Title

大麻二酚誘發初代免疫細胞凋亡之機制探討

Translated Titles

The mechanisms of cannabidiol-induced apoptosis in primary immune cells

DOI

10.6342/NTU.2012.03016

Authors

吳欣穎

Key Words

凋亡 ; 大麻二酚 ; caspase ; caveolin-1 ; HU-331 ; 脂筏 ; 淋巴球 ; 微膠細胞 ; 氧化性壓力 ; thiol流失 ; apoptosis ; cannabidiol ; caspase ; caveolin-1 ; HU-331 ; lipid raft ; lymphocyte ; microglia ; oxidative stress ; thiol depletion

PublicationName

臺灣大學獸醫學研究所學位論文

Volume or Term/Year and Month of Publication

2012年

Academic Degree Category

博士

Advisor

詹東榮

Content Language

英文

Chinese Abstract

大麻二酚是大麻生物鹼中主要不具中樞活性的成份,具有許多的藥理作用,包括免疫調節及抗發炎。本實驗的主旨在探討大麻二酚對初代免疫細胞,包括脾臟細胞及微膠細胞之促凋亡作用及其潛在之作用機制。在小鼠脾臟細胞,大麻二酚會誘發細胞凋亡、產生活性氧化物、降低細胞內glutathione(GSH)之含量,並且促進caspase-8的活化。上述大麻二酚之作用,在給予thiol類抗氧化劑N-acetyl-L-cysteine(NAC)後,即被回復。給予caspase-8的抑制劑也可以有效地回復大麻二酚誘發之凋亡作用,但是不影響大麻二酚造成的活性氧化物之生成。上述實驗結果說明大麻二酚於初代淋巴球細胞誘發之凋亡作用和氧化性壓力造成之caspase-8的活化密切相關。 由於大麻二酚已被證實可被微粒體中的酵素轉變成hydroxyquinone類的代謝物HU-331,並和細胞內的GSH形成鍵結物。為了進一步釐清大麻二酚誘發脾臟細胞凋亡之機制,本研究接著測試HU-331是否會經由造成脾臟細胞內GSH的流失而誘發凋亡。結果顯示HU-331會誘發脾臟細胞之凋亡及細胞內thiol和GSH的逐漸流失;給予thiol類抗氧化劑NAC及N-(2-mercaptopropionyl) glycine可以回復前述HU-331致凋亡及GSH流失之作用,而非thiol類的抗氧化物catalase及pyruvate則無效。在脾臟細胞也觀察到類似的結果,即大麻二酚的凋亡作用能被thiol類抗氧化劑回復,而非thiol類的抗氧化物則無效。上述結果說明大麻二酚可能是經由其活性代謝物HU-331造成細胞內thiol之流失而導致脾臟細胞的凋亡。 在小鼠初代微膠細胞,大麻二酚會誘發細胞凋亡及活化caspase-8及caspase-9,機制研究顯示抗氧化劑NAC和GSH、GPR55致效劑abnormal-CBD及vanilloid受體、CB1和CB2受體拮抗劑均無法回復大麻二酚所誘發之凋亡作用。相反地,脂筏破壞劑methyl-β-cyclodextrin (MCD)則可有效地降低大麻二酚誘發之微膠細胞凋亡和caspase的活化。此外,大麻二酚會誘發lipid raft coalescence,增加GM1 ganglioside 和caveolin-1表現,這些作用也可被MCD所回復。上述結果說明大麻二酚會經由誘發lipid raft coalescence、增加GM1 ganglioside和caveolin-1的表現而導致初代微膠細胞的凋亡。 綜合上述,本研究顯示大麻二酚分別經由thiol流失及脂筏相關之機制,誘發初代脾臟細胞及微膠細胞之凋亡,本研究首度證實大麻二酚會誘發不同之初代免疫細胞凋亡,拓展了大麻二酚促凋亡作用之範疇,並且對大麻二酚誘發免疫細胞凋亡之機制提供了新的見解,誘發免疫細胞之凋亡可能是大麻二酚免疫調節及抗發炎作用之一個重要機制。

English Abstract

Cannabidiol (CBD), the major non-psychoactive cannabinoid in marijuana, exhibits a variety of pharmacological activities, including immunomodulatory and anti-inflammatory effects. The objective of the current study is to investigate the pro-apoptotic effect of CBD on primary immune cells, including murine splenocytes and microglial cells. In splenocytes, CBD markedly enhanced the apoptosis, elicited the production of reactive oxygen species (ROS), diminished the level of intracellular glutathione (GSH), and stimulated the activation of caspase-8, all of which were remarkably attenuated by the thiol antioxidant N-acetyl-L-cysteine (NAC). Pretreatment of splenocytes with caspase-8 inhibitor significantly attenuated CBD-mediated apoptosis, but not ROS production. Collectively, these results demonstrated that CBD-induced apoptosis in primary lymphocytes is closely associated with oxidative stress-dependent activation of caspase-8. It has been reported that CBD can be metabolized by microsomal enzymes to cannabidiol hydroxyquinone (HU-331) that forms adducts with glutathione. To further investigate the mechanism of CBD-induced apoptosis in splenocytes, the present study tested the hypothesis that HU-331 could cause apoptosis via the depletion of thiols in splenocytes. HU-331 treatment resulted in splenocyte apoptosis and a gradual diminishment in the cellular thiols and glutathione. The HU-331-induced apoptosis and thiol diminishment were abrogated in the presence of thiol antioxidants, including NAC and N-(2-mercaptopropionyl) glycine, whereas the non-thiol antioxidants catalase and pyruvate were ineffective. Similar results were also observed in CBD-treated splenocytes, in which thiol antioxidants but not non-thiol antioxidants markedly attenuated CBD-induced apoptosis. These results suggest that HU-331 might be an active metabolite of CBD potentially contributing to the induction of apoptosis in splenocytes, and that the apoptosis is primarily mediated by the loss of cellular thiols. In primary microglia, CBD resulted in the induction of apoptosis and marked activation of both caspase-8 and -9. Mechanistic studies revealed that antioxidants, including NAC and GSH, the GPR55 agonist abnormal-CBD and specific antagonists for vanilloid, CB1 and CB2 cannabinoid receptors did not counteract the apoptosis induced by CBD. In contrast, methyl-β-cyclodextrin (MCD), a lipid raft disruptor, potently attenuated CBD-induced microglial apoptosis and caspase activation. In addition, CBD induced lipid raft coalescence and augmented the expression of GM1 ganglioside and caveolin-1, all of which were attenuated by MCD. These results suggest that CBD induces a marked pro-apoptotic effect in primary microglia through lipid raft coalescence and elevated expression of GM1 ganglioside and caveolin-1. In summary, the present study demonstrated the pro-apoptotic effect of CBD in primary splenocytes and microglial cells, which was predominantly mediated by the thiol depletion and lipid raft-related mechanism, respectively. The present findings extend our current understanding on the spectrum of CBD-mediated apoptosis and provide new insights to the underlying mechanisms in primary immune cells. The induction of immune cell apoptosis may be a critical mechanism contributing to the immunomodulatory and anti-inflammatory properties of CBD.

Topic Category 獸醫專業學院 > 獸醫學研究所
生物農學 > 獸醫
Reference
  1. Andradas C, Caffarel MM, Perez-Gomez E, Salazar M, Lorente M, Velasco G, Guzman M and Sanchez C. The orphan G protein-coupled receptor GPR55 promotes cancer cell proliferation via ERK. Oncogene 30: 245-252, 2010.
    連結:
  2. Baczynsky WO and Zimmerman AM. Effects of delta 9-tetrahydrocannabinol, cannabinol and cannabidiol on the immune system in mice. II. In vitro investigation using cultured mouse splenocytes. Pharmacology 26: 12-19, 1983.
    連結:
  3. Bari M, Battista N, Fezza F, Finazzi-Agro A and Maccarrone M. Lipid rafts control signaling of type-1 cannabinoid receptors in neuronal cells. Implications for anandamide-induced apoptosis. J Biol Chem 280: 12212-12220, 2005.
    連結:
  4. Ben-Shabat S, Hanus LO, Katzavian G and Gallily R. New cannabidiol derivatives: synthesis, binding to cannabinoid receptor, and evaluation of their antiinflammatory activity. J Med Chem 49: 1113-1117, 2006.
    連結:
  5. Bidinger B, Torres R, Rossetti RG, Brown L, Beltre R, Burstein S, Lian JB, Stein GS and Zurier RB. Ajulemic acid, a nonpsychoactive cannabinoid acid, induces apoptosis in human T lymphocytes. Clin Immunol 108: 95-102, 2003.
    連結:
  6. Bornheim LM and Grillo MP. Characterization of cytochrome P450 3A inactivation by cannabidiol: possible involvement of cannabidiol-hydroxyquinone as a P450 inactivator. Chem Res Toxicol 11: 1209-1216, 1998.
    連結:
  7. Borrelli F, Aviello G, Romano B, Orlando P, Capasso R, Maiello F, Guadagno F, Petrosino S, Capasso F, Di Marzo V and Izzo AA. Cannabidiol, a safe and non-psychotropic ingredient of the marijuana plant Cannabis sativa, is protective in a murine model of colitis. J Mol Med (Berl) 87: 1111-1121, 2009.
    連結:
  8. Brown AJ. Novel cannabinoid receptors. Br J Pharmacol 152: 567-575, 2007.
    連結:
  9. Cabral GA and Staab A. Effects on the immune system. Handb Exp Pharmacol: 385-423, 2005.
    連結:
  10. Cai YJ, Lu JJ, Zhu H, Xie H, Huang M, Lin LP, Zhang XW and Ding J. Salvicine triggers DNA double-strand breaks and apoptosis by GSH-depletion-driven H2O2 generation and topoisomerase II inhibition. Free Radic Biol Med 45: 627-635, 2008.
    連結:
  11. Chen YC, Kung FL, Tsai IL, Chou TH, Chen IS and Guh JH. Cryptocaryone, a natural dihydrochalcone, induces apoptosis in human androgen independent prostate cancer cells by death receptor clustering in lipid raft and nonraft compartments. J Urol 183: 2409-2418, 2010.
    連結:
  12. Correa F, Docagne F, Mestre L, Clemente D, Hernangomez M, Loria F and Guaza C. A role for CB2 receptors in anandamide signalling pathways involved in the regulation of IL-12 and IL-23 in microglial cells. Biochem Pharmacol 77: 86-100, 2009.
    連結:
  13. Costa B, Colleoni M, Conti S, Parolaro D, Franke C, Trovato AE and Giagnoni G. Oral anti-inflammatory activity of cannabidiol, a non-psychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw. Naunyn Schmiedebergs Arch Pharmacol 369: 294-299, 2004.
    連結:
  14. d'Azzo A, Tessitore A and Sano R. Gangliosides as apoptotic signals in ER stress response. Cell Death Differ 13: 404-414, 2006.
    連結:
  15. Daigle I and Simon HU. Critical role for caspases 3 and 8 in neutrophil but not eosinophil apoptosis. Int Arch Allergy Immunol 126: 147-156, 2001.
    連結:
  16. Davis W, Jr., Ronai Z and Tew KD. Cellular thiols and reactive oxygen species in drug-induced apoptosis. J Pharmacol Exp Ther 296: 1-6, 2001.
    連結:
  17. Deshpande VS and Kehrer JP. Oxidative stress-driven mechanisms of nordihydroguaiaretic acid-induced apoptosis in FL5.12 cells. Toxicol Appl Pharmacol 214: 230-236, 2006.
    連結:
  18. Dey A, Yadav S, Dhawan A, Seth PK and Parmar D. Evidence for cytochrome P450 3A expression and catalytic activity in rat blood lymphocytes. Life Sci 79: 1729-1735, 2006.
    連結:
  19. Do Y, McKallip RJ, Nagarkatti M and Nagarkatti PS. Activation through cannabinoid receptors 1 and 2 on dendritic cells triggers NF-kappaB-dependent apoptosis: novel role for endogenous and exogenous cannabinoids in immunoregulation. J Immunol 173: 2373-2382, 2004.
    連結:
  20. Downer EJ, Gowran A and Campbell VA. A comparison of the apoptotic effect of Delta(9)-tetrahydrocannabinol in the neonatal and adult rat cerebral cortex. Brain Res 1175: 39-47, 2007.
    連結:
  21. El-Gohary M and Eid MA. Effect of cannabinoid ingestion (in the form of bhang) on the immune system of high school and university students. Hum Exp Toxicol 23: 149-156, 2004.
    連結:
  22. Esposito G, De Filippis D, Maiuri MC, De Stefano D, Carnuccio R and Iuvone T. Cannabidiol inhibits inducible nitric oxide synthase protein expression and nitric oxide production in beta-amyloid stimulated PC12 neurons through p38 MAP kinase and NF-kappaB involvement. Neurosci Lett 399: 91-95, 2006.
    連結:
  23. Esposito G, Scuderi C, Savani C, Steardo L, Jr., De Filippis D, Cottone P, Iuvone T, Cuomo V and Steardo L. Cannabidiol in vivo blunts beta-amyloid induced neuroinflammation by suppressing IL-1beta and iNOS expression. Br J Pharmacol 151: 1272-1279, 2007.
    連結:
  24. Friedman H, Newton C and Klein TW. Microbial infections, immunomodulation, and drugs of abuse. Clin Microbiol Rev 16: 209-219, 2003.
    連結:
  25. Gajate C, Gonzalez-Camacho F and Mollinedo F. Lipid raft connection between extrinsic and intrinsic apoptotic pathways. Biochem Biophys Res Commun 380: 780-784, 2009.
    連結:
  26. Gajate C and Mollinedo F. Cytoskeleton-mediated death receptor and ligand concentration in lipid rafts forms apoptosis-promoting clusters in cancer chemotherapy. J Biol Chem 280: 11641-11647, 2005.
    連結:
  27. Gajate C and Mollinedo F. Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts. Blood 109: 711-719, 2007.
    連結:
  28. Galiegue S, Mary S, Marchand J, Dussossoy D, Carriere D, Carayon P, Bouaboula M, Shire D, Le Fur G and Casellas P. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 232: 54-61, 1995.
    連結:
  29. Gallily R, Even-Chena T, Katzavian G, Lehmann D, Dagan A and Mechoulam R. Gamma-irradiation enhances apoptosis induced by cannabidiol, a non-psychotropic cannabinoid, in cultured HL-60 myeloblastic leukemia cells. Leuk Lymphoma 44: 1767-1773, 2003.
    連結:
  30. Gargalovic P and Dory L. Cellular apoptosis is associated with increased caveolin-1 expression in macrophages. J Lipid Res 44: 1622-1632, 2003.
    連結:
  31. Guzman M. Effects on cell viability. Handb Exp Pharmacol: 627-642, 2005.
    連結:
  32. Haddad JJ. Redox and oxidant-mediated regulation of apoptosis signaling pathways: immuno-pharmaco-redox conception of oxidative siege versus cell death commitment. Int Immunopharmacol 4: 475-493, 2004.
    連結:
  33. Hampson AJ, Grimaldi M, Lolic M, Wink D, Rosenthal R and Axelrod J. Neuroprotective antioxidants from marijuana. Ann N Y Acad Sci 899: 274-282, 2000.
    連結:
  34. Hegde VL, Nagarkatti PS and Nagarkatti M. Role of myeloid-derived suppressor cells in amelioration of experimental autoimmune hepatitis following activation of TRPV1 receptors by cannabidiol. PLoS One 6: e18281, 2011.
    連結:
  35. Hengartner MO. The biochemistry of apoptosis. Nature 407: 770-776, 2000.
    連結:
  36. Hodges VM, Molloy GY and Wickramasinghe SN. Demonstration of mRNA for five species of cytochrome P450 in human bone marrow, bone marrow-derived macrophages and human haemopoietic cell lines. Br J Haematol 108: 151-156, 2000.
    連結:
  37. Huang HL, Fang LW, Lu SP, Chou CK, Luh TY and Lai MZ. DNA-damaging reagents induce apoptosis through reactive oxygen species-dependent Fas aggregation. Oncogene 22: 8168-8177, 2003.
    連結:
  38. Iuvone T, Esposito G, Esposito R, Santamaria R, Di Rosa M and Izzo AA. Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells. J Neurochem 89: 134-141, 2004.
    連結:
  39. Izzo AA, Borrelli F, Capasso R, Di Marzo V and Mechoulam R. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci 30: 515-527, 2009.
    連結:
  40. Jan TR, Su ST, Wu HY and Liao MH. Suppressive effects of cannabidiol on antigen-specific antibody production and functional activity of splenocytes in ovalbumin-sensitized BALB/c mice. Int Immunopharmacol 7: 773-780, 2007.
    連結:
  41. Jia W, Hegde VL, Singh NP, Sisco D, Grant S, Nagarkatti M and Nagarkatti PS. Delta9-tetrahydrocannabinol-induced apoptosis in Jurkat leukemia T cells is regulated by translocation of Bad to mitochondria. Mol Cancer Res 4: 549-562, 2006.
    連結:
  42. Jiang YN, Li YH, Ke MW, Tseng TY, Tang YB, Huang MC, Cheng WT and Ju YT. Caveolin-1 sensitizes rat pituitary adenoma GH3 cells to bromocriptine induced apoptosis. Cancer Cell Int 7: 1, 2007.
    連結:
  43. Kaminski NE. Regulation of the cAMP cascade, gene expression and immune function by cannabinoid receptors. J Neuroimmunol 83: 124-132, 1998.
    連結:
  44. Kaminski NE, Koh WS, Yang KH, Lee M and Kessler FK. Suppression of the humoral immune response by cannabinoids is partially mediated through inhibition of adenylate cyclase by a pertussis toxin-sensitive G-protein coupled mechanism. Biochem Pharmacol 48: 1899-1908, 1994.
    連結:
  45. Kim HJ and Nel AE. The role of phase II antioxidant enzymes in protecting memory T cells from spontaneous apoptosis in young and old mice. J Immunol 175: 2948-2959, 2005.
    連結:
  46. Kim JS, Kim JM, Jung HC and Song IS. Caspase-3 activity and expression of Bcl-2 family in human neutrophils by Helicobacter pylori water-soluble proteins. Helicobacter 6: 207-215, 2001.
    連結:
  47. Klein TW, Friedman H and Specter S. Marijuana, immunity and infection. J Neuroimmunol 83: 102-115, 1998.
    連結:
  48. Klein TW, Newton C, Larsen K, Lu L, Perkins I, Nong L and Friedman H. The cannabinoid system and immune modulation. J Leukoc Biol 74: 486-496, 2003.
    連結:
  49. Kogan NM, Blazquez C, Alvarez L, Gallily R, Schlesinger M, Guzman M and Mechoulam R. A cannabinoid quinone inhibits angiogenesis by targeting vascular endothelial cells. Mol Pharmacol 70: 51-59, 2006.
    連結:
  50. Kogan NM, Rabinowitz R, Levi P, Gibson D, Sandor P, Schlesinger M and Mechoulam R. Synthesis and antitumor activity of quinonoid derivatives of cannabinoids. J Med Chem 47: 3800-3806, 2004.
    連結:
  51. Kogan NM, Schlesinger M, Peters M, Marincheva G, Beeri R and Mechoulam R. A cannabinoid anticancer quinone, HU-331, is more potent and less cardiotoxic than doxorubicin: a comparative in vivo study. J Pharmacol Exp Ther 322: 646-653, 2007.
    連結:
  52. Kurita-Ochiai T, Amano S, Fukushima K and Ochiai K. Cellular events involved in butyric acid-induced T cell apoptosis. J Immunol 171: 3576-3584, 2003.
    連結:
  53. Lajoie P and Nabi IR. Lipid rafts, caveolae, and their endocytosis. Int Rev Cell Mol Biol 282: 135-163, 2010.
    連結:
  54. Lee CY, Wey SP, Liao MH, Hsu WL, Wu HY and Jan TR. A comparative study on cannabidiol-induced apoptosis in murine thymocytes and EL-4 thymoma cells. Int Immunopharmacol 8: 732-740, 2008.
    連結:
  55. Ligresti A, Moriello AS, Starowicz K, Matias I, Pisanti S, De Petrocellis L, Laezza C, Portella G, Bifulco M and Di Marzo V. Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther 318: 1375-1387, 2006.
    連結:
  56. Lim MP, Devi LA and Rozenfeld R. Cannabidiol causes activated hepatic stellate cell death through a mechanism of endoplasmic reticulum stress-induced apoptosis. Cell Death Dis 2: e170, 2011.
    連結:
  57. Lincoln JE, Boling M, Parikh AN, Yeh Y, Gilchrist DG and Morse LS. Fas signaling induces raft coalescence that is blocked by cholesterol depletion in human RPE cells undergoing apoptosis. Invest Ophthalmol Vis Sci 47: 2172-2178, 2006.
    連結:
  58. Liou GI, Auchampach JA, Hillard CJ, Zhu G, Yousufzai B, Mian S, Khan S and Khalifa Y. Mediation of cannabidiol anti-inflammation in the retina by equilibrative nucleoside transporter and A2A adenosine receptor. Invest Ophthalmol Vis Sci 49: 5526-5531, 2008.
    連結:
  59. Liu DZ, Hu CM, Huang CH, Wey SP and Jan TR. Cannabidiol attenuates delayed-type hypersensitivity reactions via suppressing T-cell and macrophage reactivity. Acta Pharmacol Sin 31: 1611-1617, 2010.
    連結:
  60. Liu J, Lee P, Galbiati F, Kitsis RN and Lisanti MP. Caveolin-1 expression sensitizes fibroblastic and epithelial cells to apoptotic stimulation. Am J Physiol Cell Physiol 280: C823-835, 2001.
    連結:
  61. Lu HR, Zhu H, Huang M, Chen Y, Cai YJ, Miao ZH, Zhang JS and Ding J. Reactive oxygen species elicit apoptosis by concurrently disrupting topoisomerase II and DNA-dependent protein kinase. Mol Pharmacol 68: 983-994, 2005.
    連結:
  62. Malfait AM, Gallily R, Sumariwalla PF, Malik AS, Andreakos E, Mechoulam R and Feldmann M. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci U S A 97: 9561-9566, 2000.
    連結:
  63. Malisan F and Testi R. GD3 ganglioside and apoptosis. Biochim Biophys Acta 1585: 179-187, 2002.
    連結:
  64. Malorni W, Giammarioli AM, Garofalo T and Sorice M. Dynamics of lipid raft components during lymphocyte apoptosis: the paradigmatic role of GD3. Apoptosis 12: 941-949, 2007.
    連結:
  65. Massi P, Vaccani A, Bianchessi S, Costa B, Macchi P and Parolaro D. The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells. Cell Mol Life Sci 63: 2057-2066, 2006.
    連結:
  66. Massi P, Vaccani A, Ceruti S, Colombo A, Abbracchio MP and Parolaro D. Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines. J Pharmacol Exp Ther 308: 838-845, 2004.
    連結:
  67. McKallip RJ, Jia W, Schlomer J, Warren JW, Nagarkatti PS and Nagarkatti M. Cannabidiol-induced apoptosis in human leukemia cells: A novel role of cannabidiol in the regulation of p22phox and Nox4 expression. Mol Pharmacol 70: 897-908, 2006.
    連結:
  68. McKallip RJ, Lombard C, Martin BR, Nagarkatti M and Nagarkatti PS. Delta(9)-tetrahydrocannabinol-induced apoptosis in the thymus and spleen as a mechanism of immunosuppression in vitro and in vivo. J Pharmacol Exp Ther 302: 451-465, 2002.
    連結:
  69. Mechoulam R. Marihuana chemistry. Science 168: 1159-1166, 1970.
    連結:
  70. Mechoulam R and Hanus L. Cannabidiol: an overview of some chemical and pharmacological aspects. Part I: chemical aspects. Chem Phys Lipids 121: 35-43, 2002.
    連結:
  71. Miljan EA and Bremer EG. Regulation of growth factor receptors by gangliosides. Sci STKE 2002: re15, 2002.
    連結:
  72. Miyaji M, Jin ZX, Yamaoka S, Amakawa R, Fukuhara S, Sato SB, Kobayashi T, Domae N, Mimori T, Bloom ET, Okazaki T and Umehara H. Role of membrane sphingomyelin and ceramide in platform formation for Fas-mediated apoptosis. J Exp Med 202: 249-259, 2005.
    連結:
  73. Nashar TO, Williams NA and Hirst TR. Cross-linking of cell surface ganglioside GM1 induces the selective apoptosis of mature CD8+ T lymphocytes. Int Immunol 8: 731-736, 1996.
    連結:
  74. Nicoletti I, Migliorati G, Pagliacci MC, Grignani F and Riccardi C. A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods 139: 271-279, 1991.
    連結:
  75. Pacifici R, Zuccaro P, Pichini S, Roset PN, Poudevida S, Farre M, Segura J and De la Torre R. Modulation of the immune system in cannabis users. Jama 289: 1929-1931, 2003.
    連結:
  76. Padwal RS and Majumdar SR. Drug treatments for obesity: orlistat, sibutramine, and rimonabant. Lancet 369: 71-77, 2007.
    連結:
  77. Pagotto U, Marsicano G, Cota D, Lutz B and Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev 27: 73-100, 2006.
    連結:
  78. Pathak N and Khandelwal S. Influence of cadmium on murine thymocytes: potentiation of apoptosis and oxidative stress. Toxicol Lett 165: 121-132, 2006.
    連結:
  79. Patton GC, Coffey C, Carlin JB, Degenhardt L, Lynskey M and Hall W. Cannabis use and mental health in young people: cohort study. BMJ 325: 1195-1198, 2002.
    連結:
  80. Perez J. Combined cannabinoid therapy via an oromucosal spray. Drugs Today (Barc) 42: 495-503, 2006.
    連結:
  81. Pietr M, Kozela E, Levy R, Rimmerman N, Lin YH, Stella N, Vogel Z and Juknat A. Differential changes in GPR55 during microglial cell activation. FEBS Lett 583: 2071-2076, 2009.
    連結:
  82. Psahoulia FH, Drosopoulos KG, Doubravska L, Andera L and Pintzas A. Quercetin enhances TRAIL-mediated apoptosis in colon cancer cells by inducing the accumulation of death receptors in lipid rafts. Mol Cancer Ther 6: 2591-2599, 2007.
    連結:
  83. Rimmerman N, Bradshaw HB, Kozela E, Levy R, Juknat A and Vogel Z. Compartmentalization of endocannabinoids into lipid rafts in a microglial cell line devoid of caveolin-1. Br J Pharmacol 165: 2436-2449, 2012.
    連結:
  84. Rosati E, Sabatini R, Ayroldi E, Tabilio A, Bartoli A, Bruscoli S, Simoncelli C, Rossi R and Marconi P. Apoptosis of human primary B lymphocytes is inhibited by N-acetyl-L-cysteine. J Leukoc Biol 76: 152-161, 2004.
    連結:
  85. Ryberg E, Larsson N, Sjogren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T and Greasley PJ. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol 152: 1092-1101, 2007.
    連結:
  86. Sacerdote P, Martucci C, Vaccani A, Bariselli F, Panerai AE, Colombo A, Parolaro D and Massi P. The nonpsychoactive component of marijuana cannabidiol modulates chemotaxis and IL-10 and IL-12 production of murine macrophages both in vivo and in vitro. J Neuroimmunol 159: 97-105, 2005.
    連結:
  87. Sancho R, de la Vega L, Appendino G, Di Marzo V, Macho A and Munoz E. The CB1/VR1 agonist arvanil induces apoptosis through an FADD/caspase-8-dependent pathway. Br J Pharmacol 140: 1035-1044, 2003.
    連結:
  88. Sandstrom PA, Mannie MD and Buttke TM. Inhibition of activation-induced death in T cell hybridomas by thiol antioxidants: oxidative stress as a mediator of apoptosis. J Leukoc Biol 55: 221-226, 1994.
    連結:
  89. Sarker KP and Maruyama I. Anandamide induces cell death independently of cannabinoid receptors or vanilloid receptor 1: possible involvement of lipid rafts. Cell Mol Life Sci 60: 1200-1208, 2003.
    連結:
  90. Scheel-Toellner D, Wang K, Craddock R, Webb PR, McGettrick HM, Assi LK, Parkes N, Clough LE, Gulbins E, Salmon M and Lord JM. Reactive oxygen species limit neutrophil life span by activating death receptor signaling. Blood 104: 2557-2564, 2004a.
    連結:
  91. Scheel-Toellner D, Wang KQ, Webb PR, Wong SH, Craddock R, Assi LK, Salmon M and Lord JM. Early events in spontaneous neutrophil apoptosis. Biochem Soc Trans 32: 461-464, 2004b.
    連結:
  92. Schicho R and Storr M. Topical and systemic cannabidiol improves trinitrobenzene sulfonic Acid colitis in mice. Pharmacology 89: 149-155, 2012.
    連結:
  93. Shrivastava A, Kuzontkoski PM, Groopman JE and Prasad A. Cannabidiol induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy. Mol Cancer Ther 10: 1161-1172, 2011.
    連結:
  94. Simons K and Toomre D. Lipid rafts and signal transduction. Nat Rev Mol Cell Biol 1: 31-39, 2000.
    連結:
  95. Srivastava MD, Srivastava BI and Brouhard B. Delta9 tetrahydrocannabinol and cannabidiol alter cytokine production by human immune cells. Immunopharmacology 40: 179-185, 1998.
    連結:
  96. Starkel P, Sempoux C, Van Den Berge V, Stevens M, De Saeger C, Desager JP and Horsmans Y. CYP 3A proteins are expressed in human neutrophils and lymphocytes but are not induced by rifampicin. Life Sci 64: 643-653, 1999.
    連結:
  97. Stella N. Endocannabinoid signaling in microglial cells. Neuropharmacology 56 Suppl 1: 244-253, 2009.
    連結:
  98. Tessitore A, del PMM, Sano R, Ma Y, Mann L, Ingrassia A, Laywell ED, Steindler DA, Hendershot LM and d'Azzo A. GM1-ganglioside-mediated activation of the unfolded protein response causes neuronal death in a neurodegenerative gangliosidosis. Mol Cell 15: 753-766, 2004.
    連結:
  99. Tietze F. Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues. Anal Biochem 27: 502-522, 1969.
    連結:
  100. Torres VA, Tapia JC, Rodriguez DA, Parraga M, Lisboa P, Montoya M, Leyton L and Quest AF. Caveolin-1 controls cell proliferation and cell death by suppressing expression of the inhibitor of apoptosis protein survivin. J Cell Sci 119: 1812-1823, 2006.
    連結:
  101. Tripathi P and Hildeman D. Sensitization of T cells to apoptosis--a role for ROS? Apoptosis 9: 515-523, 2004.
    連結:
  102. Troncoso MF, Biron VA, Longhi SA, Retegui LA and Wolfenstein-Todel C. Peltophorum dubium and soybean Kunitz-type trypsin inhibitors induce human Jurkat cell apoptosis. Int Immunopharmacol 7: 625-636, 2007.
    連結:
  103. Viola G, Fortunato E, Cecconet L, Disaro S and Basso G. Induction of apoptosis in Jurkat cells by photoexcited psoralen derivatives: Implication of mitochondrial dysfunctions and caspases activation. Toxicol In Vitro 21: 211-216, 2007.
    連結:
  104. Weiss L, Zeira M, Reich S, Har-Noy M, Mechoulam R, Slavin S and Gallily R. Cannabidiol lowers incidence of diabetes in non-obese diabetic mice. Autoimmunity 39: 143-151, 2006.
    連結:
  105. Weiss L, Zeira M, Reich S, Slavin S, Raz I, Mechoulam R and Gallily R. Cannabidiol arrests onset of autoimmune diabetes in NOD mice. Neuropharmacology 54: 244-249, 2008.
    連結:
  106. Widmer M, Hanemann CO and Zajicek J. High concentrations of cannabinoids activate apoptosis in human U373MG glioma cells. J Neurosci Res 86: 3212-3220, 2008.
    連結:
  107. Wu HY, Chang AC, Wang CC, Kuo FH, Lee CY, Liu DZ and Jan TR. Cannabidiol induced a contrasting pro-apoptotic effect between freshly isolated and precultured human monocytes. Toxicol Appl Pharmacol, 2010a.
    連結:
  108. Wu HY, Liao MH, Su ST and T.R. J. Cannabidiol activated the intrinsic apoptotic pathway in murine lymphocytes. Taiwan Veterinary Journal 36: 268-278, 2010b.
    連結:
  109. Yamada T, Ueda T, Shibata Y, Ikegami Y, Saito M, Ishida Y, Ugawa S, Kohri K and Shimada S. TRPV2 activation induces apoptotic cell death in human T24 bladder cancer cells: a potential therapeutic target for bladder cancer. Urology 76: 509 e501-507, 2010.
    連結:
  110. Yang Q, Liu HY, Zhang YW, Wu WJ and Tang WX. Anandamide induces cell death through lipid rafts in hepatic stellate cells. J Gastroenterol Hepatol 25: 991-1001, 2010.
    連結:
  111. Yao G, Yang L, Hu Y, Liang J, Liang J and Hou Y. Nonylphenol-induced thymocyte apoptosis involved caspase-3 activation and mitochondrial depolarization. Mol Immunol 43: 915-926, 2006.
    連結:
  112. Zhang QY, Dunbar D and Kaminsky LS. Characterization of mouse small intestinal cytochrome P450 expression. Drug Metab Dispos 31: 1346-1351, 2003.
    連結:
  113. Zhou J, Shao H, Cox NR, Baker HJ and Ewald SJ. Gangliosides enhance apoptosis of thymocytes. Cell Immunol 183: 90-98, 1998.
    連結:
  114. Drzewiecka A, Kwiatkowska K and Sobota A. The role of cholesterol and sphigomyelin in tyrosine phosphorylation of proteins and capping of Fcgamma receptor II. Acta Biochim Pol 46: 107-116, 1999.
  115. El-Remessy AB, Tang Y, Zhu G, Matragoon S, Khalifa Y, Liu EK, Liu JY, Hanson E, Mian S, Fatteh N and Liou GI. Neuroprotective effects of cannabidiol in endotoxin-induced uveitis: critical role of p38 MAPK activation. Mol Vis 14: 2190-2203, 2008.
  116. Herring AC and Kaminski NE. Cannabinol-mediated inhibition of nuclear factor-kappaB, cAMP response element-binding protein, and interleukin-2 secretion by activated thymocytes. J Pharmacol Exp Ther 291: 1156-1163, 1999.
  117. Kasahara Y, Iwai K, Yachie A, Ohta K, Konno A, Seki H, Miyawaki T and Taniguchi N. Involvement of reactive oxygen intermediates in spontaneous and CD95 (Fas/APO-1)-mediated apoptosis of neutrophils. Blood 89: 1748-1753, 1997.
  118. Ko YG, Lee JS, Kang YS, Ahn JH and Seo JS. TNF-alpha-mediated apoptosis is initiated in caveolae-like domains. J Immunol 162: 7217-7223, 1999.
  119. Sreevalsan S, Joseph S, Jutooru I, Chadalapaka G and Safe SH. Induction of apoptosis by cannabinoids in prostate and colon cancer cells is phosphatase dependent. Anticancer Res 31: 3799-3807, 2011.
  120. Zhu W, Friedman H and Klein TW. Delta9-tetrahydrocannabinol induces apoptosis in macrophages and lymphocytes: involvement of Bcl-2 and caspase-1. J Pharmacol Exp Ther 286: 1103-1109, 1998.