Griehl, C.

Krause–Hielscher, S.

Repository of Polessky State University (Репозиторий Полесского государственного университета)

 133  Во–вторых, биомедицинские технологии расширяют и усложняют понимание категории иден-тичности личности как совокупности культурных и природных факторов, составляющих ее онто-логическую основу. Таким образом, в поле гуманитарных наук необходимым фактором осмысле-ния происходящих процессов становится выработка новых принципов понимания и осмысления понятия идентичности с тем, чтобы научное знание соответствовало принципам новой социальной реальности, с которой уже столкнулись США и страны Западной Европы.   ЛИТЕРАТУРА 1. Картахенский протокол по биобезопасности к конвенции о биологическом разнообразии// [Электрон-ный ресурс]: –– Режим доступа: https://docs.google.com/viewer?url=http%3A%2F%2Fwww.un.org%2Fru%2Fdocuments%2Fdecl_conv%2Fconventions%2Fpdf%2Fcartagena.pdf. Время доступа: 12.01.2013 2. Кьеркегор С. Или–или. — СПб.: Издательство Русской Христианской Гуманитарной Академии: Ам-фора, 2011. — 823 с. 3. Уголовный кодекс Республики Беларусь 9 июля 1999 г. № 275–з // [Электронный ресурс]: –– Режим доступа: http://www.pravo.by/WEBNPA/text.asp?RN=hk9900275. Время доступа: 20.11.2013 4. Хабермас Ю. Будущее человеческой природы. Пер. с нем. — М.: Издательство «Весь Мир», 2002. – 144 с. 5. Identity// Stanford encyclopedia of philosophy: [Электронный ресурс]: –– Режим доступа: http://plato.stanford.edu/entries/identity/ Время доступа: 15.11.2013 6. Geach, P.T., Identity.Review of Metaphysics, 21: 3–12. –– pp. 238–247 7. Lewis, D. Philosophical Papers, vol. 1. Oxford: Oxford University Press. 1983   УДК 661.471.2  CHALLENGES AND PROSPECTS OF ALGAL BIOTECHNOLOGY FOR  THE ISOLATION AND CHARACTERIZATION OF ACTIVE PHARMACEUTICAL INGREDIENT (API) ON THE EXAMPLE OF NEW GLUTAMINYL CYCLASE (QC) INHIBITORS FOR THE TREATMENT OF ALZHEIMER'S DISEASE  S. KRAUSE–HIELSCHER, C. GRIEHL  Anhalt University of Applied Sciences,  Department of Applied Biosciences and Process Technology,  Group Algae Biotechnology, 06366 Köthen, Germany s.krause–hielscher@bwp.hs–anhalt.de; c.griehl@bwp.hs–anhalt.de  Algae are phototrophic organisms (Phycophyceen) with a great heterogeneity in morphologic organisation and physiology. Algae have a ubiquitous presence and so they grow in diverse habitats such as lakes, the sea, the soil, rocks, air, or in hot springs but also they can be found in the snow. Only about 43000 of the 500000 estimated species are classified and only 200 macroalgae and 15 microalge are used commercial. However, their use is currently limited to high value added products such as carotenoids like ß–carotene and astaxanthin, cosmetic active ingredients and PUFFA's such as DHA or EPA. Mainly Chlorella vulgaris, Haematococcus pluvialis, Porphyridium sp. Crypthecodinium sp., Schizochytrium sp. and Nannochloropsis sp. are commercially cultivated for the production of biomass, astaxanthin, phycoerythrin and DHA. So algae are use in food and cosmetic as well as in aquaculture and in environmental technology. However, today there is an intensive research for the use of algae for biofuels such as biodiesel, ethanol or hydrogen. Further it is known that these organisms produce a range of bioactive compounds, which are not commonly available from other plants or animals. This enormous potential of algae is proven previously by a multitude of identified secondary metabolites with, for example, cytostatic, antibacterial, antiviral, anti–inflammatory, or antifungal properties, many acting via the specific inhibition of enzymes (Lindequist and Schweder, 2001; Kelecom, 2002; Sakai et al., 2014; Blunt et al., 2009, 2011, 2013, 2014). The first antibacterial compound was isolated from the microalgae Chlorella sp. in 1944 by Pratt. Since then microalgae are examined for the presence of new anti–bacterial compounds because of the steady increase of multi–resistant pathogens. Approximately 60 % of cancer drugs originally derived from plant or microbial substances. In various anti–cancer screening approaches aquatic natural compounds showed high inhibition effects against different human cancer cell lines (Ulber ПолесГУ 134  et al., 2002). Therefore the search for compounds from algae is considered particularly promising (Mayer et al, 2003; Amador et al., 2003). In recent years, more and more enzymes could be associated with pathophysiological processes and represent targets for many diseases, so that enzyme–inhibiting properties of natural substances are becoming increasingly important. Algae are known for the ability to synthesize complex and highly diverse compounds with specific enzyme inhibitions and neuroactive properties (Blunt et al, 2009; 2011; 2013; 2014; Sakai et al., 2014). Therefore algae represent a potential almost untouched resource and research source in search of new leads for the treatment of heretofore incurable diseases including Alzheimer's disease.  Alzheimer's disease is characterized by the aggregation of Aβ protein fragments to senile plaques. These Aβ peptides have glutamine at the N–terminus, which can be modified to a pyroglutamyl residue (pE). This modification results in a resistance to a proteolytic N–terminal degradation and to the loss of N–terminal charge. The resulting hydrophobic residual charge (decrease in solubility) results in accelerated aggregation of the pE–peptides. Various studies have shown that these neurotoxic pE–Aβ peptide fragments represent a major component of senile plaques. Further current study was able to confirm in vivo that QC catalyzes the N–terminal pE–modification. Thus, the expression of QC is upregulated in the cortex of Alzheimer's patients and correlates with the presence of pE–modified Aβ peptides. The oral application of QC inhibitors showed in two different transgenic mouse models of Alzheimer's disease as well as a Drosophila model a reduced strain of Aβ3(pE)–42. The reduction of pE–Aβ peptide fragments by the inhibition of the QC provides an approach for the treatment of Alzheimer's disease (Schilling et al., 2008; Demuth et. al., 2010; Jawhar et al., 2011).  Due to the fact that algae have the ability to produce a large variety of bioactive compounds with specific inhibition of enzymes, algae can be expected to be a potential source of new QC inhibiting compounds. Therefore, we analyzed algal strains and crude extracts of different algae species belonging to Chlorophyceae and Eustigmatophyceae. Different algae species were cultivated in a 100 L tubular photobioreactor and the ingredients were extracted from the biomasses. This was followed by the screening of the algae extracts in a QC enzyme assay. Here 27 of the 72 tested extracts inhibited the QC. The QC inhibiting metabolites were identified by Activity–correlation analysis. This are carried out by a direct correlation of the mass spectrometry metabolite profiles with the inhibition value of the QC of each extract. By further mass spectrometric investigations the structural characterization of the correlated compounds could be realized directly from the crude extracts without purification. Five QC inhibiting compounds were identified. Molecular modeling (docking studies) confirmed QC–inhibiting potential of all five compounds. The compounds showed a similar QC inhibition like a standard substance with 81 % and 76 % in the two tested concentrations of 0.25 mg/mL and 0.025 mg/mL.  In summary QC inhibitors could be identified, characterized and isolated from algae for the first time.  Acknowledgement We thank the Ministry for Economy and Sciences of Saxony Anhalt for the financial support of this study.  REFERENCES 1. Amador, M. L., Jimeno, J., Paz–Ares, L., Cortes–Funes, H. und Hidalgo, M. Progress in the development and acquisition of anticancer agents from marine sources / / Ann. Oncol. 2003. Vol. 14, P. 1607–1615. 2. Blunt J.W., Copp B.R., Keyzers R.A., Munro M.H., Prinsep M.R. Marine natural products / / Natural Product Reports. 2013. Vol. 30, P. 237–323. 3. Blunt J.W., Copp B.R., Hu W.P., Murray H.G. Munro, Northcote P.T., Prinsep M.R. Marine natural products / / Natural Product Reports. 2009 . Vol. 26, P.170–244. 4. Blunt J.W., Copp B.R., Hu W.P., Murray H.G. Munro, Northcote P.T., Prinsep MR. (2008). Marine natural products. Natural Product Reports. 2008 . Vol. 25, P. 35–94. 5. Blunt J.W., Copp B.R., Munro M.H., Northcote P.T., Prinsep M.R. Marine natural products / / Natural Product Reports 2006 . Vol. 23, P. 26–78.  6. Demuth H.U., Cynis H., Alexandru A., Jagla W., Graubner S., v. Hoersten S., Schilling S. Inhibition of Glutaminyl Cyclase: Pharmacology and steps towards clinical development / / Alzheimer's & Dementia: The Journal of the Alzheimer's Association. 2010. Vol.  6 , Is. 4, P. 571–572. 7. Demuth H.U., Schilling S., Kleinschmidt M., Rahfeld JU., Kehlen A., Bornack, M. Glutaminyl cyclase as a diagnostic/ prognostic indicator for neurodegenerative disease / / Patent 2010. WO/2010/012828 8. Jawhar S., Wirths O., Bayer T.A. Pyroglutamate Amyloid–β (Aβ): A Hatchet Man in Alzheimer Disease / / Journal of Biological Chemistry. 2011. Vol. 286, P. 38825–38832. ПолесГУ 135  9. Kelecom A. Secondary metabolites from marine microorganisms / / Anais Da Academia Brasileira de Ciências. 2002 . Vol. 74, Is. 1. P. 151–70. 10. Lindequist U., Schweder T. Marine Biotechnology. In: Rehm, H.J.; Reed, G. (Hrsg) Biotechnology. Bd 10, 2. Aufl., Weinheim: Wiley–VCH 2001, 441–484 11. Mayer, A. M. und Gustafson, K. R. Marine pharmacology in 2000: antitumor and cytotoxic compounds / / Int. J. Cancer. 2003. Vol. 105, P. 291–299. 12. Pratt R., Daniels T.C., Eiler J.B., Gunnison J.B., Kumler W.D. et al. Chlorellin, an antibacterial substance from / / Chlorella. Science. 1944 . Vol. 99, P. 351–352. 13. Sakai R., Swanson G.T. Recent progress in neuroactive marine natural products / / Natural Products Reports. 2014 . Vol. 31. P. 273–309. 14. Ulber, R. Biotechnologische Methoden zur effizienteren Rohstoffnutzung // Habilitationsschrift, Hannover 2002 15. Schilling S., Zeitschel U., Hoffmann T., Heiser U., Francke M., Kehlen A., Holzer M., Hutter–Paier B., Prokesch M., Windisch M., Jagla W., Schlenzig D., Lindner C., Rudolph T., Reuter G., Cynis H., Montag D., Demuth H.–U., Rossner, S. Glutaminyl cyclase inhibition attenuates pyroglutamate Abeta and Alzheimer´s disease–like pathology / / Nature Medicine. 2008 Vol. 14, P. 1106–1111.    УДК 618  РОЛЬ ГЕНОВ HMMR И TP53 В ГЕНЕЗЕ РАКА МОЛОЧНОЙ ЖЕЛЕЗЫ  В.Н. КИПЕНЬ, Г.А. ПИСАРЧИК, С.Б. МЕЛЬНОВ  Международный государственный экологический университет им. А.Д. Сахарова,  г. Минск, Республика Беларусь  Введение. В последнее время все больше внимания уделяется поиску рак–ассоциированных генотипов в рамках полногеномных исследований (GWAS – Genome–wide association study). В то же время продолжаются исследования по анализу роли уже известных патогенетически значимых полиморфных вариантов генов. Так, использование биоинформатических методов (например, MDR (Multifactor dimensionality reduction) или метод нейронных сетей) позволяет с новых позиций взглянуть на известные закономерности в механизмах канцерогенеза. Pujana et al. была использо-вана стратегия нейросетевого моделирования для определения генов, потенциально связанных с повышенным риском развития рака молочной железы (РМЖ) [1]. В данном исследовании была показана вовлеченность гена HMMR (hyaluronan–mediated motility receptor), наряду с SMC3 (structural maintenance of chromosomes 3) и MAD1L1 (MAD1 mitotic arrest deficient–like 1), в про-цессы митоза. В частности, SMC3 входит в состав мультимерного Cohesin–комплекса, который скрепляет сестринские хроматиды во время митоза, что приводит к надлежащему расхождению хромосом, а MAD1L1 входит в состав белкового комплекса, предотвращающего наступление ана-фазы до образования правильно собранной метафазной пластинки [2,3]. В этой же работе была показана связь HMMR с комплексом BRCA1–BARD1 (breast cancer 1 gene; brca1–associated ring domain 1), а также с одним из ключевых регуляторов систем поддержания геномной стабильности AURKA (serine/threonine protein kinase 15). Роль некоторых полиморфных вариантов в гене HMMR была продемонстрирована в работе Kalmyrzaev B. et al. [4], а также в исследовании Pujana et al. [1]. Роль гена TP53 в развитии онкопатологии известна давно, а первые исследования, посвящен-ные связи однонуклеотидного полиморфизма (ОНП) R72P (rs1042522) с риском развития РМЖ и последующей выживаемостью в зависимости от проводимых курсов лучевой и химиотерапии, бы-ли проведены более десяти лет назад [5–7]. В работе отражены данные о связи ОНП V353A (HMMR, rs299290) и R72P (TP53, rs1042522) c риском развития РМЖ и с некоторыми клинико–морфологическими характеристиками опухоли. Материалы и методы. В исследование были включены 146 пациентов с монолатеральным РМЖ. Группа билатерального РМЖ составила: 2 случая синхронного билатерального РМЖ (вре-менной критерий синхронности билатерального рака молочной железы составил не более 12 меся-цев [8]) и 7 случаев метахронного билатерального РМЖ. Средний возраст пациентов с монолате-ральным РМЖ на момент возникновения опухоли составил 43,2±5,9 лет (возрастной интервал – 24–54 лет), пациентов с билатеральными формами РМЖ – 39,8±5,0 лет (возрастной интервал – 33–48 лет). ПолесГУ

CHALLENGES AND PROSPECTS OF ALGAL BIOTECHNOLOGY FOR THE ISOLATION AND CHARACTERIZATION OF ACTIVE PHARMACEUTICAL INGREDIENT (API) ON THE EXAMPLE OF NEW GLUTAMINYL CYCLASE (QC) INHIBITORS FOR THE TREATMENT OF ALZHEIMER'S DISEASE

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CHALLENGES AND PROSPECTS OF ALGAL BIOTECHNOLOGY FOR THE ISOLATION AND CHARACTERIZATION OF ACTIVE PHARMACEUTICAL INGREDIENT (API) ON THE EXAMPLE OF NEW GLUTAMINYL CYCLASE (QC) INHIBITORS FOR THE TREATMENT OF ALZHEIMER'S DISEASE

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