Association of Long Non-Coding RNA Malat1 with Serum Levels of Interleukin-1 Beta and Vitamin D in Patients with Ischemic Stroke

Authors

  • Afshin Borhani-Haghighi Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
  • Mahnaz Bayat Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
  • Reza Tabrizi Noncommunicable Diseases Research Center, Fasa University of Medical Science, Fasa, Iran / USERN Office, Fasa University of Medical Sciences, Fasa, Iran
  • Mohammad Saied Salehi Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
  • Najmeh Karimi Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran / Department of Neurology, Shiraz University of Medical Sciences, Shiraz, Iran
  • Moosa Rahimi Laboratory of Basic Sciences, Mohammad Rasul Allah Research Tower, Shiraz University of Medical Sciences, Shiraz, Iran
  • Etrat Hooshmandi Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
  • Niloufar Razavi moosavi Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
  • Nima Fadakar Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran / Department of Neurology, Shiraz University of Medical Sciences, Shiraz, Iran

DOI:

https://doi.org/10.31661/gmj.v12i.2457

Keywords:

Long Non-coding RNA, Malat1, nterleukin-1 Beta, Vitamin D, Ischemic Stroke

Abstract

Background:Previous studies have demonstrated the strong association of inflammatory cytokines and vitamin D (VitD) deficiency and ischemic stroke (IS) pathogenesis. Due to the negative correlation between long non-coding RNA (lncRNA) Malat1 and pro-inflammatory factors we decided to investigate the associations between Malat1 expression with serum interleukin-1β (IL-1β), and VitD levels in IS patients. Materials and Methods:In this cross-sectional study, 63 IS patients were included. We used enzyme-linked immunosorbent assays to evaluate the serum levels of VitD and IL-1β. Malat1 expression was evaluated by the real-time polymerase chain reaction test. The associations between Malat1expression with VitD and IL-1β were analysed with linear regression (Stepwise model) and Pearson’s correlation analysis. Results: The Malat1 expression was inversely correlated with stroke severity (r=-0.25, P=0.043). Stepwise regression analysis showed a significant positive relationship between VitD level and Malat1 expression (Beta=0.28, P=0.02), and also showed a non-significant negative relationship between IL-1β and stroke severity. VitD level showed a positive Pearson correlation with Malat1 (r=0.28, P=0.023) and a negative correlation with IL-1β (r=-0.29, P=0.018) while it could not detect a significantly negative correlation with stroke severity. Conclusion: For the first time the associations between Malat1 expression with IL-1β and VitD in IS patients was analyzed. We found a significant positive relationship between VitD and Malat1. This correlation needs to be investigated with a larger sample size to achieve a strong and reliable association between VitD and Malat1.[GMJ.2023;12:e2457]

References

Shaheryar ZA, Khan MA, Adnan CS, Zaidi AA, Hanggi D, Muhammad S. Neuroinflammatory Triangle Presenting Novel Pharmacological Targets for Ischemic Brain Injury. Front Immunol. 2021;12:748663. https://doi.org/10.3389/fimmu.2021.748663PMid:34691061 PMCid:PMC8529160 Ng GJL, Quek AML, Cheung C, Arumugam TV, Seet RCS. Stroke biomarkers in clinical practice: A critical appraisal. Neurochem Int. 2017;107:11-22. https://doi.org/10.1016/j.neuint.2017.01.005PMid:28088349 Shah S, Luby M, Poole K, Morella T, Keller E, Benson RT et al. Screening with MRI for Accurate and Rapid Stroke Treatment: SMART. Neurology. 2015;84(24):2438-44. https://doi.org/10.1212/WNL.0000000000001678PMid:25972494 PMCid:PMC4478034 Wan HL, Hong XY, Zhao ZH, Li T, Zhang BG, Liu Q et al. STAT3 ameliorates cognitive deficits via regulation of NMDAR expression in an Alzheimer's disease animal model. Theranostics. 2021;11(11):5511-24. https://doi.org/10.7150/thno.56541PMid:33859760 PMCid:PMC8039956 Zhu M, Li N, Luo P, Jing W, Wen X, Liang C et al. Peripheral blood leukocyte expression of lncRNA MIAT and its diagnostic and prognostic value in ischemic stroke. J Stroke Cerebrovasc Dis. 2018;27(2):326-37. https://doi.org/10.1016/j.jstrokecerebrovasdis.2017.09.009PMid:29030044 Hu Y, Zheng L, Zhang J, Shen Y, Zhang X, Lin L. LncRNA-MALAT1 is a promising biomarker for prognostic evaluation of tongue squamous cell carcinoma. Eur Arch Otorhinolaryngol. 2020;277(11):3155-60. https://doi.org/10.1007/s00405-020-06023-6PMid:32383096 Wang ML, Liu JX. MALAT1 rs619586 polymorphism functions as a prognostic biomarker in the management of differentiated thyroid carcinoma. J Cell Physiol. 2020;235(2):1700-10. https://doi.org/10.1002/jcp.29089PMid:31456244 Xu WW, Jin J, Wu XY, Ren QL, Farzaneh M. MALAT1-related signaling pathways in colorectal cancer. Cancer Cell Int. 2022;22(1):126. https://doi.org/10.1186/s12935-022-02540-yPMid:35305641 PMCid:PMC8933897 Shaker OG, Mahmoud RH, Abdelaleem OO, Ibrahem EG, Mohamed AA, Zaki OM et al. LncRNAs, MALAT1 and lnc-DC as potential biomarkers for multiple sclerosis diagnosis. Biosci Rep. 2019;39(1): BSR20181335. https://doi.org/10.1042/BSR20181335PMid:30514825 PMCid:PMC6331681 Chen J, He Y, Zhou L, Deng Y, Si L. Long noncoding RNA MALAT1 serves as an independent predictive biomarker for the diagnosis, severity and prognosis of patients with sepsis. Mol Med Rep. 2020;21(3):1365-73. https://doi.org/10.3892/mmr.2020.10923 Zhang X, Tang X, Liu K, Hamblin MH, Yin KJ. Long Noncoding RNA Malat1 Regulates Cerebrovascular Pathologies in Ischemic Stroke. J Neurosci. 2017;37(7):1797-806. https://doi.org/10.1523/JNEUROSCI.4850-04.2005https://doi.org/10.1523/JNEUROSCI.3389-16.2017PMid:28093478 PMCid:PMC5320610 Ren H, Wu F, Liu B, Song Z, Qu D. Association of circulating long non-coding RNA MALAT1 in diagnosis, disease surveillance, and prognosis of acute ischemic stroke. Braz J Med Biol Res. 2020;53(12):e9174. https://doi.org/10.1590/1414-431x20209174PMid:33111743 PMCid:PMC7584156 Wang L, Li S, Stone SS, Liu N, Gong K, Ren C et al. The Role of the lncRNA MALAT1 in Neuroprotection against Hypoxic/Ischemic Injury. Biomolecules. 2022;12(1):146. https://doi.org/10.3390/biom12010146https://doi.org/10.3390/biom10010146 Fathy N, Kortam MA, Shaker OG, Sayed NH. Long Noncoding RNAs MALAT1 and ANRIL Gene Variants and the Risk of Cerebral Ischemic Stroke: An Association Study. ACS Chem Neurosci. 2021;12(8):1351-62. https://doi.org/10.1021/acschemneuro.0c00822PMid:33818067 Doll DN, Barr TL, Simpkins JW. Cytokines: their role in stroke and potential use as biomarkers and therapeutic targets. Aging Dis. 2014;5(5):294-306. https://doi.org/10.14336/ad.2014.0500294PMid:25276489 PMCid:PMC4173796 Allan SM, Tyrrell PJ, Rothwell NJ. Interleukin-1 and neuronal injury. Nat Rev Immunol. 2005;5(8):629-40. https://doi.org/10.1038/nri1664PMid:16034365 Nilupul Perera M, Ma HK, Arakawa S, Howells DW, Markus R, Rowe CC et al. Inflammation following stroke. J Clin Neurosci. 2006;13(1):1-8. https://doi.org/10.1016/j.jocn.2005.07.005PMid:16410192 Liu T, Clark RK, McDonnell PC, Young PR, White RF, Barone FC et al. Tumor necrosis factor-alpha expression in ischemic neurons. Stroke. 1994;25(7):1481-8. https://doi.org/10.1161/01.STR.25.7.1481PMid:8023366 Kaminska B. MAPK signalling pathways as molecular targets for anti-inflammatory therapy--from molecular mechanisms to therapeutic benefits. Biochim Biophys Acta. 2005;1754(1-2):253-62. https://doi.org/10.1016/j.bbapap.2005.08.017PMid:16198162 Ahn KS, Aggarwal BB. Transcription factor NF-kappaB: a sensor for smoke and stress signals. Ann N Y Acad Sci. 2005;1056:218-33. https://doi.org/10.1196/annals.1352.026PMid:16387690 McCandless EE, Budde M, Lees JR, Dorsey D, Lyng E, Klein RS. IL-1R signaling within the central nervous system regulates CXCL12 expression at the blood-brain barrier and disease severity during experimental autoimmune encephalomyelitis. J Immunol. 2009;183(1):613-20. https://doi.org/10.4049/jimmunol.0802258PMid:19535637 PMCid:PMC2892701 Wang Q, Zhu Z, Liu Y, Tu X, He J. Relationship between serum vitamin D levels and inflammatory markers in acute stroke patients. Brain Behav. 2018;8(2):e00885. https://doi.org/10.1002/brb3.885PMid:29484258 PMCid:PMC5822590 Shademan B, Nourazarian A, Laghousi D, Karamad V, Nikanfar M. Exploring potential serum levels of Homocysteine, interleukin-1 beta, and apolipoprotein B 48 as new biomarkers for patients with ischemic stroke. J Clin Lab Anal. 2021:e23996. https://doi.org/10.1002/jcla.23996 Mazzotta G, Sarchielli P, Caso V, Paciaroni M, Floridi A, Floridi A et al. Different cytokine levels in thrombolysis patients as predictors for clinical outcome. Eur J Neurol. 2004;11(6):377-81. https://doi.org/10.1111/j.1468-1331.2004.00798.xPMid:15171733 Sotgiu S, Zanda B, Marchetti B, Fois ML, Arru G, Pes GM et al. Inflammatory biomarkers in blood of patients with acute brain ischemia. Eur J Neurol. 2006;13(5):505-13. https://doi.org/10.1111/j.1468-1331.2006.01280.xPMid:16722977 Kim HA, Perrelli A, Ragni A, Retta F, De Silva TM, Sobey CG et al. Vitamin D Deficiency and the Risk of Cerebrovascular Disease. Antioxidants (Basel). 2020;9(4): 327. https://doi.org/10.3390/antiox9040327PMid:32316584 PMCid:PMC7222411 De Silva DA, Talabucon LP, Ng EY, Ang ES, Tan EK, Lee WL. Vitamin D deficiency and its relation to underlying stroke etiology in ethnic Asian ischemic stroke patients. Int J Stroke. 2013;8(5):E18. https://doi.org/10.1111/j.1747-4949.2012.00958.xPMid:23782730 Chai B, Gao F, Wu R, Dong T, Gu C, Lin Q et al. Vitamin D deficiency as a risk factor for dementia and Alzheimer's disease: an updated meta-analysis. BMC Neurol. 2019;19(1):284. https://doi.org/10.1186/s12883-019-1500-6PMid:31722673 PMCid:PMC6854782 Huang GQ, Cheng HR, Wu YM, Cheng QQ, Wang YM, Fu JL et al. Reduced Vitamin D Levels are Associated with Stroke-Associated Pneumonia in Patients with Acute Ischemic Stroke. Clin Interv Aging. 2019;14:2305-14. https://doi.org/10.2147/CIA.S225039https://doi.org/10.2147/CIA.S230255PMid:32021127 PMCid:PMC6946633 Janjusevic M, Gagno G, Fluca AL, Padoan L, Beltrami AP, Sinagra G et al. The peculiar role of vitamin D in the pathophysiology of cardiovascular and neurodegenerative diseases. Life Sci. 2022;289:120193. https://doi.org/10.1016/j.lfs.2021.120193PMid:34864062 Hossein-Nezhad A, Mirzaei K, Keshavarz SA, Ansar H, Saboori S, Tootee A. Evidences of dual role of vitamin D through cellular energy homeostasis and inflammation pathway in risk of cancer in obese subjects. Minerva medica. 2013;104(3):295-307. Wiseman H. Vitamin D is a membrane antioxidant. Ability to inhibit iron-dependent lipid peroxidation in liposomes compared to cholesterol, ergosterol and tamoxifen and relevance to anticancer action FEBS Lett. 1993; 326(1-3): 285-288. https://doi.org/10.1016/0014-5793(93)81809-EPMid:8325381 Bayat M, Kohlmeier KA, Haghani M, Haghighi AB, Khalili A, Bayat G et al. Co-treatment of vitamin D supplementation with enriched environment improves synaptic plasticity and spatial learning and memory in aged rats. Psychopharmacology (Berl). 2021;238(8):2297-312. https://doi.org/10.1007/s00213-021-05853-4PMid:33991198 Poole KE, Loveridge N, Barker PJ, Halsall DJ, Rose C, Reeve J et al. Reduced vitamin D in acute stroke. Stroke. 2006;37(1):243-5. https://doi.org/10.1161/01.STR.0000195184.24297.c1PMid:16322500 Alfieri DF, Lehmann MF, Oliveira SR, Flauzino T, Delongui F, de Araujo MC et al. Vitamin D deficiency is associated with acute ischemic stroke, C-reactive protein, and short-term outcome. Metab Brain Dis. 2017;32(2):493-502. https://doi.org/10.1007/s11011-016-9939-2PMid:27975188 Daubail B, Jacquin A, Guilland JC, Khoumri C, Aboa-Eboule C, Giroud M et al. Association between serum concentration of vitamin D and 1-year mortality in stroke patients. Cerebrovasc Dis. 2014;37(5):364-7. https://doi.org/10.1159/000362534PMid:24970287 Evans MA, Kim HA, Ling YH, Uong S, Vinh A, De Silva TM et al. Vitamin D3 Supplementation Reduces Subsequent Brain Injury and Inflammation Associated with Ischemic Stroke. Neuromolecular medicine. 2018;20(1):147-59. https://doi.org/10.1007/s12017-018-8484-zPMid:29476479 PMCid:PMC5834596 Siniscalchi A, Lochner P, Anticoli S, Chirchiglia D, De Sarro G, Gallelli L. What is the Current Role for Vitamin D and the Risk of Stroke? Current neurovascular research. 2019;16(2):178-83. https://doi.org/10.2174/1567202616666190412152948PMid:30977444 Wajda J, Swiat M, Owczarek AJ, Brzozowska A, Olszanecka-Glinianowicz M, Chudek J. Severity of Vitamin D Deficiency Predicts Mortality in Ischemic Stroke Patients. Dis Markers. 2019;2019:3652894. https://doi.org/10.1155/2019/3652894PMid:31191749 PMCid:PMC6525921 Wei ZN, Kuang JG. Vitamin D deficiency in relation to the poor functional outcomes in nondiabetic patients with ischemic stroke. Biosci Rep. 2018;38(2): BSR20171509. https://doi.org/10.1042/BSR20171509PMid:29437901 PMCid:PMC5835715 Tabrizi R, Moosazadeh M, Akbari M, Dabbaghmanesh MH, Mohamadkhani M, Asemi Z et al. High Prevalence of Vitamin D Deficiency among Iranian Population: A Systematic Review and Meta-Analysis. Iran J Med Sci. 2018;43(2):125-39. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2019;50(12):e344-e418. https://doi.org/10.1161/STR.0000000000000211 Williams LS, Yilmaz EY, Lopez-Yunez AM. Retrospective assessment of initial stroke severity with the NIH Stroke Scale. Stroke. 2000;31(4):858-62. https://doi.org/10.1161/01.STR.31.4.858PMid:10753988 Unger T, Borghi C, Charchar F, Khan NA, Poulter NR, Prabhakaran D et al. 2020 International Society of Hypertension Global Hypertension Practice Guidelines. Hypertension. 2020;75(6):1334-57. https://doi.org/10.1161/HYPERTENSIONAHA.120.15026PMid:32370572 American Diabetes A. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2004;27 Suppl 1:S5-S10. https://doi.org/10.2337/diacare.27.2007.S5PMid:14693921 Balvers MG, Brouwer-Brolsma EM, Endenburg S, de Groot LC, Kok FJ, Gunnewiek JK. Recommended intakes of vitamin D to optimise health, associated circulating 25-hydroxyvitamin D concentrations, and dosing regimens to treat deficiency: workshop report and overview of current literature. J Nutr Sci. 2015;4:e23. https://doi.org/10.1017/jns.2015.10PMid:26090099 PMCid:PMC4463009 Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C T method. Nat Protoc. 2008;3(6):1101. https://doi.org/10.1038/nprot.2008.73PMid:18546601 Chen L, Lu F, Wang Z, Liu L, Yin L, Zhang J et al. Influence of interleukin-1beta gene polymorphism on the risk of myocardial infarction complicated with ischemic stroke. Exp Ther Med. 2018;16(6):5166-70. https://doi.org/10.3892/etm.2018.6842 Gao Q, Wang Y. Long noncoding RNA MALAT1 regulates apoptosis in ischemic stroke by sponging miR-205-3p and modulating PTEN expression. Am J Transl Res. 2020;12(6):2738-48. Xin JW, Jiang YG. Long noncoding RNA MALAT1 inhibits apoptosis induced by oxygen-glucose deprivation and reoxygenation in human brain microvascular endothelial cells. Exp Ther Med. 2017;13(4):1225-34. https://doi.org/10.3892/etm.2017.4095PMid:28413461 PMCid:PMC5377418 Liu C, Zhang C, Yang J, Geng X, Du H, Ji X et al. Screening circular RNA expression patterns following focal cerebral ischemia in mice. Oncotarget. 2017;8(49):86535. https://doi.org/10.18632/oncotarget.21238PMid:29156814 PMCid:PMC5689704 Masoumi F, Ghorbani S, Talebi F, Branton WG, Rajaei S, Power C et al. Malat1 long noncoding RNA regulates inflammation and leukocyte differentiation in experimental autoimmune encephalomyelitis. J Neuroimmunol. 2019;328:50-9. https://doi.org/10.1016/j.jneuroim.2018.11.013PMid:30583215 Nowrouzi-Sohrabi P, Kalani M, Izadpanah P, Ahmadvand H, Fakhour M, Fadaei R et al. Vitamin D status influences cytokine production and MALAT1 expression from the PBMCs of patients with coronary artery disease and healthy controls. Rev Assoc Med Bras (1992). 2020;66(12):1712-7. https://doi.org/10.1590/1806-9282.66.12.1712PMid:33331582 Durrant LR, Bucca G, Hesketh A, Moller-Levet C, Tripkovic L, Wu H et al. Vitamins D2 and D3 Have Overlapping But Different Effects on the Human Immune System Revealed Through Analysis of the Blood Transcriptome. Front Immunol. 2022;13:790444. https://doi.org/10.3389/fimmu.2022.790444PMid:35281034 PMCid:PMC8908317 Roffe-Vazquez DN, Huerta-Delgado AS, Castillo EC, Villarreal-Calderon JR, Gonzalez-Gil AM, Enriquez C et al. Correlation of Vitamin D with Inflammatory Cytokines, Atherosclerotic Parameters, and Lifestyle Factors in the Setting of Heart Failure: A 12-Month Follow-Up Study. Int J Mol Sci. 2019;20(22): 5811. https://doi.org/10.3390/ijms20225811PMid:31752330 PMCid:PMC6887713 Chen Y, Zhang J, Ge X, Du J, Deb DK, Li YC. Vitamin D receptor inhibits nuclear factor kappaB activation by interacting with IkappaB kinase beta protein. J Biol Chem. 2013;288(27):19450-8. https://doi.org/10.1074/jbc.M113.467670PMid:23671281 PMCid:PMC3707648 Nonn L, Peng L, Feldman D, Peehl DM. Inhibition of p38 by vitamin D reduces interleukin-6 production in normal prostate cells via mitogen-activated protein kinase phosphatase 5: implications for prostate cancer prevention by vitamin D. Cancer Res. 2006;66(8):4516-24. https://doi.org/10.1158/0008-5472.CAN-05-3796PMid:16618780

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2023-02-26

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