nogrЭкспериментальная и клиническая гастроэнтерологияExperimental and Clinical Gastroenterology1682-8658«Global Media Technologies»10.31146/1682-8658-ecg-196-12-102-109nogr-1805Research ArticleОБЗОРREVIEWБиологическая роль казоморфинов (часть 1)The biological role of casomorphinshttps://orcid.org/0000-0001-7308-7280ХавкинА. И.KhavkinA. I.

Хавкин Анатолий Ильич, д. м. н., профессор, главный научный сотрудник отдела гастроэнтерологии Научно-исследовательского клинического института педиатрии им. академика Ю. Е. Вельтищева

125412, Москва, ул. Талдомская, 2308015, Белгородская область, Белгород, ул. Победы, д. 85

Anatoly I. Khavkin, MD, PhD, DSc, Professor, Chief Researcher of the Department of Gastroenterology of the Scientific Research Clinical Institute of Pediatrics named after Academician Yu. E. Veltischev

125412, Moscow, st. Taldomskaya, 2308015, the Belgorod region, Belgorod, Pobedy Street, 85   

gastropedclin@gmail.comhttps://orcid.org/0000-0002-1927-6811ВасиаМ. Н.VasiaM. N.

Васиа Мари Нечеса, главный врач больницы

GA000, Аккра, а/я OS 3410 ОСУ

Marie Nechesa Vasia, MD, Chief Physician at Doctors on Duty Clinic Labadi

GA000, Accra, PO BOX OS 3410, OSU

https://orcid.org/0000-0002-0992-1709НовиковаВ. П.NovikovaV. P.

Новикова Валерия Павловна, д. м. н., профессор, зав. кафедрой пропедевтики детских болезней с курсом общего ухода за детьми, зав. лабораторией «Медико-социальных проблем в педиатрии»

194100, Санкт-Петербург, ул. Литовская, д. 2, литера Ж

Valeriya P. Novikova, MD, PhD, DSc, Professor, Head of Department of Propedeutics of Childhood Diseases with a course of general child care, head. laboratory “Medical and social problems in pediatrics”

194100, St. Petersburg, st. Litovskaya, 2, letter Zh  

Российский национальный исследовательский медицинский университет им. Н. И. Пирогова; Белгородский государственный исследовательский университет Министерства науки и высшего образования Российской ФедерацииРоссияRussian National Research Medical University named after N. I. Pirogov; Belgorod State Research University Russian FederationRussian FederationБольница “Doctors on duty clinic Labadi”ГанаDotors on duty clinic LabadiGhanaСанкт-Петербургский государственный педиатрический медицинский университетРоссияSaint Petersburg State Pediatric Medical UniversityRussian Federation202116012022012102109Copyright © Хавкин А.И., Васиа М.Н., Новикова В.П., 20222022Хавкин А.И., Васиа М.Н., Новикова В.П.Khavkin A.I., Vasia M.N., Novikova V.P.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.nogr.org/jour/article/view/1805

Обзор литературы посвящён биологически активным метаболитам казеина — результатам его гидролиза, олигопептидам—казоморфинам. Данные пептиды с длиной цепи от 4 до 11 аминокислот происходят из β-казеина молока и высвобождаются во время пищеварения, как in vivo, так и in vitro. Казеоморфины демонстрируют опиоидную и фармакологическую активность вследствие связывания с μ-рецепторами, расположенными в центральной нервной системе, желудочно-кишечном тракте и некоторых иммунных клетках. Понимание биологической роли казеоморфинов молока млекопитающих, в том числе и человека, их влияние на органы и системы, приблизит специалистов к расшифровке этиологии целой группы заболеваний.

The literature review is devoted to biologically active metabolites of casein — the results of its hydrolysis — oligopeptides casomorphins. These peptides with a chain length of 4 to 11 amino acids are derived from milk β-casein and are released during digestion, both in vivo and in vitro. Caseomorphins exhibit opioid and pharmacological activity due to binding to μ-receptors located in the central nervous system, gastrointestinal tract and some immune cells. Understanding the biological role of caseomorphins in the milk of mammals, including humans, and their effect on organs and systems, will bring specialists closer to deciphering the etiology of a whole group of diseases.

казеинказоморфинβ-казеинмолоко А1 и А2caseincasomorphinβ-caseinA1 and A2 milkReferencesMeisel H., Bockelmann W. Bioactive peptides encrypted in milk proteins: Proteolytic activation and throphofunctional properties. Antonie van Leeuwenhoek. 1999;76 (1):207–215.Meisel H., Bockelmann W. Bioactive peptides encrypted in milk proteins: Proteolytic activation and throphofunctional properties. Antonie van Leeuwenhoek. 1999;76 (1):207–215.Teschemacher H. Opioid receptor ligands derived from food proteins. Curr Pharm Des. 2003;9(16):1331–44. doi:10.2174/1381612033454856.Teschemacher H. Opioid receptor ligands derived from food proteins. Curr Pharm Des. 2003;9(16):1331–44. doi:10.2174/1381612033454856.Kostyra E., Sienkiewicz Szapka E., Jarmoowska, B., Krawczuk S., Kostyra H. Opioid peptides derived from milk proteins. Polish Journal of Food and Nutritional Science. 2004;13 (54):25–35.Kostyra E., Sienkiewicz Szapka E., Jarmoowska, B., Krawczuk S., Kostyra H. Opioid peptides derived from milk proteins. Polish Journal of Food and Nutritional Science. 2004;13 (54):25–35.Farrell H.M., Jimenez-Flores R., Bleck G. T., et al. Nomenclature of the proteins of cow’s milk. J Dairy Sci. 2004 Jun;87(6):1641–74. doi:10.3168/jds.S0022–0302(04)73319–6.Farrell H.M., Jimenez-Flores R., Bleck G. T., et al. Nomenclature of the proteins of cow’s milk. J Dairy Sci. 2004 Jun;87(6):1641–74. doi:10.3168/jds.S0022–0302(04)73319–6.Ng-Kwi-Hang K.F., Grosclaude F. Advanced Dairy Chemistry, P. F. Fox and P. L. H. McSweeney, Eds., Springer, Berlin, Germany, 1992.Ng-Kwi-Hang K.F., Grosclaude F. Advanced Dairy Chemistry, P. F. Fox and P. L. H. McSweeney, Eds., Springer, Berlin, Germany, 1992.Ho S., Woodford K., Kukuljan S., Pal S. Comparative effects of A1 versus A2 beta-casein on gastrointestinal measures: a blinded randomised cross-over pilot study. Eur J Clin Nutr. 2014 Sep;68(9):994–1000. doi:10.1038/ejcn.2014.127.Ho S., Woodford K., Kukuljan S., Pal S. Comparative effects of A1 versus A2 beta-casein on gastrointestinal measures: a blinded randomised cross-over pilot study. Eur J Clin Nutr. 2014 Sep;68(9):994–1000. doi:10.1038/ejcn.2014.127.Guantario B., Giribaldi M., Devirgiliis C., et al. A Comprehensive Evaluation of the Impact of Bovine Milk Containing Diff erent Beta-Casein Profiles on Gut Health of Ageing Mice. Nutrients. 2020 Jul 19;12(7):2147. doi:10.3390/nu12072147.Guantario B., Giribaldi M., Devirgiliis C., et al. A Comprehensive Evaluation of the Impact of Bovine Milk Containing Diff erent Beta-Casein Profiles on Gut Health of Ageing Mice. Nutrients. 2020 Jul 19;12(7):2147. doi:10.3390/nu12072147.He M., Sun J., Jiang Z. Q., Yang Y. X. Effects of cow’s milk beta-casein variants on symptoms of milk intolerance in Chinese adults: a multicentre, randomised controlled study. Nutr J. 2017 Oct 25;16(1):72. doi:10.1186/s12937–017–0275–0.He M., Sun J., Jiang Z. Q., Yang Y. X. Effects of cow’s milk beta-casein variants on symptoms of milk intolerance in Chinese adults: a multicentre, randomised controlled study. Nutr J. 2017 Oct 25;16(1):72. doi:10.1186/s12937–017–0275–0.ul Haq M. R., Kapila R., Shandilya U. K., Kapila S. Impact of milk derived β-casomorphins on physiological functions and trends in research: a review. International Journal of Food Properties, 2014;17(8):1726–1741.ul Haq M. R., Kapila R., Shandilya U. K., Kapila S. Impact of milk derived β-casomorphins on physiological functions and trends in research: a review. International Journal of Food Properties, 2014;17(8):1726–1741.Truswell A. S. The A2 milk case: a critical review. Eur J Clin Nutr. 2005 May;59(5):623–31. doi:10.1038/sj.ejcn.1602104.Truswell A. S. The A2 milk case: a critical review. Eur J Clin Nutr. 2005 May;59(5):623–31. doi:10.1038/sj.ejcn.1602104.Chia J.S.J., McRae J.L., Kukuljan S., et al. “A1 beta-casein milk protein and other environmental pre-disposing factors for type 1 diabetes. Nutr Diabetes. 2017 May 15;7(5): e274. doi:10.1038/nutd.2017.16.Chia J.S.J., McRae J.L., Kukuljan S., et al. “A1 beta-casein milk protein and other environmental pre-disposing factors for type 1 diabetes. Nutr Diabetes. 2017 May 15;7(5): e274. doi:10.1038/nutd.2017.16.McLachlan C. N. S. β-casein A1, ischaemic heart disease mortality, and other illnesses. Med Hypotheses. 2001 Feb;56(2):262–72. doi:10.1054/mehy.2000.1265.McLachlan C. N. S. β-casein A1, ischaemic heart disease mortality, and other illnesses. Med Hypotheses. 2001 Feb;56(2):262–72. doi:10.1054/mehy.2000.1265.Swaisgood H. E. Chemistry of the caseins. In Advanced Dairy Chemistry, P. F. Fox, Ed., pp. 63–110, Elsevier Applied, New York, NY, USA, 1992.Swaisgood H. E. Chemistry of the caseins. In Advanced Dairy Chemistry, P. F. Fox, Ed., pp. 63–110, Elsevier Applied, New York, NY, USA, 1992.Rasmussen L.K., Hojrup P., Petersen T. E. Localization of two interchain disulfide bridges in dimers of bovine αs2-casein. Parallel and antiparallel alignments of the polypeptide chains. Eur J Biochem. 1992 Feb 1;203(3):381–6. doi:10.1111/j.1432–1033.1992.tb16561.x.Rasmussen L.K., Hojrup P., Petersen T. E. Localization of two interchain disulfide bridges in dimers of bovine αs2-casein. Parallel and antiparallel alignments of the polypeptide chains. Eur J Biochem. 1992 Feb 1;203(3):381–6. doi:10.1111/j.1432–1033.1992.tb16561.x.Elliott R.B., Harris D. P., Hill J. P., Bibby N. J., Wasmuth H. E. Type I (insulin-dependent) diabetes mellitus and cow milk: casein variant consumption. Diabetologia. 1999 Mar;42(3):292–6. doi:10.1007/s001250051153.Elliott R.B., Harris D. P., Hill J. P., Bibby N. J., Wasmuth H. E. Type I (insulin-dependent) diabetes mellitus and cow milk: casein variant consumption. Diabetologia. 1999 Mar;42(3):292–6. doi:10.1007/s001250051153.Padberg S., Schumm-Draeger P.M., Petzoldt R., Becker F., Federlin K. Wertigkeit von A1- und A2-Antikörpern gegen beta-Kasein beim Typ-1-Diabetes mellitus [The significance of A1 and A2 antibodies against beta-casein in type-1 diabetes mellitus]. Dtsch Med Wochenschr. 1999 Dec 17;124(50):1518–21. German. doi:10.1055/s-2007–1023884.Padberg S., Schumm-Draeger P.M., Petzoldt R., Becker F., Federlin K. Wertigkeit von A1- und A2-Antikörpern gegen beta-Kasein beim Typ-1-Diabetes mellitus [The significance of A1 and A2 antibodies against beta-casein in type-1 diabetes mellitus]. Dtsch Med Wochenschr. 1999 Dec 17;124(50):1518–21. German. doi:10.1055/s-2007–1023884.Arısoy S, Çoban I, Üstün-Aytekin Ö. (March 25th 2019). Food-Derived Opioids: Production and the Effects of Opioids on Human Health, From Conventional to Innovative Approaches for Pain Treatment, Marco Cascella, IntechOpen, doi:10.5772/intechopen.84195.Arısoy S, Çoban I, Üstün-Aytekin Ö. (March 25th 2019). Food-Derived Opioids: Production and the Effects of Opioids on Human Health, From Conventional to Innovative Approaches for Pain Treatment, Marco Cascella, IntechOpen, doi:10.5772/intechopen.84195.Formaggioni P., Summer A., Malacarne M., Mariani P. Milk protein polymorphism: Detection and diffusion of the genetic variants in Bos genus. Ann. Fac. Med. Vet. Univ. Parma. 1999, 19, 127–165.Formaggioni P., Summer A., Malacarne M., Mariani P. Milk protein polymorphism: Detection and diffusion of the genetic variants in Bos genus. Ann. Fac. Med. Vet. Univ. Parma. 1999, 19, 127–165.Jinsmaa M., Yoshikawa M. Enzymatic release of neocasomorphin and β-casomorphin from bovine β-casein. Peptides. 1999;20(8):957–62. doi:10.1016/s0196–9781(99)00088–1.Jinsmaa M., Yoshikawa M. Enzymatic release of neocasomorphin and β-casomorphin from bovine β-casein. Peptides. 1999;20(8):957–62. doi:10.1016/s0196–9781(99)00088–1.Lotfi B. Optimization study for the production of an opioid-like preparation from bovine casein by mild acidic hydrolysis. International Dairy Journal. 2004; 14: 535–539.Lotfi B. Optimization study for the production of an opioid-like preparation from bovine casein by mild acidic hydrolysis. International Dairy Journal. 2004; 14: 535–539.De Noni I. Release of beta-casomorphins 5 and 7 during simulated gastro-intestinal digestion of bovine beta-casein variants and milk-based infant formulas. Food Chemistry. 2008;110 (4):897–903. doi:10.1016/j.foodchem.2008.02.077.De Noni I. Release of beta-casomorphins 5 and 7 during simulated gastro-intestinal digestion of bovine beta-casein variants and milk-based infant formulas. Food Chemistry. 2008;110 (4):897–903. doi:10.1016/j.foodchem.2008.02.077.De Noni I., Stefano C. Occurrence of β-casomorphins 5 and 7 in commercial dairy products and in their digests following in vitro simulated gastro-intestinal digestion. Food Chemistry. 2010;119 (2):560–566.De Noni I., Stefano C. Occurrence of β-casomorphins 5 and 7 in commercial dairy products and in their digests following in vitro simulated gastro-intestinal digestion. Food Chemistry. 2010;119 (2):560–566.Teschemacher H. Opioid receptor ligands derived from food proteins. Curr Pharm Des. 2003;9(16):1331–44. doi:10.2174/1381612033454856.Teschemacher H. Opioid receptor ligands derived from food proteins. Curr Pharm Des. 2003;9(16):1331–44. doi:10.2174/1381612033454856.Yin H., Miao J., Ma C., Sun G., Zhang Y. β- Casomorphin-7 cause decreasing in oxidative stress and inhibiting NFκB-iNOS-NO signal pathway in pancreas of diabetes rats. J Food Sci. 2012 Feb;77(2): C278–82. doi:10.1111/j.1750–3841.2011.02577.x.Yin H., Miao J., Ma C., Sun G., Zhang Y. β- Casomorphin-7 cause decreasing in oxidative stress and inhibiting NFκB-iNOS-NO signal pathway in pancreas of diabetes rats. J Food Sci. 2012 Feb;77(2): C278–82. doi:10.1111/j.1750–3841.2011.02577.x.Yin H., Miao J., Zhang Y. Protective eff ect of casomorphin-7 on type 1 diabetes rats induced with streptozotocin. Peptides. 2010 Sep;31(9):1725–9. doi:10.1016/j.peptides.2010.05.016.Yin H., Miao J., Zhang Y. Protective eff ect of casomorphin-7 on type 1 diabetes rats induced with streptozotocin. Peptides. 2010 Sep;31(9):1725–9. doi:10.1016/j.peptides.2010.05.016.Chang S.T., Lau O. W., Cho K. Y. The cultivation and nutritional value of Pleurotus sajor-caju. European Journal of Applied Microbiology and Biotechnology.1981;(12):58–62. doi:10.1007/BF00508120.Chang S.T., Lau O. W., Cho K. Y. The cultivation and nutritional value of Pleurotus sajor-caju. European Journal of Applied Microbiology and Biotechnology.1981;(12):58–62. doi:10.1007/BF00508120.Gomez K.A., Gomez A. A. Statistical procedures for agricultural research. 2nd ed. New York: John Wiley and Sons, 1984.Gomez K.A., Gomez A. A. Statistical procedures for agricultural research. 2nd ed. New York: John Wiley and Sons, 1984.Chang S.E., Keen J., Lane E. B., Taylor-Papadimitriou J. Establishment and characterization of SV40-transformed human breast epithelial cell lines. Cancer Res. 1982 May;42(5):2040–53. PMID:6279290.Chang S.E., Keen J., Lane E. B., Taylor-Papadimitriou J. Establishment and characterization of SV40-transformed human breast epithelial cell lines. Cancer Res. 1982 May;42(5):2040–53. PMID:6279290.De Carvalho L. P., Venault P., Potier M–C., Dodd R. H., Brown C., Chapouthier G., Rossier J. 3-(metho xy carbonyl)-amino-β-carboline, a selective antagonist of the sedative effects of benzodiazepines. Eur J Pharmacol. 1986 Oct 7;129(3):323–32. doi:10.1016/0014–2999(86)90442–5.De Carvalho L. P., Venault P., Potier M–C., Dodd R. H., Brown C., Chapouthier G., Rossier J. 3-(metho xy carbonyl)-amino-β-carboline, a selective antagonist of the sedative effects of benzodiazepines. Eur J Pharmacol. 1986 Oct 7;129(3):323–32. doi:10.1016/0014–2999(86)90442–5.Angenstein F., Matthies H., Staeck S., Reymann K. G., Staak S. The maintenance of hippocampal long-term potentiation is paralleled by a dopamine-dependent increase in glycoprotein fucosylation. Neurochem Int. 1992 Oct;21(3):403–8. doi:10.1016/0197–0186(92)90191-s.Angenstein F., Matthies H., Staeck S., Reymann K. G., Staak S. The maintenance of hippocampal long-term potentiation is paralleled by a dopamine-dependent increase in glycoprotein fucosylation. Neurochem Int. 1992 Oct;21(3):403–8. doi:10.1016/0197–0186(92)90191-s.Longobardo M., González T., Navarro-Polanco R., Caballero R., Delpón E., Tamargo J., Snyders D., Tamkun M., Valenzuela C. Effects of a quaternary bupivacaine derivative on delayed rectifier K+ currents. Br J Pharmacol. 2000 May;130(2):391–401. doi:10.1038/sj.bjp.0703334.Longobardo M., González T., Navarro-Polanco R., Caballero R., Delpón E., Tamargo J., Snyders D., Tamkun M., Valenzuela C. Effects of a quaternary bupivacaine derivative on delayed rectifier K+ currents. Br J Pharmacol. 2000 May;130(2):391–401. doi:10.1038/sj.bjp.0703334.Chen, F. Allosteric Effects of Permeating Cations on Gating Currents during K+ Channel Deactivation. J Gen Physiol. 1997 Aug;110(2):87–100. doi:10.1085/jgp.110.2.87.Chen, F. Allosteric Effects of Permeating Cations on Gating Currents during K+ Channel Deactivation. J Gen Physiol. 1997 Aug;110(2):87–100. doi:10.1085/jgp.110.2.87.Miner-Williams W.M., Stevens B. R., Moughan P. J. Are intact peptides absorbed from the healthy gut in the adult human? Nutr Res Rev. 2014 Dec;27(2):308–29. doi:10.1017/S0954422414000225.Miner-Williams W.M., Stevens B. R., Moughan P. J. Are intact peptides absorbed from the healthy gut in the adult human? Nutr Res Rev. 2014 Dec;27(2):308–29. doi:10.1017/S0954422414000225.Petrilli P., Picone D., Caporale C., Addeo F., Auricchio S., Marino G. Does casomorphin have a functional role? FEBS Lett. 1984 Apr 9;169(1):53–6. doi:10.1016/0014–5793(84)80288–4.Petrilli P., Picone D., Caporale C., Addeo F., Auricchio S., Marino G. Does casomorphin have a functional role? FEBS Lett. 1984 Apr 9;169(1):53–6. doi:10.1016/0014–5793(84)80288–4.Cieślińska A., Kaminski S., Kostyyra E., SienkiewiczSzłapka E. Beta-casomorphin 7 in raw and hydrolyzed milk derived from cows of alternative β-casein genotypes. Milchwissenschaft. 2007;(2):125–127.Cieślińska A., Kaminski S., Kostyyra E., SienkiewiczSzłapka E. Beta-casomorphin 7 in raw and hydrolyzed milk derived from cows of alternative β-casein genotypes. Milchwissenschaft. 2007;(2):125–127.De Noni I. Cattaneo S. Occurrence of beta-casomorphins 5 and 7 in commercial dairy products and in their digests following in vitro simulated gastro-intestinal digestion. Food Chem. 2010;(2):560–566.De Noni I. Cattaneo S. Occurrence of beta-casomorphins 5 and 7 in commercial dairy products and in their digests following in vitro simulated gastro-intestinal digestion. Food Chem. 2010;(2):560–566.Sienkiewicz-Szłapka E., Jarmołowska B., Krawczuk S., Kostyra E., Kostyra H., Iwan M. Contents of agonistic and antagonistic opioid peptides in different cheese varieties. Int. Dairy J. 2009;(4):258–263.Sienkiewicz-Szłapka E., Jarmołowska B., Krawczuk S., Kostyra E., Kostyra H., Iwan M. Contents of agonistic and antagonistic opioid peptides in different cheese varieties. Int. Dairy J. 2009;(4):258–263.Barbé F., Le Feunteun S., Rémond D., Ménard O., Jardin J., Henry G., Laroche B., Dupont D. Tracking the in vivo release of bioactive peptides in the gut during digestion: mass spectrometry peptidomic characterization of effluents collected in the gut of dairy matrices fed mini-pigs. Food Res Int. 2014; 63(Part B):147–156.Barbé F., Le Feunteun S., Rémond D., Ménard O., Jardin J., Henry G., Laroche B., Dupont D. Tracking the in vivo release of bioactive peptides in the gut during digestion: mass spectrometry peptidomic characterization of effluents collected in the gut of dairy matrices fed mini-pigs. Food Res Int. 2014; 63(Part B):147–156.Boutrou R., Gaudichon C., Dupont D., Jardin J., Airinei G., Marsset-Baglieri A., Benamouzig R., Tomé D., Léonil J. Sequential release of milk protein-derived bioactive peptides in the jejunum in healthy humans. Am J Clin Nutr. 2013;19:1314–1323.Boutrou R., Gaudichon C., Dupont D., Jardin J., Airinei G., Marsset-Baglieri A., Benamouzig R., Tomé D., Léonil J. Sequential release of milk protein-derived bioactive peptides in the jejunum in healthy humans. Am J Clin Nutr. 2013;19:1314–1323.Choi J., Sabikhi L., Hassan A., Anand S. Bioactive peptides in dairy products. Int J Dairy Technol. 2012;65:1–12.Choi J., Sabikhi L., Hassan A., Anand S. Bioactive peptides in dairy products. Int J Dairy Technol. 2012;65:1–12.Froetschel M. A. Bioactive peptides in digesta that regulate gastrointestinal function and intake. J Anim Sci. 1996 Oct;74(10):2500–8. doi:10.2527/1996.74102500x.Froetschel M. A. Bioactive peptides in digesta that regulate gastrointestinal function and intake. J Anim Sci. 1996 Oct;74(10):2500–8. doi:10.2527/1996.74102500x.Crocetti L., Quinn M. T., Schepetkin I. A., Gio vannoni M. P. A patenting perspective on human neutrophil elastase (HNE) inhibitors, (2014–2018) and their therapeutic applications. Expert Opin. Ther. Pat. 2019 Jul;29(7):555–578. doi:10.1080/13543776.2019.1630379.Crocetti L., Quinn M. T., Schepetkin I. A., Gio vannoni M. P. A patenting perspective on human neutrophil elastase (HNE) inhibitors, (2014–2018) and their therapeutic applications. Expert Opin. Ther. Pat. 2019 Jul;29(7):555–578. doi:10.1080/13543776.2019.1630379.Stark H., Lossner B. And Matthies H. Metabolism of (3-Casomorphin and its Derivates in Rat Brain and Liver Homogenates. Biomed. Biochim. Acta. 1987;46(10):687–94.Stark H., Lossner B. And Matthies H. Metabolism of (3-Casomorphin and its Derivates in Rat Brain and Liver Homogenates. Biomed. Biochim. Acta. 1987;46(10):687–94.Thulborn S. J., Mistry V., Brightling C. E., Moffitt K. L., Ribeiro D., Bafadhel M. Neutrophil elastase as a biomarker for bacterial infection in COPD. Respir. Res. 2019;20:170. doi:10.1186/s12931–019–1145–4Thulborn S. J., Mistry V., Brightling C. E., Moffitt K. L., Ribeiro D., Bafadhel M. Neutrophil elastase as a biomarker for bacterial infection in COPD. Respir. Res. 2019;20:170. doi:10.1186/s12931–019–1145–4Khan M. A., Ali Z. S., Sweezey N., Grasemann H., Palaniyar N. Progression of Cystic Fibrosis Lung Disease from Childhood to Adulthood: Neutrophils, Neutrophil Extracellular Trap (NET) Formation, and NET Degradation. Genes (Basel). 2019;10: E183. doi:10.3390/genes10030183.Khan M. A., Ali Z. S., Sweezey N., Grasemann H., Palaniyar N. Progression of Cystic Fibrosis Lung Disease from Childhood to Adulthood: Neutrophils, Neutrophil Extracellular Trap (NET) Formation, and NET Degradation. Genes (Basel). 2019;10: E183. doi:10.3390/genes10030183.

The authors declare that there are no conflicts of interest present.