Significant Effect of Crocin on the Gene Expression of MicroRNA-21 and MicroRNA-155 in Patients with Osteoarthritis
-
Maryam Mohebbi
,
Mahdi Atabaki
,
Jalil Tavakkol-Afshari
,
Zhaleh Shariati-Sarabi
,
Javad Poursamimi
,
Seyed Ahmad Mohajeri
,
Mojgan Mohammadi
Abstract
Osteoarthritis (OA) is the most common form of arthritis associated with gradual joint destruction. The current treatment aims to alleviate pain and inflammation and improve the quality of life. Crocin is an active ingredient in saffron, with anti-inflammatory properties. MicroRNAs are small, non-coding RNAs that regulate gene expression. We aimed to evaluate the effect of crocin on the gene expression of microRNA-146a, microRNA-155, microRNA-223, and microRNA-21 in OA patients and compare it with a placebo.
This study was approved and registered in the Iranian Registry of Clinical Trials (2015021910507N2) and ClinicalTrials.gov identifier: NCT03375814. Forty OA patients were randomly divided into two equal groups, receiving either crocin or placebo. Peripheral blood samples were collected before and four months after the intervention. The pain was assessed using the visual analog scale, and laboratory tests included C-reactive protein and erythrocyte sedimentation rate. The expression levels of microRNA-146a, microRNA-155, microRNA-223, and microRNA-21 genes were evaluated by SYBR Green real-time PCR.
The results showed that the gene expression levels of microRNA-21 and microRNA-155 in patients receiving crocin were significantly decreased and increased, respectively. No significant changes were observed in microRNA-146a and microRNA-223 gene expression levels.
In conclusion, crocin's anti-inflammatory role might be partly attributed to its effects on the gene expression of microRNA-21 and microRNA-155.
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2. Li Y-s, Luo W, Zhu S-a, Lei G-h. T cells in osteoarthritis: alterations and beyond. Frontiers in immunology. 2017;8:356.
3. Valdes AM, Spector TD. Genetic epidemiology of hip and knee osteoarthritis. Nature Reviews Rheumatology. 2011;7(1):23.
4. Blagojevic M, Jinks C, Jeffery A, Jordan K. Risk factors for onset of osteoarthritis of the knee in older adults: a systematic review and meta-analysis. Osteoarthritis and cartilage. 2010;18(1):24-33.
5. Felson DT, Lawrence RC, Dieppe PA, Hirsch R, Helmick CG, Jordan JM, et al. Osteoarthritis: new insights. Part 1: the disease and its risk factors. Annals of internal medicine. 2000;133(8):635-46.
6. Loeser RF, Collins JA, Diekman BO. Ageing and the pathogenesis of osteoarthritis. Nature Reviews Rheumatology. 2016;12(7):412.
7. Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: a disease of the joint as an organ. Arthritis & Rheumatism. 2012;64(6):1697-707.
8. Robinson WH, Lepus CM, Wang Q, Raghu H, Mao R, Lindstrom TM, et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nature Reviews Rheumatology. 2016;12(10):580.
9. Felson DT, Lawrence RC, Hochberg MC, McAlindon T, Dieppe PA, Minor MA, et al. Osteoarthritis: new insights. Part 2: treatment approaches. Annals of internal medicine. 2000;133(9):726-37.
10. Kim C, Nevitt MC, Niu J, Clancy MM, Lane NE, Link TM, et al. Association of hip pain with radiographic evidence of hip osteoarthritis: diagnostic test study. Bmj. 2015;351:h5983.
11. Birchfield PC. Osteoarthritis overview. Geriatric Nursing. 2001;22(3):124-31.
12. Pelletier J-P, Martel-Pelletier J, Rannou F, Cooper C, editors. Efficacy and safety of oral NSAIDs and analgesics in the management of osteoarthritis: Evidence from real-life setting trials and surveys. Seminars in arthritis and rheumatism; 2016: Elsevier.
13. Ding Q, Zhong H, Qi Y, Cheng Y, Li W, Yan S, et al. Anti-arthritic effects of crocin in interleukin-1β-treated articular chondrocytes and cartilage in a rabbit osteoarthritic model. Inflammation Research. 2013;62(1):17-25.
14. Khorasany AR, Hosseinzadeh H. Therapeutic effects of saffron (Crocus sativus L.) in digestive disorders: a review. Iranian journal of basic medical sciences. 2016;19(5):455.
15. Christodoulou E, Kadoglou NP, Kostomitsopoulos N, Valsami G. Saffron: a natural product with potential pharmaceutical applications. Journal of Pharmacy and Pharmacology. 2015;67(12):1634-49.
16. Poma A, Fontecchio G, Carlucci G, Chichiricco G. Anti-inflammatory properties of drugs from saffron crocus. Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Inflammatory and Anti-Allergy Agents). 2012;11(1):37-51.
17. Poursamimi J, Shariati-Sarabi Z, Tavakkol-Afshari J, Mohajeri SA, Ghoryani M, Mohammadi M. Immunoregulatory Effects of Krocina™, a Herbal Medicine Made of Crocin, on Osteoarthritis Patients: A Successful Clinical Trial in Iran. Iranian Journal of Allergy, Asthma and Immunology. 2020.
18. Sepahi S, Mohajeri SA, Hosseini SM, Khodaverdi E, Shoeibi N, Namdari M, et al. Effects of crocin on diabetic maculopathy: A placebo-controlled randomized clinical trial. American journal of ophthalmology. 2018;190:89-98.
19. Collins LJ, Chen XS. Ancestral RNA: the RNA biology of the eukaryotic ancestor. RNA biology. 2009;6(5):495-502.
20. Trachana V, Ntoumou E, Anastasopoulou L, Tsezou A. Studying microRNAs in osteoarthritis: critical overview of different analytical approaches. Mechanisms of ageing and development. 2018;171:15-23.
21. Zhang M, Lygrisse K, Wang J. Role of MicroRNA in osteoarthritis. Journal of arthritis. 2017;6(2).
22. Yu X-M, Meng H-Y, Yuan X-L, Wang Y, Guo Q-Y, Peng J, et al. MicroRNAs’ involvement in osteoarthritis and the prospects for treatments. Evidence-Based Complementary and Alternative Medicine. 2015;2015.
23. Tahamtan A, Teymoori-Rad M, Nakstad B, Salimi V. Anti-inflammatory MicroRNAs and their potential for inflammatory diseases treatment. Frontiers in immunology. 2018;9:1377.
24. Nizyaeva N, Kulikova G, Shchyogolev A, Zemskov V. The role of microRNA in regulation of the body’s immune responses. Biology Bulletin Reviews. 2016;6(6):473-82.
25. Jurkin J, Schichl YM, Koeffel R, Bauer T, Richter S, Konradi S, et al. miR-146a is differentially expressed by myeloid dendritic cell subsets and desensitizes cells to TLR2-dependent activation. The Journal of Immunology. 2010;184(9):4955-65.
26. Hezova R, Kovarikova A, Bienertova-Vasku J, Sachlova M, Redova M, Vasku A, et al. Evaluation of SNPs in miR-196-a2, miR-27a and miR-146a as risk factors of colorectal cancer. World journal of gastroenterology: WJG. 2012;18(22):2827.
27. Swingler T, Niu L, Smith P, Paddy P, Le L, Barter M, et al. The function of microRNAs in cartilage and osteoarthritis. Clinical and Experimental Rheumatology. 2019;37(5):40-7.
28. Sheedy FJ. Turning 21: induction of miR-21 as a key switch in the inflammatory response. Frontiers in immunology. 2015;6:19.
29. Antony J, McGuinness K, Moran K, Connor NEO. Feature Learning to Automatically Assess Radiographic Knee Osteoarthritis Severity. arXiv preprint arXiv:190808840. 2019.
30. Hadizadeh F, Mohajeri S, Seifi M. Extraction and purification of crocin from saffron stigmas employing a simple and efficient crystallization method. Pakistan Journal of Biological Sciences. 2010;13(14):691-8.
31. Kazemi F, Vosough I, Sepahi S, Mohajeri SA. Effect of crocin versus fluoxetine in treatment of mild to moderate obsessive‐compulsive disorder: A double blind randomized clinical trial. Human Psychopharmacology: Clinical and Experimental. 2021:e2780.
32. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. methods. 2001;25(4):402-8.
33. Rao X, Huang X, Zhou Z, Lin X. An improvement of the 2ˆ (–delta delta CT) method for quantitative real-time polymerase chain reaction data analysis. Biostatistics, bioinformatics and biomathematics. 2013;3(3):71.
34. Talaei A, Moghadam MH, Tabassi SAS, Mohajeri SA. Crocin, the main active saffron constituent, as an adjunctive treatment in major depressive disorder: a randomized, double-blind, placebo-controlled, pilot clinical trial. Journal of affective disorders. 2015;174:51-6.
35. Coventry BJ, Ashdown ML, Quinn MA, Markovic SN, Yatomi-Clarke SL, Robinson AP. CRP identifies homeostatic immune oscillations in cancer patients: a potential treatment targeting tool? Journal of translational medicine. 2009;7(1):1-8.
36. Henrotin Y, Gharbi M, Dierckxsens Y, Priem F, Marty M, Seidel L, et al. Decrease of a specific biomarker of collagen degradation in osteoarthritis, Coll2-1, by treatment with highly bioavailable curcumin during an exploratory clinical trial. BMC Complementary and Alternative Medicine. 2014;14(1):1-7.
37. Sahebkar A. Are curcuminoids effective C-reactive protein-lowering agents in clinical practice? Evidence from a meta-analysis. Phytother Res. 2014;28(5):633-42.
38. Hemshekhar M, Santhosh MS, Sunitha K, Thushara R, Kemparaju K, Rangappa K, et al. A dietary colorant crocin mitigates arthritis and associated secondary complications by modulating cartilage deteriorating enzymes, inflammatory mediators and antioxidant status. Biochimie. 2012;94(12):2723-33.
39. Alavizadeh SH, Hosseinzadeh H. Bioactivity assessment and toxicity of crocin: a comprehensive review. Food Chem Toxicol. 2014;64:65-80.
40. Lei M, Guo C, Hua L, Xue S, Yu D, Zhang C, et al. Crocin attenuates joint pain and muscle dysfunction in osteoarthritis rat. Inflammation. 2017;40(6):2086-93.
41. Jones S, Watkins G, Le Good N, Roberts S, Murphy C, Brockbank S, et al. The identification of differentially expressed microRNA in osteoarthritic tissue that modulate the production of TNF-α and MMP13. Osteoarthritis and cartilage. 2009;17(4):464-72.
42. Okuhara A, Nakasa T, Shibuya H, Niimoto T, Adachi N, Deie M, et al. Changes in microRNA expression in peripheral mononuclear cells according to the progression of osteoarthritis. Modern rheumatology. 2012;22(3):446-57.
43. Soyocak A, Kurt H, Ozgen M, Cosan DT, Colak E, Gunes HV. miRNA-146a, miRNA-155 and JNK expression levels in peripheral blood mononuclear cells according to grade of knee osteoarthritis. Gene. 2017;627:207-11.
44. Zhang Y, Jia J, Yang S, Liu X, Ye S, Tian H. MicroRNA-21 controls the development of osteoarthritis by targeting GDF-5 in chondrocytes. Experimental & molecular medicine. 2014;46(2):e79-e.
45. Canfrán‐Duque A, Rotllan N, Zhang X, Fernández‐Fuertes M, Ramírez‐Hidalgo C, Araldi E, et al. Macrophage deficiency of miR‐21 promotes apoptosis, plaque necrosis, and vascular inflammation during atherogenesis. EMBO molecular medicine. 2017;9(9):1244-62.
46. Wang X-b, Zhao F-c, Yi L-h, Tang J-l, Zhu Z-y, Pang Y, et al. MicroRNA-21-5p as a novel therapeutic target for osteoarthritis. Rheumatology. 2019;58(8):1485-97.
2. Li Y-s, Luo W, Zhu S-a, Lei G-h. T cells in osteoarthritis: alterations and beyond. Frontiers in immunology. 2017;8:356.
3. Valdes AM, Spector TD. Genetic epidemiology of hip and knee osteoarthritis. Nature Reviews Rheumatology. 2011;7(1):23.
4. Blagojevic M, Jinks C, Jeffery A, Jordan K. Risk factors for onset of osteoarthritis of the knee in older adults: a systematic review and meta-analysis. Osteoarthritis and cartilage. 2010;18(1):24-33.
5. Felson DT, Lawrence RC, Dieppe PA, Hirsch R, Helmick CG, Jordan JM, et al. Osteoarthritis: new insights. Part 1: the disease and its risk factors. Annals of internal medicine. 2000;133(8):635-46.
6. Loeser RF, Collins JA, Diekman BO. Ageing and the pathogenesis of osteoarthritis. Nature Reviews Rheumatology. 2016;12(7):412.
7. Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: a disease of the joint as an organ. Arthritis & Rheumatism. 2012;64(6):1697-707.
8. Robinson WH, Lepus CM, Wang Q, Raghu H, Mao R, Lindstrom TM, et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nature Reviews Rheumatology. 2016;12(10):580.
9. Felson DT, Lawrence RC, Hochberg MC, McAlindon T, Dieppe PA, Minor MA, et al. Osteoarthritis: new insights. Part 2: treatment approaches. Annals of internal medicine. 2000;133(9):726-37.
10. Kim C, Nevitt MC, Niu J, Clancy MM, Lane NE, Link TM, et al. Association of hip pain with radiographic evidence of hip osteoarthritis: diagnostic test study. Bmj. 2015;351:h5983.
11. Birchfield PC. Osteoarthritis overview. Geriatric Nursing. 2001;22(3):124-31.
12. Pelletier J-P, Martel-Pelletier J, Rannou F, Cooper C, editors. Efficacy and safety of oral NSAIDs and analgesics in the management of osteoarthritis: Evidence from real-life setting trials and surveys. Seminars in arthritis and rheumatism; 2016: Elsevier.
13. Ding Q, Zhong H, Qi Y, Cheng Y, Li W, Yan S, et al. Anti-arthritic effects of crocin in interleukin-1β-treated articular chondrocytes and cartilage in a rabbit osteoarthritic model. Inflammation Research. 2013;62(1):17-25.
14. Khorasany AR, Hosseinzadeh H. Therapeutic effects of saffron (Crocus sativus L.) in digestive disorders: a review. Iranian journal of basic medical sciences. 2016;19(5):455.
15. Christodoulou E, Kadoglou NP, Kostomitsopoulos N, Valsami G. Saffron: a natural product with potential pharmaceutical applications. Journal of Pharmacy and Pharmacology. 2015;67(12):1634-49.
16. Poma A, Fontecchio G, Carlucci G, Chichiricco G. Anti-inflammatory properties of drugs from saffron crocus. Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Inflammatory and Anti-Allergy Agents). 2012;11(1):37-51.
17. Poursamimi J, Shariati-Sarabi Z, Tavakkol-Afshari J, Mohajeri SA, Ghoryani M, Mohammadi M. Immunoregulatory Effects of Krocina™, a Herbal Medicine Made of Crocin, on Osteoarthritis Patients: A Successful Clinical Trial in Iran. Iranian Journal of Allergy, Asthma and Immunology. 2020.
18. Sepahi S, Mohajeri SA, Hosseini SM, Khodaverdi E, Shoeibi N, Namdari M, et al. Effects of crocin on diabetic maculopathy: A placebo-controlled randomized clinical trial. American journal of ophthalmology. 2018;190:89-98.
19. Collins LJ, Chen XS. Ancestral RNA: the RNA biology of the eukaryotic ancestor. RNA biology. 2009;6(5):495-502.
20. Trachana V, Ntoumou E, Anastasopoulou L, Tsezou A. Studying microRNAs in osteoarthritis: critical overview of different analytical approaches. Mechanisms of ageing and development. 2018;171:15-23.
21. Zhang M, Lygrisse K, Wang J. Role of MicroRNA in osteoarthritis. Journal of arthritis. 2017;6(2).
22. Yu X-M, Meng H-Y, Yuan X-L, Wang Y, Guo Q-Y, Peng J, et al. MicroRNAs’ involvement in osteoarthritis and the prospects for treatments. Evidence-Based Complementary and Alternative Medicine. 2015;2015.
23. Tahamtan A, Teymoori-Rad M, Nakstad B, Salimi V. Anti-inflammatory MicroRNAs and their potential for inflammatory diseases treatment. Frontiers in immunology. 2018;9:1377.
24. Nizyaeva N, Kulikova G, Shchyogolev A, Zemskov V. The role of microRNA in regulation of the body’s immune responses. Biology Bulletin Reviews. 2016;6(6):473-82.
25. Jurkin J, Schichl YM, Koeffel R, Bauer T, Richter S, Konradi S, et al. miR-146a is differentially expressed by myeloid dendritic cell subsets and desensitizes cells to TLR2-dependent activation. The Journal of Immunology. 2010;184(9):4955-65.
26. Hezova R, Kovarikova A, Bienertova-Vasku J, Sachlova M, Redova M, Vasku A, et al. Evaluation of SNPs in miR-196-a2, miR-27a and miR-146a as risk factors of colorectal cancer. World journal of gastroenterology: WJG. 2012;18(22):2827.
27. Swingler T, Niu L, Smith P, Paddy P, Le L, Barter M, et al. The function of microRNAs in cartilage and osteoarthritis. Clinical and Experimental Rheumatology. 2019;37(5):40-7.
28. Sheedy FJ. Turning 21: induction of miR-21 as a key switch in the inflammatory response. Frontiers in immunology. 2015;6:19.
29. Antony J, McGuinness K, Moran K, Connor NEO. Feature Learning to Automatically Assess Radiographic Knee Osteoarthritis Severity. arXiv preprint arXiv:190808840. 2019.
30. Hadizadeh F, Mohajeri S, Seifi M. Extraction and purification of crocin from saffron stigmas employing a simple and efficient crystallization method. Pakistan Journal of Biological Sciences. 2010;13(14):691-8.
31. Kazemi F, Vosough I, Sepahi S, Mohajeri SA. Effect of crocin versus fluoxetine in treatment of mild to moderate obsessive‐compulsive disorder: A double blind randomized clinical trial. Human Psychopharmacology: Clinical and Experimental. 2021:e2780.
32. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. methods. 2001;25(4):402-8.
33. Rao X, Huang X, Zhou Z, Lin X. An improvement of the 2ˆ (–delta delta CT) method for quantitative real-time polymerase chain reaction data analysis. Biostatistics, bioinformatics and biomathematics. 2013;3(3):71.
34. Talaei A, Moghadam MH, Tabassi SAS, Mohajeri SA. Crocin, the main active saffron constituent, as an adjunctive treatment in major depressive disorder: a randomized, double-blind, placebo-controlled, pilot clinical trial. Journal of affective disorders. 2015;174:51-6.
35. Coventry BJ, Ashdown ML, Quinn MA, Markovic SN, Yatomi-Clarke SL, Robinson AP. CRP identifies homeostatic immune oscillations in cancer patients: a potential treatment targeting tool? Journal of translational medicine. 2009;7(1):1-8.
36. Henrotin Y, Gharbi M, Dierckxsens Y, Priem F, Marty M, Seidel L, et al. Decrease of a specific biomarker of collagen degradation in osteoarthritis, Coll2-1, by treatment with highly bioavailable curcumin during an exploratory clinical trial. BMC Complementary and Alternative Medicine. 2014;14(1):1-7.
37. Sahebkar A. Are curcuminoids effective C-reactive protein-lowering agents in clinical practice? Evidence from a meta-analysis. Phytother Res. 2014;28(5):633-42.
38. Hemshekhar M, Santhosh MS, Sunitha K, Thushara R, Kemparaju K, Rangappa K, et al. A dietary colorant crocin mitigates arthritis and associated secondary complications by modulating cartilage deteriorating enzymes, inflammatory mediators and antioxidant status. Biochimie. 2012;94(12):2723-33.
39. Alavizadeh SH, Hosseinzadeh H. Bioactivity assessment and toxicity of crocin: a comprehensive review. Food Chem Toxicol. 2014;64:65-80.
40. Lei M, Guo C, Hua L, Xue S, Yu D, Zhang C, et al. Crocin attenuates joint pain and muscle dysfunction in osteoarthritis rat. Inflammation. 2017;40(6):2086-93.
41. Jones S, Watkins G, Le Good N, Roberts S, Murphy C, Brockbank S, et al. The identification of differentially expressed microRNA in osteoarthritic tissue that modulate the production of TNF-α and MMP13. Osteoarthritis and cartilage. 2009;17(4):464-72.
42. Okuhara A, Nakasa T, Shibuya H, Niimoto T, Adachi N, Deie M, et al. Changes in microRNA expression in peripheral mononuclear cells according to the progression of osteoarthritis. Modern rheumatology. 2012;22(3):446-57.
43. Soyocak A, Kurt H, Ozgen M, Cosan DT, Colak E, Gunes HV. miRNA-146a, miRNA-155 and JNK expression levels in peripheral blood mononuclear cells according to grade of knee osteoarthritis. Gene. 2017;627:207-11.
44. Zhang Y, Jia J, Yang S, Liu X, Ye S, Tian H. MicroRNA-21 controls the development of osteoarthritis by targeting GDF-5 in chondrocytes. Experimental & molecular medicine. 2014;46(2):e79-e.
45. Canfrán‐Duque A, Rotllan N, Zhang X, Fernández‐Fuertes M, Ramírez‐Hidalgo C, Araldi E, et al. Macrophage deficiency of miR‐21 promotes apoptosis, plaque necrosis, and vascular inflammation during atherogenesis. EMBO molecular medicine. 2017;9(9):1244-62.
46. Wang X-b, Zhao F-c, Yi L-h, Tang J-l, Zhu Z-y, Pang Y, et al. MicroRNA-21-5p as a novel therapeutic target for osteoarthritis. Rheumatology. 2019;58(8):1485-97.
| Files | ||
| Issue | Vol 21 No 3 (2022) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v21i3.9805 | |
| Keywords | ||
| Clinical trial Inflammation MicroRNAs Osteoarthritis | ||
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How to Cite
1.
Mohebbi M, Atabaki M, Tavakkol-Afshari J, Shariati-Sarabi Z, Poursamimi J, Mohajeri SA, Mohammadi M. Significant Effect of Crocin on the Gene Expression of MicroRNA-21 and MicroRNA-155 in Patients with Osteoarthritis. Iran J Allergy Asthma Immunol. 2022;21(3):322-331.
