Ectoine: From Microbial Survival Secret to Biotechnological Applications

Year 2025, Volume: 15 Issue: 1, 92 - 109, 01.03.2025

Mustafa Çiçek , Esra Çiçek , Aytaç Kocabaş

https://doi.org/10.21597/jist.1522694

Abstract

Ectoine, a compatible solute produced by physiologically and taxonomically diverse microorganism species in response to environmental stress factors such as high salinity or extreme temperatures, is a natural compound of great interest, especially in the fields of microbiology, biotechnology and environmental science. Numerous studies have been conducted to elucidate the processes underlying the cellular synthesis of ectoine, and to define its roles in stress adaptation. Ectoin, which attracted the attention of researchers due to its extraordinary biotechnological potential, finds widespread use in various sectors, especially in the cosmetic and pharmaceutical industries. While this situation accelerates studies on the discovery of new species with high ectoine production potential, it also encourages the development of cost-effective and sustainable methods for large-scale ectoine production strategies from microbial sources. This review provides a comprehensive overview of ectoine's current areas of application, highlighting its evolving role in various industries and positioning ectoine as a versatile and effective compound with far-reaching effects.

Keywords

Pharmaceuticals, Cosmetics, Stress adaptation, Compatible solute

Ektoin: Mikrobiyal Hayatta Kalma Sırrından Biyoteknolojik Uygulamalara

Abstract

Fizyolojik ve taksonomik açıdan oldukça büyük çeşitlilik sergileyen mikroorganizma türleri tarafından yüksek tuzluluk veya aşırı sıcaklık gibi çevresel stres faktörlerine yanıt olarak üretilen uyumlu çözünenlerden olan ektoin, özellikle mikrobiyoloji, biyoteknoloji ve çevre bilimi alanlarında büyük ilgi gören doğal bir bileşiktir. Olumsuz koşullar altında hücresel bütünlüğün ve işlevselliğin korunması açısından oldukça kritik bir molekül olan ektoinin hücresel sentezinin arkasında yatan mekanizmaların aydınlatılmasına ve stres adaptasyonundaki rollerinin tanımlanmasına yönelik pek çok çalışma gerçekleştirilmiştir. Sergilediği olağanüstü biyoteknolojik potansiyele bağlı olarak araştırmacıların dikkatini çeken ektoin başta kozmetik ve ilaç endüstrileri olmak üzere çeşitli sektörlerde yaygın kullanım alanı bulmaktadır. Bu durum bir yandan yüksek ektoin üretim potansiyeline sahip yeni türlerin keşfedilmesine yönelik çalışmalara hız kazandırırken bir yandan da mikrobiyal kaynaklardan; uygun maliyetli ve sürdürülebilir yöntemlerle büyük ölçekli ektoin üretim stratejilerinin geliştirilmesini teşvik etmektedir. Bu inceleme, bir yandan ektoinin mevcut uygulama alanlarına kapsamlı bir genel bakış sunarak çeşitli endüstrilerde gelişen rolünü vurgulamakta bir yandan da ektoini geniş kapsamlı etkilere sahip çok yönlü ve etkili bir bileşik olarak konumlandırmaktadır.

Keywords

İlaç, Kozmetik, Stres adaptasyonu, Uyumlu çözünen madde

Ethical Statement

Bu makalenin yazarları, bu çalışmada kullanılan materyal ve yöntemlerin etik kurul izni ve / veya yasal-özel izin gerektirmediğini beyan etmektedir.

Thanks

Makalenin inceleme ve değerlendirme aşamasında yapmış oldukları katkılardan dolayı editör ve hakem/hakemlere teşekkür ederiz.

References

• Abd Elazim, N. E., Awad, S. M., El-Naggar, M. S., & Mohamed, R. H. (2023). Topical Ectoin Versus Topical Dexpanthenol for Managing Acute Radiodermatitis Associated With Breast Cancer Radiotherapy: A Randomized Double-Blind Study. Dermatitis : contact, atopic, occupational, drug, 34(6), 516-524. https://doi.org/10.1089/DERM.2023.0055
• Abdel-Aziz, H., Wadie, W., Abdallah, D. M., Lentzen, G., & Khayyal, M. T. (2013). Novel effects of ectoine, a bacteria-derived natural tetrahydropyrimidine, in experimental colitis. Phytomedicine, 20(7), 585-591. https://doi.org/10.1016/j.phymed.2013.01.009
• Agrawal, R., Jurel, P., Deshmukh, R., Harwansh, R. K., Garg, A., Kumar, A., … Kumarasamy, V. (2024). Emerging Trends in the Treatment of Skin Disorders by Herbal Drugs: Traditional and Nanotechnological Approach. Pharmaceutics, 16(7), 869. Retrieved from https://doi.org/10.3390/pharmaceutics16070869
• Alexopoulos, A., Dakoutrou, M., Nasi, L., Thanopoulou, I., Kakourou, T., Kontara, L., … Chrousos, G. P. (2023). A randomized, observer-blind, vehicle-control, multi-center clinical investigation for assessing the efficacy and tolerability of a 1% ectoine and hyaluronic acid 0.1%-containing medical device in pediatric patients with mild-to-moderate atopic dermatitis. Pediatric dermatology, 40(1), 78-83. https://doi.org/10.1111/PDE.15117
• Arakawa, T., & Timasheff, S. N. (1985). The stabilization of proteins by osmolytes. Biophysical Journal, 47(3), 411. https://doi.org/10.1016/S0006-3495(85)83932-1
• Arora, A., Ha, C., & Park, C. B. (2004). Inhibition of insulin amyloid formation by small stress molecules. FEBS Letters, 564(1-2), 121-125. https://doi.org/10.1016/S0014-5793(04)00326-6
• Bethlehem, L., & van Echten-Deckert, G. (2021). Ectoines as novel anti-inflammatory and tissue protective lead compounds with special focus on inflammatory bowel disease and lung inflammation. Pharmacological Research, 164, 105389. Retrieved from https://doi.org/10.1016/j.phrs.2020.105389
• Bissoyi, A., & Pramanik, K. (2013). Effects Of Non-Toxic Cryoprotective Agents on the Viabılıty of Cord Blood Derived MNCs. CryoLetters (C. 34).
• Botta, C., Di Giorgio, C., Sabatier, A. S., & De Méo, M. (2008). Genotoxicity of visible light (400-800 nm) and photoprotection assessment of ectoin, l-ergothioneine and mannitol and four sunscreens. Journal of Photochemistry and Photobiology B: Biology, 91(1), 24-34. https://doi.org/10.1016/j.jphotobiol.2008.01.008
• Bownik, A., & Stępniewska, Z. (2015). Protective effects of bacterial osmoprotectant ectoine on bovine erythrocytes subjected to staphylococcal alpha-haemolysin. Toxicon, 99, 130-135. https://doi.org/10.1016/j.toxicon.2015.03.022
• Bownik, A., & Stȩpniewska, Z. (2016, Aralık 1). Ectoine as a promising protective agent in humans and animals. Arhiv za Higijenu Rada i Toksikologiju, C. 67, ss. 260-265. Institute for Medical Research and Occupational Health. https://doi.org/10.1515/aiht-2016-67-2837
• Bremer, E. (2000). Coping with osmotic challenges: osmoregulation through accumulation and release of compatible solutes in B. subtilis. Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 126, 17. https://doi.org/10.1016/S1095-6433(00)80031-8
• Bremer, Erhard, & Krämer, R. (2019). Responses of Microorganisms to Osmotic Stress. Annual review of microbiology, 73, 313-334. https://doi.org/10.1146/ANNUREV-MICRO-020518-115504
• Brown, A. D. (1976). Microbial water stress. Bacteriological Reviews, 40(4), 803. https://doi.org/10.1128/BR.40.4.803-846.1976
• Buenger, J., & Driller, H. (2004). Ectoin: An effective natural substance to prevent UVA-induced premature photoaging. Skin Pharmacology and Physiology, 17(5), 232-237. https://doi.org/10.1159/000080216
• Bujak, T., Zagórska-Dziok, M., Nizioł-Łukaszewska, Z., Majtan, J., Bucekova, M., & Jesenak, M. (2020). Complexes of Ectoine with the Anionic Surfactants as Active Ingredients of Cleansing Cosmetics with Reduced Irritating Potential. Molecules 2020, Vol. 25, Page 1433, 25(6), 1433. https://doi.org/10.3390/MOLECULES25061433
• Burg, M. B., & Ferraris, J. D. (2008, Mart 21). Intracellular organic osmolytes: Function and regulation. Journal of Biological Chemistry, C. 283, ss. 7309-7313. American Society for Biochemistry and Molecular Biology. https://doi.org/10.1074/jbc.R700042200
• Bünger, J., Degwert, J., Mag, H. (2001). The protective function of compatible solute ectoin on the skin, skin cells and its biomolecules with respect to UV radiation, immunosuppression and membrane. IFSCC Mag, 4(2).
• Cantera, S., Muñoz, R., Lebrero, R., López, J. C., Rodríguez, Y., & García-Encina, P. A. (2018). Technologies for the bioconversion of methane into more valuable products. Current Opinion in Biotechnology, C. 50, ss. 128-135. Elsevier Ltd. https://doi.org/10.1016/j.copbio.2017.12.021
• Chen, X., Lin, N., Li, J.-M., Liu, H., Abu-Romman, A., Yaman, E., … Li, D.-Q. (2024). Ectoine, from a Natural Bacteria Protectant to a New Treatment of Dry Eye Disease. Pharmaceutics, 16(2), 236. https://doi.org/10.3390/PHARMACEUTICS16020236
• Cruz, P. E., Silva, A. C., Roldão, A., Carmo, M., Carrondo, M. J. T., & Alves, P. M. (2006). Screening of novel excipients for improving the stability of retroviral and adenoviral vectors. Biotechnology Progress, 22(2), 568-576. https://doi.org/10.1021/bp050294y
• Csonka, L. N. (1989). Physiological and genetic responses of bacteria to osmotic stress. Microbiological reviews, 53(1), 121-147. https://doi.org/10.1128/MR.53.1.121-147.1989
• Czech, L., Hermann, L., Stöveken, N., Richter, A. A., Höppner, A., Smits, S. H. J., … Bremer, E. (2018). Role of the Extremolytes Ectoine and Hydroxyectoine as Stress Protectants and Nutrients: Genetics, Phylogenomics, Biochemistry, and Structural Analysis. Genes, 9(4). https://doi.org/10.3390/GENES9040177
• da Costa, M. S., Santos, H., & Galinski, E. A. (1998). An overview of the role and diversity of compatible solutes in Bacteria and Archaea. Advances in biochemical engineering/biotechnology, 61, 117-153. https://doi.org/10.1007/BFB0102291
• Dwivedi, M., Brinkkötter, M., Harishchandra, R. K., & Galla, H. J. (2014). Biophysical investigations of the structure and function of the tear fluid lipid layers and the effect of ectoine. Part B: Artificial lipid films. Biochimica et Biophysica Acta - Biomembranes, 1838(10), 2716-2727. https://doi.org/10.1016/j.bbamem.2014.05.007
• Eichel, A., Bilstein, A., Werkhäuser, N., & Mösges, R. (2014). Meta-Analysis of the Efficacy of Ectoine Nasal Spray in Patients with Allergic Rhinoconjunctivitis. Journal of Allergy, 2014, 1-12. https://doi.org/10.1155/2014/292545
• Empadinhas, N., & Da Costa, M. S. (2008). Osmoadaptation mechanisms in prokaryotes: distribution of compatible solutes. International Microbiology : the Official Journal of the Spanish Society for Microbiology, 11(3), 151-161. https://doi.org/10.2436/20.1501.01.55
• Fontbonne, A., Teme, B., Abric, E., Lecerf, G., Callejon, S., Moga, A., … Trompezinski, S. (2024). Positive and ecobiological contribution in skin photoprotection of ectoine and mannitol combined in vivo with UV filters. Journal of cosmetic dermatology, 23(1), 308-315. https://doi.org/10.1111/JOCD.15893
• Foord, R. L., & Leatherbarrow, R. J. (1998). Effect of osmolytes on the exchange rates of backbone amide protons in proteins. Biochemistry, 37(9), 2969-2978. https://doi.org/10.1021/bi9712798
• Freimark, D., Sehl, C., Weber, C., Hudel, K., Czermak, P., Hofmann, N., … Glasmacher, B. (2011). Systematic parameter optimization of a Me(2)SO- and serum-free cryopreservation protocol for human mesenchymal stem cells. Cryobiology, 63(2), 67-75. https://doi.org/10.1016/J.CRYOBIOL.2011.05.002
• Galinski, E. A., Pfeiffer, H. ‐P, & Trüper, H. G. (1985). 1,4,5,6‐Tetrahydro‐2‐methyl‐4‐pyrimidinecarboxylic acid: A novel cyclic amino acid from halophilic phototrophic bacteria of the genus Ectothiorhodospira. European Journal of Biochemistry, 149(1), 135-139. https://doi.org/10.1111/j.1432-1033.1985.tb08903.x
• Galinski, E. A., Stein, M., Amendt, B., & Kinder, M. (1997). The Kosmotropic (Structure-Forming) Effect of Compensatory Solutes. Comparative Biochemistry and Physiology Part A: Physiology, 117(3), 357-365. https://doi.org/10.1016/S0300-9629(96)00275-7
• Göller, K., & A. Galinski, E. (1999). Protection of a model enzyme (lactate dehydrogenase) against heat, urea and freeze-thaw treatment by compatible solute additives. Journal of Molecular Catalysis B: Enzymatic, 7(1-4), 37-45. https://doi.org/10.1016/S1381-1177(99)00043-0
• Graf, R., Anzali, S., Buenger, J., Pfluecker, F., & Driller, H. (2008). The multifunctional role of ectoine as a natural cell protectant. Clinics in Dermatology, 26(4), 326-333. https://doi.org/10.1016/j.clindermatol.2008.01.002
• Grein, T. A., Freimark, D., Weber, C., Hudel, K., Wallrapp, C., & Czermak, P. (2010). Alternatives to dimethylsulfoxide for serum-free cryopreservation of human mesenchymal stem cells. International Journal of Artificial Organs, 33(6), 370-380. https://doi.org/10.1177/039139881003300605
• Grether-Beck, S., Timmer, A., Felsner, I., Brenden, H., Brammertz, D., & Krutmann, J. (2005). Ultraviolet A-induced signaling involves a ceramide-mediated autocrine loop leading to ceramide de novo synthesis. Journal of Investigative Dermatology, 125(3), 545-553. https://doi.org/10.1111/j.0022-202X.2005.23782.x
• Gunde-Cimerman, N., Plemenitaš, A., & Oren, A. (2018, Mayıs 1). Strategies of adaptation of microorganisms of the three domains of life to high salt concentrations. FEMS Microbiology Reviews, C. 42, ss. 353-375. Oxford University Press. https://doi.org/10.1093/femsre/fuy009
• Harishchandra, R. K., Wulff, S., Lentzen, G., Neuhaus, T., & Galla, H. J. (2010). The effect of compatible solute ectoines on the structural organization of lipid monolayer and bilayer membranes. Biophysical Chemistry, 150(1-3), 37-46. https://doi.org/10.1016/j.bpc.2010.02.007
• Harland, B. F., & Morris, E. R. (1995). Phytate: A good or a bad food component? Nutrition Research, 15(5), 733-754. https://doi.org/10.1016/0271-5317(95)00040-P
• Hermann, L., Mais, C. N., Czech, L., Smits, S. H. J., Bange, G., & Bremer, E. (2020, Kasım 1). The ups and downs of ectoine: Structural enzymology of a major microbial stress protectant and versatile nutrient. Biological Chemistry, C. 401, ss. 1443-1468. De Gruyter Open Ltd. https://doi.org/10.1515/hsz-2020-0223
• Herzog, M., Dwivedi, M., Kumar Harishchandra, R., Bilstein, A., Galla, H. J., & Winter, R. (2019). Effect of ectoine, hydroxyectoine and β-hydroxybutyrate on the temperature and pressure stability of phospholipid bilayer membranes of different complexity. Colloids and surfaces. B, Biointerfaces, 178, 404-411. https://doi.org/10.1016/J.COLSURFB.2019.03.026
• Hu, Q., Sun, S., Zhang, Z., Liu, W., Yi, X., He, H., … Chen, G.-Q. (2024). Ectoine hyperproduction by engineered Halomonas bluephagenesis. Metabolic Engineering, 82, 238–249. Retrieved from https://doi.org/10.1016/j.ymben.2024.02.010
• Inbar, L., & Lapidot, A. (1988). The structure and biosynthesis of new tetrahydropyrimidine derivatives in actinomycin D producer Streptomyces parvulus. Use of 13C- and 15N-labeled L-glutamate and 13C and 15N NMR spectroscopy. Journal of Biological Chemistry, 263(31), 16014-16022. https://doi.org/10.1016/s0021-9258(18)37550-1
• Jaitley, S., & Saraswathi, T. R. (2012). Pathophysiology of Langerhans cells. Journal of Oral and Maxillofacial Pathology : JOMFP, 16(2), 239. https://doi.org/10.4103/0973-029X.99077
• Jorge, C. D., Borges, N., Bagyan, I., Bilstein, A., & Santos, H. (2016, Mayıs 1). Potential applications of stress solutes from extremophiles in protein folding diseases and healthcare. Extremophiles, C. 20, ss. 251-259. Springer Tokyo. https://doi.org/10.1007/s00792-016-0828-8
• Juncan, A. M., Morgovan, C., Rus, L. L., & Loghin, F. (2023). Development and Evaluation of a Novel Anti-Ageing Cream Based on Hyaluronic Acid and Other Innovative Cosmetic Actives. Polymers, 15(20). https://doi.org/10.3390/POLYM15204134
• Kanapathipillai, M., Lentzen, G., Sierks, M., & Park, C. B. (2005). Ectoine and hydroxyectoine inhibit aggregation and neurotoxicity of Alzheimer’s β-amyloid. FEBS Letters, 579(21), 4775-4780. https://doi.org/10.1016/j.febslet.2005.07.057
• Kempf, B., & Bremer, E. (1998). Uptake and synthesis of compatible solutes as microbial stress responses to high-osmolality environments. Archives of Microbiology, C. 170, ss. 319-330. Arch Microbiol. https://doi.org/10.1007/s002030050649
• Kolp, S., Pietsch, M., Galinski, E. A., & Gütschow, M. (2006). Compatible solutes as protectants for zymogens against proteolysis. Biochimica et Biophysica Acta - Proteins and Proteomics, 1764(7), 1234-1242. https://doi.org/10.1016/j.bbapap.2006.04.015
• Kunte, H., Lentzen, G., & Galinski, E. (2014). Industrial Production of the Cell Protectant Ectoine: Protection Mechanisms, Processes, and Products. Current Biotechnology, 3(1), 10-25. https://doi.org/10.2174/22115501113026660037
• Lanyi, J. K. (1974). Salt-dependent properties of proteins from extremely halophilic bacteria. Bacteriological reviews, 38(3), 272-290. https://doi.org/10.1128/BR.38.3.272-290.1974
• Lapidot, A., Ben-Asher, E., & Eisenstein, M. (1995). Tetrahydropyrimidine derivatives inhibit binding of a Tat-like, arginine-containing peptide, to HIV TAR RNA in vitro. FEBS Letters, 367(1), 33-38. https://doi.org/10.1016/0014-5793(95)00514-A
• Le Rudulier, D., Strom, A. R., Dandekar, A. M., Smith, L. T., & Valentine, R. C. (1984). Molecular biology of osmoregulation. Science, 224(4653), 1064-1068. https://doi.org/10.1126/science.224.4653.1064
• Lentzen, G., & Schwarz, T. (2006, Ekim 7). Extremolytes: Natural compounds from extremophiles for versatile applications. Applied Microbiology and Biotechnology, C. 72, ss. 623-634. Springer. https://doi.org/10.1007/s00253-006-0553-9
• Li, J.-M., Lin, N., Zhang, Y., Chen, X., Liu, Z., Lu, R., … Li, D.-Q. (2024). Ectoine protects corneal epithelial survival and barrier from hyperosmotic stress by promoting anti-inflammatory cytokine IL-37. The ocular surface. https://doi.org/10.1016/J.JTOS.2024.03.002
• Li, P., Huang, Y., Miao, L., Zhu, Z., & Shi, Z. (2024). Protective effects of ectoine on articular chondrocytes and cartilage in rats for treating osteoarthritis. PLOS ONE, 19(2), e0299351. https://doi.org/10.1371/JOURNAL.PONE.0299351
• Lippert, K., & Galinski, E. A. (1992). Enzyme stabilization be ectoine-type compatible solutes: protection against heating, freezing and drying. Applied Microbiology and Biotechnology, 37(1), 61-65. https://doi.org/10.1007/BF00174204
• Lo, C.-C., Bonner, C. A., Xie, G., D’Souza, M., & Jensen, R. A. (2009). Cohesion Group Approach for Evolutionary Analysis of Aspartokinase, an Enzyme That Feeds a Branched Network of Many Biochemical Pathways. Microbiology and Molecular Biology Reviews, 73(4), 594-651. https://doi.org/10.1128/mmbr.00024-09
• Ma, Z., Wu, C., Zhu, L., Chang, R., Ma, W., Deng, Y., & Chen, X. (2022). Bioactivity profiling of the extremolyte ectoine as a promising protectant and its heterologous production. 3 Biotech, 12(12). https://doi.org/10.1007/S13205-022-03370-5
• Marini, A., Reinelt, K., Krutmann, J., & Bilstein, A. (2014). Ectoine-containing cream in the treatment of mild to moderate atopic dermatitis: A randomised, comparator-controlled, intra-individual double-blind, multi-center trial. Skin Pharmacology and Physiology, 27(2), 57-65. https://doi.org/10.1159/000351381
• Martin, D. D., Ciulla, R. A., & Roberts, M. F. (1999). Osmoadaptation in Archaea. Applied and Environmental Microbiology, 65(5), 1815. https://doi.org/10.1128/AEM.65.5.1815-1825.1999
• Müller, D., Lindemann, T., Shah-Hosseini, K., Scherner, O., Knop, M., Bilstein, A., & Mösges, R. (2016). Efficacy and tolerability of an ectoine mouth and throat spray compared with those of saline lozenges in the treatment of acute pharyngitis and/or laryngitis: a prospective, controlled, observational clinical trial. European Archives of Oto-Rhino-Laryngology, 273(9), 2591-2597. https://doi.org/10.1007/s00405-016-4060-z
• Ng, H. S., Wan, P.-K., Kondo, A., Chang, J.-S., & Lan, J. C.-W. (2023). Production and Recovery of Ectoine: A Review of Current State and Future Prospects. Processes, 11(2), 339. Retrieved from https://doi.org/10.3390/pr11020339
• Ono, H., Sawada, K., Khunajakr, N., Tao, T., Yamamoto, M., Hiramoto, M., … Murooka, Y. (1999). Characterization of biosynthetic enzymes for ectoine as a compatible solute in a moderately halophilic eubacterium, Halomonas elongata. Journal of Bacteriology, 181(1), 91-99. https://doi.org/10.1128/jb.181.1.91-99.1999
• Onraedt, A., Walcarius, B., Soetaert, W., & Vandamme, E. J. (2003). Dynamics and optimal conditions of intracellular ectoine accumulation in Brevibacterium sp. Communications in Agricultural and Applied Biological Sciences, 68(2 Pt A), 241-246. Geliş tarihi gönderen https://europepmc.org/article/med/15296171
• Oren, A. (1999). Bioenergetic Aspects of Halophilism. Microbiology and Molecular Biology Reviews, 63(2), 334. https://doi.org/10.1128/MMBR.63.2.334-348.1999
• Oren, A. (2008). Microbial life at high salt concentrations: Phylogenetic and metabolic diversity. Saline Systems, 4(1), 1-13. https://doi.org/10.1186/1746-1448-4-2/TABLES/1
• Pastor, J. M., Salvador, M., Argandoña, M., Bernal, V., Reina-Bueno, M., Csonka, L. N., … Cánovas, M. (2010, Kasım 1). Ectoines in cell stress protection: Uses and biotechnological production. Biotechnology Advances, C. 28, ss. 782-801. Elsevier. https://doi.org/10.1016/j.biotechadv.2010.06.005
• Pérez, V., Moltó, J. L., Lebrero, R., & Muñoz, R. (2021). Ectoine Production from Biogas in Waste Treatment Facilities: A Techno-Economic and Sensitivity Analysis. ACS Sustainable Chemistry & Engineering, 9(51), 17371–17380. Retrieved from https://doi.org/10.1021/acssuschemeng.1c06772
• Peters, P., Galinski, E. A., & Trüper, H. G. (1990). The biosynthesis of ectoine. FEMS Microbiology Letters, 71(1-2), 157-162. https://doi.org/10.1016/0378-1097(90)90049-V
• Peuschel, H., Sydlik, U., Grether-Beck, S., Felsner, I., Stöckmann, D., Jakob, S., … Unfried, K. (2012). Carbon nanoparticles induce ceramide- and lipid raft-dependent signalling in lung epithelial cells: A target for a preventive strategy against environmentally-induced lung inflammation. Particle and Fibre Toxicology, 9, 48. https://doi.org/10.1186/1743-8977-9-48
• Plaza del Pino, I. M., & Sanchez-Ruiz, J. M. (1995). An Osmolyte Effect on the Heat Capacity Change for Protein Folding. Biochemistry, 34(27), 8621-8630. https://doi.org/10.1021/bi00027a011
• Poolman, B., & Glaasker, E. (1998). Regulation of compatible solute accumulation in bacteria. Molecular microbiology, 29(2), 397-407. https://doi.org/10.1046/J.1365-2958.1998.00875.X
• Qaria, M. A., Xu, C., Hu, R., Alsubki, R. A., Ali, M. Y., Sivasamy, S., … Zhu, D. (2023). Ectoine Globally Hypomethylates DNA in Skin Cells and Suppresses Cancer Proliferation. Marine Drugs, 21(12). https://doi.org/10.3390/MD21120621/S1
• Regev, R., Peri, I., Gilboa, H., & Avi-Dor, Y. (1990). 13C NMR study of the interrelation between synthesis and uptake of compatible solutes in two moderately halophilic eubacteria: Bacterium Ba1 and Vibro costicola. Archives of Biochemistry and Biophysics, 278(1), 106-112. https://doi.org/10.1016/0003-9861(90)90237-S
• Reshetnikov, A. S., Khmelenina, V. N., Mustakhimov, I. I., & Trotsenko, Y. A. (2011). Genes and enzymes of Ectoine biosynthesis in halotolerant methanotrophs. Methods in Enzymology (C. 495, ss. 15-30). Academic Press Inc. https://doi.org/10.1016/B978-0-12-386905-0.00002-4
• Rizwanuddin, S., Kumar, V., Naik, B., Singh, P., Mishra, S., Rustagi, S., & Kumar, V. (2023). Microbial phytase: Their sources, production, and role in the enhancement of nutritional aspects of food and feed additives. Journal of Agriculture and Food Research, 12, 100559. https://doi.org/10.1016/J.JAFR.2023.100559
• Roberts, M. (2005). Organic compatible solutes of halotolerant and halophilic microorganisms. Saline Systems, 1(1), 1-30. https://doi.org/10.1186/1746-1448-1-5
• Roeßler, M., & Müller, V. (2001). Osmoadaptation in bacteria and archaea: common principles and differences. Environmental microbiology, 3(12), 743-754. https://doi.org/10.1046/J.1462-2920.2001.00252.X
• Roventa, D. L. C., Pieper-Fürst, U., Acikel, C., Santos, D., Sent, U., & Mösges, R. (2023). Effectiveness and Tolerability of Ectoin® Mouth and Throat Spray Althaea Honey (ERS09) for Sore Throat due to Acute Pharyngitis and Dry Cough: A Multicentre, Actively Controlled, Open Label Study in Germany. Journal of clinical medicine, 12(18). https://doi.org/10.3390/JCM12185813
• Roychoudhury, A., Bieker, A., Häussinger, D., & Oesterhelt, F. (2013). Membrane protein stability depends on the concentration of compatible solutes - A single molecule force spectroscopic study. Biological Chemistry, 394(11), 1465-1474. https://doi.org/10.1515/hsz-2013-0173
• Salapatek, A. M., Werkhäuser, N., Ismail, B., Mösges, R., Raskopf, E., & Bilstein, A. (2021). Effects of ectoine containing nasal spray and eye drops on symptoms of seasonal allergic rhinoconjunctivitis. Clinical and Translational Allergy, 11(1). https://doi.org/10.1002/CLT2.12006
• Salmannejad, F., & Nafissi-Varcheh, N. (2017). Ectoine and hydroxyectoine inhibit thermal-induced aggregation and increase thermostability of recombinant human interferon Alfa2b. European Journal of Pharmaceutical Sciences, 97, 200-207. https://doi.org/10.1016/J.EJPS.2016.11.014
• Singh, N., Kuhar, S., Priya, K., Jaryal, R., & Yadav, R. (2018). Phytase: The Feed Enzyme, an Overview. Advances in Animal Biotechnology and its Applications, 260-327. https://doi.org/10.1007/978-981-10-4702-2_17/COVER
• Skvortsova, K., Stirzaker, C., & Taberlay, P. (2019). The DNA methylation landscape in cancer. Essays in biochemistry, 63(6), 797-811. https://doi.org/10.1042/EBC20190037
• Sonnemann, U., Scherner, O., & Werkhäuser, N. (2014). Treatment of Rhinitis Sicca Anterior with Ectoine Containing Nasal Spray. Journal of Allergy, 2014, 1-10. https://doi.org/10.1155/2014/273219
• Strong, P. J., Kalyuzhnaya, M., Silverman, J., & Clarke, W. P. (2016, Eylül 1). A methanotroph-based biorefinery: Potential scenarios for generating multiple products from a single fermentation. Bioresource Technology, C. 215, ss. 314-323. Elsevier Ltd. https://doi.org/10.1016/j.biortech.2016.04.099
• Sun, H., Glasmacher, B., & Hofmann, N. (2012). Compatible solutes improve cryopreservation of human endothelial cells. undefined.
• Sydlik, U., Gallitz, I., Albrecht, C., Abel, J., Krutmann, J., & Unfried, K. (2009). The compatible solute ectoine protects against nanoparticle-induced neutrophilic lung inflammation. American Journal of Respiratory and Critical Care Medicine, 180(1), 29-35. https://doi.org/10.1164/rccm.200812-1911OC
• Sydlik, U., Peuschel, H., Paunel-Gorgulu, A., Keymel, S., Kramer, U., Weissenberg, A., … Unfried, K. (2013). Recovery of neutrophil apoptosis by ectoine: a new strategy against lung inflammation. The European respiratory journal, 41(2), 433-442. https://doi.org/10.1183/09031936.00132211
• Tanghe, A., Van Dijck, P., & Thevelein, J. M. (2006). Why do microorganisms have aquaporins? Trends in Microbiology, 14(2), 78-85. https://doi.org/10.1016/J.TIM.2005.12.001
• Ullah, A. H. J. (1988). Production, rapid purification and catalytic characterization of extracellular phytase from Aspergillus ficuum. Preparative biochemistry, 18(4), 443-458. https://doi.org/10.1080/00327488808062543
• Vyrides, I., & Stuckey, D. C. (2017). Compatible solute addition to biological systems treating waste/wastewater to counteract osmotic and other environmental stresses: a review. Critical Reviews in Biotechnology, 37(7), 865-879. https://doi.org/10.1080/07388551.2016.1266460
• Werkhäuser, N., Bilstein, A., & Sonnemann, U. (2014). Treatment of Allergic Rhinitis with Ectoine Containing Nasal Spray and Eye Drops in Comparison with Azelastine Containing Nasal Spray and Eye Drops or with Cromoglycic Acid Containing Nasal Spray. https://doi.org/10.1155/2014/176597
• Wood, J. M., Bremer, E., Csonka, L. N., Kraemer, R., Poolman, B., Van der Heide, T., & Smith, L. T. (2001). Osmosensing and osmoregulatory compatible solute accumulation by bacteria. Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 130(3), 437-460. https://doi.org/10.1016/S1095-6433(01)00442-1
• Yancey, P. H., Clark, M. E., Hand, S. C., Bowlus, R. D., & Somero, G. N. (1982). Living with water stress: Evolution of osmolyte systems. Science, 217(4566), 1214-1222. https://doi.org/10.1126/science.7112124
• Yao, C. L., Lin, Y. M., Mohamed, M. S., & Chen, J. H. (2013). Inhibitory effect of ectoine on melanogenesis in B16-F0 and A2058 melanoma cell lines. Biochemical Engineering Journal, 78, 163-169. https://doi.org/10.1016/j.bej.2013.01.005
• Zaccai, G., Bagyan, I., Combet, J., Cuello, G. J., Demé, B., Fichou, Y., … Oesterhelt, D. (2016). Neutrons describe ectoine effects on water H-bonding and hydration around a soluble protein and a cell membrane. Scientific Reports, 6. https://doi.org/10.1038/SREP31434
• Zhang, L., Wang, Y., Zhang, C., Wang, Y., Zhu, D., Wang, C., & Nagata, S. (2006). Supplementation effect of ectoine on thermostability of phytase. Journal of bioscience and bioengineering, 102(6), 560-563. https://doi.org/10.1263/JBB.102.560