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http://dx.doi.org/10.1016/j.jgr.2019.12.006

Regulatory roles of ginseng on inflammatory caspases, executioners of inflammasome activation  

Yun, Miyong (Department of Bioindustry and Bioresource Engineering, Sejong University)
Yi, Young-Su (Department of Life Science, Kyonggi University)
Publication Information
Journal of Ginseng Research / v.44, no.3, 2020 , pp. 373-385 More about this Journal
Abstract
Inflammation is an immune response that protects against pathogens and cellular stress. The hallmark of inflammatory responses is inflammasome activation in response to various stimuli. This subsequently activates downstream effectors, that is, inflammatory caspases such as caspase-1, 4, 5, 11, and 12. Extensive efforts have been made on developing effective and safe anti-inflammatory therapeutics, and ginseng has long been traditionally used as efficacious and safe herbal medicine in treating various inflammatory and inflammation-mediated diseases. Many studies have successfully shown that ginseng plays an anti-inflammatory role by inhibiting inflammasomes and inflammasome-activated inflammatory caspases. This review discusses the regulatory roles of ginseng on inflammatory caspases in inflammatory responses and also suggests new research areas on the anti-inflammatory function of ginseng, which provides a novel insight into the development of ginseng as an effective and safe anti-inflammatory herbal medicine.
Keywords
Ginseng; Ginsenoside; Inflammasome; Inflammation; Inflammatory caspase;
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1 Broz P, Ruby T, Belhocine K, Bouley DM, Kayagaki N, Dixit VM, Monack DM. Caspase-11 increases susceptibility to Salmonella infection in the absence of caspase-1. Nature 2012;490:288-91.   DOI
2 Rathinam VA, Vanaja SK, Waggoner L, Sokolovska A, Becker C, Stuart LM, Leong JM, Fitzgerald KA. TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by gram-negative bacteria. Cell 2012;150:606-19.   DOI
3 Case CL, Kohler LJ, Lima JB, Strowig T, de Zoete MR, Flavell RA, Zamboni DS, Roy CR. Caspase-11 stimulates rapid flagellin-independent pyroptosis in response to Legionella pneumophila. Proc Natl Acad SciUS A 2013;110:1851-6.   DOI
4 Wah ST, Yi YS, Khin AA, Plabplueng C, Nuchnoi P. Prevalence of anemia and hemoglobin disorders among school children in Myanmar. Hemoglobin 2017;41:26-31.   DOI
5 Stowe I, Lee B, Kayagaki N. Caspase-11: arming the guards against bacterial infection. Immunol Rev 2015;265:75-84.   DOI
6 Ding J, Shao F. SnapShot: the noncanonical inflammasome. Cell 2017;168: 544-544 e1.   DOI
7 Ruhl S, Broz P. Caspase-11 activates a canonical NLRP3 inflammasome by promoting K(+) efflux. Eur J Immunol 2015;45:2927-36.   DOI
8 Cunha LD, Silva ALN, Ribeiro JM, Mascarenhas DPA, Quirino GFS, Santos LL, Flavell RA, Zamboni DS. AIM2 engages active but unprocessed caspase-1 to induce noncanonical activation of the NLRP3 inflammasome. Cell Rep 2017;20:794-805.   DOI
9 Janeway Jr CA, Medzhitov R. Innate immune recognition. Annu Rev Immunol 2002;20:197-216.   DOI
10 Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010;140:805-20.   DOI
11 Yi YS. Folate receptor-targeted diagnostics and therapeutics for inflammatory diseases. Immune Netw 2016;16:337-43.   DOI
12 Jang SI, Lee YW, Cho CK, Yoo HS, Jang JH. Identification of target genes involved in the antiproliferative effect of enzyme-modified ginseng extract in HepG2 hepatocarcinoma cell. Evid Based Complement Alternat Med 2013;2013:502568.
13 Kayagaki N, Stowe IB, Lee BL, O'Rourke K, Anderson K, Warming S, Cuellar T, Haley B, Roose-Girma M, Phung QT, et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 2015;526:666-71.   DOI
14 Kim SJ, Shin HJ, Lee BJ, Kim DS, Lee JH, Jeong MY, Kim HL, Park J, Lim H, Kim SH, et al. The antiinflammatory mechanism of Igongsan in mouse peritoneal macrophages via suppression of NF-kappaB/Caspase-1 activation. Phytother Res 2014;28:736-44.   DOI
15 Kim J, Ahn H, Han BC, Lee SH, Cho YW, Kim CH, Hong EJ, An BS, Jeung EB, Lee GS. Korean red ginseng extracts inhibit NLRP3 and AIM2 inflammasome activation. Immunol Lett 2014;158:143-50.   DOI
16 Kim SJ, Kwak HJ, Kim DS, Choi HM, Sim JE, Kim SH, Um JY, Hong SH. Protective mechanism of Korean Red Ginseng in cisplatin-induced ototoxicity through attenuation of nuclear factor-kappaB and caspase-1 activation. Mol Med Rep 2015;12:315-22.   DOI
17 Roh JS, Sohn DH. Damage-associated molecular patterns in inflammatory diseases. Immune Netw 2018;18:e27.   DOI
18 Yi YS, Son YJ, Ryou C, Sung GH, Kim JH, Cho JY. Functional roles of Syk in macrophage-mediated inflammatory responses. Mediators Inflamm 2014;2014:270302.   DOI
19 Yang Y, Kim SC, Yu T, Yi YS, Rhee MH, Sung GH, Yoo BC, Cho JY. Functional roles of p38 mitogen-activated protein kinase in macrophage-mediated inflammatory responses. Mediators Inflamm 2014;2014:352371.
20 Multhoff G, Molls M, Radons J. Chronic inflammation in cancer development. Front Immunol 2011;2:98.   DOI
21 Kang SJ, Lee YJ, Kang SG, Cho S, Yoon W, Lim JH, Min SH, Lee TH, Kim BM. Caspase-4 is essential for saikosaponin a-induced apoptosis acting upstream of caspase-2 and gamma-H2AX in colon cancer cells. Oncotarget 2017;8:100433-48.   DOI
22 Bian ZM, Elner SG, Elner VM. Dual involvement of caspase-4 in inflammatory and ER stress-induced apoptotic responses in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 2009;50:6006-14.   DOI
23 Ge G, Yan Y, Cai H. Ginsenoside Rh2 inhibited proliferation by inducing ROS mediated ER stress dependent apoptosis in lung cancer cells. Biol Pharm Bull 2017;40:2117-24.   DOI
24 Yang Y, Jiang G, Zhang P, Fan J. Programmed cell death and its role in inflammation. Mil Med Res 2015;2:12.   DOI
25 Goddard PJ, Sanchez-Garrido J, Slater SL, Kalyan M, Ruano-Gallego D, Marches O, Fernandez LA, Frankel G, Shenoy AR. Enteropathogenic Escherichia coli stimulates effector-driven rapid caspase-4 activation in human macrophages. Cell Rep 2019;27:1008-1017 e6.   DOI
26 Lee BL, Stowe IB, Gupta A, Kornfeld OS, Roose-Girma M, Anderson K, Warming S, Zhang J, Lee WP, Kayagaki N. Caspase-11 auto-proteolysis is crucial for noncanonical inflammasome activation. J Exp Med 2018;215:2279-88.   DOI
27 Casson CN, Yu J, Reyes VM, Taschuk FO, Yadav A, Copenhaver AM, Nguyen HT, Collman RG, Shin S. Human caspase-4 mediates noncanonical inflammasome activation against gram-negative bacterial pathogens. Proc Natl Acad Sci U S A 2015;112:6688-93.   DOI
28 Kajiwara Y, Schiff T, Voloudakis G, Gama Sosa MA, Elder G, Bozdagi O, Buxbaum JD. A critical role for human caspase-4 in endotoxin sensitivity. J Immunol 2014;193:335-43.   DOI
29 Bitto NJ, Baker PJ, Dowling JK, Wray-McCann G, De Paoli A, Tran LS, Leung PL, Stacey KJ, Mansell A, Masters SL, et al. Membrane vesicles from Pseudomonas aeruginosa activate the noncanonical inflammasome through caspase-5 in human monocytes. Immunol Cell Biol 2018;96:1120-30.   DOI
30 Vigano E, Diamond CE, Spreafico R, Balachander A, Sobota RM, Mortellaro A. Human caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes. Nat Commun 2015;6:8761.   DOI
31 Fischer H, Koenig U, Eckhart L, Tschachler E. Human caspase 12 has acquired deleterious mutations. Biochem Biophys Res Commun 2002;293:722-6.   DOI
32 Yi YS. Regulatory roles of the caspase-11 non-canonical inflammasome in inflammatory diseases. Immune Netw 2018;18:e41.   DOI
33 Ramirez MLG, Salvesen GS. A primer on caspase mechanisms. Semin Cell Dev Biol 2018;82:79-85.   DOI
34 Vande Walle L, Lamkanfi M, Pyroptosis. Curr Biol 2016;26:R568-72.   DOI
35 Yu T, Yi YS, Yang Y, Oh J, Jeong D, Cho JY. The pivotal role of TBK1 in inflammatory responses mediated by macrophages. Mediators Inflamm 2012;2012:979105.
36 Yi YS. Caspase-11 non-canonical inflammasome: a critical sensor of intracellular lipopolysaccharide in macrophage-mediated inflammatory responses. Immunology 2017;152:207-17.   DOI
37 Kachapati K, O'Brien TR, Bergeron J, Zhang M, Dean M. Population distribution of the functional caspase-12 allele. Hum Mutat 2006;27:975.
38 Scott AM, Saleh M. The inflammatory caspases: guardians against infections and sepsis. Cell Death Differ 2007;14:23-31.   DOI
39 Wang C, Li YZ, Wang XR, Lu ZR, Shi DZ, Liu XH. Panax quinquefolium saponins reduce myocardial hypoxia-reoxygenation injury by inhibiting excessive endoplasmic reticulum stress. Shock 2012;37:228-33.   DOI
40 Jiang Y, Li Z, Liu Y, Liu X, Chang Q, Liao Y, Pan R. Neuroprotective effect of water extract of Panax ginseng on corticosterone-induced apoptosis in PC12 cells and its underlying molecule mechanisms. J Ethnopharmacol 2015;159:102-12.   DOI
41 Man SM, Karki R, Kanneganti TD. Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol Rev 2017;277:61-75.   DOI
42 Lamkanfi M, Dixit VM. Mechanisms and functions of inflammasomes. Cell 2014;157:1013-22.   DOI
43 Yi YS. Functional crosstalk between non-canonical caspase-11 and canonical NLRP3 inflammasomes during infection-mediated inflammation. Immunology 2020;159:142-55.   DOI
44 Yi YS. Role of inflammasomes in inflammatory autoimmune rheumatic diseases. Korean J Physiol Pharmacol 2018;22:1-15.   DOI
45 Lamkanfi M, Declercq W, Kalai M, Saelens X, Vandenabeele P. Alice in caspase land. A phylogenetic analysis of caspases from worm to man. Cell Death Differ 2002;9:358-61.   DOI
46 Prasad KV, Prabhakar BS. Apoptosis and autoimmune disorders. Autoimmunity 2003;36:323-30.   DOI
47 Van Gorp H, Van Opdenbosch N, Lamkanfi M. Inflammasome-Dependent cytokines at the crossroads of health and autoinflammatory disease. Cold Spring Harb Perspect Biol 2019;11.
48 Du Y, Fu M, Wang YT, Dong Z. Neuroprotective effects of ginsenoside Rf on amyloid-beta-induced neurotoxicity in vitro and in vivo. J Alzheimers Dis 2018;64:309-22.   DOI
49 Oh HA, Seo JY, Jeong HJ, Kim HM. Ginsenoside Rg1 inhibits the TSLP production in allergic rhinitis mice. Immunopharmacol Immunotoxicol 2013;35:678-86.   DOI
50 Yuan C, Liu C, Wang T, He Y, Zhou Z, Dun Y, Zhao H, Ren D, Wang J, Zhang C, et al. Chikusetsu saponin IVa ameliorates high fat diet-induced inflammation in adipose tissue of mice through inhibition of NLRP3 inflammasome activation and NF-kappaB signaling. Oncotarget 2017;8:31023-40.   DOI
51 Liu C, Wang J, Yang Y, Liu X, Zhu Y, Zou J, Peng S, Le TH, Chen Y, Zhao S, et al. Ginsenoside Rd ameliorates colitis by inducing p62-driven mitophagymediated NLRP3 inflammasome inactivation in mice. Biochem Pharmacol 2018;155:366-79.   DOI
52 Song W,Wei L, Du Y,Wang Y, Jiang S. Protective effect of ginsenosidemetabolite compound K against diabetic nephropathy by inhibiting NLRP3 inflammasome activation and NF-kappaB/p38 signaling pathway in high-fat diet/streptozotocin-induced diabetic mice. Int Immunopharmacol 2018;63:227-38.   DOI
53 Kee JY, Hong SH. Ginsenoside Rg3 suppresses mast cell-mediated allergic inflammation via mitogen-activated protein kinase signaling pathway. J Ginseng Res 2019;43:282-90.   DOI
54 Su GY, Li ZY, Wang R, Lu YZ, Nan JX, Wu YL, Zhao YQ. Signaling pathways involved in p38-ERK and inflammatory factors mediated the anti-fibrosis effect of AD-2 on thioacetamide-induced liver injury in mice. Food Funct 2019;10:3992-4000.   DOI
55 Jeong MY, Park DH, Kim MC, Park J, Kim DS, Jeon YD, Kim SJ, Ahn KS, Kim SH, Lee JH, et al. Saengmaeksan inhibits inflammatory mediators by suppressing RIP-2/caspase-1 activation. Immunopharmacol Immunotoxicol 2013;35:241-50.   DOI
56 Xu Y, Yang C, Zhang S, Li J, Xiao Q, Huang W. Ginsenoside Rg1 protects against non-alcoholic fatty liver disease by ameliorating lipid peroxidation, endoplasmic reticulum stress, and inflammasome activation. Biol Pharm Bull 2018;41:1638-44.   DOI
57 Huang XP, Ding H, Lu JD, Tang YH, Deng BX, Deng CQ. Effects of the combination of the main active components of Astragalus and Panax notoginseng on inflammation and apoptosis of nerve cell after cerebral ischemia-reperfusion. Am J Chin Med 2015;43:1419-38.   DOI
58 Yuan D, Wan JZ, Deng LL, Zhang CC, Dun YY, Dai YW, Zhou ZY, Liu CQ, Wang T. Chikusetsu saponin V attenuates MPP+-induced neurotoxicity in SH-SY5Y cells via regulation of Sirt1/Mn-SOD and GRP78/caspase-12 pathways. Int J Mol Sci 2014;15:13209-22.   DOI
59 Alcendor RR, Gao S, Zhai P, Zablocki D, Holle E, Yu X, Tian B, Wagner T, Vatner SF, Sadoshima J. Sirt1 regulates aging and resistance to oxidative stress in the heart. Circ Res 2007;100:1512-21.   DOI
60 Zhang YQ, Wang XB, Xue RR, Gao XX, Li W. Ginsenoside Rg1 attenuates chronic unpredictable mild stress-induced depressive-like effect via regulating NF-kappaB/NLRP3 pathway in rats. Neuroreport 2019;30:893-900.   DOI
61 Wang S, Wang X, Luo F, Tang X, Li K, Hu X, Bai J. Panaxatriol saponin ameliorated liver injury by acetaminophen via restoring thioredoxin-1 and pro-caspase-12. Liver Int 2014;34:1068-73.   DOI
62 Slegtenhorst BR, Dor FJ, Rodriguez H, Voskuil FJ, Tullius SG. Ischemia/reperfusion injury and its consequences on immunity and inflammation. Curr Transplant Rep 2014;1:147-54.   DOI
63 Van Gorp H, Lamkanfi M. The emerging roles of inflammasome-dependent cytokines in cancer development. EMBO Rep 2019;20.
64 Hofseth LJ, Wargovich MJ. Inflammation, cancer, and targets of ginseng. J Nutr 2007;137:183S-5S.   DOI
65 Saleh M, Mathison JC, Wolinski MK, Bensinger SJ, Fitzgerald P, Droin N, Ulevitch RJ, Green DR, Nicholson DW. Enhanced bacterial clearance and sepsis resistance in caspase-12-deficient mice. Nature 2006;440:1064-8.   DOI
66 Saleh M, Vaillancourt JP, Graham RK, Huyck M, Srinivasula SM, Alnemri ES, Steinberg MH, Nolan V, Baldwin CT, Hotchkiss RS, et al. Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms. Nature 2004;429:75-9.   DOI
67 Vande Walle L, Jimenez Fernandez D, Demon D, Van Laethem N, Van Hauwermeiren F, Van Gorp H, Van Opdenbosch N, Kayagaki N, Lamkanfi M. Does caspase-12 suppress inflammasome activation? Nature 2016;534:E1-4.   DOI
68 Li H, Deng CQ, Chen BY, Zhang SP, Liang Y, Luo XG. Total saponins of Panax notoginseng modulate the expression of caspases and attenuate apoptosis in rats following focal cerebral ischemia-reperfusion. J Ethnopharmacol 2009;121:412-8.   DOI
69 Tang YH, Zhang SP, Liang Y, Deng CQ. [Effects of Panax notoginseng saponins on mRNA expressions of interleukin-1 beta, its correlative factors and cysteinyl-aspartate specific protease after cerebral ischemia-reperfusion in rats]. Zhong Xi Yi Jie He Xue Bao 2007;5:328-32.
70 Ahuja A, Kim JH, Yi YS, Cho JY. Functional role of ginseng-derived compounds in cancer. J Ginseng Res 2018;42:248-54.   DOI
71 Hong BN, Ji MG, Kang TH. The efficacy of red ginseng in type 1 and type 2 diabetes in animals. Evid Based Complement Alternat Med 2013;2013:593181.
72 Ernst E. Complementary/alternative medicine for hypertension: a mini-review. Wien Med Wochenschr 2005;155:386-91.   DOI
73 Rastogi V, Santiago-Moreno J, Dore S. Ginseng: a promising neuroprotective strategy in stroke. Front Cell Neurosci 2014;8:457.   DOI
74 Zhou W, Chai H, Lin PH, Lumsden AB, Yao Q, Chen CJ. Molecular mechanisms and clinical applications of ginseng root for cardiovascular disease. Med Sci Monit 2004;10:187-92.
75 Kim KH, Lee D, Lee HL, Kim CE, Jung K, Kang KS. Beneficial effects of Panax ginseng for the treatment and prevention of neurodegenerative diseases: past findings and future directions. J Ginseng Res 2018;42:239-47.   DOI
76 Reyes AWB, Hop HT, Arayan LT, Huy TXN, Park SJ, Kim KD, Min W, Lee HJ, Rhee MH, Kwak YS, et al. The host immune enhancing agent Korean red ginseng oil successfully attenuates Brucella abortus infection in a murine model. J Ethnopharmacol 2017;198:5-14.   DOI
77 Kim JH, Yi YS, Kim MY, Cho JY. Role of ginsenosides, the main active components of Panax ginseng, in inflammatory responses and diseases. J Ginseng Res 2017;41:435-43.   DOI
78 Yi YS. Ameliorative effects of ginseng and ginsenosides on rheumatic diseases. J Ginseng Res 2019;43:335-41.   DOI
79 Ruan B, Wang R, Yang YJ, Wang DF, Wang JW, Zhang CC, Yuan D, Zhou ZY, Wang T. [Improved effects of saponins from Panax japonicus on decline of cognitive function in natural aging rats via NLRP3 inflammasome pathway]. Zhongguo Zhong Yao Za Zhi 2019;44:344-9.
80 Lin T, Liu GA, Perez E, Rainer RD, Febo M, Cruz-Almeida Y, Ebner NC. Systemic inflammation mediates age-related cognitive deficits. Front Aging Neurosci 2018;10:236.   DOI
81 Ong WY, Farooqui T, Koh HL, Farooqui AA, Ling EA. Protective effects of ginseng on neurological disorders. Front Aging Neurosci 2015;7:129.
82 Lee SM, Bae BS, Park HW, Ahn NG, Cho BG, Cho YL, Kwak YS. Characterization of Korean red ginseng (Panax ginseng meyer): history, preparation method, and chemical composition. J Ginseng Res 2015;39:384-91.   DOI
83 Ru W, Wang D, Xu Y, He X, Sun YE, Qian L, Zhou X, Qin Y. Chemical constituents and bioactivities of Panax ginseng (C. A. Mey.). Drug Discov Ther 2015;9:23-32.   DOI
84 Chen XJ, Zhang XJ, Shui YM, Wan JB, Gao JL. Anticancer activities of protopanaxadiol-and protopanaxatriol-type ginsenosides and their metabolites. Evid Based Complement Alternat Med 2016;2016:5738694.
85 Liu Y, Deng J, Fan D. Ginsenoside Rk3 ameliorates high-fat-diet/streptozocin induced type 2 diabetes mellitus in mice via the AMPK/Akt signaling pathway. Food Funct 2019;10:2538-51.   DOI
86 Lee CH, Kim JH. A review on the medicinal potentials of ginseng and ginsenosides on cardiovascular diseases. J Ginseng Res 2014;38:161-6.   DOI
87 Yi YS. Roles of ginsenosides in inflammasome activation. J Ginseng Res 2019;43:172-8.   DOI
88 Monack DM, Raupach B, Hromockyj AE, Falkow S. Salmonella typhimurium invasion induces apoptosis in infected macrophages. Proc Natl Acad Sci U S A 1996;93:9833-8.   DOI
89 Zychlinsky A, Prevost MC, Sansonetti PJ. Shigella flexneri induces apoptosis in infected macrophages. Nature 1992;358:167-9.   DOI
90 Cookson BT, Brennan MA. Pro-inflammatory programmed cell death. Trends Microbiol 2001;9:113-4.   DOI
91 Brennan MA, Cookson BT. Salmonella induces macrophage death by caspase-1-dependent necrosis. Mol Microbiol 2000;38:31-40.   DOI
92 Siegmund B. Interleukin-1beta converting enzyme (caspase-1) in intestinal inflammation. Biochem Pharmacol 2002;64:1-8.   DOI
93 Robinson N, Ganesan R, Hegedus C, Kovacs K, Kufer TA, Virag L. Programmed necrotic cell death of macrophages: focus on pyroptosis, necroptosis, and parthanatos. Redox Biol 2019;26:101239.   DOI
94 Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, Kostura MJ, Miller DK, Molineaux SM, Weidner JR, Aunins J, et al. A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature 1992;356:768-74.   DOI
95 Ghayur T, Banerjee S, Hugunin M, Butler D, Herzog L, Carter A, Quintal L, Sekut L, Talanian R, Paskind M, et al. Caspase-1 processes IFN-gammainducing factor and regulates LPS-induced IFN-gamma production. Nature 1997;386:619-23.   DOI
96 Kuida K, Lippke JA, Ku G, Harding MW, Livingston DJ, Su MS, Flavell RA. Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme. Science 1995;267:2000-3.   DOI
97 Li P, Allen H, Banerjee S, Franklin S, Herzog L, Johnston C, McDowell J, Paskind M, Rodman L, Salfeld J, et al. Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock. Cell 1995;80:401-11.   DOI
98 Kayagaki N, Warming S, Lamkanfi M, Vande Walle L, Louie S, Dong J, Newton K, Qu Y, Liu J, Heldens S, et al. Non-canonical inflammasome activation targets caspase-11. Nature 2011;479:117-21.   DOI
99 Shi J, Zhao Y, Wang Y, Gao W, Ding J, Li P, Hu L, Shao F. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 2014;514:187-92.   DOI
100 Miao EA, Rajan JV, Aderem A. Caspase-1-induced pyroptotic cell death. Immunol Rev 2011;243:206-14.   DOI