Ho, J., Zheng, S., Comhair, S.A., Farver, C., Erzurum, S.C., Differential expression of manganese superoxide dismutase and catalase in lung cancer. Cancer Res 61:23 (2001), 8578–8585.
53. [53] Yu, C., Shin, Y.G., Kosmeder, J.W., Pezzuto, J.M., van Breemen, R.B., Liquid chromatography/tandem mass spectrometric determination of inhibition of human cytochrome P450 isozymes by resveratrol and resveratrol-3-sulfate. Rapid Commun Mass Spectrom 17:4 (2003), 307–313.
54. [54] Szaefer, H., Cichocki, M., Brauze, D., Baer-Dubowska, W., Alteration in phase I and II enzyme activities and polycyclic aromatic hydrocarbons–DNA adduct formation by plant phenolics in mouse epidermis. Nutr Cancer 48:1 (2004), 70–77.
55. [55] Aggarwal, B.B., Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3:9 (2003), 745–756 [review].
56. [56] Han, G., Xia, J., Gao, J., Inagaki, Y., Tang, W., Kokudo, N., Anti-tumor effects and cellular mechanisms of resveratrol. Drug Discov Ther 9:1 (2015), 1–12.
57. [57] Dörrie, J., Gerauer, H., Wachter, Y., Zunino, S.J., Resveratrol induces extensive apoptosis by depolarizing mitochondrial membranes and activating caspase-9 in acute lymphoblastic leukemia cells. Cancer Res 61 (2001), 4731–4739.
58. [58] Joe, A.K., Liu, H., Suzui, M., Vural, M.E., Xiao, D., Weinstein, I.B., Resveratrol induces growth inhibition, S-phase arrest, apoptosis, and changes in biomarker expression in several human cancer cell lines. Clin Cancer Res 8:3 (2002), 893–903.
59. [59] Athar, M., Back, J.H., Kopelovich, L., Bickers, D.R., Kim, A.L., Multiple molecular targets of resveratrol: anti-carcinogenic mechanisms. Arch Biochem Biophys 486:2 (2009), 95–102 [review].
60. [60] Fulda, S., Debatin, K.M., Resveratrol modulation of signal transduction in apoptosis and cell survival: a mini-review. Cancer Detect Prev 30:3 (2006), 217–223.
61. [61] Mo, W., Xu, X., Xu, L., Wang, F., Ke, A., Wang, X., et al. Resveratrol inhibits proliferation and induces apoptosis through the hedgehog signaling pathway in pancreatic cancer cell. Pancreatology 11:6 (2011), 601–609.
62. [62] Alkhalaf, M., Resveratrol-induced apoptosis is associated with activation of p53 and inhibition of protein translation in T47D human breast cancer cells. Pharmacology 80:2–3 (2007), 134–143.
63. [63] Sakamoto, T., Horiguchi, H., Oguma, E., Kayama, F., Effects of diverse dietary phytoestrogens on cell growth, cell cycle and apoptosis in estrogen-receptor-positive breast cancer cells. J Nutr Biochem 21:9 (2010), 856–864.
64. [64] Miki, H., Uehara, N., Kimura, A., Sasaki, T., Yuri, T., Yoshizawa, K., et al. Resveratrol induces apoptosis via ROS-triggered autophagy in human colon cancer cells. Int J Oncol 40:4 (2012), 1020–1028.
65. [65] Luo, H., Yang, A., Schulte, B.A., Wargovich, M.J., Wang, G.Y., Resveratrol induces premature senescence in lung cancer cells via ROS-mediated DNA damage. PLoS ONE, 8(3), 2013, e60065.
66. [66] Zhang, W., Wang, X., Chen, T., Resveratrol induces mitochondria-mediated AIF and to a lesser extent caspase-9-dependent apoptosis in human lung adenocarcinoma ASTC-a-1 cells. Mol Cell Biochem 354:1–2 (2011), 29–37.
67. [67] Gu, W., Luo, J., Brooks, C.L., Nikolaev, A.Y., Li, M., Dynamics of the p53 acetylation pathway. Novartis Found Symp 259 (2004), 197–205.
68. [68] Fulda, S., Debatin, K.M., Sensitization for tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by the chemopreventive agent resveratrol. Cancer Res 64:1 (2004), 337–346.
69. [69] Altieri, D.C., Survivin, versatile modulation of cell division and apoptosis in cancer. Oncogene 22:53 (2003), 8581–8589 [review].
70. [70] Castedo, M., Perfettini, J.L., Roumier, T., Andreau, K., Medema, R., Kroemer, G., Cell death by mitotic catastrophe: a molecular definition. Oncogene 23:16 (2004), 2825–2837 [review].
71. [71] Jeong, N.Y., Yoon, Y.G., Rho, J.H., Lee, J.S., Lee, S.Y., Yoo, K.S., et al. The novel resveratrol analog HS-1793-induced polyploid LNCaP prostate cancer cells are vulnerable to downregulation of Bcl-xL. Int J Oncol 38:6 (2011), 1597–1604.
72. [72] Chalal, M., Delmas, D., Meunier, P., Latruffe, N., Vervandier-Fasseur, D., Inhibition of cancer derived cell lines proliferation by synthesized hydroxylated stilbenes and new ferrocenyl-stilbene analogs. Comparison with resveratrol. Molecules 19:6 (2014), 7850–7868.
73. [73] Rivière, C., Richard, T., Quentin, L., Krisa, S., Mérillon, J.M., Monti, J.P., Inhibitory activity of stilbenes on Alzheimer's beta-amyloid fibrils in vitro. Bioorg Med Chem 15:2 (2007), 1160–1167.
74. [74] Marambaud, P., Zhao, H., Davies, P., Resveratrol promotes clearance of Alzheimer's disease amyloid-beta peptides. J Biol Chem 280:45 (2005), 37377–37382.
75. [75] Savaskan, E., Olivieri, G., Meier, F., Seifritz, E., Wirz-Justice, A., Müller-Spahn, F., Red wine ingredient resveratrol protects from beta-amyloid neurotoxicity. Gerontology 49:6 (2003), 380–383.
76. [76] Jang, J.H., Surh, Y.J., Protective effect of resveratrol on beta-amyloid-induced oxidative PC12 cell death. Free Radic Biol Med 34:8 (2003), 1100–1110.
77. [77] Rocha-González, H.I., Ambriz-Tututi, M., Granados-Soto, V., Resveratrol: a natural compound with pharmacological potential in neurodegenerative diseases. CNS Neurosci Ther 14:3 (2008), 234–247.
78. [78] Camandola, S., Mattson, M.P., NF-kappa, B., NF-kappa B as a therapeutic target in neurodegenerative diseases. Expert Opin Ther Targets 11:2 (2007), 123–132 [review].
79. [79] Valerio, A., Boroni, F., Benarese, M., Sarnico, I., Ghisi, V., Bresciani, L.G., et al. NF-kappaB pathway: a target for preventing beta-amyloid (Abeta)-induced neuronal damage and Abeta42 production. Eur J Neurosci 23:7 (2006), 1711–1720.
80. [80] Park, S.H., Choi, W.S., Yoon, S.Y., Ahn, Y.S., Oh, Y.J., Activation of NF-kappaB is involved in 6-hydroxydopamine-but not MPP+-induced dopaminergic neuronal cell death: its potential role as a survival determinant. Biochem Biophys Res Commun 322:3 (2004), 727–733.
81. [81] Khoshnan, A., Ko, J., Watkin, E.E., Paige, L.A., Reinhart, P.H., Patterson, P.H., Activation of the IkappaB kinase complex and nuclear factor-kappaB contributes to mutant huntingtin neurotoxicity. J Neurosci 24:37 (2004), 7999–8008.
82. [82] Lee, M.K., Kang, S.J., Poncz, M., Song, K.J., Park, K.S., Resveratrol protects SH-SY5Y neuroblastoma cells from apoptosis induced by dopamine. Exp Mol Med 39:3 (2007), 376–384.
83. [83] Chalimoniuk, M., Głowacka, J., Zabielna, A., Eckert, A., Strosznajder, J.B., Nitric oxide alters arachidonic acid turnover in brain cortex synaptoneurosomes. Neurochem Int 48:1 (2006), 1–8.
84. [84] Parker, A.J., Arango, M., Abderrahmane, S., Lambert, E., Tourette, C., Catoire, H., et al. Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons. Med Sci 21:5 (2005), 556–557.
85. [85] Wood, J.G., Rogina, B., Lavu, S., Howitz, K., Helfand, S.L., Tatar, M., et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430:7000 (2004), 686–689.
86. [86] Valenzano, D.R., Terzibasi, E., Genade, T., Cattaneo, A., Domenici, L., Cellerino, A., Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Curr Biol 16:3 (2006), 296–300.
87. [87] Juan, L.J., Shia, W.J., Chen, M.H., Yang, W.M., Seto, E., Lin, Y.S., et al. Histone deacetylases specifically down-regulate p53-dependent gene activation. J Biol Chem 275:27 (2000), 20436–20443.
88. [88] Lagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H., Lerin, C., Daussin, F., et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127:6 (2006), 1109–1122.
89. [89] Lin, J., Wu, H., Tarr, P.T., Zhang, C.Y., Wu, Z., Boss, O., et al. Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 418:6899 (2002), 797–801.
90. [90] Lin, J.N., Lin, V.C., Rau, K.M., Shieh, P.C., Kuo, D.H., Shieh, J.C., et al. Resveratrol modulates tumor cell proliferation and protein translation via SIRT1-dependent AMPK activation. J Agric Food Chem 58:3 (2010), 1584–1592.
91. [91] Park, S.J., Ahmad, F., Philp, A., Baar, K., Williams, T., Luo, H., et al. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 148:3 (2012), 421–433.
92. [92] Tennen, R.I., Michishita-Kioi, E., Chua, K.F., Finding a target for resveratrol. Cell 148:3 (2012), 387–389.
93. [93] Rondinone, C.M., Carvalho, E., Rahn, T., Manganiello, V.C., Degerman, E., Smith, U.P., Phosphorylation of PDE3B by phosphatidylinositol 3-kinase associated with the insulin receptor. J Biol Chem 275:14 (2000), 10093–10098.
94. [94] Houslay, M.D., Schafer, P., Zhang, K.Y., Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov Today 10:22 (2005), 1503–1519.