Czech J. Food Sci., 2018, 36(3):195-207 | DOI: 10.17221/283/2017-CJFS

Antioxidant and antihypertensive protein hydrolysates in fish products - a reviewReview

Klaudia KORCZEK*, Joanna TKACZEWSKA, Władysław MIGDAŁ
Department of Animal Product Technology, Food Technology, University of Agriculture in Cracow, Cracow, Poland

Fish proteins are a good source of bioactive peptides (BAPs). Such BAPs are derived through enzymatic hydrolysis of food proteins and can potentially by applied as health-promoting factors against chronic non-communicable diseases (NCDs), including arterial hypertension, cardiovascular disease and obesity. Antihypertensive and antioxidant BAPs derived from fish could represent a good alternative to synthetic drugs. This article reviews the literature on BAPs derived from fish and fish products, with an emphasis on antihypertensive and antioxidant properties and the impact of technological processes on the activity of BAPs. The review shows that BAPs isolated from fish exhibit quite good stability when applied under moderate physical conditions and after simulated in vitro digestion. Processing can increase the susceptibility of peptides to digestion in the digestive tract as well as improving absorption and immune system responses. Therefore, it is important to determine the optimal conditions under which proteins (and peptides) can be processed in order to maintain their bioactivity. Future research efforts on BAPs should be directed towards an elucidation of their activity after technological processes.

Keywords: bioactivity; functional food; fish protein hydrolysates; marine bioactive peptides; stability; technological process

Published: June 30, 2018  Show citation

ACS AIP APA ASA Harvard Chicago Chicago Notes IEEE ISO690 MLA NLM Turabian Vancouver
KORCZEK K, TKACZEWSKA J, MIGDAŁ W. Antioxidant and antihypertensive protein hydrolysates in fish products - a review. Czech J. Food Sci. 2018;36(3):195-207. doi: 10.17221/283/2017-CJFS.
Download citation

References

  1. Balti R., Nedjar-Arroume N., Bougatef A., Guillochon D., Nasri M. (2010): Three novel angiotensin I-converting enzyme (ACE) inhibitory peptides from cuttlefish (Sepia officinalis) using digestive proteases. Food Research International, 43: 1136-1143. Go to original source...
  2. Benhabiles M.S., Abdi N., Drouiche N., Lounici H., Pauss A., Goosen M.F.A., Mameri N. (2012): Fish protein hydrolysate production from sardine solid waste by crude pepsin enzymatic hydrolysis in a bioreactor coupled to an ultrafiltration unit. Material Science and Engineering C, 3: 922-928. Go to original source...
  3. Borawska J., Darewicz M., Pliszka M., Vegarud G.E. (2016a): Antioxidant properties of salmon (Salmo salar L.) protein fraction hydrolysates revealed following their ex vivo digestion and in vitro hydrolysis. Journal of the Science of Food and Agriculture, 96: 2764-2772. Go to original source... Go to PubMed...
  4. Borawska J., Darewicz M., Vegarud G.E., Minkiewicz P. (2016b): Antioxidant properties of carp (Cyprinus carpio L.) protein ex vivo and in vitro hydrolysates. Food Chemistry, 194: 770-779. Go to original source... Go to PubMed...
  5. Borawska J., Darewicz M., Vegarud G.E., Iwaniak A., Minkiewicz P. (2015): Ex vivo digestion of carp muscle tissue - ACE inhibitory and antioxidant activities of the obtained hydrolysates. Food & Function, 6: 211-218. Go to original source... Go to PubMed...
  6. Bruno B.J., Miller G.D., Lim C.S. (2013): Basics and recent advances in peptide and protein drug delivery. Therapeutic Delivery, 4: 1443-1467. Go to original source... Go to PubMed...
  7. Chalamaiah M., Jyothirmayi T., Diwan P.V., Kumar B.D. (2015): Antioxidant activity and functional properties of enzymatic protein hydrolysates from common carp (Cyprinus carpio) roe (egg). Journal of Food Science and Technoogy, 52: 5817-5825. Go to original source... Go to PubMed...
  8. Chalamaiah M., Jyothirmayi T., Bhaskarachary K., Vajreswari A., Hemalatha R., Kumar B.D. (2013): Chemical composition, molecular mass distribution and antioxidant capacity of rohu (Labeo rohita) roe (egg) protein hydrolysates prepared by gastrointestinal proteases. Food Research International, 52: 221-229. Go to original source...
  9. Cheison S.C., Wang Z., Xu S.Y. (2007): Preparation of whey proteinhydrolysates using a single- and two-stage enzymatic membranereactor and their immunological and antioxidant properties: characterization by multivariate data analysis. Journal of Agricultural and Food Chemistry, 55: 3896-3904. Go to original source... Go to PubMed...
  10. Chen J., Wanga Y., Zhong O., Wua Y., Xiaa W. (2012): Purification and characterization of a novel angiotensin-I converting enzyme (ACE) inhibitory peptide derived from enzymatic hydrolysate of grass carp protein. Peptides, 33: 52-58. Go to original source... Go to PubMed...
  11. Choonpicharn S., Jaturasitha S., Rakariyatham N., Suree N., Niamsup H. (2015): Antioxidant and antihypertensive activity of gelatin hydrolysate from Nile tilapia skin. Journal of Food Science and Technology, 52: 3134-9313. Go to original source... Go to PubMed...
  12. Darewicz M., Borawska J., Pliszka M. (2016): Carp proteins as a source of bioactive peptides - an in silico approach. Czech Journal of Food Sciences, 34: 111-117. Go to original source...
  13. Darewicz M., Borawska J., Minkiewicz P., Iwaniak A., Starowicz P. (2015a): Biologicznie aktywne peptydy uwalniane z białek żywności. Żywność. Nauka. Technologia. Jakość, 3: 26-41.
  14. Darewicz M., Borawska J., Pliszka M., Świtaj M. (2015b): Białka pstrąga tęczowego potencjalnym źródłem bioaktywnych peptydów - badania in silico. Trendy w żywieniu człowieka, 37-46.
  15. Darewicz M., Borawska J., Vegarud G.E., Minkiewicz P., Iwaniak A. (2014): Angiotensin I-converting enzyme (ACE) inhibitory activity and ACE inhibitory peptides of salmon (Salmo salar) protein hydrolysates obtained by human and porcine gastrointestinal enzymes. International Journal of Moecular Science, 15: 14077-14101. Go to original source... Go to PubMed...
  16. Darewicz M., Dziuba B., Minkiewicz P., Dziuba J. (2011): The preventive potential of milk and colostrum proteins and protein fragments. Food Reviews International, 27: 357-388. Go to original source...
  17. Di Bernardini R., Harnedy P., Bolton D., Kerry J., Neill E., Mullen A.M., Hayes M. (2011): Antioxidant and antimicrobial peptidic hydrolysates from muscle protein sources and by-products. Food Chemistry, 124: 1296-1307. Go to original source...
  18. Elavarasan K., Shamasundar B.A., Badii F., Howell N. (2016): Angiotensin I-converting enzyme (ACE) inhibitory activity and structural properties of oven- and freeze-dried protein hydrolysate from fresh water fish (Cirrhinus mrigala). Food Chemistry, 206: 210-216. Go to original source... Go to PubMed...
  19. Erdmann K., Cheung B.W.Y., Schroder H. (2008): The possible roles of food-derived bioactive peptides in reducing the risk of cardiovascular disease. The Journal of Nutritional Biochemistry, 19: 643-654. Go to original source... Go to PubMed...
  20. Ferraro V., Carvalho A.P., Piccirillo C., Santos M.M., Castro P.M., Pintado M.E. (2013): Extraction of high added value biological compounds from sardine, sardinetype fish and mackerel canning residues - a review. Materials Science & Engineering C: Materials for Biological Applications, 33: 3111-3120. Go to original source... Go to PubMed...
  21. Fu Y., Young J.F., Dalsgaard T.K., Therkildsen M. (2015): Separation of angiotensin I-converting enzyme inhibitory peptides from bovine connective tissue and their stability towards temperature, pH and digestive enzymes. International Journal of Food Science and Technology, 50: 1234-1243. Go to original source...
  22. Fujita H., Yokoyama K., Yasumoto R., Yoshikawa M. (1995): Antihypertensive effect of thermolysin digest of dried bonito in spontaneously hypertensive rat. Clinical and Experimental Pharmacology and Physiology. 22 (Supplement): S304-S305. Go to original source... Go to PubMed...
  23. Garcia-Mora P., Peñas E., Frias J., Gomez R., MartinezVillaluenga C. (2015): High-pressure improves enzymatic proteolysis and the release of peptides with angiotensin I converting enzyme inhibitory and antioxidant activities from lentil proteins. Food Chemistry, 171: 224-232. Go to original source... Go to PubMed...
  24. Gringer N., Safafar H., du Mesnildot A., Nielsen H.H., Rogowska-Wrzesinska A., Undeland I., Baron C.P. (2016): Antioxidative low molecular weight compounds in marinated Herring (Clupea harengus) salt brine. Food Chemistry, 194: 1164-1171. Go to original source... Go to PubMed...
  25. Gu R.Z., Li C.Y., Liu W.Y., Yi W.X., Cai M.Y. (2011): Angiotensin I-converting enzyme inhibitory activity of low-molecular-weight peptides from Atlantic salmon (Salmo salar L.) skin. Food Research International, 44: 1536-1540. Go to original source...
  26. Halldorsdottir S.M., Sveinsdottir H., Gudmundsdottir A., Thorkelsson G., Kristinsson H.G. (2014): High quality fish protein hydrolysates prepared from by-product material with Fucus vesiculosus extract. Journal of Functional Foods, 9: 10-17. Go to original source...
  27. Han Y., Byun S.-H., Park Y.-H., Kim S.-B. (2015): Bioactive properties of enzymatic hydrolysates from abdominal skin gelatin of yellowfin tuna (Thunnus albacares). Food Science & Technology, 50: 1996-2003. Go to original source...
  28. He R., Alashi A., Malomo S.A., Girgih A.T., Chao D., Ju X., Aluko R.E. (2013): Antihypertensive and free radical scavenging properties of enzymatic rapeseed protein hydrolysates. Food Chemistry, 141: 153-159. Go to original source... Go to PubMed...
  29. Hsu K.C. (2010): Purification of antioxidative peptides prepared from enzymatic hydrolysates of tuna dark muscle by-product. Food Chemistry, 122: 42-48. Go to original source...
  30. Huang B.-B., Lin H.-C., Chang Y.-W. (2015): Analysis of proteins and potential bioactive peptides from tilapia (Oreochromis spp.) processing co-products using proteomic techniques coupled with BIOPEP database. Journal of Functional Foods, 19: 629-640. Go to original source...
  31. Hwang J. (2010): Impact of processing on stability of angiotensin I-converting enzyme (ACE) inhibitory peptides obtained from tuna cooking juice. Food Research International, 43: 902-906. Go to original source...
  32. Je J., Lee K., Lee M.H., Ahn C. (2009): Antioxidant and antihypertensive protein hydrolysates produced from tuna liver by enzymatic hydrolysis. Food Research International, 42: 1266-1272. Go to original source...
  33. Je J.Y., Park P.J., Byun H.G., Jung W.K., Kim S.K. (2005): Angiotensin I converting enzyme (ACE) inhibitory peptide derived from the sauce of fermented blue mussel, Mytilus edulis. Bioresource Technology, 96: 1624-1629. Go to original source... Go to PubMed...
  34. Kim H.-J., Seong-Gook K., Jaiswal L., Li J., Choi J.-H., Moon S.-M., Cho J.-Y., Ham K.S. (2016): Identification of four new angiotensin I-converting enzyme inhibitory peptides from fermented anchovy sauce. Applied Biological Chemistry, 59: 25-31. Go to original source...
  35. Kim S.-R., Byun H.-G. (2012): The novel angiotensin I converting enzyme inhibitory peptide from rainbow trout muscle hydrolysate. Fisheries and Aquatic Science, 15, 183-190. Go to original source...
  36. Kim S.K., Wijesekara I. (2010): Development and biological activities of marine-derived bioactive peptides: a review. Journal of Functional Foods, 2: 1-9. Go to original source...
  37. Kristinsson H.G., Rasco B.A. (2000): Fish protein hydrolysates: production, biochemical, and functional properties. Critical Reviews in Food Science and Nutrition, 40: 43-81. Go to original source... Go to PubMed...
  38. Lafarga T., Hayes M. (2016): Bioactive protein hydrolysates in the functional food ingredient industry: overcoming current challenges. Food Reviews International, 33: 217-246. Go to original source...
  39. Lassoued I., Mora L., Barkia A., Aristoy M., Nasr M., Toldra F. (2015): Bioactive peptides identified in thornback ray skin's gelatin hydrolysates by proteases from Bacillus subtilis and Bacillus amyloliquefaciens. Journal of Proteomics, 128: 8-17. Go to original source... Go to PubMed...
  40. Lee S.H., Qian Z.J., Kim S.K. (2010): A novel angiotensin I converting enzyme inhibitory peptide from tuna frame protein hydrolysate and its antihypertensive effect in spontaneously hypertensive rats. Food Chemistry, 118: 96-102. Go to original source...
  41. Lemes A.C., Sala L., Ores Jda C., Braga A.R., Eqea M.B., Fernandes K.F. (2016): A review of the latest advances in encrypted bioactive peptides from protein-rich waste. International Journal of Molecular Sciences, 17: 950-974. Go to original source... Go to PubMed...
  42. Leygonie C., Britz T.J., Hoffman L.C. (2012): Impact of freezing and thawing on the quality of meat: review. Meat Science, 91: 93-98. Go to original source... Go to PubMed...
  43. Li Y., Yu J. (2015): Research Progress in structure-activity relationship of bioactive peptides. Journal of Medicinal Food, 18: 147-156. Go to original source... Go to PubMed...
  44. Li X., Luo Y., Shenb H., Youa J. (2012): Antioxidant activities and functional properties of grass carp (Ctenopharyngodon idellus) protein hydrolysates. Journal of the Science of Food and Agriculture, 92: 292-298. Go to original source... Go to PubMed...
  45. Li-Chan E.C.Y. (2015): Bioactive peptides and protein hydrolysates: research trends and challenges for application as nutraceuticals and functional food ingredients. Current Opinion in Food Science, 1: 28-37. Go to original source...
  46. Łuczyńska J., Tońska E., Borejszo Z. (2011): Zawartość makro- i mikroelementów oraz kwasów tłuszczowych w mięśniach łososia (Salmo salar L.), pstrąga tęczowego (Oncorhynchus mykiss Walb.) i karpia (Cyprinus carpio L.). Żywność. Nauka. Technologia. Jakość, 3: 162- 172 Go to original source...
  47. Madureira A.R., Tavares T., Gomes A.M.P., Pintado M.E., Malcata F.X. (2010): Invited review: Physiological properties of bioactive peptides obtained from whey proteins. Journal of Dairy Science, 93: 437-455. Go to original source... Go to PubMed...
  48. Manikkama V., Vasiljevica T., Donkora O.N., Mathaia M.L. (2016): A Review of potential marine-derived hypotensive and anti-obesity peptides. Critical Reviews in Food Science and Nutrition, 56: 92-112. Go to original source... Go to PubMed...
  49. Mora L., Gallego M., Reig M., Toldrá F. (2017): Challenges in the quantitation of naturally generated bioactive peptides in processed meats. Trends in Food Science & Technology, 69: 306-314. Go to original source...
  50. Mora L., Reig M., Toldrá F. (2014): Bioactive peptides generated from meat industry by products. Food Research International, 65: 344-349. Go to original source...
  51. Möller N.P., Scholz-Ahrens K.E., Roos N., Schrezenmeir J. (2008): Bioactive peptides and proteins from foods: Indication for health effects. European Journal of Nutrition, 47: 171-182. Go to original source... Go to PubMed...
  52. Murray B.A., FitzGerald R.J. (2007): Angiotensin convertingenzyme inhibitory peptides derived from food proteins: Biochemistry, bioactivity and production. Current Pharmaceutical Design, 13: 773-791. Go to original source... Go to PubMed...
  53. Neves A.C., Harnedy P.A., O'Keeffe M.B., FitzGerald R.J. (2017): Bioactive peptides from Atlantic salmon (Salmo salar) with angiotensin converting enzyme and dipeptidyl peptidase IV inhibitory, andantioxidant activities. Food Chemistry, 218: 396-405. Go to original source... Go to PubMed...
  54. Ovissipour M., Rasco B., Shiroodi S.G., Modanlow M., Gholamid S., Nematie M. (2013): Antioxidant activity of protein hydrolysates from whole anchovy sprat (Clupeonella engrauliformis) prepared using endogenous enzymes and commercial proteases. Journal of the Science of Food and Agriculture, 3: 1718-1726. Go to original source... Go to PubMed...
  55. Phadke G., Elavarasan K., Shamasundar B.A. (2014): Angiotensin-I converting enzyme (ACE) inhibitory activity and antioxidant activity of fermented fish product ngari as influenced by fermentation period. International Journal of Pharma and Bio Sciences, 5: 134-142.
  56. Power O., Fernández A., Norris R., Riera F.A., FitzGerald R.J. (2014): Selective enrichment of bioactive properties during ultrafiltration of a tryptic digest of β-lactoglobulin. Journal of Functional Foods, 9: 38-47. Go to original source...
  57. Rajapakse N., Mendis E., Jung W.K., Je J.Y., Kim S.K. (2005): Purification of a radical scavenging peptide from fermented mussel sauce and its antioxidant properties. Food Research International, 38: 175-182. Go to original source...
  58. Rao Q., Kamdar A.K., Labuza T.P. (2016): Storage stability of food protein hydrolysates - a review. Critical Reviews in Food Science and Nutrition, 56: 1169-1192. Go to original source... Go to PubMed...
  59. Rao R.K. (1991): Biologically active peptides in the gastrointestinal lumen. Life Sciences, 48: 1685-1704. Go to original source... Go to PubMed...
  60. Rasika D.M.D., Ranadheera C.S., Vidanarachchi J.K. (2013): Applications of Marine-derived Peptides and Proteins in the Food Industry. In: Kim S.-K. (ed.): Marine Proteins and Peptides Biological Activities and Applications. Oxford, Wiley-Blackwell: 545-587. Go to original source...
  61. Rasyad F., Huang T.C., Hsu J.L., Fadjar M. (2016): Screening of Novel angiotensin I converting enzyme inhibitory peptides derived from enzymatic hydrolysis of salmon protamine. Journal of Life Science and Biomeicine, 6: 100-105
  62. Rombensoa A.N., Trushenskia J.T., Schwarz M.H. (2016): Fish oil replacement in feeds for juvenile Florida Pompano: Composition of alternative lipid influences degree of tissue fatty acid profile distortion. Aquaculture, 458: 177-186. Go to original source...
  63. Rousseau-Ralliard D., Goirand F., Tardivel S., Lucas A., Algaron F., Mollé D., Robert V., Auchere D., Boudier J.F., Gailard J.L., Monnet V., Tauzin J., Grynberg A. (2010): Inhibitory effect of αS1- and αS2-casein hydrolysates on angiotensin I-converting enzyme in human endothelial cells in vitro, rat aortic tissue ex vivo, and renovascular hypertensive rats in vivo. Journal of Dairy Science, 93: 2906-2921. Go to original source... Go to PubMed...
  64. Saito K., Jin D.H., Ogawa T., Muramoto K., Hatakeyama E., Yasuhara T., Nokihara K. (2003): Antioxidant properties of tripeptide libraries prepared by the combinatorial chemistry. Journal of Agricultural and Food Chemistry, 1, 51: 3668-3674. Go to original source... Go to PubMed...
  65. Savjani K.T., Gajjar A.K., Savjani J.K. (2012): Drug solubility: importance and enhancement techniques. ISRN Pharmaceutics, 2012, Article ID 195727. doi: 10.5402/2012/195727 Go to original source... Go to PubMed...
  66. Singh B.P., Vij S., Hati S. (2014): Functional significance of bioactive peptides derived from soybean. Peptides, 54: 171-179. Go to original source... Go to PubMed...
  67. Skanderby M. (1994): Protein hydrolysates: their functionality and applications. European Food Research and Technology, 199: 141.
  68. Slizyte R., Rommi K., Mozuraityte R., Eck P., Five K., Rustad T. (2016): Bioactivities of fish protein hydrolysates from defatted salmon backbones. Biotechnology Reports, 11: 99-109. Go to original source... Go to PubMed...
  69. Song R., Wei R.-B., Ruan G.-G., Luo H.Y. (2015): Isolation and identification of antioxidative peptides from peptic hydrolysates of half-fin anchovy (Setipinna taty). LWTFood Science and Technology, 60: 221-229. Go to original source...
  70. Toopcham T., Roytrakul S., Yongsawatdigul J. (2015): Characterization and identification of angiotensin I-converting enzyme (ACE) inhibitory peptides derived from tilapia using Virgibacillus halodenitrificans SK1-3-7 proteinases. Journal of Functional Foods, 14: 435-444. Go to original source...
  71. Traore S., Aubry S., Gatellier P., Przybylski W., Jaworska D., Kajak-Siemaszko K., Santé-Lhoutellier V. (2012): Effect of heat treatment on protein oxidation in pig meat. Meat Science, 91: 14-21. Go to original source... Go to PubMed...
  72. Tsai J.S., Chen J.L., Pan B.S. (2008): ACE-inhibitory peptides identified from the muscle protein hydrolysate of hard clam (Meretrix lusoria). Process Biochemistry, 43: 743-747. Go to original source...
  73. Vieira E.F., Ferreira I.M.P.L.V.O. (2017): Antioxidant and antihypertensive hydrolysates obtained from by-products of cannery sardine and brewing industries. International Journal of Food Properties, 20: 662-673. Go to original source...
  74. Wang J., Hu J., Cui J., Bai X., Dua Y., Miyaguchi Y., Lin B. (2008a): Purification and identification of a ACE-inhibitory peptide from oyster proteins hydrolyzate and the antihypertensive effect of hydrolyzate in spontaneously hypertensive rats. Food Chemistry, 111: 302-308. Go to original source... Go to PubMed...
  75. Wang J.R., Teng D., Tian Z.G. (2008b): Preparation and mechanism of functional antioxidant peptides. Natural Product Research and Development, 20: 371-375
  76. Wiriyaphan C., Chitsomboon B., Yongsawadigul J. (2012): Antioxidant activity of protein hydrolysates derived from threadfin bream surimi byproducts. Food Chemistry, 132: 104-111. Go to original source... Go to PubMed...
  77. Wu J., Aluko R.E., Nakai S. (2006): Structural requirements of angiotensin I-converting enzyme inhibitory peptides: Quantitative structure-activity relationship study of diand tripeptides. Journal of Agricultural and Food Chemistry, 54: 732-738. Go to original source... Go to PubMed...
  78. Yang P., Ke H., Hong P., Zeng S., Cao W. (2011): Antioxidant activity of bigeye tuna (Thunnus obesus) head protein hydrolysate prepared with Alcalase. International Journal of Food Science and Technology, 46: 2460-2466. Go to original source...
  79. Yokoyama K., Chiba H., Yoshikawa M. (1992): Peptide inhibitors for angiotensin I-converting enzyme from thermolysin digest of dried bonito. Bioscience, Biotechnology, and Biochemistry, 56: 1541-1545. Go to original source... Go to PubMed...
  80. Yongsawatdigul J., Hemung B.-O. (2010): Structural changes and functional properties of threadfin bream sarcoplasmic proteins subjected to pH-shifting treatments and lyophilization. Journal of Food Science, 7: 251-257. Go to original source... Go to PubMed...
  81. Yongsawatdigul J., Park J.W. (2003): Thermal denaturation and aggregation of threadfin bream actomyosin. Food Chemistry, 83: 408-416. Go to original source...
  82. Zhang R., Chen J., Jiang V., Yin L., Zhang X. (2016a): Antioxidant and hypoglycaemic effects of tilapia skin collagen peptide in mice. International Journal of Food Science and Technology, 51: 2157-2163. Go to original source...
  83. Zhang C., Zhang N., Li Z., Tian Y., Zhang L., Zheng B. (2016b): Stability of antioxidant peptides prepared from large yellow croaker (Pseudosciaena crocea). Current Topics in Nutraceutical Research, 14: 37-47.
  84. Zhao T., Xu J., Zhao H., Jiang W., Guo X., Zhao M., Sun-Waterhouse D., Zhao Q., Su G. (2017): Antioxidant and antiacetylcholinesterase activities of anchovy (Coilia mystus) protein hydrolysates and their memory-improving effects on scopolamine-induced amnesia mice. International Journal of Food Science and Technology, 52: 504-510. Go to original source...
  85. Zhu Y.H., Liu R., Wu H., Wang L.C. (2012): Progress of structure-activity relationship of bioactive peptides. China Journal of Traditional Chinese Medicine and Pharmacy, 27: 2625-2628. (in Chinese)

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY NC 4.0), which permits non-comercial use, distribution, and reproduction in any medium, provided the original publication is properly cited. No use, distribution or reproduction is permitted which does not comply with these terms.