Immunoregulatory Effects of Krocina™, a Herbal Medicine Made of Crocin, on Osteoarthritis Patients: A Successful Clinical Trial in Iran
-
Javad Poursamimi
,
Zhaleh Shariati-Sarabi
,
Jalil Tavakkol-Afshari
,
Seyed Ahmad Mohajeri
,
Mohsen Ghoryani
,
Mojgan Mohammadi
Abstract
Osteoarthritis (OA) is the major cause of joint pain and disability. This research was planned to examine the effects of Krocina™, aherbal medicine made of crocin, an ingredient of saffron, in patients with OA.
Forty patients suffering from OA were enrolled in our study and randomly divided into two groups, receiving Krocina™ and placebo, and the clinical trial continued for four months.Peripheral blood was taken from all patients and the percentage ofvarious subsets of T cells in addition to the levels of forkhead box protein P3 (FOXP3) and interleukin (IL)-17 were measured by flow cytometry technique.
The visualan alog scale (VAS) index analysis decreased significantly in both groups (krocinaTM and placebo) (p<0.05). Assessment of the C-reactive protein (CRP) level in serum showed a significant decrease in the krocinaTM group (p<0.05). Moreover, we found a meaningful increase in the percentage of regulatory T cells (Tregs)cellin samples gathered from Krocina™ group (P=0.02) patients. The mean percentages of T helper (Th) 17 cellsinthe Krocina™ group and CD8+ T cellsin the placebo group patients were also meaningfully reduced (p<0.05). The geometric mean fluorescence intensity (GMFI) for IL-17 showed a significant decrease and increase in Krocina™ and placebo groups, respectively (p<0.05). No noticeable difference was observed in the percentages of Th cells and GMFI-FOXP3 in either group. Treg/Th17 ratio was shifted towards Tregscell in Krocina™ group at the end of the intervention.
It is concluded that Krocina™ has immunoregulatory effects on patients with OA, ameliorating the disease.
1. Krasnokutsky S, Samuels J, Abramson SB. Osteoarthritis in 2007. Bulletin-Hospital for joint diseases New York. 2007;65(3):222-8.
2. Berenbaum F, Eymard F, Houard X. Osteoarthritis, inflammation and obesity. CurrOpinRheumatol. 2013;25(1):114-8.
3. Hopps E, Caimi G. Matrix metalloproteinases in metabolic syndrome. Eur J Intern Med. 2012;23(2):99-104.
4. Linton MF, Fazio S. Macrophages, inflammation, and atherosclerosis. Int J Obes. 2003;27(3):35-40.
5. Sakkas LI, Platsoucas CD. The role of T cells in the pathogenesis of osteoarthritis. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 2007;56(2):409-24.
6. Mohamadpour AH, Ayati Z, Parizadeh MR, Rajbai O, Hosseinzadeh H. Safety evaluation of crocin (a constituent of saffron) tablets in healthy volunteers. Iranian Journal of Basic Medical Sciences. 2013;16(1):39-46.
7. Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). 2012;64(4):465-74.
8. Richmond JC. Surgery for osteoarthritis of the knee. Rheumatic Disease Clinics of North America. 2008;34(3):815-25.
9. Abdullaev FI, Espinosa-Aguirre JJ. Biomedical properties of saffron and its potential use in cancer therapy and chemoprevention trials. Cancer Detect Prev. 2004;28(6):426-32.
10. Ochiai T, Shimeno H, Mishima K-i, Iwasaki K, Fujiwara M, Tanaka H, et al. Protective effects of carotenoids from saffron on neuronal injury in vitro and in vivo. Biochimica et Biophysica Acta (BBA)-General Subjects. 2007;1770(4):578-84.
11. Liu W, Sun Y, Cheng Z, Guo Y, Liu P, Wen Y. Crocin exerts anti-inflammatory and anti-arthritic effects on type II collagen-induced arthritis in rats. Pharm Biol. 2018; 56(1):209-16.
12. Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, et al. Development of criteria for the classification and reporting of osteoarthritis: classification of osteoarthritis of the knee. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 1986;29(8):1039-49.
13. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. The Journal of rheumatology. 1988;15(12):1833-40.
14. Kellgren JH, Lawrence JS. Radiological Assessment OfOsteo-Arthrosis. Annals of the rheumatic diseases. 1957;16(4):494.
15. Lequesne MG, Mery C, Samson M, Gerard P. Indexes of severity for osteoarthritis of the hip and knee: validation–value in comparison with other assessment tests. Scand J Rheumatol. 1987;16(65):85-9.
16. Köchli S, Endes K, Steiner R, Engler L, Infanger D, Schmidt-Trucksäss A, et al. Obesity, High Blood Pressure, and Physical Activity Determine Vascular Phenotype in Young Children: The EXAMIN YOUTH Study. Hypertension. 2019;73(1):153-61.
17. Lopresti AL, Drummond PD. Efficacy of curcumin, and a saffron/curcumin combination for the treatment of
major depression: A randomised, double-blind,
placebo-controlled study. J Affect Disord. 2017;207:188-96.
18. Shakiba M, Moazen-Zadeh E, Noorbala AA, Jafarinia M, Divsalar P, Kashani L, et al. Saffron (Crocus sativus) versus duloxetine for treatment of patients with fibromyalgia: A randomized double-blind clinical
trial. Avicenna journal of phytomedicine. 2018;8(6):513-23.
19. Pavelka K. A comparison of the therapeutic efficacy of diclofenac in osteoarthritis: a systematic review of randomised controlled trials. Curr Med Res Opin. 2012;28(1):163-78.
20. 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 Complement Altern Med. 2014;14(1):159.
21. Shi G, Hua M, Xu Q, Ren T. Resveratrol improves treatment outcome and laboratory parameters in patients with Takayasu arteritis: A randomized double-blind and placebo-controlled trial. Immunobiology 2017;222(2):164-68.
22. Sharif M, Elson CJ, Dieppe PA, Kirwan JR. Elevated serum C-reactive protein levels in osteoarthritis. British journal of rheumatology. 1997;36(1):140-1.
23. Zhang L, Li J-m, Liu X-g, Ma D-x, Hu N-w, Li Y-g, et al. Elevated Th22 cells correlated with Th17 cells in patients with rheumatoid arthritis. J Clin Immunol. 2011;31(4):606-14.
24. Vosooghi S, Mahmoudabady M, Neamati A, Aghababa H. Preventive effects of hydroalcoholic extract of saffron on hematological parameters of experimental asthmatic rats. Avicenna journal of phytomedicine. 2013;3(2):279-87.
25. Zengin G, Aumeeruddy MZ, Diuzheva A, Jekő J, Cziáky Z, Yıldıztugay A, et al. A comprehensive appraisal on Crocus chrysanthus (Herb.) Herb. flower extracts with HPLC–MS/MS profiles, antioxidant and enzyme inhibitory properties. J Pharm Biomed Anal. 2019;164:581-9.
26. Kagami S, Rizzo HL, Lee JJ, Koguchi Y, Blauvelt A. Circulating Th17, Th22, and Th1 cells are increased in psoriasis. J Invest Dermatol. 2010;130(5):1373-83.
27. Guo SY, Ding YJ, Li L, Zhang T, Zhang ZZ, Zhang ES. Correlation of CD. Genet Mol Res. 2015;14(3):7290-6.
28. Ponchel F, Burska AN, Hensor EMA, Raja R, Campbell M, Emery P, et al. Changes in peripheral blood immune cell composition in osteoarthritis. Osteoarthritis Cartilage. 2015;23(11):1870-8.
29. Faridi S, Delirezh N, Froushani SMA. Beneficial effects of hydroalcoholic extract of saffron in alleviating experimental autoimmune diabetes in C57bl/6 mice. Iranian Journal of Allergy, Asthma and Immunology. 2019;18(1):38-47.
30. Hussein MR, Fathi NA, El-Din AME, Hassan HI, Abdullah F, Eman A-H, et al. Alterations of the CD4+, CD8+ T cell subsets, interleukins-1β, IL-10, IL-17, tumor necrosis factor-α and soluble intercellular adhesion molecule-1 in rheumatoid arthritis and osteoarthritis: preliminary observations. Pathology & Oncology Research. 2008;14(3):321-8.
31. Ishii H, Tanaka H, Katoh K, Nakamura H, Nagashima M, Yoshino S. Characterization of infiltrating T cells and Th1/Th2-type cytokines in the synovium of patients with osteoarthritis. Osteoarthritis Cartilage. 2002;10(4):277-81.
32. Niu X, He D, Zhang X, Yue T, Li N, Zhang JZ, et al. IL-21 regulates Th17 cells in rheumatoid arthritis. Hum Immunol. 2010;71(4):334-41.
33. Li Y-s, Luo W, Zhu S-a, Lei G-h. T cells in osteoarthritis: alterations and beyond. Front Immunol. 2017;8:356.
34. Dudler J, Renggli-Zulliger N, Busso N, Lotz M, So A. Effect of interleukin 17 on proteoglycan degradation in murine knee joints. Ann Rheum Dis. 2000;59(7):529-32.
35. Magyari L, Varszegi D, Kovesdi E, Sarlos P, Farago B, Javorhazy A, et al. Interleukins and interleukin receptors in rheumatoid arthritis: Research, diagnostics and clinical implications. World journal of orthopedics. 2014;5(4):516.
36. Liu Y, Peng H, Meng Z, Wei M. Correlation of IL-17 level in synovia and severity of knee osteoarthritis. Medical science monitor: international medical journal of experimental and clinical research. 2015;21:1732-6.
37. Raghavan S, Cao D, Widhe M, Roth K, Herrath J, Engström M, et al. FOXP3 expression in blood, synovial fluid and synovial tissue during inflammatory arthritis and intra-articular corticosteroid treatment. Ann Rheum Dis. 2009;68(12):1908-15.
38. Ding J, Su J, Zhang L, Ma J. Crocetin activates Foxp3 through TIPE2 in asthma-associated Treg cells. Cell PhysiolBiochem. 2015;37(6):2425-33.
39. Ferraro A, Socci C, Stabilini A, Valle A, Monti P, Piemonti L, et al. Expansion of Th17 cells and functional defects in T regulatory cells are key features of the pancreatic lymph nodes in patients with type 1 diabetes. Diabetes. 2011;60(11):2903-13.
2. Berenbaum F, Eymard F, Houard X. Osteoarthritis, inflammation and obesity. CurrOpinRheumatol. 2013;25(1):114-8.
3. Hopps E, Caimi G. Matrix metalloproteinases in metabolic syndrome. Eur J Intern Med. 2012;23(2):99-104.
4. Linton MF, Fazio S. Macrophages, inflammation, and atherosclerosis. Int J Obes. 2003;27(3):35-40.
5. Sakkas LI, Platsoucas CD. The role of T cells in the pathogenesis of osteoarthritis. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 2007;56(2):409-24.
6. Mohamadpour AH, Ayati Z, Parizadeh MR, Rajbai O, Hosseinzadeh H. Safety evaluation of crocin (a constituent of saffron) tablets in healthy volunteers. Iranian Journal of Basic Medical Sciences. 2013;16(1):39-46.
7. Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). 2012;64(4):465-74.
8. Richmond JC. Surgery for osteoarthritis of the knee. Rheumatic Disease Clinics of North America. 2008;34(3):815-25.
9. Abdullaev FI, Espinosa-Aguirre JJ. Biomedical properties of saffron and its potential use in cancer therapy and chemoprevention trials. Cancer Detect Prev. 2004;28(6):426-32.
10. Ochiai T, Shimeno H, Mishima K-i, Iwasaki K, Fujiwara M, Tanaka H, et al. Protective effects of carotenoids from saffron on neuronal injury in vitro and in vivo. Biochimica et Biophysica Acta (BBA)-General Subjects. 2007;1770(4):578-84.
11. Liu W, Sun Y, Cheng Z, Guo Y, Liu P, Wen Y. Crocin exerts anti-inflammatory and anti-arthritic effects on type II collagen-induced arthritis in rats. Pharm Biol. 2018; 56(1):209-16.
12. Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, et al. Development of criteria for the classification and reporting of osteoarthritis: classification of osteoarthritis of the knee. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 1986;29(8):1039-49.
13. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. The Journal of rheumatology. 1988;15(12):1833-40.
14. Kellgren JH, Lawrence JS. Radiological Assessment OfOsteo-Arthrosis. Annals of the rheumatic diseases. 1957;16(4):494.
15. Lequesne MG, Mery C, Samson M, Gerard P. Indexes of severity for osteoarthritis of the hip and knee: validation–value in comparison with other assessment tests. Scand J Rheumatol. 1987;16(65):85-9.
16. Köchli S, Endes K, Steiner R, Engler L, Infanger D, Schmidt-Trucksäss A, et al. Obesity, High Blood Pressure, and Physical Activity Determine Vascular Phenotype in Young Children: The EXAMIN YOUTH Study. Hypertension. 2019;73(1):153-61.
17. Lopresti AL, Drummond PD. Efficacy of curcumin, and a saffron/curcumin combination for the treatment of
major depression: A randomised, double-blind,
placebo-controlled study. J Affect Disord. 2017;207:188-96.
18. Shakiba M, Moazen-Zadeh E, Noorbala AA, Jafarinia M, Divsalar P, Kashani L, et al. Saffron (Crocus sativus) versus duloxetine for treatment of patients with fibromyalgia: A randomized double-blind clinical
trial. Avicenna journal of phytomedicine. 2018;8(6):513-23.
19. Pavelka K. A comparison of the therapeutic efficacy of diclofenac in osteoarthritis: a systematic review of randomised controlled trials. Curr Med Res Opin. 2012;28(1):163-78.
20. 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 Complement Altern Med. 2014;14(1):159.
21. Shi G, Hua M, Xu Q, Ren T. Resveratrol improves treatment outcome and laboratory parameters in patients with Takayasu arteritis: A randomized double-blind and placebo-controlled trial. Immunobiology 2017;222(2):164-68.
22. Sharif M, Elson CJ, Dieppe PA, Kirwan JR. Elevated serum C-reactive protein levels in osteoarthritis. British journal of rheumatology. 1997;36(1):140-1.
23. Zhang L, Li J-m, Liu X-g, Ma D-x, Hu N-w, Li Y-g, et al. Elevated Th22 cells correlated with Th17 cells in patients with rheumatoid arthritis. J Clin Immunol. 2011;31(4):606-14.
24. Vosooghi S, Mahmoudabady M, Neamati A, Aghababa H. Preventive effects of hydroalcoholic extract of saffron on hematological parameters of experimental asthmatic rats. Avicenna journal of phytomedicine. 2013;3(2):279-87.
25. Zengin G, Aumeeruddy MZ, Diuzheva A, Jekő J, Cziáky Z, Yıldıztugay A, et al. A comprehensive appraisal on Crocus chrysanthus (Herb.) Herb. flower extracts with HPLC–MS/MS profiles, antioxidant and enzyme inhibitory properties. J Pharm Biomed Anal. 2019;164:581-9.
26. Kagami S, Rizzo HL, Lee JJ, Koguchi Y, Blauvelt A. Circulating Th17, Th22, and Th1 cells are increased in psoriasis. J Invest Dermatol. 2010;130(5):1373-83.
27. Guo SY, Ding YJ, Li L, Zhang T, Zhang ZZ, Zhang ES. Correlation of CD. Genet Mol Res. 2015;14(3):7290-6.
28. Ponchel F, Burska AN, Hensor EMA, Raja R, Campbell M, Emery P, et al. Changes in peripheral blood immune cell composition in osteoarthritis. Osteoarthritis Cartilage. 2015;23(11):1870-8.
29. Faridi S, Delirezh N, Froushani SMA. Beneficial effects of hydroalcoholic extract of saffron in alleviating experimental autoimmune diabetes in C57bl/6 mice. Iranian Journal of Allergy, Asthma and Immunology. 2019;18(1):38-47.
30. Hussein MR, Fathi NA, El-Din AME, Hassan HI, Abdullah F, Eman A-H, et al. Alterations of the CD4+, CD8+ T cell subsets, interleukins-1β, IL-10, IL-17, tumor necrosis factor-α and soluble intercellular adhesion molecule-1 in rheumatoid arthritis and osteoarthritis: preliminary observations. Pathology & Oncology Research. 2008;14(3):321-8.
31. Ishii H, Tanaka H, Katoh K, Nakamura H, Nagashima M, Yoshino S. Characterization of infiltrating T cells and Th1/Th2-type cytokines in the synovium of patients with osteoarthritis. Osteoarthritis Cartilage. 2002;10(4):277-81.
32. Niu X, He D, Zhang X, Yue T, Li N, Zhang JZ, et al. IL-21 regulates Th17 cells in rheumatoid arthritis. Hum Immunol. 2010;71(4):334-41.
33. Li Y-s, Luo W, Zhu S-a, Lei G-h. T cells in osteoarthritis: alterations and beyond. Front Immunol. 2017;8:356.
34. Dudler J, Renggli-Zulliger N, Busso N, Lotz M, So A. Effect of interleukin 17 on proteoglycan degradation in murine knee joints. Ann Rheum Dis. 2000;59(7):529-32.
35. Magyari L, Varszegi D, Kovesdi E, Sarlos P, Farago B, Javorhazy A, et al. Interleukins and interleukin receptors in rheumatoid arthritis: Research, diagnostics and clinical implications. World journal of orthopedics. 2014;5(4):516.
36. Liu Y, Peng H, Meng Z, Wei M. Correlation of IL-17 level in synovia and severity of knee osteoarthritis. Medical science monitor: international medical journal of experimental and clinical research. 2015;21:1732-6.
37. Raghavan S, Cao D, Widhe M, Roth K, Herrath J, Engström M, et al. FOXP3 expression in blood, synovial fluid and synovial tissue during inflammatory arthritis and intra-articular corticosteroid treatment. Ann Rheum Dis. 2009;68(12):1908-15.
38. Ding J, Su J, Zhang L, Ma J. Crocetin activates Foxp3 through TIPE2 in asthma-associated Treg cells. Cell PhysiolBiochem. 2015;37(6):2425-33.
39. Ferraro A, Socci C, Stabilini A, Valle A, Monti P, Piemonti L, et al. Expansion of Th17 cells and functional defects in T regulatory cells are key features of the pancreatic lymph nodes in patients with type 1 diabetes. Diabetes. 2011;60(11):2903-13.
| Files | ||
| Issue | Vol 19, No 3 (2020) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v19i3.3453 | |
| PMID | 32615659 | |
| Keywords | ||
| Clinical trial Crocin Immune regulation Inflammation Osteoarthritis T helper cells | ||
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How to Cite
1.
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. Iran J Allergy Asthma Immunol. 2020;19(3):253-263.
