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Irene, Mackraj
- Biochemical, Phytochemical Profile and Angiotensin-1 Converting Enzyme Inhibitory Activity of the Hydro-methanolic Extracts of Tulbaghia acutiloba Harv.
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Authors
Affiliations
1 School of Laboratory Medicine and Medical Sciences, Discipline of Human Physiology, University of KwaZulu-Natal, Westville Campus, Durban, Private Bag X54001, 4000, ZA
2 School of Chemistry and Physics, Discipline of Chemistry, University of KwaZulu-Natal, Westville Campus, Durban, Private Bag X54001, 4000, ZA
1 School of Laboratory Medicine and Medical Sciences, Discipline of Human Physiology, University of KwaZulu-Natal, Westville Campus, Durban, Private Bag X54001, 4000, ZA
2 School of Chemistry and Physics, Discipline of Chemistry, University of KwaZulu-Natal, Westville Campus, Durban, Private Bag X54001, 4000, ZA
Source
Journal of Natural Remedies, Vol 19, No 4 (2019), Pagination: 221-235Abstract
Phytotherapeutic treatments have been on the ascendancy over the years as the quest for alternate and easily accessible health care is on the rise. Tulbaghia acutiloba has been used by both traditional healers and the South African population for the management of chronic conditions, but lacks scientific authentication. Hydro-methanolic extracts (ischolar_mains, rhizomes, leaves and flowers) of the plant were evaluated for their antioxidant activities, biochemical and phytochemical profile. Additionally, the heavy metal content and antihypertensive effects including Angiotensin 1-Converting Enzyme Inhibitory (ACEI) activities were investigated. The antioxidant ability of the hydro-methanolic extracts were determined by 2, 2-diphenyl-1-picryl hydrazyl (DPPH), hydrogen peroxide and nitric oxide scavenging activities. Phytochemical profile was assessed using qualitative and quantitative methods whereas the heavy metal toxicity was determined by using Inductively- Coupled Plasma-Optical Emission Spectrometry (ICP-OES). In vitro ACEI activity was determined by the hydrolysis of the tripeptide, hippuryl –L-Histidyl-L-leucine (Hip-His-Leu). All the extracts showed potent antioxidant activities which was concentration dependent. Phytochemical analysis showed the presence of phenols, amino acids and alkaloids in all the extracts. The leaves showed a relatively higher total phenolic content of 43.26±1.15 mgGAE/g. Gas Chromatography–Mass Spectrometry (GC-MS) analysis showed the presence of major compounds such as α-linolenic acid in the leaves as well as oleic acid and palmitic acid in other parts of the plants. Toxicity of heavy metal was undetected in all extracts of the plant. All the extracts of the plants showed a >50% ACE inhibition at different concentrations with the leaves showing a relatively higher inhibitory activity (76.66 ± 1.65, IC50; 154.23 μg/ml) compared with the other parts of the plants. It is therefore concluded in this study that the biological activities and phytochemical component of the hydro-methanolic extracts of T. acutiloba is indicative of its possible use for the treatment as well as prevention of hypertension and oxidative stressrelated diseases.
Keywords
Angiotensin 1-Converting Enzyme, Antioxidant, Heavy Metal Toxicity, Tulbaghia acutiloba, Phytochemical.Full Text
References
- Poulter NR, Schutte AE, Tomaszewski M, Lackland DT. May measurement month: A new joint global initiative by the International Society of Hypertension and the World Hypertension League to raise awareness of raised blood pressure. Journal of Hypertension. 2017; 35(5):1126-28. https://doi.org/10.1097/HJH.0000000000001346. PMid: 28306637.
- James PB, Kamara H, Bah AJ, Steel A, Wardle J. Herbal medicine use among hypertensive patients attending public and private health facilities in Freetown Sierra Leone. Complementary Therapies in Clinical Practice. 2018. https://doi.org/10.1016/j.ctcp.2018.01.001. PMid: 29705483.
- Yessoufou K, Daru BH, Muasya AM. Phylogenetic exploration of commonly used medicinal plants in South Africa. Molecular Ecology Resources. 2015; 15(2):405-13. https://doi.org/10.1111/1755-0998.12310. PMid: 25066923.
- Hughes GD, Aboyade OM, Clark BL, Puoane TR. The prevalence of traditional herbal medicine use among hypertensives living in South African communities. BMC Complementary and Alternative Medicine. 2013; 13(1):38. https://doi.org/10.1186/1472-6882-13-38. PMid: 23414344, PMCid: PMC3598715.
- Audet CM, Ngobeni S, Wagner RG. Traditional healer treatment of HIV persists in the era of ART: A mixed methods study from rural South Africa. BMC Complement Altern. Med. 2017; 17(1):434. https://doi.org/10.1186/s12906-0171934-6. PMid: 28854905, PMCid: PMC5577748.
- Mahomoodally MF. Traditional medicines in Africa: An appraisal of ten potent African medicinal plants. EvidenceBased Complementary and Alternative Medicine. 2013; 2013: 14. Article ID 617459. https://doi.org/10.1155/2013/617459. PMid: 24367388, PMCid: PMC3866779.
- Van Wyk B-E, Wink M. Medicinal plants of the world. Medicinal Plants of the World. 2017 (Ed. 2). https://doi.org/10.1079/9781786393258.0000.
- Valko M, Jomova K, Rhodes CJ, Kuča K, Musílek K. Redoxand non-redox-metal-induced formation of free radicals and their role in human disease. Archives of Toxicology. 2016; 90(1):1-37.https://doi.org/10.1007/s00204-015-15795. PMid: 26343967.
- Lagouge M, Larsson NG. The role of mitochondrial DNA mutations and free radicals in disease and ageing. Journal of Internal Medicine. 2013; 273(6):529-43. https:// doi.org/10.1111/joim.12055. PMid: 23432181, PMCid: PMC3675642.
- Sarrafchi A, Bahmani M, Shirzad H, Rafieian-Kopaei M. Oxidative stress and Parkinson’s disease: New hopes in treatment with herbal antioxidants. Current Pharmaceutical Design. 2016; 22(2):238-46. https://doi.org/10.2174/138161 2822666151112151653. PMid: 26561062.
- Phaniendra A, Jestadi DB, Periyasamy L. Free radicals: Properties, sources, targets, and their implication in various diseases. Indian Journal of Clinical Biochemistry. 2015; 30(1):11-26. https://doi.org/10.1007/s12291-014-0446-0. PMid: 25646037, PMCid: PMC4310837.
- Li H, Xia N, Förstermann U. Nitric Oxide Synthesis in Vascular Physiology and Pathophysiology. Endothelial Signaling in Development and Disease: Springer; 2015. p. 381-97. https://doi.org/10.1007/978-1-4939-2907-8_16.
- Adrees M, Ali S, Rizwan M, Zia-ur-Rehman M, Ibrahim M, Abbas F, et al. Mechanisms of silicon-mediated alleviation of heavy metal toxicity in plants: A review. Ecotoxicology and Environmental Safety. 2015; 119:186-97. https://doi.org/10.1016/j.ecoenv.2015.05.011. PMid: 26004359.
- Aremu AO, Van Staden J. The genus Tulbaghia (Alliaceae)-A review of its ethnobotany, pharmacology, phytochemistry and conservation needs. Journal of Ethnopharmacology. 2013; 149(2):387-400. https://doi.org/10.1016/j.jep.2013.06.046. PMid: 23838476.
- Zobolo A, Mkabela Q. Traditional knowledge transfer of activities practised by Zulu women to manage medicinal and food plant gardens. African Journal of Range and Forage Science. 2006; 23(1):77-80. https://doi.org/10.2989/10220110609485889.
- Watt JM, Breyer-Brandwijk MG. The Medicinal and Poisonous Plants of Southern and Eastern Africa being an Account of their Medicinal and other Uses, Chemical Composition, Pharmacological Effects and Toxicology in Man and Animal. 1962 (Edn 2).
- Ncube B, Ngunge V, Finnie J, Van Staden J. A comparative study of the antimicrobial and phytochemical properties between outdoor grown and micropropagated Tulbaghia violacea Harv. plants. Journal of Ethnopharmacology. 2011; 134(3):775-80. https://doi.org/10.1016/j.jep.2011.01.039. PMid: 21291985.
- Moodley K, Joseph K, Naidoo Y, Islam S, Mackraj I. Antioxidant, antidiabetic and hypolipidemic effects of Tulbaghia violacea Harv. (wild garlic) rhizome methanolic extract in a diabetic rat model. BMC Complementary and Alternative Medicine. 2015; 15(1):408. https://doi.org/10.1186/s12906-015-0932-9. PMid: 26577219, PMCid: PMC4647322.
- Chidambara Murthy KN, Jayaprakasha GK, Singh RP. Studies on antioxidant activity of pomegranate (Punica granatum) peel extract using in vivo models. J. Agric. Food Chem. 2002; 50(17):4791-95. https://doi.org/10.1021/jf0255735. PMid: 12166961.
- Keser S, Celik S, Turkoglu S, Yilmaz O, Turkoglu I. Hydrogen peroxide radical scavenging and total antioxidant activity of hawthorn. Chemistry Journal. 2012; 2(1):9-12.
- Govindarajan R, Vijayakumar M, Pushpangadan P. Antioxidant approach to disease management and the role of ‘Rasayana’ herbs of Ayurveda. J. Ethnopharmacol. 2005; 99(2):165-78. https://doi.org/10.1016/j.jep.2005.02.035. PMid: 15894123.
- Kang DG, Lee YS, Kim HJ, Lee YM, Lee HS. Angiotensin converting enzyme inhibitory phenylpropanoid glycosides from Clerodendron trichotomum. J. Ethnopharmacol. 2003; 89(1):15154. https://doi.org/10.1016/S0378-8741(03)00274-5.
- Keeler RF, Binns W. Teratogenic compounds of veratrum californicum (durand): I. preparation and characterization of fractions and alkaloids for biologic testing. Can. J. Biochem. 1966; 44(6):819-28. https://doi.org/10.1139/o66100. PMid: 5919283.
- Soloway S, Wilen SH. Improved ferric chloride test for phenols. Anal. Chem. 1952; 24(6):979-83. https://doi.org/10.1021/ac60066a017.
- Edeoga HO, Okwu D, Mbaebie B. Phytochemical constituents of some Nigerian medicinal plants. African Journal of Biotechnology. 2005; 4(7):685-88. https://doi.org/10.5897/AJB2005.000-3127.
- Lewis P, Lobban MC. The chemical specificity of the Schultz test for steroids. J. Histochem. Cytochem. 1961; 9(1):2-10. https://doi.org/10.1177/9.1.2. PMid: 14464899.
- Czeczot H, Tudek B, Kusztelak J, Szymczyk T, Dobrowolska B, Glinkowska G, et al. Isolation and studies of the mutagenic activity in the Ames test of flavonoids naturally occurring in medical herbs. Mutation Research/Genetic Toxicology. 1990; 240(3):209-16. https://doi.org/10.1016/0165-1218(90)90060-F.
- Magalhães AF, Tozzi AMGdA, Santos CC, Serrano DR, Zanotti-Magalhães EM, Magalhães EG, et al. Saponins from Swartzia langsdorffii: Biological activities. Mem. Inst. Oswaldo. Cruz. 2003; 98(5):713-18. https://doi.org/10.1590/S0074-02762003000500022. PMid: 12973543.
- Firdouse S, Alam P. Phytochemical investigation of extract of Amorphophallus campanulatus tubers. International Journal of Phytomedicine. 2011; 3(1):32.
- Saxena V, Chaturvedi S. Cardiac glycosides from the ischolar_mains of Streblus asper. Planta. Med. 1985; 51(04):343-44. https:// doi.org/10.1055/s-2007-969509. PMid: 17340531.
- Yemm E, Cocking E, Ricketts R. The determination of amino-acids with ninhydrin. Analyst. 1955; 80(948):20914. https://doi.org/10.1039/an9558000209.
- Free AH, Adams EC, Kercher ML, Free HM, Cook MH. Simple specific test for urine glucose. Clin. Chem. 1957; 3(3):163-68.
- Waterhouse AL. Determination of total phenolics. Current Protocols in Food Analytical Chemistry. 2002; 6(1):8. https://doi.org/10.1002/0471142913.fai0101s06.
- Kong I-C, Bitton G, Koopman B, Jung K-H. Heavy metal toxicity testing in environmental samples. Rev. Environ. Contam. Toxicol: Springer; 1995. p. 119-47. https://doi.org/10.1007/978-1-4612-4252-9_5. PMid: 7652196.
- Leung AA, Daskalopoulou SS, Dasgupta K, McBrien K, Butalia S, Zarnke KB, et al. Hypertension Canada’s 2017 guidelines for diagnosis, risk assessment, prevention, and treatment of hypertension in adults. Canadian Journal of Cardiology. 2017; 33(5):557-76. https://doi.org/10.1016/j.cjca.2017.03.005. PMid: 28449828.
- Wright JM, Musini VM, Gill R. First‐line drugs for hypertension. Cochrane Database of Systematic Reviews. 2018; (4). https://doi.org/10.1002/14651858.CD001841.pub3. PMCid: PMC6513559.
- Beladi-Mousavi SS, Hajibabaei K, Tamadon M-R, RafieianKopaei M. Relationship between free radicals and risk of kidney diseases; the role of antioxidants and their reaction mechanisms. Annals of Research in Antioxidants. 2016; 1(1).
- Takaidza S, Mtunzi F, Pillay M. Analysis of the phytochemical contents and antioxidant activities of crude extracts from Tulbaghia species. Journal of Traditional Chinese Medicine. 2018; 38(2):272-79. https://doi.org/10.1016/j.jtcm.2018.04.005.
- Eid HH, Metwally GF. Phytochemical and biological study of callus cultures of Tulbaghia violacea Harv. cultivated in Egypt. Natural Product Research. 2017; 31(15):1717-24. https://doi.org/10.1080/14786419.2017.1289206. PMid: 28278648.
- Saibu G, Katerere D, Rees D, Meyer M. In vitro cytotoxic and pro-apoptotic effects of water extracts of Tulbaghia violacea leaves and bulbs. Journal of Ethnopharmacology. 2015; 164:203-09. https://doi.org/10.1016/j.jep.2015.01.040. PMid: 25683299.
- Li H, Horke S, Förstermann U. Vascular oxidative stress, nitric oxide and atherosclerosis. Atherosclerosis. 2014; 237(1):20819. https://doi.org/10.1016/j.atherosclerosis.2014.09.001. PMid: 25244505.
- Hecht F, Pessoa CF, Gentile LB, Rosenthal D, Carvalho DP, Fortunato RS. The role of oxidative stress on breast cancer development and therapy. Tumor Biology. 2016; 37(4):4281-91. https://doi.org/10.1007/s13277-016-4873-9. PMid: 26815507.
- Takaidza S, Pillay M, Mtunzi F. Biological activities of species in the genus Tulbaghia: A review. African Journal of Biotechnology. 2015; 14(45):3037-43. https://doi.org/10.5897/AJB2015.14970.
- Ahmadvand H, Jamor P. Effects of alpha lipoic acid on level of NO and MPO activity in diabetic rats. Annals of Research in Antioxidants. 2017; 2(2).
- Nakkala JR, Mata R, Sadras SR. The antioxidant and catalytic activities of green synthesized gold nanoparticles from Piper longum fruit extract. Process Safety and Environmental Protection. 2016; 100:288-94. https://doi.org/10.1016/j.psep.2016.02.007.
- Niki E. Antioxidant capacity of foods for scavenging reactive oxidants and inhibition of plasma lipid oxidation induced by multiple oxidants. Food and Function. 2016; 7(5):215668. https://doi.org/10.1039/C6FO00275G. PMid: 27090496.
- Fischer BM, Voynow JA, Ghio AJ. COPD: Balancing oxidants and antioxidants. International Journal of Chronic Obstructive Pulmonary Disease. 2015; 10:261. https://doi.org/10.2147/COPD.S42414. PMid: 25673984, PMCid: PMC4321570.
- Radi R. Oxygen radicals, nitric oxide, and peroxynitrite: Redox pathways in molecular medicine. Proceedings of the National Academy of Sciences. 2018; 115(23):5839-48. https://doi.org/10.1073/pnas.1804932115. PMid: 29802228, PMCid: PMC6003358.
- Miller M, Sadowska-Krowicka H, Chotinaruemol S, Kakkis JL, Clark DA. Amelioration of chronic ileitis by nitric oxide synthase inhibition. Journal of Pharmacology and Experimental Therapeutics. 1993; 264(1):11-16.
- Heydarpour P, Rahimian R, Fakhfouri G, Khoshkish S, Fakhraei N, Salehi-Sadaghiani M, et al. Behavioral despair associated with a mouse model of Crohn’s disease: Role of nitric oxide pathway. Progress in NeuroPsychopharmacology and Biological Psychiatry. 2016; 64:131-41. https://doi.org/10.1016/j.pnpbp.2015.08.004. PMid: 26268932.
- Benyahya S, Aouf C, Caillol S, Boutevin B, Pascault JP, Fulcrand H. Functionalized green tea tannins as phenolic prepolymers for bio-based epoxy resins. Industrial Crops. and Products. 2014; 53:296-307. https://doi.org/10.1016/j.indcrop.2013.12.045.
- Valls R-M, Farràs M, Suárez M, Fernández-Castillejo S, Fitó M, Konstantinidou V, et al. Effects of functional olive oil enriched with its own phenolic compounds on endothelial function in hypertensive patients. A Randomised Controlled Trial. Food Chemistry. 2015; 167:30-35. https:// doi.org/10.1016/j.foodchem.2014.06.107. PMid: 25148955.
- McSweeney C, Palmer B, McNeill D, Krause D. Microbial interactions with tannins: Nutritional consequences for ruminants. Animal Feed Science and Technology. 2001; 91(1):83-93. https://doi.org/10.1016/S0377-8401(01)002322.
- Sultana S, Muhammad Asif H. Medicinal plants combating against hypertension: A green antihypertensive approach. Pakistan Journal of Pharmaceutical Sciences. 2017; 30(6).
- Ullah MF, Abuduhier FM. Inhibition of angiotensin converting enzyme by Rhazya stricta, Moringa peregrina and Achillea fragrantissima, used in traditional system of medicine in Arabian Peninsula: Implication in the management of hypertension. Journal of Medicinal Plants Research. 2016; 10(8):93-99. https://doi.org/10.5897/JMPR2015.6043.
- Ojeda D, Jiménez-Ferrer E, Zamilpa A, Herrera-Arellano A, Tortoriello J, Alvarez L. Inhibition of Angiotensin Convertin Enzyme (ACE) activity by the anthocyanins delphinidinand cyanidin-3-O-sambubiosides from Hibiscus sabdariffa. Journal of Ethnopharmacology. 2010; 127(1):7-10. https:// doi.org/10.1016/j.jep.2009.09.059. PMid: 19808084.
- Diallo M, Traore M, Balde M, Camara A, Baldé E, Traore S, et al. Prevalence, management and ethnobotanical investigation of hypertension in two Guinean urban districts. Journal of Ethnopharmacology. 2019; 231:73-79. https://doi.org/10.1016/j.jep.2018.07.028. PMid: 30056206.
- Cenci F, Louvandini H, McManus C, DelľPorto A, Costa D, Araújo Sd, et al. Effects of condensed tannin from Acacia mearnsii on sheep infected naturally with gastrointestinal helminthes. Veterinary Parasitology. 2007; 144(1):13237. https://doi.org/10.1016/j.vetpar.2006.09.021. PMid: 17067741.
- Roberts MF. Alkaloids: biochemistry, ecology, and medicinal applications: Springer Science and Business Media; 2013.
- Aniszewski T. Alkaloids: Chemistry, Biology, Ecology, and Applications: Elsevier; 2015. https://doi.org/10.1016/B9780-444-59433-4.00002-X.
- Krstin S, Sobeh M, Braun M, Wink M. Tulbaghia violacea and Allium ursinum extracts exhibit anti-parasitic and antimicrobial activities. Molecules. 2018; 23(2):313. https:// doi.org/10.3390/molecules23020313. PMid: 29393867, PMCid: PMC6017524.
- Stafford GI, Wikkelsø MJ, Nancke L, Jäger AK, Möller M, Rønsted N. The first phylogenetic hypothesis for the southern African endemic genus Tulbaghia (Amaryllidaceae, Allioideae) based on plastid and nuclear DNA sequences. Botanical Journal of the Linnean Society. 2016; 181(2):15670. https://doi.org/10.1111/boj.12417.
- Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ. Heavy metal toxicity and the environment. Molecular, Clinical and Environmental Toxicology: Springer; 2012. p. 13364. https://doi.org/10.1007/978-3-7643-8340-4_6. PMid: 22945569, PMCid: PMC4144270.
- Styger G, Aboyade OM, Gibson D, Hughes G. Tulbaghia-A Southern African Phytomedicine. The Journal of Alternative and Complementary Medicine. 2016; 22(4):255-61. https:// doi.org/10.1089/acm.2014.0406. PMid: 27008423.
- Madike LN, Takaidza S, Pillay M. Preliminary phytochemical screening of crude extracts from the leaves, stems, and ischolar_mains of Tulbaghia violacea. Int. J. Pharmacogn. Phytochem. Res. 2017; 9(10):1300-08. https://doi.org/10.25258/phyto.v9i10.10453.
- Moodley K, Mackraj I. Metabolic effects of Tulbaghia violacea Harv. in a diabetic model. African Journal of Traditional, Complementary and Alternative Medicines. 2016; 13(4):11322. https://doi.org/10.21010/ajtcam.v13i4.16. PMid: 28852727, PMCid: PMC5566134.
- de Souza CO, Valenzuela CA, Baker EJ, Miles EA, Rosa Neto JC, Calder PC. Palmitoleic acid has stronger anti‐ inflammatory potential in human endothelial cells compared to oleic and palmitic acids. Molecular Nutrition and Food Research. 2018; 62(20):1800322. https://doi.org/10.1002/mnfr.201800322. PMid: 30102465.
- Liu X, Kris‐Etherton PM, West SG, Lamarche B, Jenkins DJ, Fleming JA, et al. Effects of canola and high‐oleic‐acid canola oils on abdominal fat mass in individuals with central obesity. Obesity. 2016; 24(11):2261-68. https:// doi.org/10.1002/oby.21584. PMid: 27804268, PMCid: PMC5119743.
- Pieters DJ, Zock PL, Fuchs D, Mensink RP. Effect of α-linolenic acid on 24-h ambulatory blood pressure in untreated high-normal and stage I hypertensive subjects. British Journal of Nutrition. 2019; 121(2):155-63. https:// doi.org/10.1017/S0007114518003094. PMid: 30392473.
- Blondeau N. The nutraceutical potential of omega-3 alphalinolenic acid in reducing the consequences of stroke. Biochimie. 2016; 120:49-55. https://doi.org/10.1016/j.biochi.2015.06.005. PMid: 26092420.
- Balk E, Lichtenstein A. Omega-3 fatty acids and cardiovascular disease: Summary of the 2016 agency of healthcare research and quality evidence review. Nutrients. 2017; 9(8):865. https://doi.org/10.3390/nu9080865. PMid: 28800093, PMCid: PMC5579658.
- Islam MS, Mia M, Islam MA, Halder J, Rahman MF, Islam M, et al. A comprehensive review on region based traditional Ayurvedic practitioner’s plants secondary metabolites and their phytochemical activities in Bangladesh. Journal of Pharmacognosy and Phytochemistry. 2015; 3(6):202-16.
- Florence T, Hines M. Topical skin care formulations comprising plant extracts. US Patent App. 15/297, 550; 2018.
- Florence T, Hines M. Topical skin care formulations comprising plant extracts. Google Patents; 2016.
- Ramulondi M, de Wet H, van Vuuren S. Toxicology of medicinal plants and combinations used in rural northern KwaZulu-Natal (South Africa) for the treatment of hypertension. Journal of Herbal Medicine. 2018; 100251. https://doi.org/10.1016/j.hermed.2018.12.001.
- Imam MU, Ismail M, Ooi DJ, Azmi NH, Sarega N, Chan KW, et al. Are bioactive-rich fractions functionally richer? Critical Reviews in Biotechnology. 2016; 36(4):585-93.
- Koo Y, Song J, Bae S. Use of plant and herb derived medicine for therapeutic usage in cardiology. Medicines. 2018; 5(2):38. https://doi.org/10.3390/medicines5020038. PMid: 29690545, PMCid: PMC6023439.
- Perez-Gregorio R, Simal-Gandara J. A critical review of bioactive food components, and of their functional mechanisms, biological effects and health outcomes. Current Pharmaceutical Design. 2017; 23(19):2731-41. https://doi.org/10.2174/1381612823666170317122913. PMid: 28317483.