2023 10 1 0 82

Characteristics of Diminutive Colorectal Polyps in Patients Undergoing Colonoscopy in an Educational, Therapeutic Hospital in Western Iran 2 2 Background and Aims: Limited information is available on the frequency of advanced adenomas in diminutive colon polyps. Thus, this study aimed to investigate the pathological characteristics and the frequency of high-grade dysplasia in diminutive colorectal polyps in individuals referred to colonoscopy examination in Kermanshah, Iran. Materials and Methods: Demographics characteristics, location and diameter of the polyp, histological assessment of the polyps, grade, and others were retrieved from colonoscopy reports. Results and Conclusions: During the study period, 250 diminutive colorectal polyps were detected. The histological assessment showed that 36.4% were adenomatous, 32.8% were hyperplastic, and 30.8% were inflammatory polyps. Only two diminutive polyps (0.8%) had high-grade dysplasia, and the frequency of adenocarcinoma in our study was 0.4%. Besides, the frequency of adenomatous polyps was higher in the proximal versus the distal colon. These findings emphasize the urgent need for a colorectal cancer screening plan in the Iranian population to improve therapeutic outcomes. 1 6 2021/11/28 1400/9/7 2023/03/1 1401/12/10 همایون بشیری Homayoon Bashiri Infectious Diseases Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran ایران hbashirimd@yahoo.com Mahsa Madani Mahsa Madani Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran ایران lotfollah.asgari@yahoo.com لطفالله عسگری Lotfollah Asgari Department of Internal Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran. Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran ایران آرزو بزرگ امید Arezoo Bozorgomid Infectious Diseases Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran ایران Adenomatous polyps Colonoscopy Diminutive colorectal polyps Histopathology [1]. Pickhardt PJ, Pooler BD, Kim DH, Hassan C, Matkowskyj KA, Halberg RB. The natural history of colorectal polyps: overview of predictive static and dynamic features. Gastroenterol Clin. 2018; 47(3): 515-36.##[2]. Amersi F, Agustin M, Ko CY. Colorectal cancer: epidemiology, risk factors, and health services. Clinics in colon and rectal surgery. Clin Colon Rectal Surg. 2005; 18(3): 133-40. ##[3]. Dolatkhah R, Somi MH, Kermani IA, Ghojazadeh M, Jafarabadi MA, Farassati F, et al. Increased colorectal cancer incidence in Iran: a systematic review and meta-analysis. BMC Public Health 2015; 15(1): 1-14.##[4]. Heijnen ML, Landsdorp-Vogelaar I. CRC screening in the Netherlands. From pilot to national programme. 2014. Available from: http://www.rivm.nl/en/Topics/B/Bowel_cancer_screening_programme.##[5]. Wang LM, East JE. Diminutive polyp cancers and the DISCARD strategy: Much ado about nothing or the end of the affair? Gastrointest Endosc. 2015; 82(2): 385-88.##[6]. Long X, Li X, Ma L, Lu J, Liao S, Gui R. Clinical and endoscopic-pathological characteristics of colorectal polyps: an analysis of 1,234 cases. Int J Clin Exp Med. 2015; 8(10): 19367. ##[7]. Jeong YH, Kim KO, Park CS, Kim SB, Lee SH, Jang BI. Risk factors of advanced adenoma in small and diminutive colorectal polyp. J Korean Med Sci. 2016; 31(9): 1426-430.##[8]. Kim DH, Pickhardt PJ, Taylor AJ, Leung WK, Winter TC, Hinshaw JL, et al. CT colonography versus colonoscopy for the detection of advanced neoplasia. N Engl J Med. 2007; 357(14): 1403-412.##[9]. Kruger J, Katsidzira L, Setshedi M, Thomson S. Prevalence and characteristics of incidental colorectal polyps in patients undergoing colonoscopy at a South African tertiary institution. S Afr Med J. 2020; 110(12): 1191-194.##[10]. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 2008; 371(9612): 569-78.##[11]. Trabulo D, Ribeiro S, Martins C, Teixeira C, Cardoso C, Mangualde J, et al. Metabolic syndrome and colorectal neoplasms: An ominous association. World J Gastroenterol. 2015; 21(17): 5320.##[12]. Vleugels JL, Hazewinkel Y, Fockens P, Dekker E. Natural history of diminutive and small colorectal polyps: a systematic literature review. Gastrointest Endosc. 2017; 85(6): 1169-176.## ##

Neutrophil Extracellular Traps in Inflammatory and Autoimmune Diseases and Cancer 2 1 نوتروفیل ها فاگوسیت های ذاتی سیستم ایمنی هستند که نقش اصلی را در دفاع از ایمنی ایفا می کنند. آنها حاوی مواد ضد میکروبی موثر هستند که عمدتاً در گرانول های تخصصی ذخیره می شوند بنابراین می تواند به بافت میزبان نیز آسیب برساند. استقرار نوتروفیل ها به شدت از طریق استراتژی های مختلفی تنظیم می شود، از جمله فاگوسیتوز، تولید گونه های اکسیژن فعال (ROS)، دگرانوله شدن و تشکیل تله های خارج سلولی نوتروفیل. کشف تله های خارج سلولی نوتروفیل  در سال 2004 فصل جدیدی را در کشتن میکروب ها توسط سیستم ایمنی باز کرد. برینکمن و همکارانش نشان دادند که نوتروفیل ها هنگامی که به طور فاجعه بار تحریک می شوند، تحت شکل جدیدی از مرگ سلولی برنامه ریزی شده به نام NETosis قرار می گیرند. در طی تشکیل NET، غشای پلاسمایی به صورت برنامه ریزی شده پاره می شود. این نشان می دهد که تشکیل NET شامل یک برنامه خودکشی است که از نظر مورفولوژیکی متفاوت از انواع دیگر مرگ سلولی، مانند آپوپتوز و نکروز است. NET ها ساختارهای منحصر به فردی از DNA و پپتیدهای ضد میکروبی دارند. فعالیت ضد میکروبی یکی از عملکردهای نوتروفیل ها به عنوان اولین پاسخ به التهاب است. NET در پاتوفیزیولوژی بیماری های مختلفی خصوصا بیماری های التهابی و خودایمیون نظیر لوپوس و آرتریت روماتوئید نقش محوری و مهمی دارد. 2 Neutrophils are innate immune system phagocytes that play a central role in immunity defense. They are equipped with effective antimicrobial that is mainly stored in specialized granules. Considering that, it can also damage host tissue. Neutrophil deployment is heavily regulated through various strategies, including phagocytosis, reactive oxygen species, production degranulation, and the formation of neutrophil extracellular traps (NET). This review article will discuss its role in inflammatory, autoimmune diseases, and cancer and place it as a therapeutic target. It depicts that NET formation includes a suicide program morphologically different from other types of cell death, such as apoptosis and necrosis. Besides, NETs have unique DNA and antimicrobial peptide structures, and antimicrobial activity is among the functions of neutrophils as the first response to inflammation. So, it plays a pivotal role in the pathophysiology of various diseases, especially inflammatory and autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. As a result, it can be effective in the pathogenesis of many diseases, and its pathogenic role can be used as a therapeutic target. 7 22 2021/11/282022/07/1 1401/4/10 2023/03/12023/02/27 1401/12/8 کاوه طاری Kaveh Tari Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran ایران k.tari@modares.ac.ir آیت عباسی شاهکوه Ayat Abbasi-Shahkouh Student Research Committee, School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran ایران ayat.abbasi.sh@gmail.com سیده فاطمه ازغدی Seyedeh Fatemeh Azghadi Student Research Committee, School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran ایران azghadifafa@gmail.com کیمیا رشیدان Kimiya Rashidan Student Research Committee, School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran ایران kimiyarashidan79@gmail.com زهرا سادات موسوی Zahra-Sadat Mousavi Student Research Committee, School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran ایران zahraaa.mousavi79@gmail.com مبارکه عجم حسینی Mobarakeh Ajam-Hosseini Department of Cell and Molecular Biology, Faculty of Basic Sciences, Kharazmi University, Karaj, Iran ایران mobarake.ajamhoseini@khu.ac.ir ریحانه ابریان Reyhaneh Abriyan Student Research Committee, School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran ایران reyhan037071@gmail.com امیر آتشی Amir Atashi Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran ایران atashia@shmu.ac.ir Autoimmune Inflammatory Neutrophil Neutrophil extracellular traps تله های خارج سلولی نوتروفیل بیماری های التهابی بیماری های خود ایمنی نوتروفیل ها [1]. Mulay SR, Anders HJ. Neutrophils and neutrophil extracellular traps regulate immune responses in health and disease. Multidisciplinary Digital Publishing Institute; 2020, p. 2130.##[2]. Sollberger G, Amulic B, Zychlinsky A. Neutrophil extracellular trap formation is independent of de novo gene expression. PLoS One 2016; 11(6): 157454.##[3]. Cooper PR, Palmer LJ, Chapple IL. Neutrophil extracellular traps as a new paradigm in innate immunity: friend or foe? Periodontol. 2013; 63(1): 165-97.##[4]. Van Avondt K, Hartl D. Mechanisms and disease relevance of neutrophil extracellular trap formation. European Journal of Clinical Investigation 2018; 48: 12919.##[5]. Ravindran M, Khan MA, Palaniyar N. Neutrophil extracellular trap formation: physiology, pathology, and pharmacology. Biomolecules 2019; 9(8): 365.##[6]. Estúa-Acosta GA, Zamora-Ortiz R, Buentello-Volante B, García-Mejía M, Garfias Y. Neutrophil extracellular traps: current perspectives in the eye. Cells 2019; 8(9): 979.##[7]. Leshner M, Wang S, Lewis C, Zheng H, Chen XA, Santy L, et al. PAD4 mediated histone hyper-citrullination induces heterochromatin decondensation and chromatin unfolding to form neutrophil extracellular trap-like structures. Frontiers Immunol. 2012; 3: 307.##[8]. Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol. 2007; 176(2): 231-41.##[9]. Amini P, Stojkov D, Felser A, Jackson CB, Courage C, Schaller A, et al. Neutrophil extracellular trap formation requires OPA1-dependent glycolytic ATP production. Nature Communica. 2018; 9(1): 1-16.##[10]. Amulic B, Knackstedt SL, Abed UA, Deigendesch N, Harbort CJ, Caffrey BE, et al. Cell-cycle proteins control production of neutrophil extracellular traps. Developmental cell. 2017; 43(4): 449-62.##[11]. Medina E. Neutrophil extracellular traps: a strategic tactic to defeat pathogens with potential consequences for the host. Journal of Innate Immunity 2009; 1(3): 176-80.##[12]. Yousefi S, Mihalache C, Kozlowski E, Schmid I, Simon HU. Viable neutrophils release mitochondrial DNA to form neutrophil extracellular traps. Cell Death & Differentiation 2009; 16(11): 1438-444.##[13]. de Bont CM, Boelens WC, Pruijn GJ. NETosis, complement, and coagulation: a triangular relationship. Cellular Molecular Immunol. 2019; 16(1): 19-27.##[14]. Zou Y, Chen X, Xiao J, Zhou DB, Lu XX, Li W, et al. Neutrophil extracellular traps promote lipopolysaccharide-induced airway inflammation and mucus hypersecretion in mice. Oncotarget 2018; 9(17): 13276.##[15]. Dąbrowska D, Jabłońska E, Garley M, Ratajczak‐Wrona W, Iwaniuk A. New aspects of the biology of neutrophil extracellular traps. Scandinavian Journal of Immunology 2016; 84(6): 317-22.##[16]. Nauseef WM, Kubes P. Pondering neutrophil extracellular traps with healthy skepticism. Cellular microbiology 2016; 18(10): 1349-357.##[17]. Urban CF, Ermert D, Schmid M, Abu-Abed U, Goosmann C, Nacken W, et al. Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathogens 2009; 5(10): 1000639.##[18]. Rosazza T, Warner J, Sollberger G. NET formation–mechanisms and how they relate to other cell death pathways. The FEBS Journal 2021; 288(11): 3334-350.##[19]. Liu L, Mao Y, Xu B, Zhang X, Fang C, Ma Y, et al. Induction of neutrophil extracellular traps during tissue injury: Involvement of STING and Toll‐like receptor 9 pathways. Cell Proliferation 2019; 52(3): 12579.##[20]. Papayannopoulos V, Metzler KD, Hakkim A, Zychlinsky A. Neutrophil elastase and myelo-peroxidase regulate the formation of neutrophil extracellular traps. Journal of Cell Biology 2010; 191(3): 677-91.##[21]. Desai J, Kumar SV, Mulay SR, Konrad L, Romoli S, Schauer C, et al. PMA and crystal‐induced neutrophil extracellular trap formation involves RIPK1‐RIPK3‐MLKL signaling. European Journal of Immunology 2016; 46(1): 223-29.##[22]. Brinkmann V. Neutrophil extracellular traps in the second decade. Journal of Innate Immunity 2018; 10(5-6): 414-21.##[23]. Hakkim A, Fuchs TA, Martinez NE, Hess S, Prinz H, Zychlinsky A, et al. Activation of the Raf-MEK-ERK pathway is required for neutrophil extracellular trap formation. Nature Chemical Biology 2011; 7(2): 75-7.##[24]. Douda DN, Khan MA, Grasemann H, Palaniyar N. SK3 channel and mitochondrial ROS mediate NADPH oxidase-independent NETosis induced by calcium influx. Proceedings of the National Academy of Sciences 2015; 112(9): 2817-822.##[25]. Björnsdottir H, Welin A, Michaëlsson E, Osla V, Berg S, Christenson K, et al. Neutrophil NET formation is regulated from the inside by myeloperoxidase-processed reactive oxygen species. Free Radical Biology and Medicine 2015; 89(12): 1024-1035.##[26]. Pieterse E, Rother N, Yanginlar C, Gerretsen J, Boeltz S, Munoz LE, et al. Cleaved N-terminal histone tails distinguish between NADPH oxidase (NOX)-dependent and NOX-independent pathways of neutrophil extracellular trap formation. Annals of the Rheumatic Diseases 2018; 77(12): 1790-798.##[27]. Yipp BG, Kubes P. NETosis: how vital is it? Blood, The Journal of the American Society of Hematology 2013; 122(16): 2784-794.##[28]. Pieterse E, Rother N, Yanginlar C, Hilbrands LB, Van der Vlag J. Neutrophils discriminate between lipopolysaccharides of different bacterial sources and selectively release neutrophil extracellular traps. Frontiers in Immunology 2016; 7(11):484.##[29]. Sharma A, Simonson TJ, Jondle CN, Mishra BB, Sharma J. Mincle-mediated neutrophil extracellular trap formation by regulation of autophagy. The Journal of Infectious Diseases 2017; 215(7): 1040-1048.##[30]. Stojkov D, Amini P, Oberson K, Sokollik C, Duppenthaler A, Simon HU, et al. ROS and glutathionylation balance cytoskeletal dynamics in neutrophil extracellular trap formation. Journal of Cell Biology 2017; 216(12): 4073-90.##[31]. Kolaczkowska E, Jenne CN, Surewaard BG, Thanabalasuriar A, Lee WY, Sanz MJ, et al. Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature. Nature Communications 2015; 6(1): 1-13.##[32]. Chapman EA, Lyon M, Simpson D, Mason D, Beynon RJ, Moots RJ, et al. Caught in a trap? Proteomic analysis of neutrophil extracellular traps in rheumatoid arthritis and systemic lupus erythematosus. Frontiers in immunology 2019:423.##[33]. Yu Y, Su K. Neutrophil extracellular traps and systemic lupus erythematosus. J Clin Cell Immunol. 2013; 4(4): 139.##[34]. Kambas K, Chrysanthopoulou A, Vassilopoulos D, Apostolidou E, Skendros P, Girod A, et al. Tissue factor expression in neutrophil extracellular traps and neutrophil derived microparticles in antineutrophil cytoplasmic antibody associated vasculitis may promote thromboinflammation and the thrombophilic state associated with the disease. Annals of the Rheumatic Diseases 2014; 73(10): 1854-863.##[35]. Watanabe S, Iwata Y, Fukushima H, Saito K, Tanaka Y, Hasegawa Y, et al. Neutrophil extracellular traps are induced in a psoriasis model of interleukin-36 receptor antagonist-deficient mice. Scientific Reports 2020; 10(1): 1-11.##[36]. Cristinziano L, Modestino L, Loffredo S, Varricchi G, Braile M, Ferrara AL, et al. Anaplastic thyroid cancer cells induce the release of mitochondrial extracellular DNA traps by viable neutrophils. The Journal of Immunology 2020; 204(5): 1362-372.##[37]. Leffler J, Stojanovich L, Shoenfeld Y, Bogdanovic G, Hesselstrand R, Blom AM. Degradation of neutrophil extracellular traps is decreased in patients with antiphospholipid syndrome. Clin Exp Rheumatol 2014; 32(1): 66-70.##[38]. Watanabe-Kusunoki K, Abe N, Nakazawa D, Karino K, Hattanda F, Fujieda Y, et al. A case report dysregulated neutrophil extracellular traps in a patient with propylthiouracil-induced antineutrophil cytoplasmic antibody-associated vasculitis. Medicine 2019; 98(17): 15328.##[39]. Monsalve DM, Acosta-Ampudia Y, Ramírez-Santana C, Polo JF, Anaya JM. Neutrophil extracellular traps in autoimmune diseases. Revista Colombiana de Reumatología 2020; 27(10): 4-14.##[40]. Leffler J, Martin M, Gullstrand B, Tydén H, Lood C, Truedsson L, et al. Neutrophil extracellular traps that are not degraded in systemic lupus erythematosus activate complement exacerbating the disease. The Journal of Immunology 2012; 188(7): 3522-531.##[41]. Basta F, Fasola F, Triantafyllias K, Schwarting A. Systemic lupus erythematosus (SLE) therapy: the old and the new. Rheumatology and Therapy 2020; 7(3): 433-46.##[42]. Song L, Wang Y, Zhang J, Song N, Xu X, Lu Y. The risks of cancer development in systemic lupus erythematosus (SLE) patients: a systematic review and meta-analysis. Arthritis research & therapy 2018; 20(1):1-13.##[43]. Lande R, Ganguly D, Facchinetti V, Frasca L, Conrad C, Gregorio J, et al. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA–peptide complexes in systemic lupus erythematosus. Science Translational Medicine 2011; 3(73): 1-9.##[44]. Jeremic I, Djuric O, Nikolic M, Vlajnic M, Nikolic A, Radojkovic D, et al. Neutrophil extracellular traps-associated markers are elevated in patients with systemic lupus erythematosus. Rheumatology International 2019; 39(11): 1849-857.##[45]. Hakkim A, Fürnrohr BG, Amann K, Laube B, Abed UA, Brinkmann V, et al. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proceedings of the National Academy of Sciences 2010; 107(21): 9813-818.##[46]. Kraaij T, Kamerling SW, de Rooij EN, van Daele PL, Bredewold OW, Bakker JA, et al. The NET-effect of combining rituximab with belimumab in severe systemic lupus erythematosus. Journal of Autoimmunity 2018; 91: 45-54.##[47]. McInnes IB, Schett G. La patogenia de la artritis reumatoide. N Engl J Med 2011; 365(23): 2205-219.##[48]. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham III CO, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/ European League Against Rheumatism collaborative initiative. Arthritis & Rheumatism 2010; 62(9): 2569-5681.##[49]. Song W, Ye J, Pan N, Tan C, Herrmann M. Neutrophil extracellular traps tied to rheumatoid arthritis: points to ponder. Frontiers in Immunology 2021; 11: 578129.##[50]. Fan L, He D, Wang Q, Zong M, Zhang H, Yang L, et al. Citrullinated vimentin stimulates proliferation, proinflammatory cytokine secretion, and PADI4 and RANKL expression of fibroblast-like synoviocytes in rheumatoid arthritis. Scandinavian Journal of Rheumatology 2012; 41(5): 354-58.##[51]. Bartok B, Firestein GS. Fibroblast‐like synoviocytes: key effector cells in rheumatoid arthritis. Immunological Reviews 2010; 233(1): 233-55.##[52]. Corsiero E, Carlotti E, Jagemann L, Perretti M, Pitzalis C, Bombardieri M. H and L chain affinity maturation and/or Fab N-glycosylation influence immunoreactivity toward neutrophil extracellular trap antigens in rheumatoid arthritis synovial B cell clones. The Journal of Immunology 2020; 204(9): 2374-379.##[53]. Lundberg K, Nijenhuis S, Vossenaar ER, Palmblad K, van Venrooij WJ, Klareskog L, et al. Citrullinated proteins have increased immunogenicity and arthritogenicity and their presence in arthritic joints correlates with disease severity. Arthritis Research & Therapy 2005; 7(3): 1-10.##[54]. Khandpur R, Carmona-Rivera C, Vivekanandan-Giri A, Gizinski A, Yalavarthi S, Knight JS, et al. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Science Translational Medicine 2013; 5(178): 178.##[55]. Caturegli P, De Remigis A, Rose N. Hashimoto thyroiditis: clinical and diagnostic criteria. Autoimmunity reviews 2014; 13(4-5): 391-97.##[56]. Lorini R, Gastaldi R, Traggiai C, Perucchin PP. Hashimoto's thyroiditis. Pediatric endocrinology reviews: PER 2003; 12 (S 2): 205-11.##[57]. Pedersen IB, Knudsen N, Jørgensen T, Perrild H, Ovesen L, Laurberg P. Thyroid peroxidase and thyroglobulin autoantibodies in a large survey of populations with mild and moderate iodine deficiency. Clinical Endocrinology 2003; 58(1):36-42.##[58]. Xiao F, Jiang Y, Wang X, Jiang W, Wang L, Zhuang X, et al. NETosis may play a role in the pathogenesis of Hashimoto’s thyroiditis. International Journal of Clinical and Experimental Pathology 2018; 11(2): 537.##[59]. Tillack K, Naegele M, Haueis C, Schippling S, Wandinger KP, Martin R, et al. Gender differences in circulating levels of neutrophil extracellular traps in serum of multiple sclerosis patients. Journal of Neuroimmunology 2013; 261(1-2):108-19.##[60]. Mutukula N, Man Z, Takahashi Y, Martinez FI, Morales M, Carreon-Guarnizo E, et al. Generation of RRMS and PPMS specific iPSCs as a platform for modeling Multiple Sclerosis. Stem Cell Research 2021; 53: 102319.##[61]. Calabrese R, Zampieri M, Mechelli R, Annibali V, Guastafierro T, Ciccarone F, et al. Methylation-dependent PAD2 upregulation in multiple Sclerosis peripheral blood. Multiple Sclerosis Journal 2012; 18(3): 299-304.##[62]. Wang Y, Xiao Y, Zhong L, Ye D, Zhang J, Tu Y, et al. Increased neutrophil elastase and proteinase 3 and augmented NETosis are closely associated with β-cell autoimmunity in patients with type 1 diabetes. Diabetes 2014; 63(12): 4239-248.##[63]. Moscarello MA, Mastronardi FG, Wood DD. The role of citrullinated proteins suggests a novel mechanism in the pathogenesis of multiple Sclerosis. Neurochemical Research 2007; 32(2): 251-56.##[64]. O'Malley D, Dinan TG, Cryan JF. Altered expression and secretion of colonic interleukin-6 in a stress-sensitive animal model of brain-gut axis dysfunction. Journal of neuroimmunology 2011; 235(1-2):48-55.##[65]. Qin J, Fu S, Speake C, Greenbaum C, Odegard J. NETosis-associated serum biomarkers are reduced in type 1 diabetes in association with neutrophil count. Clinical & Experimental Immunology 2016; 184(3): 318-22.##[66]. Parackova Z, Zentsova I, Vrabcova P, Klocperk A, Sumnik Z, Pruhova S, et al. Neutrophil extracellular trap induced dendritic cell activation leads to Th1 polarization in type 1 diabetes. Frontiers in immunology 2020; 11(4):661.##[67]. Huang J, Xiao Y, Xu A, Zhou Z. Neutrophils in type 1 diabetes. J Diabetes Investig. 2016; 7(5): 652-63.##[68]. Wang S, Demers M, Wagner D. Diabetes primes neutrophils to undergo NETosis which severely impairs wound healing. Nat Med 2015; 21(7): 815-19.##[69]. Diana J, Simoni Y, Furio L, Beaudoin L, Agerberth B, Barrat F, et al. Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes. Nature Medicine 2013; 19(1): 65-73.##[70]. de Bont CM, Stokman ME, Faas P, Thurlings RM, Boelens WC, Wright HL, et al. Autoantibodies to neutrophil extracellular traps represent a potential serological biomarker in rheumatoid arthritis. Journal of Autoimmunity 2020; 113: 102484.##[71]. Fox S, Leitch AE, Duffin R, Haslett C, Rossi AG. Neutrophil apoptosis: relevance to the innate immune response and inflammatory disease. Journal of Innate Immunity 2010; 2(3): 216-27.##[72]. Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nature Reviews Endocrinology 2018; 14(2): 88-98.##[73]. Njeim R, Azar WS, Fares AH, Azar ST, Kassouf HK, Eid AA. NETosis contributes to the pathogenesis of diabetes and its complications. Journal of Molecular Endocrinology 2020; 65(4): 65-76.##[74]. Nijhuis J, Rensen SS, Slaats Y, Van Dielen FM, Buurman WA, Greve JWM. Neutrophil activation in morbid obesity, chronic activation of acute inflammation. Obesity 2009; 17(11): 2014-2018.##[75]. Wang Q, Xie Z, Zhang W, Zhou J, Wu Y, Zhang M, et al. Myeloperoxidase deletion prevents high-fat diet–induced obesity and insulin resistance. Diabetes 2014; 63(12): 4172-185.##[76]. Talukdar S, Oh DY, Bandyopadhyay G, Li D, Xu J, McNelis J, et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nature Medicine 2012; 18(9): 1407-412.##[77]. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nature Medicine 2018; 24(7): 908-22.##[78]. Luci C, Bourinet M, Leclère PS, Anty R, Gual P. Chronic inflammation in nonalcoholic steatohepatitis: molecular mechanisms and therapeutic strategies. Frontiers in Endocrinology Front Endocrinol. 2020; 11(12): 597648.##[79]. Antonucci L, Porcu C, Timperi E, Santini SJ, Iannucci G, Balsano C. Circulating neutrophils of nonalcoholic steatohepatitis patients show an activated phenotype and suppress T lymphocytes activity. J Immunol Res. 2020; 6: 4570219.##[80]. Hwang S, He Y, Xiang X, Seo W, Kim SJ, Ma J, et al. Interleukin‐22 ameliorates neutrophil‐driven nonalcoholic steatohepatitis through multiple targets. Hepatology 2020; 72(2): 412-29.##[81]. Du J, Zhang J, Chen X, Zhang S, Zhang C, Liu H, et al. Neutrophil extracellular traps induced by proinflammatory cytokines enhance procoagulant activity in NASH patients. Clinics and Research in Hepatology and Gastroenterology 2022; 46(1): 101697.##[82]. Randhawa PK, Singh K, Singh N, Jaggi AS. A review on chemical-induced inflammatory bowel disease models in rodents. The Korean journal of physiology & pharmacology 2014; 18(4):279-88.##[83]. Wallace KL, Zheng LB, Kanazawa Y, Shih DQ. Immunopathology of inflammatory bowel disease. World Journal of Gastroenterology 2014; 20(1): 6-15.##[84]. dos Santos Ramos A, Viana GCS, de Macedo Brigido M, Almeida JF. Neutrophil extracellular traps in inflammatory bowel diseases: Implications in pathogenesis and therapeutic targets. Pharmacological Research 2021; 171: 105779.##[85]. Stephens M, Liao S, Von der Weid PY. Mesenteric lymphatic alterations observed during DSS induced intestinal inflammation are driven in a TLR4-PAMP/DAMP discriminative manner. Front Immunol. 2019; 10(3): 557.##[86]. Li T, Wang C, Liu Y, Li B, Zhang W, Wang L, et al. Neutrophil extracellular traps induce intestinal damage and thrombotic tendency in inflammatory bowel disease. Journal of Crohn's and Colitis 2020; 14(2): 240-53.##[87]. Lin EYH, Lai HJ, Cheng YK, Leong KQ, Cheng LC, Chou YC, et al. Neutrophil extracellular traps impair intestinal barrier function during experimental colitis. Biomedicines 2020; 8(8): 275.##[88]. Levy ML. Is spirometry essential in diagnosing asthma? No. Br J Gen Pract. 2016; 66(650): 485-92.##[89]. Choy DF, Hart KM, Borthwick LA, Shikotra A, Nagarkar DR, Siddiqui S, et al. TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma. Science Translational Medicine 2015; 7(301): 129-33.##[90]. Douwes J, Gibson P, Pekkanen J, Pearce N. Non-eosinophilic asthma: importance and possible mechanisms. Thorax 2002; 57(7): 643-48.##[91]. Chen F, Yu M, Zhong Y, Wang L, Huang H. Characteristics and role of neutrophil extracellular traps in asthma. Inflammation 2021: 1-8.##[92]. Zhang S, Shen H, Shu X, Peng Q, Wang G. Abnormally increased low-density granulocytes in peripheral blood mononuclear cells are associated with interstitial lung disease in dermatomyositis. Modern Rheumatology 2017; 27(1): 122-29.##[93]. Peng Y, Zhang S, Zhao Y, Liu Y, Yan B. Neutrophil extracellular traps may contribute to interstitial lung disease associated with anti-MDA5 autoantibody positive dermatomyositis. Clinical Rheumatology 2018; 37(1): 107-15.##[94]. Duvvuri B, Pachman LM, Morgan G, Khojah AM, Klein‐Gitelman M, Curran ML, et al. Neutrophil extracellular traps in tissue and periphery in juvenile dermatomyositis. Arthritis & Rheumatology 2020; 72(2): 348-58.##[95]. Zhang S, Shu X, Tian X, Chen F, Lu X, Wang G. Enhanced formation and impaired degradation of neutrophil extracellular traps in dermatomyositis and polymyositis: a potential contributor to interstitial lung disease complications. Clinical & Experimental Immunology 2014; 177(1):134-41.##[96]. Wójcik P, Garley M, Wroński A, Jabłońska E, Skrzydlewska E. Cannabidiol modifies the formation of NETs in neutrophils of psoriatic patients. International Journal of Molecular Sciences 2020; 21(18): 6795.##[97]. Hu SCS, Yu HS, Yen FL, Lin CL, Chen GS, Lan CCE. Neutrophil extracellular trap formation is increased in Psoriasis and induces human β-defensin-2 production in epidermal keratinocytes. Scientific Reports 2016; 6(1): 1-14.##[98]. Lin AM, Rubin CJ, Khandpur R, Wang JY, Riblett M, Yalavarthi S, et al. Mast cells and neutrophils release IL-17 through extracellular trap formation in Psoriasis. The Journal of Immunology 2011; 187(1): 490-500.##[99]. Snoderly HT, Boone BA, Bennewitz MF. Neutrophil extracellular traps in breast cancer and beyond: current perspectives on NET stimuli, thrombosis and metastasis, and clinical utility for diagnosis and treatment. Breast Cancer Research 2019; 21(1): 1-13.##[100]. Miller-Ocuin JL, Liang X, Boone BA, Doerfler WR, Singhi AD, Tang D, et al. DNA released from neutrophil extracellular traps (NETs) activates pancreatic stellate cells and enhances pancreatic tumor growth. Oncoimmunology 2019; 8(9): 1605822.##[101]. Masucci MT, Minopoli M, Del Vecchio S, Carriero MV. The emerging role of neutrophil extracellular traps (NETs) in tumor progression and metastasis. Frontiers in Immunology 2020; 11(9): 1749.##[102]. Cools-Lartigue J, Spicer J, McDonald B, Gowing S, Chow S, Giannias B, et al. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. The Journal of Clinical Investigation 2013; 123(8): 3446-458.##[103]. Demers M, Wagner DD. Neutrophil extracellular traps: A new link to cancer-associated thrombosis and potential implications for tumor progression. Oncoimmunology 2013; 2(2): 22946.##[104]. Huang H, Zhang H, Onuma AE, Tsung A. Neutrophil elastase and neutrophil extracellular traps in the tumor microenvironment. Adv Exp Med Biol. 2020; 1263: 13-23.##[105]. Tsai CY, Hsieh SC, Liu CW, Lu CS, Wu CH, Liao HT, et al. Cross-talk among polymorphonuclear neutrophils, immune, and non-immune cells via released cytokines, granule proteins, microvesicles, and neutrophil extracellular trap formation: a novel concept of biology and pathobiology for neutrophils. International Journal of Molecular Sciences 2021; 22(6): 3119.##[106]. Alfaro C, Teijeira A, Oñate C, Pérez G, Sanmamed MF, Andueza MP, et al. Tumor-produced interleukin-8 attracts human myeloid-derived suppressor cells and elicits extrusion of neutrophil extracellular traps (NETs). Clinical Cancer Research 2016; 22(15): 3924-936.##[107]. de Andrea CE, Ochoa MC, Villalba‐Esparza M, Teijeira Á, Schalper KA, Abengozar‐Muela M, et al. Heterogenous presence of neutrophil extracellular traps in human solid tumours is partially dependent on IL‐8. The Journal of Pathology 2021; 255(2): 190-201.##[108]. Buckland RL, Wilson AS, Brüstle A. Quantification of neutrophil extracellular traps isolated from mouse tissues. Current Protocols in Mouse Biology 2020; 10(3): 78.##[109]. Rada B. Neutrophil extracellular traps. NADPH Oxidases: Springer; 2019, p. 517-28.##[110]. Gavillet M, Martinod K, Renella R, Harris C, Shapiro NI, Wagner DD, et al. Flow cytometric assay for direct quantification of neutrophil extracellular traps in blood samples. American Journal of Hematology 2015; 90(12): 1155-158.##[111]. Otawara M, Roushan M, Wang X, Ellett F, Yu YM, Irimia D. Microfluidic assay measures increased neutrophil extracellular traps circulating in blood after burn injuries. Scientific Reports 2018; 8(1): 1-9.##[112]. Berends ET, Horswill AR, Haste NM, Monestier M, Nizet V, von Köckritz-Blickwede M. Nuclease expression by Staphylococcus aureus facilitates escape from neutrophil extracellular traps. Journal of Innate Immunity 2010; 2(6): 576-86.##[113]. Skendros P, Mitsios A, Chrysanthopoulou A, Mastellos DC, Metallidis S, Rafailidis P, et al. Complement and tissue factor–enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis. The Journal of Clinical Investigation 2020; 130(11): 6151-157.##[114]. Remijsen Q, Kuijpers T, Wirawan E, Lippens S, Vandenabeele P, Vanden Berghe T. Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality. Cell Death & Differentiation 2011; 18(4): 581-88.##[115]. Saitoh T, Komano J, Saitoh Y, Misawa T, Takahama M, Kozaki T, et al. Neutrophil extracellular traps mediate a host defense response to human immunodeficiency virus-1. Cell Host & Microbe 2012; 12(1): 109-16.##[116]. Buhr Nd, Köckritz-Blickwede MV. Detection, visualization, and quantification of neutrophil extracellular traps (NETs) and NET markers. Neutrophil: Springer; 2020, p. 425-42.## ##

The Inhibitory Effects of Lactobacillus Agilis Against Pseudomonas Aeruginosa Biofilm Formation and Evaluation of PpyR (PA2663) and algD Gene Expression 2 2 Background and Aims: Hospital infections and their antibiotic resistance have become a global concern recently. One of the most prominent factors in hospital infections is Pseudomonas aeruginosa (P. aeruginosa), which can become resistant to many antibiotics due to its ability to form biofilms. Recently, scientists have tried to replace antibiotic therapy with alternative therapies such as probiotics which can reduce or eliminate the pathogenic bacteria's ability to form biofilms. Therefore, the present study revealed that some genes, such as algD and PpyR, were involved in biofilm formation in P. aeruginosa. Furthermore, the inhibitory effect of the supernatant of lactobacillus agilis on the biofilm formation of P. aeruginosa was evaluated in the current study. Materials and Methods: In this study, the effect of the supernatant of probiotic Lactobacillus agilis on the biofilm formation of P. aeruginosa and also the expression of two genes effective in biofilm formation (algD and PpyR) were investigated. Antibiograms were performed to detect the most resistant bacteria since there is a link between biofilm formation and antibiotic resistance. Further, the effects of probiotics on the expression of PpyR and algD genes were discussed. Results: Results showed that the biofilm formation of P. aeruginosa was significantly reduced in the presence of lactobacillus agilis. Conclusions: According to the current study, it could be concluded that because of antibiotics resistance and their associated mechanisms, probiotics could be used as a replacement for antibiotics in many treatments. 23 34 2021/11/282022/07/12022/07/27 1401/5/5 2023/03/12023/02/272022/10/31 1401/8/9 یاسمن عیسی زاده Yasaman Issazadeh Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran, Iran ایران yasamanissazadeh@gmail.com محدثه فرنقی زاد Mohadeseh Farnaghizad Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran, Iran ایران mohadesehfarnaghizad@gmail.com سروناز فلسفی Sarvenaz Falsafi Department of Molecular Biology, Pasteur Institute of Iran, Tehran, Iran ایران sarvenaz_falsafi@yahoo.com حورا مظاهری Hoora Mazaheri Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran, Iran ایران hooram22@yahoo.com شکوفه غازی Shokoofeh Ghazi Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran, Iran ایران shokoofeh_ghazi@gmail.com آوا بهروزی Ava Behrouzi Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran, Iran ایران ava.behrouzi@gmail.com algD Biofilm Gene expression PpyR Pseudomonas aeruginosa [1]. Kamali E, Jamali A, Ardebili A, Ezadi F, Mohebbi A. Evaluation of antimicrobial resistance, biofilm forming potential, and the presence of biofilm-related genes among clinical isolates of Pseudomonas aeruginosa. BMC Research Notes 2020; 13(1): 1-6.##[2]. Stewart PS, Costerton JW. Antibiotic resistance of bacteria in biofilms. Lancet 2001; 358(9276): 135-38.##[3]. Mah TF. Biofilm-specific antibiotic resistance. Future Microbiol. 2012; 7(9): 1061-1072.##[4]. Rocha AJ, Barsottini MRO, Rocha RR, Laurindo MV, Moraes FLL, Rocha SLD. Pseudomonas aeruginosa: virulence factors and antibiotic resistance genes. Brazilian Archiv Biol Technol. 2019; 62.##[5]. Ghazalibina M, Morshedi K, Farahani RK, Babadi M, Khaledi A. Study of virulence genes and related with biofilm formation in Pseudomonas aeruginosa isolated from clinical samples of Iranian patients; A systematic review. Gene Reports 2019; 17: 100471.##[6]. Ghotaslou R, Salahieshlaqghi B. Biofilm of pseudomonas aeruginosa and new preventive measures and anti-biofilm agents. Journal of Rafsanjan Univ Med Sci. 2013; 12(9): 747-68.##[7]. Vetrivel A, Ramasamy M, Vetrivel P, Natchimuthu S, Arunachalam S, Kim GS, et al. Pseudomonas aeruginosa biofilm formation and its control. Biologics 2021; 1(3): 312-36.##[8]. Karballaei Mirzahosseini H, Hadadi-Fishani M, Morshedi K, Khaledi A. Meta-Analysis of biofilm formation, antibiotic resistance pattern, and biofilm-related genes in Pseudomonas aeruginosa isolated from clinical samples. microbial drug resist. 2020; 26(7): 815-24.##[9]. Thi MTT, Wibowo D, Rehm BH. Pseudomonas aeruginosa biofilms. International J Mol Sci. 2020; 21(22): 8671.##[10]. Chellaiah ER, Ravi P, Uthandakalaipandian R. High fluoride resistance and virulence profile of environmental Pseudomonas isolated from water sources. Folia Microbiol. 2021; 66(4): 569-78.##[11]. Attila C, Ueda A, Wood TK. PA2663 (PpyR) increases biofilm formation in Pseudomonas aeruginosa PAO1 through the psl operon and stimulates virulence and quorum-sensing phenotypes. Appl Microbiol Biotechnol. 2008; 78(2): 293-307.##[12]. Jones CJ, Grotewold N, Wozniak DJ, Gloag ES. Pseudomonas aeruginosa initiates a rapid and specific transcriptional response during surface attachment. J Bacteriol. 2022; 204(5): 86-22.##[13]. Ghadaksaz A, Fooladi AAI, Hosseini HM, Amin M. The prevalence of some Pseudomonas virulence genes related to biofilm formation and alginate production among clinical isolates. J Appl Biomed. 2015; 13(1): 61-8.##[14]. Safari Zanjani L, Shapoury R, Dezfulian M, Mahdavi M, Shafieeardestani M. Preparation of PLGA (poly lactic-co-glycolic acid) nanoparticles containing Pseudomonas aeruginosa alginate, LPS and exotoxin A as a nano-vaccine. Biologic J Microorgan. 2018; 7(26): 11-27.##[15]. Rossoni RD, de Barros PP, de Alvarenga JA, Ribeiro FdC, Velloso MdS, Fuchs BB, et al. Antifungal activity of clinical Lactobacillus strains against Candida albicans biofilms: identification of potential probiotic candidates to prevent oral candidiasis. Biofouling 2018; 34(2): 212-25.##[16]. Dogonchi AA, Ghaemi EA, Ardebili A, Yazdansetad S, Pournajaf A. Metallo-β-lactamase-mediated resistance among clinical carbapenem-resistant Pseudomonas aeruginosa isolates in northern Iran: A potential threat to clinical therapeutics. Tzu-Chi Medical Journal. 2018; 30(2): 90.##[17]. Stepanović S, Vuković D, Hola V, Bonaventura GD, Djukić S, Ćirković I, et al. Quantification of biofilm in microtiter plates: overview of testing conditions and practical recommendations for assessment of biofilm production by staphylococci. APMIS 2007; 115(8): 891-99.##[18]. Lebeer S, Vanderleyden J, De Keersmaecker SC. Genes and molecules of lactobacilli supporting probiotic action. Microbiol Mol Biol Rev. 2008; 72(4): 728-64.##[19]. Shi S, Cheng B, Gu B, Sheng T, Tu J, Shao Y, et al. Evaluation of the probiotic and functional potential of Lactobacillus agilis 32 isolated from pig manure. Lett Appl Microbiol. 2021; 73(1): 9-19.##[20]. Al-Mathkhury HJF, Ali AS, Ghafil JA. Antagonistic effect of bacteriocin against urinary catheter associated Pseudomonas aeruginosa biofilm. North Am J Med Sci. 2011; 3(8): 367.##[21]. Singhi SC, Kumar S. Probiotics in critically ill children. F1000Res. 2016; 5(29): 5.##[22]. Dallal MS, Davoodabadi A, Abdi M, Hajiabdolbaghi M, Yazdi MS, Douraghi M, et al. Inhibitory effect of Lactobacillus plantarum and Lb. fermentum isolated from the faeces of healthy infants against nonfermentative bacteria causing nosocomial infections. New Microbes And New Infections 2017; 15(1): 9-18.##[23]. Jeong JJ, Park HJ, Cha MG, Park E, Won SM, Ganesan R, et al. The lactobacillus as a probiotic: Focusing on liver diseases. Microorganisms 2022; 10(2): 288.##[24]. Ramos AN, Sesto Cabral ME, Noseda D, Bosch A, Yantorno OM, Valdez JC. Antipathogenic properties of L actobacillus plantarum on P seudomonas aeruginosa: the potential use of its supernatants in the treatment of infected chronic wounds. Wound Repair Regenerat. 2012; 20(4): 552-62.##[25]. Varma P, Nisha N, Dinesh KR, Kumar AV, Biswas R. Anti-infective properties of Lactobacillus fermentum against Staphylococcus aureus and Pseudomonas aeruginosa. J Mol Microbiol Biotechnol. 2011; 20(3): 137-43.##[26]. Jeyanathan A, Ramalhete R, Blunn G, Gibbs H, Pumilia CA, Meckmongkol T, et al. Lactobacillus cell‐free supernatant as a novel bioagent and biosurfactant against Pseudomonas aeruginosa in the prevention and treatment of orthopedic implant infection. Journal of Biomedical Materials Research Part B: Appl Biomat. 2021; 109(10): 1634-343.##[27]. Ahmed A, Dachang W, Lei Z, Jianjun L, Juanjuan Q, Yi X. Effect of lactobacillus species on Streptococcus mutans biofilm formation. Pak J Pharm Sci. 2014; 27(S 5): 1523-528.##[28]. Fusco A, Savio V, Stelitano D, Baroni A, Donnarumma G. The intestinal biofilm of pseudomonas aeruginosa and staphylococcus aureus is inhibited by antimicrobial peptides HBD-2 and HBD-3. Appl Sci. 2021; 11(14): 6595.##[29]. Béatrice J, Maud P, Stéphane A, François C, Frédéric G, Benoit G, et al. Relative expression of Pseudomonas aeruginosa virulence genes analyzed by a real time RT-PCR method during lung infection in rats. FEMS Microbiol lett. 2005; 243(1): 271-78.##[30]. Jaffe RI, Lane JD, Bates CW. Real‐time identification of Pseudomonas aeruginosa direct from clinical samples using a rapid extraction method and polymerase chain reaction (PCR). J Clin Lab Analysis 2001; 15(3): 131-37.## ##

MiR-1 Variations in Colorectal Cancer: Possible Implementation as a Potential Accessory Biomarker ارزیابی miR-1 به عنوان یک بیومارکر بالقوه در سرطان کولورکتال 2 1 مقدمه: سرطان کولورکتال (CRC) یکی از شایع ترین سرطان ها در انسان است که هنوز پاتوژنز آن مبهم است. MiRNA ها از نظر فیزیولوژیکی فرآیندهای متابولیک مختلف را تنظیم می کنند و نشان داده شده است که در طیف وسیعی از سرطان ها تیغیر پیدا می کنند. تحقیق حاضر برای ارزیابی miR-1 به عنوان نشانگر زیستی برای CRC انجام شد. مواد و روش‌ها: نمونه‌های CRC و بافت مجاور از 24 بیمار گرفته شد. علاوه بر این، سرم از گروه بیمار و 24 گروه کنترل سالم همسان با سن و جنس جمع آوری شد. RNA کل از نمونه های بافت استخراج و cDNA سنتز شد. بیان miR-1 با Real-time PCR تعیین شد. سطوح سرمی آنتی ژن کارسینومبریونیک (CEA) با استفاده از کیت تجاری اندازه گیری شد. نتایج: سطح miR-1 در تومورهای CRC به طور قابل توجهی کاهش یافت. MiR-1 تفاوت معنی داری را در اندازه های مختلف تومور نشان داد. علاوه بر این، کاهش بیان miR-1 در بیماران مبتلا به متاستاز بیشتر از بیماران بدون متاستاز بود. اما این تفاوت از نظر آماری معنی دار نبود. نتیجه‌گیری: این مطالعه نشان داد که سطح miR-1 در بیماران مبتلا به سرطان کولورکتال کاهش می‌یابد که پتانسیل آن را دارد که به عنوان یک نشانگر زیستی برای این سرطان در نظر گرفته شود. به موازاتCEA سنجش miR-1 ممکن است داده های بیشتری را در مدیریت و پیگیری بیماران ارائه دهد، هرچند، چنین کاربرد بالینی نیاز به مطالعات بیشتری دارد. 2 Background and Aims: Colorectal cancer (CRC) is one of the most common human cancers. Currently, carcinoembryonic antigen (CEA) is used as the main standard biomarker of CRC, though this biomarker is not specifically made for CRC and, in a minority of cases, shows inadequate sensitivity. Therefore, searching for novel accessory biomarkers may fill these gaps in clinical management. miRNAs physiologically regulate various metabolic processes and are misregulated in various cancers. Therefore, the present investigation was conducted to evaluate miR-1 levels in CRC samples. Materials and Methods: The CRC and adjacent tissue samples were obtained from 24 patients. In addition, sera were collected from the patient group and 24 healthy controls. Total RNA was extracted from tissue samples, and cDNA was synthesized. Real-time PCR determined the expression of miR-1. Serum levels of CEA were also measured using a Monobind ELISA assay kit. Results: The level of miR-1 in CRC tumors was significantly down-regulated. Moreover, patients with metastasis showed lower expression of miR-1 compared to cases without metastasis; however, this difference was not statistically significant. The ROC curve for miR-1 showed an AUC of 0.69. In addition, ROC analysis revealed a sensitivity of 70.27% and a specificity of 62.96% for miR-1. Conclusion: There is still a need for new upcoming markers in addition to the main CRC biomarker, CEA. The levels of miR-1 in colorectal cancer tissue samples may provide additional information for the management and follow-up of CRC patients; though, the clinical application needs further studies. 35 45 2021/11/282022/07/12022/07/272022/05/16 1401/2/26 2023/03/12023/02/272022/10/312023/03/4 1401/12/13 الهه پیرزاده Elahe Pirzadeh Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran ایران pirzadehe971@mums.ac.ir سیدحمید آقایی بختیاری 2- Seyed Hamid Aghaee-Bakhtiari Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran ایران aghaeibh@mums.ac.ir ندا یعقوبی Neda Yaghoubi Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran ایران yaghoubin1@mums.ac.ir علی محمودی Ali Mahmoudi Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran ایران mahmoudia971@mums.ac.ir لیدا جراحی Lida Jarahi Department of Community Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran ایران JarahiL@mums.ac.ir عباس عبداللهی Abbas Abdollahi Department of Surgury, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran ایران AbdollahiA@mums.ac.ir سداسحاق هاشمی Seyed Isaac Hashemy Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran ایران hashemyi@mums.ac.ir سیدمهدی حسنیان Seyed Mahdi Hassanian Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran ایران HasanianMehrM@mums.ac.ir فرناز زاهدی اول Farnaz Zahedi Avval Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran ایران zahediaf@mums.ac.ir Carcinoembryonic antigen Colorectal cancer miR-1 Tumor biomarker نشانگر زیستی آنتی ژن کارسینوامبریونیک کانسر کولورکتال mir-1 [1]. Sung H, Ferlay J, Siegel RL. Global cancer statistics 2020: GLOBOCAN Estimates of incidence and mortality worldwide for 36 cancers in 185 countries. cancer journal for clinicians 2021; 71(3): 209-49.##[2]. Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global patterns and trends in colorectal cancer incidence and mortality. Gut. 2017; 66(4): 683-91.##[3]. Carr PR, Weigl K, Edelmann D, Jansen L, Chang-Claude J, Brenner H, et al. Estimation of absolute risk of colorectal cancer based on healthy lifestyle, genetic risk, and colonoscopy status in a population-based study. BMC Med. 2020; 159(1): 129-38.##[4]. Kim SB, Kim KO. Prevalence and risk factors of gastric and colorectal cancer after cholecystectomy. Gastroenterol. 2020; 35(42): 354.##[5]. Sawicki T, Ruszkowska M, Danielewicz A, Niedźwiedzka E, Arłukowicz T, Przybyłowicz KE. A review of colorectal cancer in terms of epidemiology, risk factors, development, symptoms and diagnosis. Cancers (Basel). 2021; 13(9): 2025.##[6]. Xu W, He Y, Wang Y, Li X, Young J, Ioannidis JPA, et al. Risk factors and risk prediction models for colorectal cancer metastasis and recurrence: An umbrella review of systematic reviews and meta-analyses of observational studies. BMC Medicine 2020, 18(1): 1-19. ##[7]. Ni Y, Xie G, Jia W. Metabonomics of human colorectal cancer: new approaches for early diagnosis and biomarker discovery. J Proteome Res. 2014; 13(9): 3857-870.##[8]. Zhao L, Pang Y, Luo Z, Fu K, Yang T, Zhao L, et al. Role of [(68)Ga]Ga-DOTA-FAPI-04 PET/CT in the evaluation of peritoneal carcinomatosis and comparison with [(18)F]-FDG PET/CT. European Journal of Nuclear Medicine and Molecular Imaging 2021; 48(6): 1944-955.##[9]. Van 't Sant I, van Eden WJ, Engbersen MP, Kok NFM, Woensdregt K, Lambregts DMJ, et al. Diffusion-weighted MRI assessment of the peritoneal cancer index before cytoreductive surgery. Br J Surg. 2019; 106(4): 491-98.##[10]. Dienstmann R, Salazar R, Tabernero J. Personalizing colon cancer adjuvant therapy: selecting optimal treatments for individual patients. J Clin Oncol. 2015; 33(16): 1787-796.##[11]. Stiksma J, Grootendorst DC, van der Linden PW. CA 19-9 as a marker in addition to CEA to monitor colorectal cancer. Clin Colorectal Cancer 2014; 13(4): 239-44.##[12]. Cai D, Huang ZH, Yu HC, Wang XL, Bai LL, Tang GN, et al. Prognostic value of preoperative carcinoembryonic antigen/tumor size in rectal cancer. World J Gastroenterol. 2019; 25(33): 4945-958.##[13]. Tong G, Xu W, Zhang G, Liu J, Zheng Z, Chen Y, et al. The role of tissue and serum carcinoembryonic antigen in stages I to III of colorectal cancer-A retrospective cohort study. Cancer Med. 2018; 7(11): 5327-338.##[14]. Duffy MJ, Lamerz R, Haglund C, Nicolini A, Kalousová M, Holubec L, et al. Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update. Int J Cancer 2014; 134(11): 2513-522.##[15]. Locker GY, Hamilton S, Harris J, Jessup JM, Kemeny N, Macdonald JS, et al. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol. 2006; 24(33): 5313-327.##[16]. Lee RC, Feinbaum RL, Ambros V. The C. Elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993; 75(5): 843-54.##[17]. Ali Syeda Z, Langden SSS, Munkhzul C, Lee M, Song SJ. Regulatory mechanism of MicroRNA expression in cancer. Int J Mol Sci. 2020; 21(5).##[18]. Farazi TA, Hoell JI, Morozov P, Tuschl T. MicroRNAs in human cancer. MicroRNA cancer Regulation 2013: 1-20.##[19]. Hussen BM, Hidayat HJ, Salihi A, Sabir DK, Taheri M, Ghafouri-Fard S. MicroRNA: A signature for cancer progression. Biomedicine & Pharmacotherapy 2021; 138: 111528.##[20]. Peng Y, Croce CM. The role of MicroRNAs in human cancer. Signal Transduc Target Therapy 2016; 1(1): 1-9.##[21]. Han C, Shen JK, Hornicek FJ, Kan Q, Duan Z. Regulation of microRNA-1 (miR-1) expression in human cancer. Biochim Biophys Acta Gene Regul Mech. 2017; 1860(2): 227-32.##[22]. Rao PK, Missiaglia E, Shields L, Hyde G, Yuan B, Shepherd CJ, et al. Distinct roles for miR‐1 and miR‐133a in the proliferation and differentiation of rhabdomyosarcoma cells. The FASEB J. 2010; 24(9): 3427-37.##[23]. Liu PJ, Chen YH, Tsai KW, Yeah HY, Yeh CY, Tu YT, et al. Involvement of MicroRNA-1-FAM83A axis dysfunction in the growth and motility of lung cancer cells. Int J Mol Sci. 2020; 21(22): 8833.##[24]. Zhu F, Li J, Wang L. MicroRNA-1-3p inhibits the growth and metastasis of ovarian cancer cells by targeting DYNLT3. Eur Rev Med Pharmacol Sci. 2020; 24(17): 8713-721.##[25]. Li Y, Ma H, Shi C, Feng F, Yang L. Mutant ACTB mRNA 3′-UTR promotes hepatocellular carcinoma development by regulating miR-1 and miR-29a. Cel Signal. 2020; 67: 109479.##[26]. Chen Y, Liu M, Jin H, Peng B, Dai L, Wang S, et al. Synthetic evaluation of MicroRNA-1-3p expression in head and neck squamous cell carcinoma based on microarray chips and MicroRNA sequencing. BioMed Research International 2021; 8(24): 6529255.##[27]. Chen WS, Leung CM, Pan HW, Hu LY, Li SC, Ho MR, et al. Silencing of miR-1-1 and miR-133a-2 cluster expression by DNA hypermethylation in colorectal cancer. Oncol Rep. 2012; 28(3): 1069-1076.##[28]. Wu X, Li S, Xu X, Wu S, Chen R, Jiang Q, et al. The potential value of miR-1 and miR-374b as biomarkers for colorectal cancer. Int J Clin Exp Pathol. 2015; 8(3): 2840-851.##[29]. Wu Y, Pu N, Su W, Yang X, Xing C. Downregulation of miR-1 in colorectal cancer promotes radioresistance and aggressive phenotypes. Journal of Cancer 2020; 11(16): 4832.##[30]. Xu W, Zhang Z, Zou K, Cheng Y, Yang M, Chen H, et al. MiR-1 suppresses tumor cell proliferation in colorectal cancer by inhibition of Smad3-mediated tumor glycolysis. Cell Death Dis. 2017; 8(5): 2761.##[31]. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 2001; 25(4): 402-408.##[32]. Furukawa S, Kawasaki Y, Miyamoto M, Hiyoshi M, Kitayama J, Akiyama T. The miR-1-NOTCH3-Asef pathway is important for colorectal tumor cell migration. PLoS One 2013; 8(11): 80609.##[33]. Slattery ML, Herrick JS, Pellatt DF, Mullany LE, Stevens JR, Wolff E, et al. Site-specific associations between miRNA expression and survival in colorectal cancer cases. Oncotarget 2016; 7(37): 60193-60205.##[34]. Röhr C, Kerick M, Fischer A, Kühn A, Kashofer K, Timmermann B, et al. High-throughput miRNA and mRNA sequencing of paired colorectal normal, tumor and metastasis tissues and bioinformatic modeling of miRNA-1 therapeutic applications. PLoS One 2013; 8(7): 67461.##[35]. Sarver AL, French AJ, Borralho PM, Thayanithy V, Oberg AL, Silverstein KAT, et al. Human colon cancer profiles show differential microRNA expression depending on mismatch repair status and are characteristic of undifferentiated proliferative states. BMC Cancer 2009; 9(3): 401-409.##[36]. Du G, Yu X, Chen Y, Cai W. MiR-1-3p suppresses colorectal cancer cell proliferation and metastasis by inhibiting YWHAZ-mediated epithelial-mesenchymal transition. Front Oncol. 2021; 11: 264.##[37]. Pidíkova P, Reis R, Herichova I. miRNA clusters with down-regulated expression in human colorectal cancer and their regulation. 2020; 21(13): 4633.##[38]. Xu X, Wu X, Jiang Q, Sun Y, Liu H, Chen R, et al. Downregulation of microRNA-1 and microRNA-145 contributes synergistically to the development of colon cancer. Int J Mol Med. 2015; 36(6): 1630-638.##[39]. Migliore C, Martin V, Leoni VP, Restivo A, Atzori L, Petrelli A, et al. MiR-1 downregulation cooperates with MACC1 in promoting MET overexpression in human colon cancer. Clin Cancer Res. 2012; 18(3): 737-47.##[40]. Xu L, Zhang Y, Wang H, Zhang G, Ding Y, Zhao L. Tumor suppressor miR-1 restrains epithelial-mesenchymal transition and metastasis of colorectal carcinoma via the MAPK and PI3K/AKT pathway. Int J Mol Sci. 2014; 12(2): 244.##[41]. Si W, Shen J, Zheng H, Fan W. The role and mechanisms of action of microRNAs in cancer drug resistance. Clinical Epigenetics 2019; 11(1): 1-24.##[42]. Xu B, Shen X, Yang Z, Zhao T, Liu B, Gao S, et al. Plasma miR-1, but not extracellular vesicle miR-1, functions as a potential biomarker for colorectal cancer diagnosis. Clin Lab. 2021; 67(1).##[43]. Tétreault N, De Guire V. miRNAs: their discovery, biogenesis and mechanism of action. Clin Biochem. 2013; 46(10-11): 842-45.##[44]. Li X, Chen R, Li Z, Luo B, Geng W, Wu X. Diagnostic value of combining miRNAs, CEA measurement and the FOBT in colorectal cancer screening. Cancer Manag Res. 2020; 12(1): 2549.## ##

Evaluation of DNA Damage and Repair In In Vitro Expanded Cord Blood CD 34 Positive Hematopoietic Stem Cell بررسی شکست کروموزومی واصلاح آن در سلولهای تکثیر یافته CD34 مثبت هماتو پوئیتک استم سل 2 1 هدف : یکی از منابع استم سل جهت پیوند، سلول های بندناف می­باشد،شیوع شکست کروموزومی یک رشته یا دو رشته یکی از موانع مهم در ثکثیر سلول های بندناف می باشد. شکست کروموزومی می تواند نتایج ناخواسته از جمله موتاسیون، مرگ سلولی را به دنبال داشته باشد. مطالعه کنونی به منظور بررسی صدمات به DNA و ژنهای مشارکت کننده در ترمیم DNA پس از کشت سلولی انجام شده شده است. روش ها و متدها : خون بندناف با روش MACS جدا شده با روش فلوسیتومتری مرگ سلولی بررسی شد. برای برسی شکست کروموزومی از روش comet assay استفاده شد نتایج: تعداد سلولها بعد از کشت به مدت سه روز 9/1 برابر شد. تعداد سلولهای مرده کم و قابل اغماض (2/0%) می باشد. با بررسی ژنهای دخیل در ترمیم DNA مثل  KU70 ، KU80،RAD51 و XRCC1 مشخص شدافزایش قابل توجه­ای نداشته است. نتیجه­گیری: شکست کروموزومی قابل توجه و صدمه به DNA ملاحظه نشد.   2 Background and Aims: The occurrence of single and double-strand breaks of DNA damage is the major obstacle for proliferation under various environmental factors and, if not repaired, can result in many consequences, including mutation, cell death, and others. So, the present study was conducted to evaluate the damage of DNA and the expression status of DNA repair system genes before and after stem cell proliferation. Materials and Methods: The MACS method isolated the umbilical cord blood hematopoietic stem cells (UCB-HSCs). In order to investigate cell death, the study of Annexin V/PI was done by flow cytometry. Comet assay made observation and identification of DNA breaks, and the expression of genes normally involved in the repair of DNA breaks was evaluated by real-time polymerase chain reaction. Results: The average number of stem cells increased by 1.9-fold after three days of proliferation. The apoptotic percentage of cells was negligible (less than 0.2%), and the purity of the CD34+ cells was reduced by about one-third in three days (67%). By examining the expression of DNA repair genes, including KU70, KU80, RAD51, and XRCC1, their increased fold change was not significant. In a microscopic examination of stem cells in the comet assay, there was no significant difference between DNA damage before (1.33% ± 0.31) and after (2.08% ± 0.92) replication. Conclusion: In our investigation, neither DNA damage nor changes in the DNA break repair were observed. However, further studies are required to clarify the DNA break repair by recruiting more UCB-HSCs samples. 46 56 2021/11/282022/07/12022/07/272022/05/162022/12/5 1401/9/14 2023/03/12023/02/272022/10/312023/03/42023/02/4 1401/11/15 محمد شکوهیان Mohammad Shokouhian Department of Hematology and Blood Transfusion, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran ایران mohammad.shekuhian@yahoo.com حسین مزدارانی Hossein Mozdarani Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran ایران mozdarah@modares.ac.ir مسعود سلیمانی Masoud Soleimani Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran ایران soleim_m@modares.ac.ir مجید صفا Majid Safa Department of Hematology and Blood Transfusion, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran ایران majidsafa@gmail.com محمد رضا رضوانی Mohammad Reza Rezvany Department of Hematology and Blood Transfusion, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran. Pediatric Growth and Development Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran. Department of Oncology-Pathology, BioClinicum, Karolinska University Hospital Solna and Karolinska Institute, Stockholm 17176, Sweden ایران mohrezrez@yahoo.com Cord blood stem cells DNA damage Comet assay Ku80 KU70 Comet assay تست ژن Ku80 ژن KU70 [1]. Chow T, Mueller S, Rogers IM. Advances in umbilical cord blood therapy: hematopoietic stem cell transplantation and beyond. Advances in Stem Cell Therapy; 2017, Springer, pp. 139-68. ##[2]. Wagner JE, Brunstein CG, Boitano AE, DeFor TE, McKenna D, Sumstad D, et al., Phase I/II trial of StemRegenin-1 expanded umbilical cord blood hematopoietic stem cells supports testing as a stand-alone graft. Cell Stem Cell 2016; 18(1): 144-155.##[3]. Kode J, Khattry N, Bakshi A, Amrutkar V, Bagal B, Karandikar R, , et al. Study of stem cell homing & self-renewal marker gene profile of ex vivo expanded human CD34+ cells manipulated with a mixture of cytokines & stromal cell-derived factor 1. The Indian Journal of Medical Research 2017;146(1): 56.##[4]. Bonab MM, Alimoghaddam K, Talebian F, Ghaffari SH, Ghavamzadeh A, Nikbin B. Aging of mesenchymal stem cell in vitro. BMC Cell Biology 2006; 7(1): 1-7##[5]. Rübe CE, Fricke A, Widmann TA, Fürst T, Madry H, Pfreundschuh M, et al. Accumulation of DNA damage in hematopoietic stem and progenitor cells during human aging. PloS one 2011; 6(3): 17487.##[6]. Nagaria P, Robert C, Rassool FV. DNA double‐strand break response in stem cells: mechanisms to maintain genomic integrity. Biochimica et Biophysica Acta (BBA)-General Subjects. 2013; 1830(2): 2345-353.##[7]. Polo LM, Xu Y, Hornyak P, Garces F, Zeng Z, Hailstone R, et al. Efficient single-strand break repair requires binding to both poly (ADP-ribose) and DNA by the central BRCT domain of XRCC1. Cell Reports 2019; 26(3): 573-81.##[8]. Lim JW, Kim H, Kim KH. Expression of ##Ku70 and Ku80 mediated by NF-κB and cyclooxygenase-2 is related to proliferation of human gastric cancer cells. J Biol Chem. 2002; 277(48): 46093-6100.##[9]. Xu Z, Zhang J, Xu M, Ji W, Yu M, Tao Y, , et al. Rice RAD 51 paralogs play essential roles in somatic homologous recombination for DNA repair. The Plant Journal. 2018; 95(2): 282-95.##[10]. Gong C, Yang Z, Zhang L, Wang Y, Gong W, Liu Y. Quercetin suppresses DNA double-strand break repair and enhances the radiosensitivity of human ovarian cancer cells via p53-dependent endoplasmic reticulum stress pathway. OncoTargets and Therapy 2017; 17(12): 17-27.##[11]. Yahata T, Takanashi T, Muguruma Y, Ibrahim AA, Matsuzawa H, Uno T, et al. Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells. Blood 2011; 118(11): 2941-950.##[12]. Biechonski S, Yassin M, Milyavsky M. DNA-damage response in hematopoietic stem cells: an evolutionary trade-off between blood regeneration and leukemia suppression. Carcinogenesis 2017; 38(4): 367-77.##[13]. Slack J, Albert MH, Balashov D, Belohradsky BH, Bertaina A, Bleesing J, Booth C, et al. Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders. Journal of Allergy and Clinical Immunology 2018; 141(1): 322-28.##[14]. Mohrin M, Bourke E, Alexander D, Warr MR, Barry-Holson K, Le Beau MM, et al. Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis. Cell Stem Cell 2010; 7(2): 174-85.##[15]. Casamayor-Genescà A, Pla A, Oliver-Vila I, Pujals-Fonts N, Marín-Gallén S, Caminal M, et al. Clinical-scale expansion of CD34+ cord blood cells amplifies committed progenitors and rapid scid repopulation cells. N Biotechnol. 2017; 35: 19-29.##[16]. Mortazavi SM, Shabestani-Monfared A, Ghiassi-Nejad M, Mozdarani H. Radioadaptive responses induced in lymphocytes of the inhabitants in Ramsar, Iran. InInternational Congress Series; 2005, Elsevier, pp. 201-203.##[17]. Dircio-Maldonado R, Flores-Guzman P, Corral-Navarro J, Mondragón-García I, Hidalgo-Miranda A, Beltran-Anaya FO, et al. Functional integrity and gene expression profiles of human cord blood-derived hematopoietic stem and progenitor cells generated in vitro. Stem Cells Translational Medicine 2018; 7(8): 602-614.##[18]. Jung JJ, Buisman SC, de Haan G. Do hematopoietic stem cells get old? Leukemia 2017; 31(3): 529-31.##[19]. Niedernhofer LJ. DNA repair is crucial for maintaining hematopoietic stem cell function. DNA Repair 2008; 7(3): 523-29.##[20]. Amirizadeh N, Oodi A, Mehrasa R, Nikougoftar M. Apoptosis, dap-kinase1 expression and the influences of cytokine milieu and mesenchymal stromal cells on ex vivo expansion of umbilical cord blood-derived hematopoietic stem cells. Indian Journal of Hematology and Blood Transfusion 2016; 32(1): 67-77.##[21]. Durdik M, Kosik P, Kruzliakova J, Jakl L, Markova E, Belyaev I. Hematopoietic stem/ progenitor cells are less prone to undergo apoptosis than lymphocytes despite similar DNA damage response. Oncotarget 2017; 8(30): 48846.##[22]. Philpott NJ, Turner AJ, Scopes J, Westby M, Marsh JC, Gordon-Smith EC, et al. The use of 7-amino actinomycin D in identifying apoptosis: simplicity of use and broad spectrum of application compared with other techniques. Blood 1996; 87(6): 2244-251.##[23]. Yoon JH, Choudhury JR, Park J, Prakash S, Prakash L. A role for DNA polymerase θ in promoting replication through oxidative DNA lesion, thymine glycol, in human cells. Journal of Biological Chemistry 2014; 289(19): 13177-3185.##[24]. Wang CX, Mao P, Zhang YP, Duan HX, QH D. [DNA damage during umbilical cord blood expansion ex vivo]. Zhongguo shi yan xue ye xue za zhi 2010; 18(2): 450-53.##[25]. Hermeto LC, Oliveira RJ, Matuo R, Jardim PH, DeRossi R, Antoniolli AC, et al. Evaluation of pH effects on genomic integrity in adipose-derived mesenchymal stem cells using the comet assay. Genet Mol Res. 2015; 14(1): 339-48.##[26]. Fuchs R, Stelzer I, Drees CM, Rehnolt C, Schraml E, Sadjak A, et al. Modification of the alkaline comet assay with human mesenchymal stem cells. Cell Biology International 2012; 36(1): 113-17.## ##

Hematological and Biochemical Parameters of β-Thalassemia Major Patients in Bushehr City: A Comparative Analysis ارزیابی پارامترهای هماتولوژی و بیوشیمیایی در بیماران تالاسمی ماژور شهر بوشهر 2 1 زمینه و هدف  بتا تالاسمی گروهی از اختلات هموگلوبینی است که فرم هموزیگوت آن به عنوان تالاسمی ماژور بتا شناخته می‌شود. هدف از این مطالعه ارزیابی پارامترهای هماتولوژی و بیوشیمیایی در بیماران تالاسمی ماژور شهر بوشهر می‌باشد. مواد و روش ها در این مطالعه 94 بیمار تالاسمی ماژور بتا با 94 فرد سالم (کنترل) مقایسه شد. ارزیابی‌های هماتولوژی شاملHb ، Hct، MCV، MCH  و MCHC بودند. پارامترهای بیوشیمیایی شامل تست‌های عملکرد کلیه، کبد، تیروئید، پروفایل لیپیدی، آلبومین(Alb)، سدیم(Na) ، پتاسیم(K)، کلسیم(Ca)، فسفر(Ph)، قند خون ناشتا(FBS) و فریتین سرم بود.   نتایج در بیماران تمام پارامترهای هماتولوژی Hb،Hct ، MCH و MCV در مقایسه با گروه کنترل کاهش معنی‌داری داشتند (P<0.05) به جز MCHC که تفاوت ناچیزی با گروه کنترل داشت (P>0.05). سطح سرمی TG، Ph، FBS، AST، ALT، ALP،  UAو  Biliدربیماران  مقایسه با گروه کنترل بالاتر بود و  سطح سرمی کلسترول (Chol)، لیپوپروتئین با چگالی بالا (HDL) و لیپوپروتئین با تراکم پایین (LDL) در بیماران در مقایسه با گروه کنترل پایین‌تر بود(P<0.05). بین سطح سرمی  Na،K ، Ca و Alb در بیماران در مقایسه با گروه کنترل تفاوت معناداری مشاهده نشد. شیوع هایپوتیروئیدیسم اولیه 5.31% گزارش شد. نتیجه گیری  این مطالعه تاکید می‌کند که پیگیری و ارزیابی منظم  بیماران تالاسمی ماژور می‌تواند پروتکل های درمانی را بهبود ببخشد.   2 Background and Aims: β-thalassemia is the most common genetic disorder worldwide. β-thalassemia major results in severe anemia and serious complications. So, this study aims to evaluate the hematological and biochemical markers in β-thalassemia major patients in Bushehr city. Materials and Methods: Our study included 94 transfusion-dependent β-thalassemia major were compared with 94 normal healthy subjects as controls. Hematological assessments included complete blood count indices. The biochemical evaluations included liver, kidney, and thyroid function tests, lipid profile, sodium, potassium, calcium, phosphorus, fasting blood sugar, and serum ferritin. Results: All hematological parameters in patients, such as hemoglobin (p < 0.01), hematocrit (p < 0.01), mean corpuscular volume (p < 0.05), and mean corpuscular hemoglobin (p <0.05), were significantly reduced compared to the control group except mean corpuscular hemoglobin concentration which was insignificant (p > 0.05). Higher levels of triglyceride, phosphorus, fasting blood sugar, aspartate aminotransferase, alanine transaminase, alkaline phosphatase, uric acid, total and direct bilirubin, and lower levels of cholesterol, high-density lipoprotein, and low-density lipoprotein were observed in patients in comparison to the control group (p < 0.05). Serum sodium, potassium, calcium, and albumin was not significantly different from the control group (p > 0.05). The prevalence of primary hypothyroidism (thyroid stimulating hormone > 4.5 mIU/l and T4 < 5.6 μg/dl) was reported at 5.31%. Conclusions: This study emphasized the necessity for regular follow-up and evaluation of β-thalassemia, which could be used to improve treatment protocols. 57 66 2021/11/282022/07/12022/07/272022/05/162022/12/52023/01/9 1401/10/19 2023/03/12023/02/272022/10/312023/03/42023/02/42023/03/7 1401/12/16 زینب قره داغی zeynab gharehdaghi Department of Hematology, School of Para Medicine, Bushehr University of Medical Sciences, Bushehr, Iran ایران z.gharehdaghi1993@gmail.com شقایق رستمی Shaghayegh Rostami Department of Hematology, School of Para Medicine, Bushehr University of Medical Sciences, Bushehr, Iran ایران sh.rostami.lab.70@gmail.com Hematological characteristics Iron overload Serum ferritin β-thalassemia major اضافه‌بار آهن بتا تالاسمی ماژور پارامترهای بیوشیمیایی [1]. Hailan YMA, Sayed G, Yassin MA. COVID‐19 in a pregnant patient with beta‐thalassemia major: A case report. Clinical Case Reports 2021; 9(7): 12-20.##[2]. Hashemizadeh H, Noori R. Assessment hepatomegaly and liver enzymes in 100 patients with beta thalassemia major in Mashhad, Iran. Iranian Journal of Pediatric Hematology and Oncology 2012; 2(4): 171-79.##[3]. Ansari S, Baghersalimi A, Azarkeivan A, Nojomi M, Rad AH. Quality of life in patients with thalassemia major. Iranian Journal of Pediatric Hematology and Oncology 2014; 4(2): 57-69.##[4]. De Sanctis V, Kattamis C, Canatan D, Soliman AT, Elsedfy H, Karimi M, et al. β-thalassemia distribution in the old world: an ancient disease seen from a historical standpoint. Mediterranean Journal of Hematology and Infectious Diseases 2017; 9(1): 78-95.##[5]. Asad ZT, Ghazanfari M, Naleini SN, Sabagh A, Kooti W. Evaluation of serum levels in T3, T4 and TSH in beta-thalassemic patients referred to the Abuzar hospital in Ahwaz. Electronic Physician 2016; 8(7): 2620-632.##[6]. Lioudaki E, Whyte M. Acute cardiac decompensation in a patient with beta‐thalassemia and diabetes mellitus following cessation of chelation therapy. Clinical Case Reports 2016; 4(10): 992-96.##[7]. Rasool M, Malik A, Jabbar U, Begum I, Qazi MH, Asif M, et al. Effect of iron overload on renal functions and oxidative stress in beta thalassemia patients. Saudi Medical Journal 2016; 37(11): 1239-250.##[8]. Jaidev S, Meena V, Sangeeta P. Study of serum ferritin level, SGOT, SGPT and hepatitis B status in multi transfused thalassemia patients. JARBS 2011; 3(2): 63-5.##[9]. De Sanctis V, Soliman AT, Canatan D, Yassin MA, Daar S, Elsedfy H, et al. Thyroid Disorders in homozygous β-Thalassemia: Current knowledge, emerging issues and Open problems. Mediter-ranean Journal of Hematology and Infectious Diseases 2019; 11(1): 38-59.##[10]. Karim MF, Ismail M, Hasan AM, Shekhar HU. Hematological and biochemical status of Beta-thalassemia major patients in Bangladesh: A comparative analysis. International Journal of Hematology-Oncology and Stem Cell Research 2016; 10(1): 7-20.##[11]. Rivella S. Iron metabolism under conditions of ineffective erythropoiesis in β-thalassemia. Blood 2019; 133(1): 51-8.##[12]. Azami M, Sharifi A, Norozi S, Mansouri A, Sayehmiri K. Prevalence of diabetes, impaired fasting glucose and impaired glucose tolerance in patients with thalassemia major in Iran: A meta-analysis study. Caspian Journal of Internal Medicine 2017; 8(1): 1-15.##[13]. Chahkandi T, Norouziasl S, Farzad M, Ghanad F. Endocrine disorders in beta thalassemia major patients. International Journal of Pediatrics 2017; 5(8): 5531-538.##[14]. Sultan S, Irfan SM, Ahmed SI. Biochemical markers of bone turnover in patients with β-thalassemia major: a single center study from southern Pakistan. Advances in Hematology 2016; 12(5): 167-78.##[15]. Surchi O, Ali S. Biochemical status of beta-thalassemia major patients in Erbil City. Erbil Dental Journal (EDJ) 2018; 1(1): 1-9.##[16]. Eghbali A, Taherahmadi H, Shahbazi M, Bagheri B, Ebrahimi L. Association between serum ferritin level, cardiac and hepatic T2-star MRI in patients with major β-thalassemia. Iranian Journal of Pediatric Hematology and Oncology 2014; 4(1): 17-32.##[17]. Ayyash H, Sirdah M. Hematological and biochemical evaluation of β-thalassemia major (βTM) patients in Gaza Strip: A cross-sectional study. International Journal of Health Sciences 2018; 12(6): 18-30.##[18]. Suman RL, Sanadhya A, Meena P, Goyal S. Correlation of liver enzymes with serum ferritin levels in β-thalassemia major. International Journal of Research in Medical Sciences 2017; 4(8): 3271-274.##[19]. Kanbour I, Chandra P, Soliman A, De Sanctis V, Nashwan A, Abusamaan S, et al. Severe liver iron concentrations (LIC) in 24 patients with β-thalassemia major: correlations with serum ferritin, liver enzymes and endocrine complications. Mediterranean J Hematol Infect Dis. 2018; 10(1): 33-49.##[20]. Sultana N, Sadiya S, Rahman M. Correlation between serum bilirubin and serum ferritin level in thalassaemia patients. Bangladesh Journal of Medical Biochemistry. 2011; 4(2): 6-12.##[21]. Khubchandani A, Solanki V, Solanki M. Estimation of serum lipid profiles in patients with beta thalassemia major. Int J Res Med. 2014; 3(2): 65-7.##[22]. Shams S, Ashtiani MTH, Monajemzadeh M, Koochakzadeh L, Irani H, Jafari F, et al. Evaluation of serum insulin, glucose, lipid profile, and liver function in β-thalassemia major patients and their correlation with iron overload. Lab Med. 2010; 41(8): 486-89.##[23]. Ragab SM, Safan MA, Sherif AS. Lipid profiles in β thalassemic children. Menoufia Medical Journal 2014; 27(1): 66-74.##[24]. Haghpanah S, Davani M, Samadi B, Ashrafi A, Karimi M. Serum lipid profiles in patients with beta-thalassemia major and intermedia in southern Iran. Journal of Isfahan University of Medical Sciences 2010; 15(3): 150-63.##[25]. Adil A, Sobani ZA, Jabbar A, Adil SN, Awan S. Endocrine complications in patients of beta thalassemia major in a tertiary care hospital in Pakistan. Journal of the Pakistan Medical Association 2012; 62(3): 307-318.##[26]. Aldudak B, Bayazit AK, Noyan A, Özel A, Anarat A, Sasmaz I, et al. Renal function in pediatric patients with β-thalassemia major. Pediatric Nephrology. 2000; 15(1-2): 109-112.##[27]. Şen V, Ece A, Uluca Ü, Söker M, Güneş A, Kaplan İ, et al. Urinary early kidney injury molecules in children with beta-thalassemia major. Renal Failure 2015; 37(4): 607-613.##[28]. Ahmadzadeh A, Jalali A, Assar S, Khalilian H, Zandian K, Pedram M. Renal tubular dysfunction in pediatric patients with beta-thalassemia major. Saudi Journal of Kidney Diseases and Transplantation 2011; 22(3): 497-510.##[29]. Hashemieh M, Radfar M, Azarkeivan A, Tabatabaei SMTH, Nikbakht S, Yaseri M, et al. Renal hemosiderosis among Iranian transfusion dependent β-thalassemia major patients. Int J Hematology-Oncol nd Stem Cell Res. 2017; 11(2): 133-42.##[30]. Annayev A, Karakaş Z, Karaman S, Yalçıner A, Yılmaz A, Emre S. Glomerular and tubular functions in children and adults with transfusion-dependent thalassemia. Turkish Journal of Hematology 2018; 35(1): 66-78.##[31]. Adly A, Toaima DN, Mohamed N, El Seoud K. Subclinical renal abnormalities in young thalassemia major and intermedia patients and its relation to chelation therapy. Egyptian Journal of Medical Human Genetics. 2014; 15(4): 369-77.##[32]. Ahmed Z. Study of serum calcium, phosphorus and vitamin D status in multitransfused β-thalassemia major children and adolescents of Jharkhand, India. International Journal of Contemporary Pediatrics. 2019; 6(2): 598-610.##[33]. Aslan I, Canatan D, Balta N, Kacar G, Dorak C, Ozsancak A, et al. Bone mineral density in thalassemia major patients from Antalya, Turkey. Int J Endocrinol. 2012; 7(4): 23-31.##[34]. Najafipour F. Evaluation of endocrine disorders in patients with thalassemia major. Int Iran J Endocrinol Metabol. 2008; 6(2): 104-113.##[35]. Mostafavi H, Afkhamizadeh M, Rezvanfar M. Endocrine disorders in patients with thalassemia major. Int Iran J Endocrinol Metabol. 2005; 7(2): 143-47.## ##

A Mouse Monoclonal Antibody Against Human IFN-γ and its Characters ی 2 1 ی 2 Background and Aims: A monoclonal antibody (mAb) can unambiguously identify, quantify, and purify an antigen or particular epitope at a large scale. The superiority of these antibodies lies in their specificity for the antigenic determinant. So, this study aims to prepare mouse mAb-secreting hybridoma against human gamma interferon (IFN-γ) and determine the produced antibody's characters. Materials and Methods: Mouse splenic B lymphocytes immunized with recombinant human IFN-γ were fused with mouse SP2/0 cells. The hybridized cells were selected by hypoxanthine-aminopterin-thymidine and hypoxanthine-thymidine media to obtain monoclonal antibody-producing hybridoma cells. Finally, indirect enzyme-linked immunosorbent assay (ELISA), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and western blot were used to confirm the creation of antibody-secreting hybridoma cells. Results: mAb against IFN-γ were produced by fusing SP2/0 mouse non-secretory myeloma cell line with the spleen cells of immunized mice. This antibody's indirect ELISA optical density was 2.055 on average, and the desired antibody bands were confirmed in SDS-PAGE compared to Septicol® (commercial antibody). Also, in the western blot, the desired antibody could bind to the antigen. IFN-γ transferred on nitrocellulose membrane. In ELISA and western blot tests, anti-mouse IgG conjugated antibodies were used; therefore, the mAb IgG isotype was taken into consideration. Conclusion: In this study, a mouse mAb was obtained by immunization of Balb/C mice and fusion of spleen cells of these mice with the SP2/0 cells, which can specifically bind to recombinant human IFN-γ and can be used to detect IFN-γ secretion in all types of intracellular infections, including latent tuberculosis. 67 74 2021/11/282022/07/12022/07/272022/05/162022/12/52023/01/92022/12/1 1401/9/10 2023/03/12023/02/272022/10/312023/03/42023/02/42023/03/72023/01/15 1401/10/25 عرفان ذاکر Erfan Zaker Department of Medical Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran ایران fatemezare91@gmail.com فاطمه زارع Fateme Zare Reproductive Immunology Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran ایران fatemezare91@yahoo.com سیدحسین حجازی Seyed Hossein Hejazi Department of Parasitology and Mycology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran ایران ijml.office@gmail.com حسین خان احمد Hossein Khanahmad Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran ایران hossein_khanahmad@yahoo.com سیدمهدی کلانتر Seyed Mehdi Kalantar Department of Medical Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran ایران smkalantar@yahoo.com Hybridoma IFN-γ Monoclonal antibody SP2/0 [1]. Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon‐γ: an overview of signals, mechanisms and functions. J Leukocyte Biol. 2004; 75(2): 163-89.##[2]. Robertsen B. The role of type I interferons in innate and adaptive immunity against viruses in Atlantic salmon. Developmental & Comparative Immunology 2018; 80(1): 41-52.##[3]. Wagner SC, Ichim TE, Bogin V, Min WP, Silva F, Patel AN, et al. Induction and characterization of antitumor endothelium immunity elicited by ValloVax therapeutic cancer vaccine. Oncotarget 2017; 8(17): 28595.##[4]. Hamana A, Takahashi Y, Uchida T, Nishikawa M, Imamura M, Chayama K, et al. Evaluation of antiviral effect of type I, II, and III interferons on direct-acting antiviral-resistant hepatitis C virus. Antiviral Research 2017; 146(1): 130-38.##[5]. Qin Y, Wang Q, Zhou Y, Duan Y, Gao Q. Inhibition of IFN-γ-induced nitric oxide dependent antimycobacterial activity by miR-155 and C/EBPβ. International Journal of Molecular Sciences 2016; 17(4): 535.##[6]. Gessani S, Conti L, Cornò MD, Belardelli F. Type I interferons as regulators of human antigen presenting cell functions. Toxins 2014; 6(6): 1696-723.##[7]. Kak G, Raza M, Tiwari BK. Interferon-gamma (IFN-γ): Exploring its implications in infectious diseases. Biomolecular Concepts 2018 ; 9(1): 64-79.##[8]. Müller E, Speth M, Christopoulos PF, Lunde A, Avdagic A, Øynebråten I, et al. Both type I and type II interferons can activate antitumor M1 macrophages when combined with TLR stimulation. Frontiers in Immunology 2018; 9(12): 2520.##[9]. Ishidome T, Yoshida T, Hanayama R. Induction of live cell phagocytosis by a specific combination of inflammatory stimuli. EBioMedicine 2017; 22(1): 89-99.##[10]. Kroetz DN, Allen RM, Schaller MA, Cavallaro C, Ito T, Kunkel SL. Type I interferon induced epigenetic regulation of macrophages suppresses innate and adaptive immunity in acute respiratory viral infection. PLoS Pathogens 2015; 11(12): 1005338.##[11]. Zhan C, Yan Q, Patskovsky Y, Li Z, Toro R, Meyer A, et al. Biochemical and structural characterization of the human TL1A ectodomain. Biochemistry 2009; 48(32): 7636-645.##[12]. Cooper MA. Optical biosensors in drug discovery. Nature Reviews Drug Discovery 2002; 1(7): 515-28.##[13]. Pai M, Denkinger CM, Kik SV, Rangaka MX, Zwerling A, Oxlade O, et al. Gamma interferon release assays for detection of Mycobacterium tuberculosis infection. Clin Microbiol Rev. 2014; 27(1): 3-20.##[14]. Oleszak E, Feickert HJ, Mecs I, Fox F. Mouse monoclonal antibody with specificity for human interferon gamma. Hybridoma 1983; 2(4): 439-49.##[15]. Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975; 256(5517): 495-97.##[16]. Dueva EV, Panchin AY. Homeopathy in disguise. Comment on Don et al.: Dose-dependent antiviral activity of released-active form of antibodies to interferon-gamma against influenza A/California/07/09 (H1N1) in murine model. Journal of Medical Virology 2017; 89(7): 1125-126.##[17]. Lin FC, Young HA. Interferons: success in antiviral immunotherapy. Cytokine & Growth Factor Reviews 2014; 25(4): 369-76.##[18]. Novick D, Eshhar Z, Fischer DG, Friedlander J, Rubinstein M. Monoclonal antibodies to human interferon-gamma: production, affinity purification and radioimmunoassay. The EMBO Journal 1983; 2(9): 1527-530.##[19]. Ahkong Q, Fisher D, Tampion W, Lucy J. Mechanisms of cell fusion. Nature 1975; 253(5488): 194-95.##[20]. Ma WT, Liu Q, Ning MX, Qi YX, Rehman S, Chen D-K. Development and applications of a monoclonal antibody against caprine interferon-gamma. BMC Biotechnology 2019; 19(1): 1-7.##[21]. Prandota J, Elleboudy NAF, Ismail KA, Zaki OK, Shehata HH. Increased seroprevalence of chronic toxoplasmosis in autistic children: Special reference to the pathophysiology of IFN-g and NO overproduction. International Journal of Neurology Research 2015; 1(3): 102-22.##[22]. Novick D, Eshhar Z, Fischer D, Friedlander J, Rubinstein M. Monoclonal antibodies to human interferon‐gamma: production, affinity purification and radioimmunoassay. The EMBO Journal 1983; 2(9): 1527-530.##[23]. Shulman M, Wilde C, Köhler G. A better cell line for making hybridomas secreting specific antibodies. Nature 1978; 276(5685): 269-70.## ##

Effects of Ubiquinone on Oxidant and Antioxidant Status in Hepatocellular Carcinoma Cell Line کارسینوما و اکسیداتیو استرس  2 1 کارسینوما و اکسیداتیو استرس  دکتر بحرینی 2 Background and Aims: The concomitant use of antioxidants during chemotherapy is controversial. It is unknown whether antioxidants increase or decrease the effectiveness of anticancer drugs. Therefore, the present study aimed to investigate ubiquinone's cytotoxic and antioxidant effects on the HepG2 cell line. Materials and Methods: The HepG2 cell line was chosen as an experimental model for hepatocellular carcinoma in this study. The cytotoxic effect of ubiquinone was assessed as a function of time and concentration using the colorimetric MTT assay. The half-maximal inhibitory concentration (IC50) was determined to assess the cytotoxic effects of different ubiquinone concentrations. The protective impacts of ubiquinone on HepG2 cells were evaluated by assessing the oxidative stress profile. Results: The MTT showed that the IC50 after treatment with ubiquinone was 350 and 335 μM at 24 and 48 hours, respectively. Evaluation of redox homeostasis in HepG2 cells using three doses of ubiquinone, including IC50 and one dose higher and one dose lower than IC50, showed a decrease in oxidative stress and an increase in the antioxidant capacity of HepG2 cells in a dose-dependent manner (p < 0.01). An increase in redox hemostasis decreased the viability of HepG2 cells. Conclusion: Our results showed ubiquinone could reduce cancer cell survival by interfering in redox oxidative-redox status. Therefore, ubiquinone can be used as an antioxidant supplement along with chemotherapy drugs. 75 82 2021/11/282022/07/12022/07/272022/05/162022/12/52023/01/92022/12/12022/11/20 1401/8/29 2023/03/12023/02/272022/10/312023/03/42023/02/42023/03/72023/01/152023/01/28 1401/11/8 نفیسه حیدری کلوانی Nafiseh Heidari-Kalvani Department of Biochemistry, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran ایران nafise.heidari.95@gmail.com سودابه فلاح Sudabeh Fallah Department of Biochemistry, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran ایران فرشته برجسته Fereshte Barjasteh Department of Biochemistry, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran ایران الهام بحرینی Elham Bahreini Department of Biochemistry, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran ایران Bahreini.e@iums.ac.ir Hepatocellular carcinoma HepG2 cell line Oxidative stress Ubiquinone [1]. Jeon JS, Kwon S, Ban K, Kwon Hong Y, Ahn C, Sung JS, et al. Regulation of the intracellular ROS level is critical for the antiproliferative effect of quercetin in the hepatocellular carcinoma cell line HepG2. Nutrition and Cancer 2019; 71(5): 861-69.##[2]. Gheena S, Ezhilarasan D. Syringic acid triggers reactive oxygen species–mediated cytotoxicity in HepG2 cells. Human & Experimental Toxicology 2019; 38(6): 694-702.##[3]. Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nature Reviews Gastroenterology & Hepatology 2019; 16(10): 589-604.##[4]. Greten FR, Grivennikov SI. Inflammation and cancer: triggers, mechanisms, and consequences. Immunity 2019; 51(1): 27-41.##[5]. Hayes JD, Dinkova-Kostova AT, Tew KD. Oxidative stress in cancer. Cancer Cell 2020; 38(2): 167-97.##[6]. Checa J, Aran JM. Reactive oxygen species: drivers of physiological and pathological processes. Journal of Inflammation Research 2020; 13(9): 1057.##[7]. Arfin S, Jha NK, Jha SK, Kesari KK, Ruokolainen J, Roychoudhury S, et al. Oxidative stress in cancer cell metabolism. Antioxidants 2021; 10(5): 642.##[8]. Harris IS, DeNicola GM. The complex interplay between antioxidants and ROS in cancer. Trends in Cell Biology 2020; 30(6): 440-51.##[9]. Kumari S, Badana AK, Malla R. Reactive oxygen species: a key constituent in cancer survival. Biomarker Insights 2018; 13: 1-9.##[10]. Aggarwal V, Tuli HS, Varol A, Thakral F, Yerer MB, Sak K, et al. Role of reactive oxygen species in cancer progression: molecular mechanisms and recent advancements. Biomolecules 2019; 9(11): 735.##[11]. Ushio-Fukai M, Nakamura Y. Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy. Cancer Letters 2008; 266(1): 37-52.##[12]. El-Attar E, Kamel A, Karmouty A, Wehida N, Nassra R, El Nemr M, et al. Assessment of serum CoQ10 levels and other antioxidant markers in breast cancer. Asian Pacific Journal of Cancer Prevention: APJCP. 2020; 21(2): 465.##[13]. Saini R. Coenzyme Q10: The essential nutrient. J Pharm Bioallied Sci. 2011; 3(3): 466-67.##[14]. Liu HT, Huang YC, Cheng SB, Huang YT, Lin PT. Effects of coenzyme Q10 supplementation on antioxidant capacity and inflammation in hepatocellular carcinoma patients after surgery: a randomized, placebo-controlled trial. Nutr J. 2016; 15(1): 85. ##[15]. Hargreaves IP, Duncan AJ, Heales SJ, Land JM. The effect of HMG-CoA reductase inhibitors on coenzyme Q10. Drug safety 2005; 28(8): 659-76.##[16]. Kobori Y, Ota S, Sato R, Yagi H, Soh S, Arai G, et al. Antioxidant cosupplementation therapy with vitamin C, vitamin E, and coenzyme Q10 in patients with oligoasthenozoospermia. Archivio Italiano di Urologia e Andrologia 2014; 86(1): 1-4.##[17]. Mendelsohn AR, Larrick JW. Paradoxical effects of antioxidants on cancer. Rejuvenation Research 2014; 17(3): 306-11.##[18]. George S, Abrahamse H. Redox potential of antioxidants in cancer progression and prevention. Antioxidants 2020; 9(11): 1156.##[19]. Poljsak B, Milisav I. The role of antioxidants in cancer, friends or foes? Current Pharmaceutical Design 2018; 24(44): 5234-244.##[20]. Fouad AA, Al-Mulhim AS, Jresat I. Therapeutic effect of coenzyme Q10 against experimentally-induced hepatocellular carcinoma in rats. Environ Toxicol Pharmacol. 2013; 35(1): 100-108. ##[21]. Al-Megrin WA, Soliman D, Kassab RB, Metwally DM, Ahmed EAM, El-Khadragy MF. Coenzyme Q10 activates the antioxidant machinery and inhibits the inflammatory and apoptotic cascades against lead acetate-induced renal injury in rats. Front Physiol. 2020; 11(2): 64.##[22]. Salehi B, Martorell M, Arbiser JL, Sureda A, Martins N, Maurya PK, et al. Antioxidants: positive or negative actors? Biomolecules 2018; 8(4): 124-35.##[23]. Singh K, Bhori M, Kasu YA, Bhat G, Marar T. Antioxidants as precision weapons in war against cancer chemotherapy induced toxicity–Exploring the armoury of obscurity. Saudi Pharmaceutical Journal 2018; 26(2): 177-90.##[24]. Tasdogan A, Ubellacker JM, Morrison SJ. Redox regulation in cancer cells during metastasis. Cancer Discovery 2021; 11(11): 2682-692.##[25]. Kong H, Chandel NS. Regulation of redox balance in cancer and T cells. Journal of Biological Chemistry 2018; 293(20): 7499-507.##[26]. Alimohammadi M, Rahimi A, Faramarzi F, Golpour M, Jafari-Shakib R, Alizadeh-Navaei R, et al. Effects of coenzyme Q10 supplementation on inflammation, angiogenesis, and oxidative stress in breast cancer patients: a systematic review and meta-analysis of randomized controlled-trials. Inflammopharmacology 2021; 29(3): 579-93.##[27]. Pala R, Orhan C, Tuzcu M, Sahin N, Ali S, Cinar V, et al. Coenzyme Q10 supplementation modulates NFκB and Nrf2 pathways in exercise training. Journal of Sports Science & Medicine 2016; 15(1): 196.##[28]. Hodges S, Hertz N, Lockwood K, Lister R. CoQ10: could it have a role in cancer management? Biofactors 1999; 9(2-4): 365-70.## ##