تأثیر رزوراترول بر توانایی مهاجرت و تکثیر سلول‌های بنیادی مشتق از خون قاعدگی زنان مبتلا به اندومتریوز
محورهای موضوعی : سلولی ملکولی
هدی فضائلی
1
,
نسیم حیاتی رودباری
2
*
,
احسان احسانی
3
,
آذر شیخ الاسلامی
4
1 - دانشجوی دکتری، گروه زیست‌شناسی، دانشکده علوم و فناوری‌های همگرا، واحد علوم و تحقیقات، دانشگاه آزاد اسلامی، تهران، ایران.
2 - دانشیار، گروه زیست‌شناسی، دانشکده علوم و فناوری‌های همگرا، واحد علوم و تحقیقات، دانشگاه آزاد اسلامی، تهران، ایران
3 - استادیار، گروه زیست‌شناسی، دانشکده علوم، واحد رودهن، دانشگاه آزاد اسلامی، رودهن، ایران
4 - استادیار، گروه سلول‌های بنیادی مزانشیمی، جهاد دانشگاهی، واحد قم، قم، ایران.
کلید واژه: اندومتریوز, رزوراترول, سلول‌های بنیادی, خون قاعدگی, زنان.,
چکیده مقاله :
هدف: 10 درصد از زنان در سنین باروری اندومتریوز را به عنوان یک بیماری التهابی و وابسته به هورمون تجربه می‌‌کنند. به دلیل نارسایی رویکردهای درمانی فعلی، استفاده از داروهای جدید و جایگزین برای بهبود درمان‌های اندومتریوز ضروری است. رزوراترول به دلیل اثرات بیولوژیکی متعددی مانند خواص آنتی نئوپلاستیک، آنتی اکسیدانی، ضد رگ‌زایی، ضد تکثیری، ضد التهابی و پیش آپوپتوزی، مورد توجه بسیاری قرار گرفته است. پروفایل بیان ژن سلول‌های بنیادی مشتق از خون قاعدگی (MenSCs) زنان اندومتریوزی و غیراندومتریوزی متفاوت است. بنابراین، در پژوهش حاضر تلاش شد که اثرات رزوراترول بر مهاجرت سلولی و میزان بیان ژنهای VEGF،KRAS و- IDO1 به عنوان عوامل مرتبط با تکثیر سلولی- درMenSCs بیماران مبتلا به اندومتریوز ارزیابی شوند.
مواد و روش‌‌ها: با استفاده از محلول فایکول، MenSCs زنان سالم (NE-MenSCs) و مبتلا به اندومتریوز (E-MenSCs) جدا شده و در آزمایشگاه کشت داده شدند. E-MenSCs با 100 µM رزوراترول به مدت 72 ساعت تیمار شدند، در حالی‌که در گروه‌های NE-MenSCs و E-MenSCs، سلول‌ها طی این مدت هیچ درمانی دریافت نکردند. بررسی توانایی مهاجرت و سطح بیان ژن‌‌ها، با استفاده از آزمون خراش وReal-time PCR انجام شد.
یافته‌ها: پس از 36 ساعت، در هر دو گروه NE-MenSCs و Resveratrol درصد بسته شدن خراش به طور معنی‌داری کمتر از گروه E-MenSCs بود. همچنین بیان ژنهای KRAS و VEGF در گروه Resveratrol به‌طور معنی‌داری کمتر از گروه E-MenSCs بود.
نتیجه‌‌گیری: رزوراترول می‌تواند پیشرفت اندومتریوز را از طریق کاهش توانایی مهاجرت سلول‌ها و کاهش بیان VEGF و KRAS کاهش دهد.
Objective: 10% of women of reproductive age experience endometriosis as an inflammatory and hormone-dependent disease. Due to the failure of current treatment approaches, it is necessary to use new and alternative drugs to improve endometriosis treatments. Resveratrol has received much attention due to its many biological effects such as antineoplastic, antioxidant, anti-angiogenic, anti-proliferative, anti-inflammatory and pro-apoptotic properties. The gene expression profile of menstrual blood-derived stem cells (MenSCs) of endometriotic and non-endometriotic women is different. Therefore, in the present study, an attempt was made to evaluate the effects of resveratrol on cell migration and the expression levels of VEGF, KRAS, and IDO1 genes as factors related to cell proliferation in MenSCs of patients with endometriosis.
Materials and methods: MenSCs from healthy women (NE-MenSCs) and endometriosis (E-MenSCs) were isolated and cultured in the laboratory using Faycol solution. E-MenSCs were treated with 100 µM resveratrol for 72 hours, while in
NE-MenSCs and E-MenSCs groups, the cells did not receive any treatment during this period. Investigating the ability of migration and expression level of genes was done using scratch test and real-time PCR.
Findings: After 36 hours, in both NE-MenSCs and Resveratrol groups, the scratch closure percentage was significantly lower than the E-MenSCs group. Also, the expression of KRAS and VEGF genes in the Resveratrol group was significantly lower than the E-MenSCs group.
Conclusion: Resveratrol can reduce the progression of endometriosis by reducing the ability of cells to migrate and reducing the expression of VEGF and KRAS.
1. Strowitzki T, Germeyer A, Popovici R & von Wolff M. The human endometrium as a fertility-determining factor. Hum Reprod Update. 2006; 12(5): 617-30.
2. Artemova D, Vishnyakova P, Gantsova E, Elchaninov A, Fatkhudinov T & Sukhikh G. The prospects of cell therapy for endometriosis. J Assist Reprod Genet. 2023; 40(5): 955-67.
3. Zondervan KT, Becker CM & Missmer SA. Endometriosis. The New England journal of medicine. 2020; 382(13): 1244-56.
4. Zhang L, Xiong W, Xiong Y, Liu H & Liu Y. 17 β-Estradiol promotes vascular endothelial growth factor expression via the Wnt/β-catenin pathway during the pathogenesis of endometriosis. Mol Hum Reprod. 2016; 22(7): 526-35.
5. Kajiyama H, Suzuki S, Yoshihara M, Tamauchi S, Yoshikawa N, Niimi K & et al. Endometriosis and cancer. Free radical biology & medicine. 2019; 133: 186-92.
6. Janša V, Klančič T, Pušić M, Klein M, Vrtačnik Bokal E, Ban Frangež H & et al. Proteomic analysis of peritoneal fluid identified COMP and TGFBI as new candidate biomarkers for endometriosis. Scientific Reports. 2021; 11(1): 20870.
7. Jiang L, Wan Y, Feng Z, Liu D, Ouyang L, Li Y & et al. Long Noncoding RNA UCA1 Is Related to Autophagy and Apoptosis in Endometrial Stromal Cells. Frontiers in oncology. 2020; 10: 618472.
8. Maruyama T. A Revised Stem Cell Theory for the Pathogenesis of Endometriosis. Journal of personalized medicine. 2022; 12(2).
9. Sampson JA. Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. The American journal of pathology. 1927; 3(2).
10. Halme J, Hammond MG, Hulka JF, Raj SG & Talbert LM. Retrograde menstruation in healthy women and in patients with endometriosis. Obstetrics and gynecology. 1984; 64(2): 151-4.
11. Sasson IE & Taylor HS. Stem cells and the pathogenesis of endometriosis. Annals of the New York Academy of Sciences. 2008; 1127: 106.
12. Gargett CE & Masuda H. Adult stem cells in the endometrium. Molecular human reproduction. 2010; 16(11): 818-34.
13. Gargett CE, Schwab KE, Brosens JJ, Puttemans P, Benagiano G & Brosens I. Potential role of endometrial stem/progenitor cells in the pathogenesis of early-onset endometriosis. Molecular human reproduction. 2014; 20(7): 591-8.
14. Meng X, Ichim TE, Zhong J, Rogers A, Yin Z, Jackson J & et al. Endometrial regenerative cells: a novel stem cell population. Journal of translational medicine. 2007; 5(1): 1-10.
15. Murphy MP, Wang H, Patel AN, Kambhampati S, Angle N, Chan K & et al. Allogeneic endometrial regenerative cells: An" Off the shelf solution" for critical limb ischemia? Journal of translational medicine. 2008; 6(1): 1-8.
16. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D & et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006; 8(4): 315-7.
17. Kazemnejad S, Zarnani A-H, Khanmohammadi M & Mobini S. Chondrogenic differentiation of menstrual blood-derived stem cells on nanofibrous scaffolds. Stem Cell Nanotechnology. 2013.1058: 149-69.
18. Khanjani S, Khanmohammadi M, Zarnani AH, Talebi S, Edalatkhah H, Eghtesad S & et al. Efficient generation of functional hepatocyte‐like cells from menstrual blood‐derived stem cells. Journal of tissue engineering and regenerative medicine. 2015; 9(11): E124-E3.
19. Khanjani S, Khanmohammadi M, Zarnani A-H, Akhondi M-M, Ahani A, Ghaempanah Z & et al. Comparative evaluation of differentiation potential of menstrual blood-versus bone marrow-derived stem cells into hepatocyte-like cells. PLoS One. 2014; 9(2): e86075.
20. Sahraei SS, Davoodi Asl F, Kalhor N, Sheykhhasan M, Fazaeli H, Moud SS & et al. A Comparative Study of Gene Expression in Menstrual Blood-Derived Stromal Cells between Endometriosis and Healthy Women. BioMed Research International. 2022.
DOI: 10.1155/2022/7053521
21. Kalaitzopoulos DR, Samartzis N, Kolovos GN, Mareti E, Samartzis EP, Eberhard M & et al. Treatment of endometriosis: a review with comparison of 8 guidelines. BMC women's health. 2021; 21(1): 397.
22. Chen J, Wang H, Dong Z, Liu J, Qin Z, Bao M & et al. GnRH-a-Induced Perimenopausal Rat Modeling and Black Cohosh Preparations' Effect on Rat's Reproductive Endocrine. Front Endocrinol (Lausanne). 2021; 12.
23. Della Corte L, Noventa M, Ciebiera M, Magliarditi M, Sleiman Z, Karaman E & et al. Phytotherapy in endometriosis: an up-to-date review. Journal of complementary & integrative medicine. 2020; 17(3).
24. Zakhari A, Delpero E, McKeown S, Tomlinson G, Bougie O & Murji A. Endometriosis recurrence following post-operative hormonal suppression: a systematic review and
meta-analysis. Hum Reprod Update. 2021; 27(1): 96-107.
25. Jiang T, Chen Y, Gu X, Miao M, Hu D, Zhou H & et al. Review of the Potential Therapeutic Effects and Molecular Mechanisms of Resveratrol on Endometriosis. International journal of women's health. 2023; 15.
26. Bruner-Tran KL, Osteen KG, Taylor HS, Sokalska A, Haines K & Duleba AJ. Resveratrol inhibits development of experimental endometriosis in vivo and reduces endometrial stromal cell invasiveness in vitro. Biology of reproduction. 2011; 48(1).
27. Sahraei SS, Davoodi Asl F, Kalhor N, Sheykhhasan M, Fazaeli H, Moud SS & et al. A Comparative Study of Gene Expression in Menstrual Blood-Derived Stromal Cells between Endometriosis and Healthy Women. Biomed Res Int. 2022; 2022: 7053521.
28. Kolahdouz-Mohammadi R, Shidfar F, Khodaverdi S, Arablou T, Heidari S, Rashidi N & et al. Resveratrol treatment reduces expression of MCP-1, IL-6, IL-8 and RANTES in endometriotic stromal cells. J Cell Mol Med. 2021; 25(2): 1116-27.
29. Dufour A, Sampson NS, Zucker S & Cao J. Role of the hemopexin domain of matrix metalloproteinases in cell migration. J Cell Physiol. 2008; 217(3): 643-51.
30. Matsuzaki S & Darcha C. Involvement of the Wnt/β-catenin signaling pathway in the cellular and molecular mechanisms of fibrosis in endometriosis. PLoS One. 2013; 8(10): e76808.
31. Yang Z & Xia L. Resveratrol inhibits the proliferation, invasion, and migration, and induces the apoptosis of human gastric cancer cells through the MALAT1/miR-383-5p/DDIT4 signaling pathway. Journal of Gastrointestinal Oncology. 2022; 13(3): 985-96.
32. Sun Y, Zhou QM, Lu YY, Zhang H, Chen QL, Zhao M & et al. Resveratrol Inhibits the Migration and Metastasis of MDA-MB-231 Human Breast Cancer by Reversing TGF-β1-Induced Epithelial-Mesenchymal Transition. Molecules (Basel, Switzerland). 2019;
24(6).
33. Mei J, Jin LP, Ding D, Li MQ, Li DJ & Zhu XY. Inhibition of IDO1 suppresses cyclooxygenase-2 and matrix metalloproteinase-9 expression and decreases proliferation, adhesion and invasion of endometrial stromal cells. Mol Hum Reprod. 2012; 18(10):
467-76.
34. Munn DH, Mellor AL, Rossi M & Young JW. Dendritic cells have the option to express IDO-mediated suppression or not. Blood. 2005; 105(6): 2618.
35. Jeddi-Tehrani M, Abbasi N, Dokouhaki P, Ghasemi J, Rezania S, Ostadkarampour M &
et al. Indoleamine 2,3-dioxygenase is expressed in the endometrium of cycling mice throughout the oestrous cycle. J Reprod Immunol. 2009; 80(1-2): 41-8.
36. Yang H-L & Li M-Q. Indoleamine 2,3-Dioxygenase in Endometriosis. Reproductive and Developmental Medicine. 2019; 3(2): 110-6.
37. Young A, Lou D & McCormick F. Oncogenic and Wild-type Ras Play Divergent Roles in the Regulation of Mitogen-Activated Protein Kinase Signaling. Cancer Discovery. 2013; 3(1): 112-23.
38. Schubbert S, Shannon K & Bollag G. Hyperactive Ras in developmental disorders and cancer. Nature reviews Cancer. 2007; 7(4): 295-308.
39. Nikoo S, Ebtekar M, Jeddi-Tehrani M, Shervin A, Bozorgmehr M, Vafaei S & et al. Menstrual blood-derived stromal stem cells from women with and without endometriosis reveal different phenotypic and functional characteristics. Mol Hum Reprod. 2014; 20(9): 905-18.
40. Grechukhina O, Petracco R, Popkhadze S, Massasa E, Paranjape T, Chan E & et al. A polymorphism in a let-7 microRNA binding site of KRAS in women with endometriosis. EMBO molecular medicine. 2012; 4(3): 206-17.
41. Saud SM, Li W, Morris NL, Matter MS, Colburn NH, Kim YS & et al. Resveratrol prevents tumorigenesis in mouse model of Kras activated sporadic colorectal cancer by suppressing oncogenic Kras expression. Carcinogenesis. 2014; 35(12): 2778-86.
42. Lin H-C, Yang C-J, Kuan Y-D, Wang W-K, Chang W-W & Lee C-H. The inhibition of indoleamine 2, 3-dioxygenase 1 by connexin 43. International Journal of Medical Sciences. 2017; 14(12): 1181-8.
43. Kolahdouz Mohammadi R & Arablou T. Resveratrol and endometriosis: In vitro and
animal studies and underlying mechanisms (Review). Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2017; 91: 220-8.
44. Gazvani R & Templeton A. Peritoneal environment, cytokines and angiogenesis in the pathophysiology of endometriosis. Reproduction (Cambridge, England). 2002; 123(2):
217-26.
45. Rocha AL, Reis FM & Taylor RN. Angiogenesis and endometriosis. Obstetrics and gynecology international. 2013; 2013: 859619.
46. Kuroki M, Voest EE, Amano S, Beerepoot LV, Takashima S, Tolentino M & et al. Reactive oxygen intermediates increase vascular endothelial growth factor expression in vitro and in vivo. J Clin Invest. 1996; 98(7): 1667-75.
47. Arablou T, Aryaeian N, Khodaverdi S, Kolahdouz-Mohammadi R, Moradi Z, Rashidi
N & et al. The effects of resveratrol on the expression of VEGF, TGF-β, and MMP-9 in endometrial stromal cells of women with endometriosis. Sci Rep. 2021; 11(1): 6054.