Koronavirüs-19 Hastalığının Makro ve Moleküler Olarak İncelenmesi: Derleme

Year 2021, Volume: 3 Issue: 2, 110 - 166, 30.12.2021

Sami Karagöz , Erkan Özbay

Abstract

Dünya Sağlık Örgütü verilerine göre, dünyada Ağustos 2021’in ortalarında (4.400.284’ü ölüm) 4.562.256.778, ülkemizde ise (53.891’i ölüm) 86.413.722 doğrulanmış Korona-virus 19 vakası bildirilmiştir.
Korona-virus 19, sitokin salıverilme ile karakterize olan şiddetli akut solunum sendromu oluşturur. Sitokin aracılı hiperinflamasyon olası tedavileri artan ölüm oranlarını azaltmak amacıyla ivedilikle araştırılmaktadır.

Günümüzde uzun vadeli etkileri bilinmemekle birlikte aşı uygulamaları yapılmasına rağmen, halen, Korona-viruslara karşı kesin onaylanmış bir tedavi uygulaması bulunmamaktadır. Deneyim ve bulunabilirliğe göre çok sayıda ilaç ampirik olarak kullanılmaktadır. Etkinliklerini ve güvenliğini gösteren çalışmalar hala yayınlanacaktır. Ancak bazı potansiyel tedaviler ve doğal tedaviler önerilmiştir. Çok sayıda aromatik bitki ve fitokimyasallar, koronaviruslar da dahil olmak üzere genetik ve işlevsel olarak farklı viruslara karşı terapötik kullanım için beklemektedir.

Türkiye, zengin etnomedikal deneyimi ve zengin florasıyla (% 34 endemik) bu konuda araştırma yapmak için yüksek potansiyele sahiptir. Yüzyıllardır influenzaya karşı kullanılan bitkiler etkili alternatifler sunabilir.

Keywords

Koronavirus-19, sitokin, antiviral, TRP kanalları, NF-Kβ, STAT

References

• [1] Pehote, G.,& Vij, N. (2020). Autophagy Augmentation to Alleviate Immune Response Dysfunction, and Resolve Respiratory and COVID-19 Exacerbations. Cells, 9(9), 1952.
• [2] Zhu, H., Zhang, Y., Ye, G., Li, Z., Zhou, P., & Huang, C. (2009). In vivo and in vitro antiviral activities of calycosin-7-O-β-D-glucopyranoside against coxsackie virus B3. Biological and Pharmaceutical Bulletin, 32(1), 68-73.
• [3] Alaoui-Jamali, M. (Ed.). (2010). Alternative and complementary therapies for cancer: Integrative approaches and discovery of conventional drugs. Springer Science & Business Media.
• [4] ERTUĞ, F. (2004). Wild edible plants of the Bodrum area (Muğla, Turkey). Turkish Journal of Botany, 28(1-2), 161-174.
• [5] Zhou, Y., Hou, Y., Shen, J., Huang, Y., Martin, W., & Cheng, F. (2020d). Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell discovery, 6(1), 1-18.
• [6] Chen, Z.,& Nakamura, T. (2004). Statistical evidence for the usefulness of Chinese medicine in the treatment of SARS. Phytotherapy Research: An International Journal Devoted to Pharmacological and Toxicological Evaluation of Natural Product Derivatives, 18(7), 592-59410
• [7] Van Der Hoek, L. (2007). Human coronaviruses: what do they cause?. Antiviral therapy, 12(4 B).
• [8] Wang, W., Lin, X. D., Guo, W. P., Zhou, R. H., Wang, M. R., Wang, C. Q., ... & Holmes, E. C. (2015b). Discovery, diversity and evolution of novel coronaviruses sampled from rodents in China. Virology, 474, 19-27.
• [9] Arora, P., Jafferany, M., Lotti, T., Sadoughifar, R., & Goldust, M. (2020). Learning from history: Coronavirus outbreaks in the past. Dermatologic Therapy, e13343.
• [10] Berry, M., Gamieldien, J., & Fielding, B. C. (2015). Identification of new respiratory viruses in the new millennium. Viruses, 7(3), 996-1019.
• [11] Nieto-Torres, J. L., DeDiego, M. L., Verdiá-Báguena, C., Jimenez-Guardeño, J. M., Regla-Nava, J. A., Fernandez-Delgado, R., ... & Enjuanes, L. (2014). Severe acute respiratory syndrome coronavirus envelope protein ion channel activity promotes virus fitness and pathogenesis. PLoS Pathog, 10(5), e1004077.
• [12] Hemida, M. G., Perera, R. A., Wang, P., Alhammadi, M. A., Siu, L. Y., Li, M., ... & Peiris, M. (2013). Middle East Respiratory Syndrome (MERS) coronavirus seroprevalence in domestic livestock in Saudi Arabia, 2010 to 2013. Eurosurveillance, 18(50), 20659.
• [13] Paraskevis, D., Kostaki, E. G., Magiorkinis, G., Panayiotakopoulos, G., Sourvinos, G., & Tsiodras, S. (2020). Full-genome evolutionary analysis of the novel corona virus (2019-nCoV) rejects the hypothesis of emergence as a result of a recent recombination event. Infection, Genetics and Evolution, 79, 104212.
• [14] Zhou, Z., Zhao, N., Shu, Y., Han, S., Chen, B., & Shu, X. (2020). Effect of Gastrointestinal Symptoms in Patients With COVID-19. Gastroenterology, 158(8), 2294.
• [15] Schoeman, D.,& Fielding, B. C. (2019). Coronavirus envelope protein: current knowledge. Virology journal, 16(1), 1-22.
• [16] Gralinski, L. E.,& Baric, R. S. (2015). Molecular pathology of emerging coronavirus infections. The Journal of pathology, 235(2), 185-195.
• [17] Luo, S., Zhang, X., & Xu, H. (2020). Don't overlook digestive symptoms in patients with 2019 novel coronavirus disease (COVID-19). Clinical Gastroenterology and Hepatology, 18(7), 1636.
• [18] Li, Y. C., Bai, W. Z., & Hashikawa, T. (2020). The neuroinvasive potential of SARS‐CoV2 may play a role in the respiratory failure of COVID‐19 patients. Journal of medical virology, 92(6), 552-555.
• [19] Helms, J., Kremer, S., Merdji, H., Clere-Jehl, R., Schenck, M., Kummerlen, C., ... & Anheim, M. (2020). Neurologic features in severe SARS-CoV-2 infection. New England Journal of Medicine.
• [20] Masters, P. S. (2006). The molecular biology of coronaviruses. Advances in virus research, 66, 193-292.
• [21] Yamada, Y.,& Liu, D. X. (2009). Proteolytic activation of the spike protein at a novel RRRR/S motif is implicated in furin-dependent entry, syncytium formation, and infectivity of coronavirus infectious bronchitis virus in cultured cells. Journal of virology, 83(17), 8744-8758.
• [22] Yamada, Y., Liu, X. B., Fang, S. G., Tay, F. P., & Liu, D. X. (2009). Acquisition of cell–cell fusion activity by amino acid substitutions in spike protein determines the infectivity of a coronavirus in cultured cells. PloS one, 4(7), e6130.
• [23] Zheng, J., Yamada, Y., Fung, T. S., Huang, M., Chia, R., & Liu, D. X. (2018). Identification of N-linked glycosylation sites in the spike protein and their functional impact on the replication and infectivity of coronavirus infectious bronchitis virus in cell culture. Virology, 513, 65-74.
• [24] Ho, T. Y., Wu, S. L., Chen, J. C., Li, C. C., & Hsiang, C. Y. (2007). Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction. Antiviral research, 74(2), 92-101
• [25] Kuba, K., Imai, Y., Rao, S., Gao, H., Guo, F., Guan, B., ... & Bao, L. (2005). A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury. Nature medicine, 11(8), 875-879.
• [26] Millet, J. K.,& Whittaker, G. R. (2015). Host cell proteases: Critical determinants of coronavirus tropism and pathogenesis. Virus research, 202, 120-134.
• [27] De Haan, C. A., Vennema, H., & Rottier, P. J. (2000). Assembly of the coronavirus envelope: homotypic interactions between the M proteins. Journal of virology, 74(11), 4967-4978.
• [28] Liang, J. Q., Fang, S., Yuan, Q., Huang, M., Chen, R. A., Fung, T. S., & Liu, D. X. (2019). N-Linked glycosylation of the membrane protein ectodomain regulates infectious bronchitis virus-induced ER stress response, apoptosis and pathogenesis. Virology, 531, 48-56
• [29] Ou, X., Liu, Y., Lei, X., Li, P., Mi, D., Ren, L., ... & Xiang, Z. (2020). Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nature communications, 11(1), 1-12.
• [30] Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., ... & Müller, M. A. (2020). SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell.
• [31] Zhou, P., Yang, X. L., Wang, X. G., Hu, B., Zhang, L., Zhang, W., ... & Chen, H. D. (2020c). A pneumonia outbreak associated with a new coronavirus of probable bat origin. nature, 579(7798), 270-273.
• [32] Gurwitz, D. (2020). Angiotensin receptor blockers as tentative SARS‐CoV‐2 therapeutics. Drug development research.
• [33] Letko, M., Marzi, A., & Munster, V. (2020). Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nature microbiology, 5(4), 562-569.
• [34] Rabi, F. A., Al Zoubi, M. S., Kasasbeh, G. A., Salameh, D. M., & Al-Nasser, A. D. (2020). SARS-CoV-2 and coronavirus disease 2019: what we know so far. Pathogens, 9(3), 231.
• [35] Wrapp, D., Wang, N., Corbett, K. S., Goldsmith, J. A., Hsieh, C. L., Abiona, O., ... & McLellan, J. S. (2020). Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science, 367(6483), 1260-1263.
• [36] Xu, X., Chen, P., Wang, J., Feng, J., Zhou, H., Li, X., ... & Hao, P. (2020). Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Science China Life Sciences, 63(3), 457-460.
• [37] Inoue, Y., Tanaka, N., Tanaka, Y., Inoue, S., Morita, K., Zhuang, M., ... & Sugamura, K. (2007). Clathrin-dependent entry of severe acute respiratory syndrome coronavirus into target cells expressing ACE2 with the cytoplasmic tail deleted. Journal of virology, 81(16), 8722-8729.
• [38] Prompetchara, E., Ketloy, C., & Palaga, T. (2020). Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol, 38(1), 1-9.
• [39] Walls, A. C., Park, Y. J., Tortorici, M. A., Wall, A., McGuire, A. T., & Veesler, D. (2020). Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell.
• [40] Zhang, H., Penninger, J. M., Li, Y., Zhong, N., & Slutsky, A. S. (2020c). Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive care medicine, 46(4), 586-590.
• [41] Lu, R., Zhao, X., Li, J., Niu, P., Yang, B., Wu, H., ... & Bi, Y. (2020). Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. The Lancet, 395(10224), 565-574.
• [42] De Felice, F. G., Tovar-Moll, F., Moll, J., Munoz, D. P., & Ferreira, S. T. (2020). Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and the Central Nervous System. Trends in neurosciences.
• [43] Chen, Y., Guo, Y., Pan, Y., & Zhao, Z. J. (2020). Structure analysis of the receptor binding of 2019-nCoV. Biochemical and biophysical research communications.
• [44] Butowt, R.,& Bilinska, K. (2020). SARS-CoV-2: olfaction, brain infection, and the urgent need for clinical samples allowing earlier virus detection. ACS Chemical Neuroscience, 11(9), 1200-1203.
• [45] Navarese, E. P., Musci, R. L., Frediani, L., Gurbel, P. A., & Kubica, J. (2020). Ion channel inhibition against COVID-19: A novel target for clinical investigation. Cardiology Journal, 27(4), 421-424.
• [46] Yi, L., Li, Z., Yuan, K., Qu, X., Chen, J., Wang, G., ... & Chen, L. (2004). Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells. Journal of virology, 78(20), 11334-11339.
• [47] De Wit, E., Van Doremalen, N., Falzarano, D., & Munster, V. J. (2016). SARS and MERS: recent insights into emerging coronaviruses. Nature Reviews Microbiology, 14(8), 523.
• [48] Simmons, G., Gosalia, D. N., Rennekamp, A. J., Reeves, J. D., Diamond, S. L., & Bates, P. (2005). Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proceedings of the National Academy of Sciences, 102(33), 11876-11881.
• [49] Iwata-Yoshikawa, N., Okamura, T., Shimizu, Y., Hasegawa, H., Takeda, M., & Nagata, N. (2019). TMPRSS2 contributes to virus spread and immunopathology in the airways of murine models after coronavirus infection. Journal of virology, 93(6).
• [50] Báez-Santos, Y. M., John, S. E. S., & Mesecar, A. D. (2015). The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds. Antiviral research, 115, 21-38.
• [51] Venkataraman, S., Prasad, B. V., & Selvarajan, R. (2018). RNA dependent RNA polymerases: insights from structure, function and evolution. Viruses, 10(2), 76.
• [52] Shadrick, W. R., Ndjomou, J., Kolli, R., Mukherjee, S., Hanson, A. M., & Frick, D. N. (2013). Discovering new medicines targeting helicases: challenges and recent progress. Journal of biomolecular screening, 18(7), 761-781.
• [53] Ivanov, K. A., Thiel, V., Dobbe, J. C., Van Der Meer, Y., Snijder, E. J., & Ziebuhr, J. (2004). Multiple enzymatic activities associated with severe acute respiratory syndrome coronavirus helicase. Journal of virology, 78(11), 5619-5632.
• [54] McBride, R., Van Zyl, M., & Fielding, B. C. (2014). The coronavirus nucleocapsid is a multifunctional protein. Viruses, 6(8), 2991-3018.
• [55] Lu, W., Zheng, B. J., Xu, K., Schwarz, W., Du, L., Wong, C. K., ... & Sun, B. (2006). Severe acute respiratory syndrome-associated coronavirus 3a protein forms an ion channel and modulates virus release. Proceedings of the National Academy of Sciences, 103(33), 12540-12545.
• [56] Wu, C., Liu, Y., Yang, Y., Zhang, P., Zhong, W., Wang, Y., ... & Zheng, M. (2020). Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharmaceutica Sinica B.
• [57] Liu, D. X.,& Inglis, S. C. (1991). Association of the infectious bronchitis virus 3c protein with the virion envelope. Virology, 185(2), 911-917.
• [58] Liu, D. X., Cavanagh, D., Green, P., & Inglis, S. C. (1991). A polycistronic mRNA specified by the coronavirus infectious bronchitis virus. Virology, 184(2), 531-544.
• [59] Lim, K. P.,& Liu, D. X. (2001). The missing link in coronavirus assembly retention of the avian coronavirus infectious bronchitis virus envelope protein in the pre-golgi compartments and physical interaction between the envelope and membrane proteins. Journal of Biological Chemistry, 276(20), 17515-17523.
• [60] Liu, D. X., Yuan, Q., & Liao, Y. (2007). Coronavirus envelope protein: a small membrane protein with multiple functions. Cellular and Molecular Life Sciences, 64(16), 2043-2048.
• [61] Bos, E. C., Luytjes, W., Van Der Meulen, H., Koerten, H. K., & Spaan, W. J. (1996). The production of recombinant infectious DI-particles of a murine coronavirus in the absence of helper virus. Virology, 218(1), 52-60.
• [62] Vennema, H., Godeke, G. J., Rossen, J. W., Voorhout, W. F., Horzinek, M. C., Opstelten, D. J., & Rottier, P. J. (1996). Nucleocapsid‐independent assembly of coronavirus‐like particles by co‐expression of viral envelope protein genes. The EMBO journal, 15(8), 2020-2028.
• [63] Kuo, L.,& Masters, P. S. (2003). The small envelope protein E is not essential for murine coronavirus replication. Journal of virology, 77(8), 4597-4608.
• [64] DeDiego, M. L., Álvarez, E., Almazán, F., Rejas, M. T., Lamirande, E., Roberts, A., ... & Enjuanes, L. (2007). A severe acute respiratory syndrome coronavirus that lacks the E gene is attenuated in vitro and in vivo. Journal of virology, 81(4), 1701-1713.
• [65] DeDiego, M. L., Nieto-Torres, J. L., Jiménez-Guardeño, J. M., Regla-Nava, J. A., Alvarez, E., Oliveros, J. C., ... & Enjuanes, L. (2011). Severe acute respiratory syndrome coronavirus envelope protein regulates cell stress response and apoptosis. PLoS pathog, 7(10), e1002315.
• [66] Jimenez-Guardeño, J. M., Nieto-Torres, J. L., DeDiego, M. L., Regla-Nava, J. A., Fernandez-Delgado, R., Castaño-Rodriguez, C., & Enjuanes, L. (2014). The PDZ-binding motif of severe acute respiratory syndrome coronavirus envelope protein is a determinant of viral pathogenesis. PLoS Pathog, 10(8), e1004320.
• [67] Skariyachan, S., Challapilli, S. B., Packirisamy, S., Kumargowda, S. T., & Sridhar, V. S. (2019). Recent aspects on the pathogenesis mechanism, animal models and novel therapeutic interventions for Middle East respiratory syndrome coronavirus infections. Frontiers in microbiology, 10, 569.
• [68] Fung, T. S., Huang, M., & Liu, D. X. (2014). Coronavirus-induced ER stress response and its involvement in regulation of coronavirus–host interactions. Virus research, 194, 110-123.
• [69] Imai, Y., Kuba, K., Neely, G. G., Yaghubian-Malhami, R., Perkmann, T., van Loo, G., ... & Liu, H. (2008). Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell, 133(2), 235-249.
• [70] Jones, D. P. (2006). Redefining oxidative stress. Antioxidants & redox signaling, 8(9-10), 1865-1879.
• [71] He, L., He, T., Farrar, S., Ji, L., Liu, T., & Ma, X. (2017). Antioxidants maintain cellular redox homeostasis by elimination of reactive oxygen species. Cellular Physiology and Biochemistry, 44(2), 532-553.
• [72] Pisoschi, A. M.,& Pop, A. (2015). The role of antioxidants in the chemistry of oxidative stress: A review. European journal of medicinal chemistry, 97, 55-74.
• [73] Sies, H. (2015). Oxidative stress: a concept in redox biology and medicine. Redox biology, 4, 180-183.
• [74] Gravier-Hernández, R., Gil-del Valle, L., Valdes-Alonso, L., Hernández-Ayala, N., Bermúdez-Alfonso, Y., Hernández-Requejo, D., ... & Hernández-González-Abreu, M. C. (2020). Oxidative stress in hepatitis C virus–human immunodeficiency virus co-infected patients. Annals of Hepatology, 19(1), 92-98.
• [75] Zhang, Z., Rong, L., & Li, Y. P. (2019). Flaviviridae viruses and oxidative stress: implications for viral pathogenesis. Oxidative medicine and cellular longevity, 2019.
• [76] Camini, F. C., da Silva Caetano, C. C., Almeida, L. T., & de Brito Magalhaes, C. L. (2017). Implications of oxidative stress on viral pathogenesis. Archives of virology, 162(4), 907-917.
• [77] Schreck, R. M. B. M., Meier, B., Männel, D. N., Dröge, W., & Baeuerle, P. A. (1992). Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. The Journal of experimental medicine, 175(5), 1181-1194.
• [78] Channappanavar, R.,& Perlman, S. (2017, July). Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. In Seminars in immunopathology (Vol. 39, No. 5, pp. 529-539). Springer Berlin Heidelberg.
• [79] Wu, D.,& Yang, X. O. (2020). TH17 responses in cytokine storm of COVID-19: An emerging target of JAK2 inhibitor Fedratinib. Journal of Microbiology, Immunology and Infection.
• [80] Ye, S., Lowther, S., & Stambas, J. (2015). Inhibition of reactive oxygen species production ameliorates inflammation induced by influenza A viruses via upregulation of SOCS1 and SOCS3. Journal of virology, 89(5), 2672-2683.
• [81] Bogden, J. D., Baker, H., Frank, O. S. C. A. R., Perez, G. E. O. R. G. E., Kemp, F., Bruening, K., & Louria, D. (1990). Micronutrient status and human immunodeficiency virus (HIV) infection. Annals of the New York Academy of Sciences, 587, 189.
• [82] Chrobot, A. M., Szaflarska-Szczepanik, A., & Drewa, G. (2000). Antioxidant defense in children with chronic viral hepatitis B and C. Medical Science Monitor, 6(4), 713-718.
• [83] Reshi, M. L., Su, Y. C., & Hong, J. R. (2014). RNA viruses: ROS-mediated cell death. International journal of cell biology, 2014.
• [84] Direskeneli, H. (2001). Behcet's disease: infectious aetiology, new autoantigens, and HLA-B51. Annals of the rheumatic diseases, 60(11), 996-1002.
• [85] Kökçam, I.,& Nazıroǧlu, M. (2002). Effects of vitamin E supplementation on blood antioxidants levels in patients with Behçet’s disease. Clinical biochemistry, 35(8), 633-639.
• [86] Youn, Y. K., LaLonde, C., & Demling, R. (1991). Use of antioxidant therapy in shock and trauma. Circulatory shock, 35(4), 245-249. [87] McCord, J. M. (1993). Oxygen-derived free radicals. New horizons (Baltimore, Md.), 1(1), 70.
• [88] Cuzzocrea, S., Riley, D. P., Caputi, A. P., & Salvemini, D. (2001). Antioxidant therapy: a new pharmacological approach in shock, inflammation, and ischemia/reperfusion injury. Pharmacological reviews, 53(1), 135-159.
• [89] Nazıroğlu, M. (2007). New molecular mechanisms on the activation of TRPM2 channels by oxidative stress and ADP-ribose. Neurochemical research, 32(11), 1990-2001.
• [90] Bréchard, S.,& Tschirhart, E. J. (2008). Regulation of superoxide production in neutrophils: role of calcium influx. Journal of leukocyte biology, 84(5), 1223-1237.
• [91] Droy-Lefaix, M. T., Drouet, Y., Geraud, G., Hosford, D., & Braquet, P. (1991). Superoxide dismutase (SOD) and the PAF-antagonist (BN 52021) reduce small intestinal damage induced by ischemia-reperfusion. Free radical research communications, 13(1), 725-735.
• [92] Haglind, E., Xia, G. U. A. N. G. C. H. I., & Rylander, R. (1994). Effects of antioxidants and PAF receptor antagonist in intestinal shock in the rat. Circulatory shock, 42(2), 83-91.
• [93] Xia, Z. F., HoUyoak, M., Barrow, R. E., He, F., Muller, M. J., & Herndon, D. N. (1995). Superoxide dismutase and leupeptin prevent delayed reperfusion injury in the rat small intestine during burn shock. The Journal of burn care & rehabilitation, 16(2), 111-117.
• [94] Fantone, J. C.,& Ward, P. (1982). Role of oxygen-derived free radicals and metabolites in leukocyte-dependent inflammatory reactions. The american journal of pathology, 107(3), 395.
• [95] Li, Y., Ferrante, A., Poulos, A., & Harvey, D. P. (1996). Neutrophil oxygen radical generation. Synergistic responses to tumor necrosis factor and mono/polyunsaturated fatty acids. The Journal of clinical investigation, 97(7), 1605-1609.
• [96] Boughton-Smith, N. K., Evans, S. M., Laszlo, F., Whittle, B. J., & Moncada, S. (1993). The induction of nitric oxide synthase and intestinal vascular permeability by endotoxin in the rat. British journal of pharmacology, 110(3), 1189.
• [97] Salvemini, D., Jensen, M. P., Riley, D. P., & Misko, T. P. (1998). Therapeutic manipulations of peroxynitrite. Drug news & perspectives, 11(4), 204.
• [98] Dix, T. A., Hess, K. M., Medina, M. A., Sullivan, R. W., Tilly, S. L., & Webb, T. L. (1996). Mechanism of site-selective DNA nicking by the hydrodioxyl (perhydroxyl) radical. Biochemistry, 35(14), 4578-4583.
• [99] Beckman, J. S., Beckman, T. W., Chen, J., Marshall, P. A., & Freeman, B. A. (1990). Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proceedings of the National Academy of Sciences, 87(4), 1620-1624.
• [100] Ischiropoulos, H., Zhu, L., & Beckman, J. S. (1992). Peroxynitrite formation from macrophage-derived nitric oxide. Archives of biochemistry and biophysics, 298(2), 446-451.
• [101] Beckman, J. S.,& Crow, J. P. (1993). Pathological implications of nitric oxide, superoxide and peroxynitrite formation.
• [102] Salvemini, D., Mazzon, E., Dugo, L., Riley, D. P., Serraino, I., Caputi, A. P., & Cuzzocrea, S. (2001). Pharmacological manipulation of the inflammatory cascade by the superoxide dismutase mimetic, M40403. British journal of pharmacology, 132(4), 815-827.
• [103] Tan, W.,& Aboulhosn, J. (2020). The cardiovascular burden of coronavirus disease 2019 (COVID-19) with a focus on congenital heart disease. International Journal of Cardiology.
• [104] Schwartz, M. D., Moore, E. E., Moore, F. A., Shenkar, R., Moine, P., Haenel, J. B., & Abraham, E. (1996). Nuclear factor-kappa B is activated in alveolar macrophages from patients with acute respiratory distress syndrome. Critical care medicine, 24(8), 1285-1292.
• [105] Peters, R. T., Liao, S. M., & Maniatis, T. (2000). IKKε is part of a novel PMA-inducible IκB kinase complex. Molecular cell, 5(3), 513-522.
• [106] Bowie, A.,& O’Neill, L. A. (2000). Oxidative stress and nuclear factor-κB activation: a reassessment of the evidence in the light of recent discoveries. Biochemical pharmacology, 59(1), 13-23.
• [107] Sunderman Sr, F. W. (1992). The extended therapeutic role of dithiocarb (sodium diethyldithiocarbamate) from nickel poisoning to AIDS. Annals of Clinical & Laboratory Science, 22(4), 245-248.
• [108] Baldwin, A. S. (2001). Series introduction: the transcription factor NF-κβ and human disease. The Journal of clinical investigation, 107(1), 3-6.
• [109] Menegazzi, M., Di Paola, R., Mazzon, E., Muià, C., Genovese, T., Crisafulli, C., ... & Cuzzocrea, S. (2006). Hypericum perforatum attenuates the development of carrageenan-induced lung injury in mice. Free Radical Biology and Medicine, 40(5), 740-753.
• [110] Pfitzner, E., Kliem, S., Baus, D., & Litterst, M. C. (2004). The role of STATs in inflammation and inflammatory diseases. Current pharmaceutical design, 10(23), 2839-2850.
• [111] Darnell, J. E., Kerr, I. M., & Stark, G. R. (1994). Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science, 264(5164), 1415-1421.
• [112] Levy, D. E.,& Lee, C. K. (2002). What does Stat3 do?. The Journal of clinical investigation, 109(9), 1143-1148.
• [113] Kotiadis, V. N., Duchen, M. R., & Osellame, L. D. (2014). Mitochondrial quality control and communications with the nucleus are important in maintaining mitochondrial function and cell health. Biochimica et Biophysica Acta (BBA)-General Subjects, 1840(4), 1254-1265.
• [114] Sena, L. A.,& Chandel, N. S. (2012). Physiological roles of mitochondrial reactive oxygen species. Molecular cell, 48(2), 158-167.
• [115] Galluzzi, L., Kepp, O., & Kroemer, G. (2012). Mitochondria: master regulators of danger signalling. Nature reviews Molecular cell biology, 13(12), 780-788.
• [116] Chen, C. Y., Ping, Y. H., Lee, H. C., Chen, K. H., Lee, Y. M., Chan, Y. J., ... & Chen, Y. M. A. (2007). Open reading frame 8a of the human severe acute respiratory syndrome coronavirus not only promotes viral replication but also induces apoptosis. The Journal of infectious diseases, 196(3), 405-415.
• [117] Favreau, D. J., Meessen-Pinard, M., Desforges, M., & Talbot, P. J. (2012). Human coronavirus-induced neuronal programmed cell death is cyclophilin d dependent and potentially caspase dispensable. Journal of virology, 86(1), 81-93.
• [118] Xu, X., Xu, Y., Zhang, Q., Yang, F., Yin, Z., Wang, L., & Li, Q. (2019). Porcine epidemic diarrhea virus infections induce apoptosis in Vero cells via a reactive oxygen species (ROS)/p53, but not p38 MAPK and SA.
• [119] Siddiqi, H. K.,& Mehra, M. R. (2020). COVID-19 illness in native and immunosuppressed states: A clinical–therapeutic staging proposal. The Journal of Heart and Lung Transplantation, 39(5), 405.
• [120] Wu, Y. H., Tseng, C. P., Cheng, M. L., Ho, H. Y., Shih, S. R., & Chiu, D. T. Y. (2008). Glucose-6-phosphate dehydrogenase deficiency enhances human coronavirus 229E infection. The Journal of infectious diseases, 197(6), 812-816.
• [121] Hu, G.,& Chrıstman, J. W. (2019). Alveolar Macrophages in Lung Inflammation and Resolution. Frontiers in immunology, 10, 2275. [122] Joshi, N., Walter, J. M., & Misharin, A. V. (2018). Alveolar macrophages. Cellular immunology, 330, 86-90.
• [123] Hussell, T.,& Bell, T. J. (2014). Alveolar macrophages: plasticity in a tissue-specific context. Nature reviews immunology, 14(2), 81-93.
• [124] Ye, Q., Wang, B., & Mao, J. (2020). Cytokine storm in COVID-19 and treatment. Journal of Infection.
• [125] Wang, C., Xie, J., Zhao, L., Fei, X., Zhang, H., Tan, Y., ... & Zhang, Y. (2020b). Aveolar macrophage activation and cytokine storm in the pathogenesis of severe COVID-19.
• [126] Yan, R., Zhang, Y., Li, Y., Xia, L., Guo, Y., & Zhou, Q. (2020). Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science, 367(6485), 1444-1448.
• [127] Verdecchia, P., Cavallini, C., Spanevello, A., & Angeli, F. (2020). The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. European Journal of Internal Medicine.
• [128] Chen, C., Yang, S., Zhang, M., Zhang, Z., Zhang, S. B., Wu, B., ... & Zhang, L. (2017). Triptolide mitigates radiation-induced pneumonitis via inhibition of alveolar macrophages and related inflammatory molecules. Oncotarget, 8(28), 45133.
• [129] Fehr, A. R.,& Perlman, S. (2015). Coronaviruses: an overview of their replication and pathogenesis. In Coronaviruses (pp. 1-23). Humana Press, New York, NY.
• [130] Rabaan, A. A., Al-Ahmed, S. H., Sah, R., Tiwari, R., Yatoo, M. I., Patel, S. K., ... & Bonilla-Aldana, D. K. (2020). SARS-CoV-2/COVID-19 and Advances in Developing Potential Therapeutics and Vaccines to Counter this Emerging Pandemic Virus–A Review.
• [131] Shang, J., Ye, G., Shi, K., Wan, Y., Luo, C., Aihara, H., ... & Li, F. (2020). Structural basis of receptor recognition by SARS-CoV-2. Nature, 581(7807), 221-224.
• [132] Zhang, L., Lin, D., Sun, X., Curth, U., Drosten, C., Sauerhering, L., ... & Hilgenfeld, R. (2020a). Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science, 368(6489), 409-412.
• [133] Yin, W., Mao, C., Luan, X., Shen, D. D., Shen, Q., Su, H., ... & Chang, S. (2020). Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir. Science.
• [134] Zhang, Y.,& Kutateladze, T. G. (2020). Molecular structure analyses suggest strategies to therapeutically target SARS-CoV-2. Nature Communications, 11(1), 1-4.
• [135] Lai, C. C., Liu, Y. H., Wang, C. Y., Wang, Y. H., Hsueh, S. C., Yen, M. Y., ... & Hsueh, P. R. (2020). Asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARSCoV-2): facts and myths. Journal of Microbiology, Immunology and Infection.
• [136] McKee, D. L., Sternberg, A., Stange, U., Laufer, S., & Naujokat, C. (2020). Candidate drugs against SARS-CoV-2 and COVID-19. Pharmacological Research, 104859.
• [137] Al-Tawfiq, J. A., Momattin, H., Dib, J., & Memish, Z. A. (2014). Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study. International Journal of Infectious Diseases, 20, 42-46.
• [138] Ferron, F., Subissi, L., De Morais, A. T. S., Le, N. T. T., Sevajol, M., Gluais, L., ... & Imbert, I. (2018). Structural and molecular basis of mismatch correction and ribavirin excision from coronavirus RNA. Proceedings of the National Academy of Sciences, 115(2), E162-E171.
• [139] Martín, J. F. B., Jiménez, J. L., & MuEóz-Fernández, A. (2003). Pentoxifylline and severe acute respiratory syndrome (SARS): a drug to be considered. Medical Science Monitor, 9(6), SR29-SR34.
• [140] Gordon, C. J., Tchesnokov, E. P., Feng, J. Y., Porter, D. P., & Götte, M. (2020). The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus. Journal of Biological Chemistry, 295(15), 4773-4779.
• [141] Cascella, M., Rajnik, M., Cuomo, A., Dulebohn, S. C., & Di Napoli, R. (2020). Features, evaluation and treatment coronavirus (COVID-19). In Statpearls [internet]. StatPearls Publishing.
• [142] Miroshnychenko, K.,& Shestopalova, A. V. (2020). Combined use of amentoflavone and ledipasvir could interfere with binding of spike glycoprotein of SARS-CoV-2 to ACE2: the results of molecular docking study.
• [143] Mayo Clinic. 2021. Different types of COVID-19 vacciness: How they work. https://www.mayoclinic.org/diseases-conditions/coronavirus/in-depth/different-types-of-covid-19-vacci1nes/art-20506465. Erişim Tarihi: 23.08.2021.
• [144] T.C. Sağlık Bakanlığı. 2021. COVID-19 Aşısı Bilgilendirme Platformu. https://covid19asi.saglik.gov.tr/EN-80240/covid-19-vaccine-production-technologies.html. Erişim Tarihi: 23.08.2021.
• [145] ClinicalTrials.gov; Efficacy, Immunogenicity, and Safety of the Inactivated COVID-19 Vaccine (TURKOVAC) Versus the CoronaVac Vaccine. https://clinicaltrials.gov/ct2/show/NCT04942405. Erişim Tarihi: 21.08.2021.
• [146] Ledford, H. (2020). What the immune response to the coronavirus says about the prospects for a vaccine. Nature, 585(7823), 20-21.
• [147] Seow, J., Graham, C., Merrick, B., Acors, S., Steel, K. J. A., Hemmings, O., ... & Galao, R. Longitudinal evaluation and decline of antibody responses in SARS-CoV-2 infection. medRxiv 2020. Google Scholar.
• [148] Long, Q. X., Liu, B. Z., Deng, H. J., Wu, G. C., Deng, K., Chen, Y. K., ... & Wang, D. Q. (2020). Antibody responses to SARS-CoV-2 in patients with COVID-19. Nature medicine, 1-4.
• [149] Rodda, L. B., Netland, J., Shehata, L., Pruner, K. B., Morawski, P. M., Thouvenel, C., ... & Fahning, M. L. (2020). Functional SARS-CoV-2-specific immune memory persists after mild COVID-19. medRxiv.
• [150] Le Bert, N., Tan, A. T., Kunasegaran, K., Tham, C. Y., Hafezi, M., Chia, A., ... & Chia, W. N. (2020). SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature, 584(7821), 457-462.
• [151] Sette, A.,& Crotty, S. (2020). Pre-existing immunity to SARS-CoV-2: the knowns and unknowns. Nature Reviews Immunology, 20(8), 457-458.
• [152] Mateus, J., Grifoni, A., Tarke, A., Sidney, J., Ramirez, S. I., Dan, J. M., ... & Mallal, S. (4). August 2020. Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science doi, 10.
• [153] Abrial, C., Delyle, S. G., Buenestado, A., Naline, E., Papke, R., & Devillier, P. (2012). Role of nicotinic receptors in the regulation of cytokines production by human lung macrophages.
• [154] Lu, B., Kwan, K., Levine, Y. A., Olofsson, P. S., Yang, H., Li, J., ... & Tracey, K. J. (2014). α7 nicotinic acetylcholine receptor signaling inhibits inflammasome activation by preventing mitochondrial DNA release. Molecular medicine, 20(1), 350-358.
• [155] Báez-Pagán, C. A., Delgado-Vélez, M., & Lasalde-Dominicci, J. A. (2015). Activation of the macrophage α7 nicotinic acetylcholine receptor and control of inflammation. Journal of Neuroimmune Pharmacology, 10(3), 468-476.
• [156] de Jonge, W. J., van der Zanden, E. P., The, F. O., Bijlsma, M. F., van Westerloo, D. J., Bennink, R. J., ... & Boeckxstaens, G. E. (2005). Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nature immunology, 6(8), 844-851.
• [157] Changeux, J. P., Amoura, Z., Rey, F. A., & Miyara, M. (2020). A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications. Comptes Rendus. Biologies, 343(1), 33-39.
• [158] Borovikova, L. V., Ivanova, S., Zhang, M., Yang, H., Botchkina, G. I., Watkins, L. R., ... & Tracey, K. J. (2000). Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature, 405(6785), 458-462.
• [159] Wang, H., Yu, M., Ochani, M., Amella, C. A., Tanovic, M., Susarla, S., ... & Al-Abed, Y. (2003). Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature, 421(6921), 384-388.
• [160] Liu, T., Zhang, L., Joo, D., & Sun, S. C. (2017). NF-κB signaling in inflammation. Signal transduction and targeted therapy, 2(1), 1-9.
• [161] Yamada, M.,& Ichinose, M. (2018). The cholinergic anti-inflammatory pathway: an innovative treatment strategy for respiratory diseases and their comorbidities. Current Opinion in Pharmacology, 40, 18-25.
• [162] Ayub, K.,& Hallett, M. B. (2004). Ca2+ influx shutdown during neutrophil apoptosis: importance and possible mechanism. Immunology, 111(1), 8.
• [163] Nazıroğlu, M. (2011). TRPM2 cation channels, oxidative stress and neurological diseases: where are we now?. Neurochemical research, 36(3), 355-366.
• [164] Nazıroğlu, M., Dikici, D. M., & Dursun, Ş. (2012). Role of oxidative stress and Ca 2+ signaling on molecular pathways of neuropathic pain in diabetes: focus on TRP channels. Neurochemical research, 37(10), 2065-2075.
• [165] Heiner, I., Eisfeld, J., & Lückhoff, A. (2003). Role and regulation of TRP channels in neutrophil granulocytes. Cell calcium, 33(5-6), 533-540. [166] Vadász, I.,& Sznajder, J. I. (2017). Gas exchange disturbances regulate alveolar fluid clearance during acute lung injury. Frontiers in immunology, 8, 757.
• [167] Gandhirajan, R. K., Meng, S., Chandramoorthy, H. C., Mallilankaraman, K., Mancarella, S., Gao, H., ... & Koch, W. J. (2013). Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation. The Journal of clinical investigation, 123(2).
• [168] Menendez, J. A. (2020). Metformin and SARS-CoV-2: mechanistic lessons on air pollution to weather the cytokine/thrombotic storm in COVID-19. Aging, 12(10).
• [169] Wang, G., Zhang, J., Xu, C., Han, X., Gao, Y., & Chen, H. (2016). Inhibition of SOCs attenuates acute lung injury induced by severe acute pancreatitis in rats and PMVECs injury induced by lipopolysaccharide. Inflammation, 39(3), 1049-1058.
• [170] Alvarez, D. F., King, J. A., Weber, D., Addison, E., Liedtke, W., & Townsley, M. I. (2006). Transient receptor potential vanilloid 4–mediated disruption of the alveolar septal barrier: a novel mechanism of acute lung injury. Circulation research, 99(9), 988-995.
• [171] Goldenberg, N. M., Ravindran, K., & Kuebler, W. M. (2015). TRPV4: physiological role and therapeutic potential in respiratory diseases. Naunyn-Schmiedeberg's archives of pharmacology, 388(4), 421-436.
• [172] Morty, R. E.,& Kuebler, W. M. (2014). TRPV4: an exciting new target to promote alveolocapillary barrier function. American Journal of Physiology-Lung Cellular and Molecular Physiology, 307(11), L817-L821.
• [173] Yin, J., Hoffmann, J., Kaestle, S. M., Neye, N., Wang, L., Baeurle, J., ... & Kuebler, W. M. (2008). Negative-feedback loop attenuates hydrostatic lung edema via a cGMP-dependent regulation of transient receptor potential vanilloid 4. Circulation research, 102(8), 966-974.
• [174] Yin, J., Michalick, L., Tang, C., Tabuchi, A., Goldenberg, N., Dan, Q., ... & Witzenrath, M. (2016). Role of transient receptor potential vanilloid 4 in neutrophil activation and acute lung injury. American journal of respiratory cell and molecular biology, 54(3), 370-383.
• [175] Balakrishna, S., Song, W., Achanta, S., Doran, S. F., Liu, B., Kaelberer, M. M., ... & Eidam, H. S. (2014). TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury. American Journal of Physiology-Lung Cellular and Molecular Physiology, 307(2), L158-L172.
• [176] Dutta, B., Arya, R. K., Goswami, R., Alharbi, M. O., Sharma, S., & Rahaman, S. O. (2019). Role of macrophage TRPV4 in inflammation. Laboratory investigation, 1-8.
• [177] Hamanaka, K., Jian, M. Y., Townsley, M. I., King, J. A., Liedtke, W., Weber, D. S., ... & Parker, J. C. (2010). TRPV4 channels augment macrophage activation and ventilator-induced lung injury. American Journal of Physiology-Lung Cellular and Molecular Physiology, 299(3), L353-L362.
• [178] Hamanaka, K., Jian, M. Y., Weber, D. S., Alvarez, D. F., Townsley, M. I., Al-Mehdi, A. B., ... & Parker, J. C. (2007). TRPV4 initiates the acute calcium-dependent permeability increase during ventilator-induced lung injury in isolated mouse lungs. American Journal of Physiology-Lung Cellular and Molecular Physiology, 293(4), L923-L932.
• [179] Pairet, N., Mang, S., Fois, G., Keck, M., Kühnbach, M., Gindele, J., ... & Lamb, D. J. (2018). TRPV4 inhibition attenuates stretch-induced inflammatory cellular responses and lung barrier dysfunction during mechanical ventilation. PloS one, 13(4), e0196055.
• [180] Rayees, S., Joshi, J. C., Tauseef, M., Anwar, M., Baweja, S., Rochford, I., ... & Mehta, D. (2019). PAR2-mediated cAMP generation suppresses TRPV4-dependent Ca2+ signaling in alveolar macrophages to resolve TLR4-induced inflammation. Cell reports, 27(3), 793-805.
• [181] Scheraga, R. G., Abraham, S., Niese, K. A., Southern, B. D., Grove, L. M., Hite, R. D., ... & Olman, M. A. (2016). TRPV4 mechanosensitive ion channel regulates lipopolysaccharide-stimulated macrophage phagocytosis. The Journal of Immunology, 196(1), 428-436.
• [182] Zhao, P., Lieu, T., Barlow, N., Sostegni, S., Haerteis, S., Korbmacher, C., ... & Bunnett, N. W. (2015). Neutrophil elastase activates protease-activated receptor-2 (PAR2) and transient receptor potential vanilloid 4 (TRPV4) to cause inflammation and pain. Journal of Biological Chemistry, 290(22), 13875-13887.
• [183] Michalick, L., Erfinanda, L., Weichelt, U., van der Giet, M., Liedtke, W., & Kuebler, W. M. (2017). Transient Receptor Potential Vanilloid 4 and Serum Glucocorticoid–regulated Kinase 1 Are Critical Mediators of Lung Injury in Overventilated Mice In Vivo. Anesthesiology: The Journal of the American Society of Anesthesiologists, 126(2), 300-311.
• [184] Yu, Q., Wang, D., Wen, X., Tang, X., Qi, D., He, J., ... & Zhu, T. (2020). Adipose-derived exosomes protect the pulmonary endothelial barrier in ventilator-induced lung injury by inhibiting the TRPV4/Ca2+ signaling pathway. American Journal of Physiology-Lung Cellular and Molecular Physiology.
• [185] Huh, D., Leslie, D. C., Matthews, B. D., Fraser, J. P., Jurek, S., Hamilton, G. A., ... & Ingber, D. E. (2012). A human disease model of drug toxicity–induced pulmonary edema in a lung-on-a-chip microdevice. Science translational medicine, 4(159), 159ra147-159ra147.
• [186] Thorneloe, K. S., Cheung, M., Bao, W., Alsaid, H., Lenhard, S., Jian, M. Y., ... & Gordon, E. (2012). An orally active TRPV4 channel blocker prevents and resolves pulmonary edema induced by heart failure. Science translational medicine, 4(159), 159ra148-159ra148.
• [187] Willette, R. N., Bao, W., Nerurkar, S., Yue, T. L., Doe, C. P., Stankus, G., ... & Sulpizio, A. (2008). Systemic activation of the transient receptor potential vanilloid subtype 4 channel causes endothelial failure and circulatory collapse: Part 2. Journal of Pharmacology and Experimental Therapeutics, 326(2), 443-452.
• [188] Li, J., Wen, A. M., Potla, R., Benshirim, E., Seebarran, A., Benz, M. A., ... & Levy, O. (2019). AAV-mediated gene therapy targeting TRPV4 mechanotransduction for inhibition of pulmonary vascular leakage. APL bioengineering, 3(4), 046103.
• [189] Feske, S., Wulff, H., & Skolnik, E. Y. (2015). Ion channels in innate and adaptive immunity. Annual review of immunology, 33, 291-353.
• [190] Waldron, R. T., Chen, Y., Pham, H., Go, A., Su, H. Y., Hu, C., ... & Ramos, S. (2019). The Orai Ca2+ channel inhibitor CM4620 targets both parenchymal and immune cells to reduce inflammation in experimental acute pancreatitis. The Journal of physiology, 597(12), 3085-3105.
• [191] Wen, L., Voronina, S., Javed, M. A., Awais, M., Szatmary, P., Latawiec, D., ... & Begg, M. (2015). Inhibitors of ORAI1 prevent cytosolic calcium-associated injury of human pancreatic acinar cells and acute pancreatitis in 3 mouse models. Gastroenterology, 149(2), 481-492.
• [192] Seeley, E. J., Rosenberg, P., & Matthay, M. A. (2013). Calcium flux and endothelial dysfunction during acute lung injury: a STIMulating target for therapy. The Journal of clinical investigation, 123(3), 1015-1018.
• [193] Brooks, C. A., Barton, L. S., Behm, D. J., Eidam, H. S., Fox, R. M., Hammond, M., ... & Patterson, J. R. (2019). Discovery of GSK2798745: a clinical candidate for inhibition of transient receptor potential vanilloid 4 (TRPV4). ACS medicinal chemistry letters, 10(8), 1228-1233.
• [194] ClinicalTrials.gov; U.S. National Library of Medicine. A First Time in Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GSK2798745 in Healthy Subjects and Stable Heart Failure Patients. https://clinicaltrials.gov/ct2/show/study/NCT02119260. 2018 [last updated September 27, 2018].
• [195] ClinicalTrials.gov; U.S. National Library of Medicine. A Study to Assess the Effectiveness and Side Effects of GSK2798745 in Participants With Chronic Cough. https://clinicaltrials.gov/ct2/show/NCT03372603. 2019 [last updated October 2, 2019].
• [196] Goyal, N., Skrdla, P., Schroyer, R., Kumar, S., Fernando, D., Oughton, A., ... & Cheriyan, J. (2019). Clinical pharmacokinetics, safety, and tolerability of a novel, first-in-class TRPV4 ion channel inhibitor, GSK2798745, in healthy and heart failure subjects. American Journal of Cardiovascular Drugs, 19(3), 335-342.
• [197] Stewart, G. M., Johnson, B. D., Sprecher, D. L., Reddy, Y. N., Obokata, M., Goldsmith, S., ... & Borlaug, B. A. (2020). Targeting pulmonary capillary permeability to reduce lung congestion in heart failure: a randomized, controlled pilot trial. European Journal of Heart Failure.
• [198] Qian, Z., Dominguez, S. R., & Holmes, K. V. (2013). Role of the spike glycoprotein of human Middle East respiratory syndrome coronavirus (MERS-CoV) in virus entry and syncytia formation. PloS one, 8(10), e76469.
• [199] Tang, T., Bidon, M., Jaimes, J. A., Whittaker, G. R., & Daniel, S. (2020). Coronavirus membrane fusion mechanism offers as a potential target for antiviral development. Antiviral research, 104792.
• [200] Basso, L. G., Vicente, E. F., Crusca Jr, E., Cilli, E. M., & Costa-Filho, A. J. (2016). SARS-CoV fusion peptides induce membrane surface ordering and curvature. Scientific reports, 6, 37131.
• [201] De Haan, C. A.,& Rottier, P. J. (2005). Molecular interactions in the assembly of coronaviruses. Advances in virus research, 64, 165-230.
• [202] Raffaello, A., Mammucari, C., Gherardi, G., & Rizzuto, R. (2016). Calcium at the center of cell signaling: interplay between endoplasmic reticulum, mitochondria, and lysosomes. Trends in biochemical sciences, 41(12), 1035-1049.
• [203] Huotari, J.,& Helenius, A. (2011). Endosome maturation. The EMBO journal, 30(17), 3481-3500.
• [204] Pryor, P. R., Mullock, B. M., Bright, N. A., Gray, S. R., & Luzio, J. P. (2000). The role of intraorganellar Ca2+ in late endosome–lysosome heterotypic fusion and in the reformation of lysosomes from hybrid organelles. The Journal of cell biology, 149(5), 1053-1062.
• [205] Kuebler, W. M., Jordt, S. E., & Liedtke, W. B. (2020). Urgent reconsideration of lung edema as a preventable outcome in COVID-19: Inhibition of TRPV4 represents a promising and feasible approach. American Journal of Physiology-Lung Cellular and Molecular Physiology, 318(6), L1239-L1243.
• [206] Seth, R. K., Das, S., Dattaroy, D., Chandrashekaran, V., Alhasson, F., Michelotti, G., ... & Liedtke, W. (2017). TRPV4 activation of endothelial nitric oxide synthase resists nonalcoholic fatty liver disease by blocking CYP2E1-mediated redox toxicity. Free Radical Biology and Medicine, 102, 260-273.
• [207] Echtermeyer, F., Eberhardt, M., Risser, L., Herzog, C., Gueler, F., Khalil, M., ... & Leffler, A. (2019). Acetaminophen‐induced liver injury is mediated by the ion channel TRPV4. The FASEB Journal, 33(9), 10257-10268.
• [208] Scheraga, R. G., Abraham, S., Grove, L. M., Southern, B. D., Crish, J. F., Perelas, A., ... & Olman, M. A. (2020). TRPV4 Protects the lung from bacterial pneumonia via MAPK molecular pathway switching. The Journal of Immunology, 204(5), 1310-1321.
• [209] Michalick, L.,& Kuebler, W. M. (2020). TRPV4—a missing link between mechanosensation and immunity. Frontiers in Immunology, 11.
• [210] Radovanovic, D., Rizzi, M., Pini, S., Saad, M., Chiumello, D. A., & Santus, P. (2020). Helmet CPAP to treat acute hypoxemic respiratory failure in patients with COVID-19: a management strategy proposal. Journal of clinical medicine, 9(4), 1191.
• [211] Mangan, D. F., Welch, G. R., & Wahl, S. M. (1991). Lipopolysaccharide, tumor necrosis factor-alpha, and IL-1 beta prevent programmed cell death (apoptosis) in human peripheral blood monocytes. The Journal of Immunology, 146(5), 1541-1546.
• [212] Arends, MJ, A. (1991). Wyllie AH. Apoptosis: mechanisms and roles in pathology. Int Rev Exp Pathol, 32, 223-254.
• [213] Thompson, C. B. (1995). Apoptosis in the pathogenesis and treatment of disease. Science, 267(5203), 1456-1462
• [214] Reed, J. C. (1994). Bcl-2 and the regulation of programmed cell death. The Journal of cell biology, 124(1-2), 1-6.
• [215] Stauderman, K. A. (2018). CRAC channels as targets for drug discovery and development. Cell Calcium, 74, 147-159.
• [216] Stauderman, K., Miller, J., Chaudhry, K., Sabagha, N., Wilson, K., Hope, H., ... & Hebbar, S. (2019, November). Pharmacodynamic (PD)/Pharmacokinetic (PK) Study of CM4620 Injectable Emulsion in Patients With Acute Pancreatitis. In PANCREAS (Vol. 48, No. 10, pp. 1527-1527). TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA: LIPPINCOTT WILLIAMS & WILKINS.
• [217] Miller, J., Bruen, C., Schnaus, M., Zhang, J., Ali, S., Lind, A., ... & Hebbar, S. (2020). Auxora versus standard of care for the treatment of severe or critical COVID-19 pneumonia: results from a randomized controlled trial. Critical Care, 24(1), 1-9.
• [218] Choi, H. J., Kim, J. H., Lee, C. H., Ahn, Y. J., Song, J. H., Baek, S. H., & Kwon, D. H. (2009). Antiviral activity of quercetin 7-rhamnoside against porcine epidemic diarrhea virus. Antiviral Research, 81(1), 77-81.
• [219] Song, J. H., Shim, J. K., & Choi, H. J. (2011). Quercetin 7-rhamnoside reduces porcine epidemic diarrhea virus replication via independent pathway of viral induced reactive oxygen species. Virology journal, 8(1), 1-6.
• [220] Tomar, P. P. S.,& Arkin, I. T. (2020). SARS-CoV-2 E protein is a potential ion channel that can be inhibited by Gliclazide and Memantine. Biochemical and Biophysical Research Communications, 530(1), 10-14.
• [221] Chen, C. C., Krüger, J., Sramala, I., Hsu, H. J., Henklein, P., Chen, Y. M. A., & Fischer, W. B. (2011). ORF8a of SARS-CoV forms an ion channel: experiments and molecular dynamics simulations. Biochimica et Biophysica Acta (BBA)-Biomembranes, 1808(2), 572-579.
• [222] Castaño-Rodriguez, C., Honrubia, J. M., Gutiérrez-Álvarez, J., DeDiego, M. L., Nieto-Torres, J. L., Jimenez-Guardeño, J. M., ... & Kochan, G. (2018). Role of severe acute respiratory syndrome coronavirus viroporins E, 3a, and 8a in replication and pathogenesis. MBio, 9(3).
• [223] Verdiá-Báguena, C., Nieto-Torres, J. L., Alcaraz, A., DeDiego, M. L., Torres, J., Aguilella, V. M., & Enjuanes, L. (2012). Coronavirus E protein forms ion channels with functionally and structurally-involved membrane lipids. Virology, 432(2), 485-494.
• [224] Nieto-Torres, J. L., Verdiá-Báguena, C., Jimenez-Guardeño, J. M., Regla-Nava, J. A., Castaño-Rodriguez, C., Fernandez-Delgado, R., ... & Enjuanes, L. (2015). Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome. Virology, 485, 330-339.
• [225] Lai, A. L., Millet, J. K., Daniel, S., Freed, J. H., & Whittaker, G. R. (2017). The SARS-CoV fusion peptide forms an extended bipartite fusion platform that perturbs membrane order in a calcium-dependent manner. Journal of molecular biology, 429(24), 3875-3892.
• [226] Straus, M. R., Tang, T., Lai, A. L., Flegel, A., Bidon, M., Freed, J. H., ... & Whittaker, G. R. (2020). Ca2+ ions promote fusion of Middle East Respiratory Syndrome coronavirus with host cells and increase infectivity. Journal of Virology.
• [227]Sell, T. S., Belkacemi, T., Flockerzi, V., & Beck, A. (2014). Protonophore properties of hyperforin are essential for its pharmacological activity. Scientific reports, 4, 7500.
• [228] Kim, D. W., Seo, K. H., Curtis-Long, M. J., Oh, K. Y., Oh, J. W., Cho, J. K., ... & Park, K. H. (2014). Phenolic phytochemical displaying SARS-CoV papain-like protease inhibition from the seeds of Psoralea corylifolia. Journal of enzyme inhibition and medicinal chemistry, 29(1), 59-63.
• [229] Yu, M. S., Lee, J., Lee, J. M., Kim, Y., Chin, Y. W., Jee, J. G., ... & Jeong, Y. J. (2012). Identification of myricetin and scutellarein as novel chemical inhibitors of the SARS coronavirus helicase, nsP13. Bioorganic & medicinal chemistry letters, 22(12), 4049-4054.
• [230] Tekerlek, P. (2013). Bazı bryofit türlerinin antimikrobiyal aktivitesinin belirlenmesi (Master's thesis, Niğde Üniversitesi).
• [231] Altuner, E. M. Y.,& Çetin, B. T. D. (2008). Bazı karayosunu türlerinin antimikrobiyal aktivitesinin belirlenmesi (Doctoral dissertation, Ankara Üniversitesi Fen Bilimleri Enstitüsü Biyoloji Anabilim Dalı).
• [232] Burnaz, N. A. (2007). Viburnum opulus ve V. orientale bitki ekstraktlarının kimyasal bileşimi ve biyolojik aktiviteleri (Doctoral dissertation, Karadeniz Teknik Üniversitesi/Fen Bilimleri Enstitüsü/Kimya Anabilim Dalı).
• [233] Akyüz, E. (2007). Polygonum bistorta ssp. carneum bitki ekstraktlarının kromatografik yöntemlerle kimyasal bileşiminin belirlenmesi ve antioksidan ve antimikrobiyal aktiviteleri (Doctoral dissertation, Karadeniz Teknik Üniversitesi/Fen Bilimleri Enstitüsü/Kimya Anabilim Dalı).
• [234] Öztürk, H. (2009). Jurinea consanguinea'nın antioksidan ve antibakteriyel aktivitesinin belirlenmesi (Master's thesis, Trakya Üniversitesi Fen Bilimleri Enstitüsü).
• [235] Panche, A. N., Diwan, A. D., & Chandra, S. R. (2016). Flavonoids: an overview. Journal of nutritional science, 5.
• [236] D’Amelia, V., Aversano, R., Chiaiese, P., & Carputo, D. (2018). The antioxidant properties of plant flavonoids: their exploitation by molecular plant breeding. Phytochemistry Reviews, 17(3), 611-625.
• [237] LeJeune, T. M., Tsui, H. Y., Parsons, L. B., Miller, G. E., Whitted, C., Lynch, K. E., ... & Adams, C. B. (2015). Mechanism of action of two flavone isomers targeting cancer cells with varying cell differentiation status. PLoS One, 10(11), e0142928.
• [238] Abreu, A. C., Coqueiro, A., Sultan, A. R., Lemmens, N., Kim, H. K., Verpoorte, R., ... & Choi, Y. H. (2017). Looking to nature for a new concept in antimicrobial treatments: Isoflavonoids from Cytisus striatus as antibiotic adjuvants against MRSA. Scientific Reports, 7(1), 1-16.
• [239] Solnier, J., Martin, L., Bhakta, S., & Bucar, F. (2020). Flavonoids as novel efflux pump inhibitors and antimicrobials against both environmental and pathogenic intracellular mycobacterial species. Molecules, 25(3), 734.
• [240] Wang, H. K., Xia, Y., Yang, Z. Y., Natschke, S. L. M., & Lee, K. H. (1998). Recent advances in the discovery and development of flavonoids and their analogues as antitumor and anti-HIV agents. In Flavonoids in the living system (pp. 191-225). Springer, Boston, MA.
• [241] Catarino, M. D., Talhi, O., Rabahi, A., Silva, A. M. S., & Cardoso, S. M. (2016). The antiinflammatory potential of flavonoids: Mechanistic aspects. In Studies in Natural Products Chemistry (Vol. 48, pp. 65-99). Elsevier.
• [242] Yang, Y., Islam, M. S., Wang, J., Li, Y., & Chen, X. (2020). Traditional Chinese medicine in the treatment of patients infected with 2019-new coronavirus (SARS-CoV-2): a review and perspective. International journal of biological sciences, 16(10), 1708.
• [243] Actis-Goretta, L., Ottaviani, J. I., & Fraga, C. G. (2006). Inhibition of angiotensin converting enzyme activity by flavanol-rich foods. Journal of agricultural and food chemistry, 54(1), 229-234.
• [244] Guerrero, L., Castillo, J., Quiñones, M., Garcia-Vallvé, S., Arola, L., Pujadas, G., & Muguerza, B. (2012). Inhibition of angiotensin-converting enzyme activity by flavonoids: structure-activity relationship studies. PloS one, 7(11), e49493.
• [245] Balasuriya, B. N.,& Rupasinghe, H. V. (2011). Plant flavonoids as angiotensin converting enzyme inhibitors in regulation of hypertension. Functional foods in health and disease, 1(5), 172-188.
• [246] Dong, W., Wei, X., Zhang, F., Hao, J., Huang, F., Zhang, C., & Liang, W. (2014). A dual character of flavonoids in influenza A virus replication and spread through modulating cell-autonomous immunity by MAPK signaling pathways. Scientific reports, 4, 7237.
• [247] Delgado-Roche, L.,& Mesta, F. (2020). Oxidative stress as key player in severe acute respiratory syndrome coronavirus (SARS-CoV) infection. Archives of Medical Research.
• [248] Liang, W., He, L., Ning, P., Lin, J., Li, H., Lin, Z., ... & Zhang, Y. (2015). (+)-Catechin inhibition of transmissible gastroenteritis coronavirus in swine testicular cells is involved its antioxidation. Research in veterinary science, 103, 28-33.
• [249] Do Carmo, S., Jacomy, H., Talbot, P. J., & Rassart, E. (2008). Neuroprotective effect of apolipoprotein D against human coronavirus OC43-induced encephalitis in mice. Journal of Neuroscience, 28(41), 10330-10338.
• [250] Ganfornina, M. D., Do Carmo, S., Lora, J. M., Torres‐Schumann, S., Vogel, M., Allhorn, M., ... & Sanchez, D. (2008). Apolipoprotein D is involved in the mechanisms regulating protection from oxidative stress. Aging cell, 7(4), 506-515.
• [251] Ding, L., Zhao, X., Huang, Y., Du, Q., Dong, F., Zhang, H., ... & Tong, D. (2013). Regulation of ROS in transmissible gastroenteritis virus-activated apoptotic signaling. Biochemical and biophysical research communications, 442(1-2), 33-37.
• [252] Zhang, R., Wang, X., Ni, L., Di, X., Ma, B., Niu, S., ... & Reiter, R. J. (2020). COVID-19: Melatonin as a potential adjuvant treatment. Life sciences, 117583.
• [253] Kim, S. J., Um, J. Y., Hong, S. H., & Lee, J. Y. (2011). Anti-inflammatory activity of hyperoside through the suppression of nuclear factor-κB activation in mouse peritoneal macrophages. The American journal of Chinese medicine, 39(01), 171-181., 318(4), L723-L741.
• [254] Wu, S., Zhang, Y., Ren, F., Qin, Y., Liu, J., Liu, J., ... & Zhang, H. (2018). Structure–affinity relationship of the interaction between phenolic acids and their derivatives and β-lactoglobulin and effect on antioxidant activity. Food chemistry, 245, 613-619.