Estradiol mediates colonic epithelial protection in aged mice after stroke and is associated with shifts in the gut microbiome

References

• Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Després J-P, Fullerton HJ, Howard VJ, et al. Heart disease and stroke statistics—2015 update. Circulation. 2015;131(4):e29. doi:10.1161/CIR.0000000000000152.
   PubMed Web of Science ®Google Scholar
• Chauhan A, Moser H, McCullough Louise D. Sex differences in ischaemic stroke: potential cellular mechanisms. Clin Sci. 2017;131(7):533–14. doi:10.1042/CS20160841.
   Web of Science ®Google Scholar
• Spychala MS, Honarpisheh P, McCullough LD. Sex differences in neuroinflammation and neuroprotection in ischemic stroke. J Neurosci Res. 2017;95(1–2):462–471. doi:10.1002/jnr.23962.
   PubMed Web of Science ®Google Scholar
• Markle JG, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, von Bergen M, McCoy KD, Macpherson AJ, Danska JS, et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Sci. 2013;339(6123):1084–1088. doi:10.1126/science.1233521.
   PubMed Web of Science ®Google Scholar
• Yurkovetskiy L, Burrows M, Khan AA, Graham L, Volchkov P, Becker L, Antonopoulos D, Umesaki Y, Chervonsky A. Gender bias in autoimmunity is influenced by microbiota. Immunity. 2013;39(2):400–412. doi:10.1016/j.immuni.2013.08.013.
   PubMed Web of Science ®Google Scholar
• Klein SL. The effects of hormones on sex differences in infection: from genes to behavior. Neurosci Biobehav Rev. 2000;24(6):627–638. doi:10.1016/S0149-7634(00)00027-0.
   PubMed Web of Science ®Google Scholar
• Dhandapani KM, Brann DW. Protective effects of estrogen and selective estrogen receptor modulators in the brain. Biol Reprod. 2002;67(5):1379–1385. doi:10.1095/biolreprod.102.003848.
   PubMed Web of Science ®Google Scholar
• Green PS, Simpkins JW. Neuroprotective effects of estrogens: potential mechanisms of action. Int J Dev Neurosci. 2000;18:347–358. doi:10.1016/S0736-5748(00)00017-4.
   PubMed Web of Science ®Google Scholar
• Hurn PD, Macrae IM. Estrogen as a neuroprotectant in stroke. J Cereb Blood Flow Metab. 2000;20:631–652. doi:10.1097/00004647-200004000-00001.
   PubMed Web of Science ®Google Scholar
• Murphy S, McCullough L, Littleton-Kearney M, Hurn P. Estrogen and selective estrogen receptor modulators: neuroprotection in the women’s Health initiative era. Endocrine. 2003;21:17–26. doi:10.1385/ENDO:21:1:17.
   PubMed Web of Science ®Google Scholar
• Wise PM, Dubal DB. Estradiol protects against ischemic brain injury in middle-aged rats. Biol Reprod. 2000;63(4):982–985. doi:10.1095/biolreprod63.4.982.
   PubMed Web of Science ®Google Scholar
• McCullough LD, Alkayed NJ, Traystman RJ, Williams MJ, Hurn PD. Postischemic estrogen reduces hypoperfusion and secondary ischemia after experimental stroke. Stroke. 2001;32(3):796–802. doi:10.1161/01.STR.32.3.796.
   PubMed Web of Science ®Google Scholar
• Harukuni I, Hurn PD, Crain BJ. Deleterious effect of β-estradiol in a rat model of transient forebrain ischemia. Brain Res. 2001;900(1):137–142. doi:10.1016/S0006-8993(01)02278-8.
   PubMed Web of Science ®Google Scholar
• Wang L, Kitano H, Hurn PD, Murphy SJ. Estradiol attenuates neuroprotective benefits of isoflurane preconditioning in ischemic mouse brain. J Cereb Blood Flow Metab. 2008;28:1824–1834. doi:10.1038/jcbfm.2008.70.
   PubMed Web of Science ®Google Scholar
• Santizo RA, Xu HL, Ye S, Baughman VL, Pelligrino DA. Loss of benefit from estrogen replacement therapy in diabetic ovariectomized female rats subjected to transient forebrain ischemia. Brain Res. 2002;956(1):86–95. doi:10.1016/S0006-8993(02)03484-4.
   PubMed Web of Science ®Google Scholar
• Liu F, Benashski SE, Xu Y, Siegel M, McCullough LD. Effects of chronic and acute oestrogen replacement therapy in aged animals after experimental stroke. J Neuroendocrinol. 2012;24(2):319–330. doi:10.1111/j.1365-2826.2011.02248.x.
   PubMed Web of Science ®Google Scholar
• Cai M, Ma YL, Qin P, Li Y, Zhang LX, Nie H, Peng Z, Dong H, Dong H-L, Hou W-G, et al. The loss of estrogen efficacy against cerebral ischemia in aged postmenopausal female mice. Neurosci Lett. 2014;558:115–119. doi:10.1016/j.neulet.2013.11.007.
   PubMed Web of Science ®Google Scholar
• Paganini-Hill A, Ross RK, Henderson BE. Postmenopausal oestrogen treatment and stroke: a prospective study. BMJ ( Clinical research ed). 1988;297(6647):519–522. doi: 10.1136/bmj.297.6647.519.
   PubMedGoogle Scholar
• Hunt K, Vessey M, McPherson K. Mortality in a cohort of long-term users of hormone replacement therapy: an updated analysis. Br J Obstet Gynaecol. 1990;97(12):1080–1086. doi:10.1111/j.1471-0528.1990.tb02494.x.
   PubMedGoogle Scholar
• Finucane FF, Madans JH, Bush TL, Wolf PH, Kleinman JC. Decreased risk of stroke among postmenopausal hormone users. Results From a National Cohort. Arch Intern Med. 1993;153(1):73–79. doi:10.1001/archinte.153.1.73.
   PubMedGoogle Scholar
• Falkeborn M, Persson I, Terént A, Adami HO, Lithell H, Bergström R. Hormone replacement therapy and the risk of stroke. Follow-up of a population-based cohort in Sweden. Arch Intern Med. 1993;153(10):1201–1209. doi:10.1001/archinte.1993.00410100035005.
   PubMedGoogle Scholar
• Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SAA, Howard BV, Johnson KC et al. Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women’s Health initiative randomized controlled trial. JAMA. 2002;288(3):321–333. doi:10.1001/jama.288.3.321.
   PubMed Web of Science ®Google Scholar
• Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B et al. Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the women’s Health initiative randomized controlled trial. JAMA. 2004;291(14):1701–1712.
   PubMed Web of Science ®Google Scholar
• Mohammed K, Abu Dabrh AM, Benkhadra K, Al Nofal A, Carranza Leon BG, Prokop LJ, Montori VM, Faubion SS, Murad MH. Oral vs Transdermal estrogen therapy and vascular events: a systematic review and meta-analysis. J Clin Endocr Metab. 2015;100(11):4012–4020. doi:10.1210/jc.2015-2237.
   PubMed Web of Science ®Google Scholar
• Marjoribanks J, Farquhar C, Roberts H, Lethaby A, Lee J. Long term hormone therapy for perimenopausal and postmenopausal women Cochrane Database Syst Rev. 2017; 1(1): Cd004143. doi:10.1002/14651858.
   Google Scholar
• Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med. 2001;345(17):1243–1249. doi:10.1056/NEJMoa010534.
   PubMed Web of Science ®Google Scholar
• Hodis HN, Mack WJ, Henderson VW, Shoupe D, Budoff MJ, Hwang-Levine J, Li Y, Feng M, Dustin L, Kono N, et al. Vascular effects of Early versus late postmenopausal treatment with Estradiol. N Engl J Med. 2016;374(13):1221–1231. doi:10.1056/NEJMoa1505241.
   PubMed Web of Science ®Google Scholar
• Park MJ, Pilla R, Panta A, Pandey S, Sarawichitr B, Suchodolski J, Sohrabji F. Reproductive senescence and ischemic stroke remodel the gut microbiome and modulate the effects of estrogen treatment in female rats. Transl Stroke Res. 2020;11(4):812–830. doi:10.1007/s12975-019-00760-5.
   PubMed Web of Science ®Google Scholar
• Ahnstedt H, Patrizz A, Chauhan A, Roy-O’Reilly M, Furr JW, Spychala MS, D’Aigle J, Blixt FW, Zhu L, Bravo Alegria J, et al. Sex differences in T cell immune responses, gut permeability and outcome after ischemic stroke in aged mice. Brain Behav Immun. 2020;87:556–567. doi:10.1016/j.bbi.2020.02.001.
   PubMed Web of Science ®Google Scholar
• Benakis C, Brea D, Caballero S, Faraco G, Moore J, Murphy M, Sita G, Racchumi G, Ling L, Pamer EG, et al. Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells. Nat Med. 2016;22(5):516. doi:10.1038/nm.4068.
   PubMed Web of Science ®Google Scholar
• Singh V, Roth S, Llovera G, Sadler R, Garzetti D, Stecher B, Dichgans M, Liesz A. Microbiota dysbiosis controls the neuroinflammatory response after stroke. J Neurosci. 2016;36(28):7428. doi:10.1523/JNEUROSCI.1114-16.2016.
   PubMed Web of Science ®Google Scholar
• Spychala MS, Venna VR, Jandzinski M, Doran SJ, Durgan DJ, Ganesh BP, Ajami NJ, Putluri N, Graf J, Bryan RM, et al. Age-related changes in the gut microbiota influence systemic inflammation and stroke outcome. Ann Neurol. 2018;84(1):23–36. doi:10.1002/ana.25250.
   PubMed Web of Science ®Google Scholar
• Lee J, d’Aigle J, Atadja L, Quaicoe V, Honarpisheh P, Ganesh BP, Hassan A, Graf J, Petrosino J, Putluri N, et al. Gut microbiota–derived short-chain fatty acids promote poststroke recovery in aged mice. Circ Res. 2020;127(4):453–465. doi:10.1161/CIRCRESAHA.119.316448.
   PubMed Web of Science ®Google Scholar
• Crapser J, Ritzel R, Venna VR, Liu F, Chauhan A, Koellhoffer E, Koellhoffer E, Patel A, Ricker A, Maas K, et al. Ischemic stroke induces gut permeability and enhances bacterial translocation leading to sepsis in aged mice. Aging. 2016;8(5):1049–1063. doi:10.18632/aging.100952.
   PubMedGoogle Scholar
• Stanley D, Mason LJ, Mackin KE, Srikhanta YN, Lyras D, Prakash MD, Nurgali K, Venegas A, Hill MD, Moore RJ, et al. Translocation and dissemination of commensal bacteria in post-stroke infection. Nat Med. 2016;22(11):1277–1284. doi:10.1038/nm.4194.
   PubMed Web of Science ®Google Scholar
• Artis D. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nat Rev Immunol. 2008;8(6):411. doi:10.1038/nri2316.
   PubMed Web of Science ®Google Scholar
• Ouellette AJ. Paneth cells and innate mucosal immunity. Curr Opin Gastroenterol. 2010;26(6):547–553. doi:10.1097/MOG.0b013e32833dccde.
   PubMed Web of Science ®Google Scholar
• Pelaseyed T, Bergström JH, Gustafsson JK, Ermund A, Birchenough GMH, Schütte A, van der Post S, Svensson F, Rodríguez‐Piñeiro AM, Nyström EEL, et al. The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunol Rev. 2014;260(1):8–20. doi:10.1111/imr.12182.
   PubMed Web of Science ®Google Scholar
• Pereira FC, Berry D. Microbial nutrient niches in the gut. Environ Microbiol. 2017;19(4):1366–1378. doi:10.1111/1462-2920.13659.
   PubMed Web of Science ®Google Scholar
• McCullough LD, Hurn PD. Estrogen and ischemic neuroprotection: an integrated view. Trends Endocrinol Metab. 2003;14(5):228–235. doi:10.1016/S1043-2760(03)00076-6.
   PubMed Web of Science ®Google Scholar
• Vaishnava S, Yamamoto M, Severson KM, Ruhn KA, Yu X, Koren O, Ley R, Wakeland EK, Hooper LV. The antibacterial lectin RegIIIγ promotes the spatial segregation of microbiota and host in the intestine. Sci. 2011;334(6053):255–258. doi:10.1126/science.1209791.
   PubMed Web of Science ®Google Scholar
• Ismail AS, Severson KM, Vaishnava S, Behrendt CL, Yu X, Benjamin JL, Ruhn KA, Hou B, DeFranco AL, Yarovinsky F, et al. γδ intraepithelial lymphocytes are essential mediators of host–microbial homeostasis at the intestinal mucosal surface. Proc Natl Acad Sci USA. 2011;108(21):8743–8748. doi:10.1073/pnas.1019574108.
   PubMed Web of Science ®Google Scholar
• Lee J, Park EJ, Yuki Y, Ahmad S, Mizuguchi K, Ishii KJ, Shimaoka M, Kiyono H. Profiles of microRNA networks in intestinal epithelial cells in a mouse model of colitis. Sci Rep. 2015;5(1):18174. doi:10.1038/srep18174.
   PubMedGoogle Scholar
• Lee J, Mohsen A, Banerjee A, McCullough LD, Mizuguchi K, Shimaoka M, Kiyono H, Park EJ. Distinct age-specific miRegulome profiling of isolated small and large intestinal epithelial cells in mice. Int J Mol Sci. 2021;22(7):3544. doi:10.3390/ijms22073544.
   PubMed Web of Science ®Google Scholar
• Ismail AS, Behrendt CL, Hooper LV. Reciprocal interactions between commensal bacteria and γδ intraepithelial lymphocytes during mucosal injury. J Immunol. 2009;182(5):3047–3054. doi:10.4049/jimmunol.0802705.
   PubMed Web of Science ®Google Scholar
• Cash HL, Whitham CV, Behrendt CL, Hooper LV. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Sci. 2006;313(5790):1126–1130. doi:10.1126/science.1127119.
   PubMed Web of Science ®Google Scholar
• AP C. Mucins: a biologically relevant glycan barrier in mucosal protection. Biochim et Biophys Acta (BBA) - Gen Subj. 2015;1850(1):236–252. doi:10.1016/j.bbagen.2014.05.003.
   PubMed Web of Science ®Google Scholar
• Riehl TE, Santhanam S, Foster L, Ciorba M, Stenson WF. CD44 and TLR4 mediate hyaluronic acid regulation of Lgr5+ stem cell proliferation, crypt fission, and intestinal growth in postnatal and adult mice. Am J Physiol Gastrointest Liver Physiol. 2015;309(11):G874–87. doi:10.1152/ajpgi.00123.2015.
   PubMed Web of Science ®Google Scholar
• Yu H, Li Q, Zhou X, Kolosov VP, Perelman JM. Role of hyaluronan and CD44 in reactive oxygen species-induced mucus hypersecretion. Mol Cell Biochem. 2011;352(1–2):65–75. doi:10.1007/s11010-011-0740-6.
   PubMed Web of Science ®Google Scholar
• Magalhães A, Rossez Y, Robbe-Masselot C, Maes E, Gomes J, Shevtsova A, Bugaytsova J, Borén T, Reis CA. Muc5ac gastric mucin glycosylation is shaped by FUT2 activity and functionally impacts Helicobacter pylori binding. Sci Rep. 2016;6(1):25575. doi:10.1038/srep25575.
   PubMedGoogle Scholar
• Harmsen H, Prieur D, Jeanthon C. Group-specific 16S rRNA-targeted oligonucleotide probes to identify thermophilic bacteria in marine hydrothermal vents. Appl Environ Microb. 1997;63(10):4061–4068. doi:10.1128/aem.63.10.4061-4068.1997.
   PubMed Web of Science ®Google Scholar
• Alkayed NJ, Harukuni I, Kimes AS, London ED, Traystman RJ, Hurn PD. Gender-linked brain injury in experimental stroke. Stroke ( discussion 66). 1998;29(1):159–165. doi: 10.1161/01.STR.29.1.159.
   PubMed Web of Science ®Google Scholar
• Liu F, Benashski SE, Xu Y, Siegel M, McCullough LD. Effects of chronic and acute oestrogen replacement therapy in aged animals after experimental stroke. J Neuroendocrinol. 2011;24(2):319–330. doi:10.1111/j.1365-2826.2011.02248.x.
   Web of Science ®Google Scholar
• Dubal DB, Zhu H, Yu J, Rau SW, Shughrue PJ, Merchenthaler I, Kindy MS, Wise PM. Estrogen receptor α, not β, is a critical link in estradiol-mediated protection against brain injury. Proc Natl Acad Sci U S A. 2001;98(4):1952–1957. doi:10.1073/pnas.98.4.1952.
   PubMed Web of Science ®Google Scholar
• Manwani B, Liu F, Scranton V, Hammond MD, Sansing LH, McCullough LD. Differential effects of aging and sex on stroke induced inflammation across the lifespan. Exp Neurol. 2013;249:120–131. doi:10.1016/j.expneurol.2013.08.011.
   PubMed Web of Science ®Google Scholar
• Engevik MA, Luk B, Chang-Graham AL, Hall A, Herrmann B, Ruan W, Endres BT, Shi Z, Garey KW, Hyser JM, et al. Bifidobacterium dentium fortifies the intestinal mucus layer via autophagy and calcium signaling pathways. mBio. 2019;10(3):10. doi:10.1128/mBio.01087-19.
   Web of Science ®Google Scholar
• Schroeder BO, Birchenough GMH, Ståhlman M, Arike L, Johansson MEV, Hansson GC, Bäckhed F. Bifidobacteria or fiber protects against diet-induced microbiota-mediated colonic mucus deterioration. Cell Host & Microbe. 2018;23(1):27–40.e7. doi:10.1016/j.chom.2017.11.004.
   PubMed Web of Science ®Google Scholar
• Saleh TM, Connell BJ, Legge C, Cribb AE. Estrogen attenuates neuronal excitability in the insular cortex following middle cerebral artery occlusion. Brain Res. 2004;1018(1):119–129. doi:10.1016/j.brainres.2004.05.074.
   PubMed Web of Science ®Google Scholar
• Koren T, Yifa R, Amer M, Krot M, Boshnak N, Ben-Shaanan TL, Azulay-Debby H, Zalayat I, Avishai E, Hajjo H, et al. Insular cortex neurons encode and retrieve specific immune responses. Cell. 2021;184(24):5902–15.e17. doi:10.1016/j.cell.2021.10.013.
   PubMed Web of Science ®Google Scholar
• Bullitt E. Expression of c-fos-like protein as a marker for neuronal activity following noxious stimulation in the rat. J Comp Neurol. 1990;296(4):517–530. doi:10.1002/cne.902960402.
   PubMed Web of Science ®Google Scholar
• McCullough LD, Blizzard K, Simpson ER, Öz OK, Hurn PD. Aromatase cytochrome P450 and extragonadal estrogen play a role in ischemic neuroprotection. J Neurosci. 2003;23(25):8701. doi:10.1523/JNEUROSCI.23-25-08701.2003.
   PubMed Web of Science ®Google Scholar
• Liu F, Yuan R, Benashski SE, McCullough LD. Changes in experimental stroke outcome across the life span. J Cereb Blood Flow Metab. 2009;29(4):792–802. doi:10.1038/jcbfm.2009.5.
   PubMed Web of Science ®Google Scholar
• Amabebe E, Anumba DOC. The vaginal microenvironment: the physiologic role of lactobacilli. Front Med. 2018;5:181. doi:10.3389/fmed.2018.00181.
   PubMed Web of Science ®Google Scholar
• Gupta S, Kumar N, Singhal N, Kaur R, Manektala U. Vaginal microflora in postmenopausal women on hormone replacement therapy. Indian J Pathol Microbiol. 2006;49:457–461.
   PubMedGoogle Scholar
• Flores R, Shi J, Gail MH, Gajer P, Ravel J, Goedert JJ, Highlander SK. Association of fecal microbial diversity and taxonomy with selected enzymatic functions. PloS One. 2012;7(6):e39745. doi:10.1371/journal.pone.0039745.
   PubMed Web of Science ®Google Scholar
• Acharya KD, Gao X, Bless EP, Chen J, Tetel MJ. Estradiol and high fat diet associate with changes in gut microbiota in female ob/ob mice. Sci Rep. 2019;9(1):20192. doi:10.1038/s41598-019-56723-1.
   PubMedGoogle Scholar
• Montalbano MJ, Shane Tubbs R. Lateralization of the insular cortex. In: Turgut M, Yurttaş C Tubbs R, editors Island of Reil (insula) in the human brain: anatomical, functional, clinical and surgical aspects. Cham: Springer International Publishing; 2018. pp. 129–132.
   Google Scholar
• McCullough LD, Mirza MA, Xu Y, Bentivegna K, Steffens EB, Ritzel R, Liu F. Stroke sensitivity in the aged: sex chromosome complement vs. gonadal hormones. Aging (Albany NY). 2016;8(7):1432–1441. doi:10.18632/aging.100997.
   PubMedGoogle Scholar
• Lapchak PA, Zhang JH, Noble-Haeusslein LJ. RIGOR guidelines: escalating STAIR and STEPS for effective translational research. Transl Stroke Res. 2013;4(3):279–285. doi:10.1007/s12975-012-0209-2.
   PubMed Web of Science ®Google Scholar
• McCullough LD, Zeng Z, Blizzard KK, Debchoudhury I, Hurn PD. Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J Cereb Blood Flow Metab. 2005;25:502–512. doi:10.1038/sj.jcbfm.9600059.
   PubMed Web of Science ®Google Scholar
• McCullough LD, Roy-O’Reilly M, Lai YJ, Patrizz A, Xu Y, Lee J, Holmes A, Kraushaar DC, Chauhan A, Sansing LH, et al. Exogenous inter-α inhibitor proteins prevent cell death and improve ischemic stroke outcomes in mice. J Clin Invest. 2021;131(17):131. doi:10.1172/JCI144898.
   Web of Science ®Google Scholar
• Ganesh BP, Hall A, Ayyaswamy S, Nelson JW, Fultz R, Major A, Haag A, Esparza M, Lugo M, Venable S, et al. Diacylglycerol kinase synthesized by commensal Lactobacillus reuteri diminishes protein kinase C phosphorylation and histamine-mediated signaling in the mammalian intestinal epithelium. Mucosal Immunol. 2017;11(2):380–393. doi:10.1038/mi.2017.58.
   PubMed Web of Science ®Google Scholar
• Honarpisheh P, Reynolds CR, Blasco Conesa MP, Moruno Manchon JF, Putluri N, Bhattacharjee MB, Urayama A, McCullough LD, Ganesh BP. Dysregulated gut homeostasis observed prior to the accumulation of the brain amyloid-β in Tg2576 mice. Int J Mol Sci. 2020;21(5):1711. doi:10.3390/ijms21051711.
   PubMed Web of Science ®Google Scholar
• Rosshart SP, Vassallo BG, Angeletti D, Hutchinson DS, Morgan AP, Takeda K, Hickman HD, McCulloch JA, Badger JH, Ajami NJ, et al. Wild mouse gut microbiota promotes host fitness and improves disease resistance. Cell. 2017;171(5):1015–28.e13. doi:10.1016/j.cell.2017.09.016.
   PubMed Web of Science ®Google Scholar
• Segata N, Izard J, Waldron L, Gevers D, Miropolsky L, Garrett WS, Huttenhower C. Metagenomic biomarker discovery and explanation. Genome Biol. 2011;12(6):R60. doi:10.1186/gb-2011-12-6-r60.
   PubMed Web of Science ®Google Scholar