Mehmet TUZCU, Tansel Ansal BALCI, Beşir ER, Zeynep TUZCU, Mehmet ERDOĞAN

Metotreksat Uygulanan Ratlarda Arjinin Silikat İnositol Kompleksinin Kemik Hasarı Üzerine Etkileri

Antineoplastik bir ilaç olan metotreksat (MTX), kemik deformasyonlarına neden olmaktadır. Arjinin- silikat-inositol (ASİ) kompleksi, kemik sağlığı üzerinde faydalı etkileri olduğu gösterilen arginin, silikon ve inositolün bir bileşimidir. Bu çalışmada, ratlarda ASİ uygulamasının MTX kaynaklı kemik hasarına karşı potansiyel koruyucu rolü araştırıldı. Bu amaçla toplam 28 adet Sprague-Dawley erkek rat dört gruba ayrıldı: i) Kontrol, ii) ASİ; ratlara 15 gün boyunca 25 mg/kg/gün dozunda oral gavaj ile ASİ verildi, iii) MTX; ratlara 8-12. günler arasında 5 gün boyunca subkutan olarak 0.75 mg/kg dozunda MTX enjekte edildi, iv) ASİ+MTX; ratlara 15 gün boyunca 25 mg/kg/gün dozda oral gavaj ile ASİ verildi ve 8-12. günler arasında 5 gün boyunca subkutan olarak 0.75 mg/kg dozunda MTX enjekte edildi. MTX; serum aspartat aminotransferaz (AST), alanin aminotransferaz (ALT), üre (BUN) ve kreatin düzeylerini anlamlı derecede artırırken, tibia osteokalsin düzeyini azaltmıştır (P

Effects of Arginine Silicate Inositol Complex on Bone Damage in Rats Treated with Methotrexate

Methotrexate (MTX), an antineoplastic drug, causes bone deformations. Arginine-silicate- inositol (ASI) complex is a combination of arginine, silicon and inositol that have been shown to have beneficial effects on bone health. In this study, it was investigated the potential protective role of ASI against MTX induced bone damage in rats. For this purpose, a total of 28 Sprague-Dawley male rats were divided into four groups: i) Control; ii) ASI, the rats were treated orally with 25 mg/kg/day of ASI for 15 days; iii) MTX, the rats were injected subcutaneously with 0.75 mg/kg of MTX on 8th and 12th days for 5 days, and iv) ASI+ MTX, the rats were treated orally with 25 mg/kg/day of ASI for 15 days and injected with MTX on 8th and 12th days for 5 days. MTX significantly increased aspartateaminotransferase (AST), alanineaminotransferase (ALT), urea (BUN) and creatine levels, while decreased tibia osteocalcin levels (P

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1. Chen J, Chen X, Yang Z, et al. Preparation and characterization of folic acid functionalized bioactive glass for targeted delivery and sustained release of methotrexate. J Biomed Mater Res A 2018; 1: 1-11.
2. Fan C, Cool JC, Scherer MA, et al. Damaging effects of chronic low-dose methotrexate usage on primary bone formation in young rats and potential protective effects of folinic acid supplementary treatment. Bone 2009; 44: 61- 70.
3. Fan C, Foster BK, Hui SK et al. Prevention of bone growth defects, ıncreased bone resorption and marrow adiposity with folinic acid in rats receiving long-term methotrexate. PLoS One 2012; 7: e46915.
4. Fan C, Garcia M, Scherer M, et al. Potential roles of metallothioneins I and II in protecting bone growth following acute methotrexate chemotherapy. J Chemotherapy 2014; 26: 37-48.
5. Gao Q, Zhou G, Lin SJ, et al. How chemotherapy and radiotherapy damage the tissue: comparative biology lessons from feather and hair models. Exp Dermatol 2018; 1: 1-18.
6. Athanassiadou F, Tragiannidis A, Rousso I, et al. Bone mineral density in survivors of childhood acute lymphoblastic leukemia. Turk J Pediatr 2006; 48: 101- 104.
7. Brufsky AM. Cancer treatment-ınduced bone loss: Pathophysiology and clinical perspectives. The Oncologist 2008; 13: 187-195.
8. Fan J, Su YW, Hassanshahi MH, et al. β-Catenin signaling is important for osteogenesis and hematopoiesis recovery following methotrexate chemotherapy in rats. J Cell Physiol 2021; 236: 3740-3751.
9. Nadhanan RR, Fan CM, Su YW, et al. Fish oil in comparison to folinic acid for protection against adverse effects of methotrexate chemotherapy on bone. J Orthop Res 2014; 32: 587-596.
10. King TJ, Georgiou KR, Cool JC, et al. Methotrexate chemotherapy promotesosteoclast formation in the long bone of rats via increased pro-inflammatory cytokines and enhanced nf-kappab activation. Am J Pathol 2012; 181: 121-129.
11. King TJ, Shandala T, Lee AM, et al. Potential effects of phytoestrogen genistein in modulating acute methotrexate chemotherapy-ınduced osteoclastogenesis and bone damage in rats. Int J Mol Sci 2015; 16: 18293-18311.
12. Al Maruf A, O'Brien PJ, Naserzadeh P, et al. Methotrexate induced mitochondrial injury and cytochrome c release in rat liver hepatocytes. Drug and Chem Toxicol 2017; 1: 1- 11.
13. Crofton PM, Ahmed SF, Wade JC, et al. Effects of intensive chemotherapy on bone and collagen turnover and the growth hormone axis in childrenwith acute lymphoblastic leukemia. J Clin Endocrinol Metab 1998; 83: 3121-3129.
14. Crofton PM, Ahmed SF, Wade JC, et al. Bone turnover and growth during and after continuing chemotherapy in children with acute lymphoblastic leukemia. Pediatr Res 2000; 48: 490-496.
15. Georgiou KR, Hui SK, Xian CJ. Regulatory pathways associated with bone loss and bone marrow adiposity caused by aging, chemotherapy, glucocorticoid therapy and radiotherapy. Am J Stem Cells 2012; 1: 205-224.
16. Georgiou KR, King TJ, Scherer MA, et al. Attenuated Wnt/β-catenin signalling mediates methotrexate chemotherapy-induced bone loss and marrow adiposity in rats. Bone 2012; 50: 1223-1233.
17. Georgiou KR, Scherer MA, Fan CM, et al. Methotrexate chemotherapy reducesosteogenesis but increases adipogenesis potential in the bone marrow. J Cell Physiol 2012; 227: 909-918.
18. Garg A, Leitzel K, Ali S, et al. Antiresorptive therapy in the management of cancer treatment-induced bone loss. Curr Osteoporos Rep 2015; 13: 73-77.
19. Boquete-Castro A, Gomez-Moreno G, Calvo-Guirado JL, et al. Denosumab and osteonecrosis of the jaw. A systematic analysis of events reported in clinical trials. Clin Oral Implants Res 2015; 27: 367-375.
20. Domschke C, Schuetz F. Side effects of bone-targeted therapies in advanced breast cancer. Breast Care 2014; 9: 332-336.
21. Raghu Nadhanan R, Skinner J, Chung R, et al. Supplementation with fish oil and genistein, individually or in combination, protectsbone against the adverse effects of methotrexate chemotherapy in rats. PLoS One 2013; 8: e71592.
22. Xian CJ, Cool JC, Scherer MA, et al. Folinic acid attenuates methotrexate chemotherapy-induced damages on bone growth mechanisms and pools of bone marrow stromal cells. J Cell Physiol 2008; 214: 777-78
23. Liao GS, Apaya MK, Shyur, LF. Herbal medicine and acupuncture for breast cancer palliative care and adjuvant therapy. Evid Based Complement Alternat Med 2013; 1- 17.
24. Sahin K, Ojalvo SP, Akdemir F, et al. Effect of inositol - stabilized arginine silicate on arthritis in a rat model. Food Chem Toxicol 2019; 125: 242-251.
25. Bellati U, Liberati M. Experience regarding the use of arginine-lysine-lactose treatment in menopausal osteoporosis. Minerva Med 1994; 85: 327-332.
26. Clementi G, Fiore CE, Mangano NG, et al. Role of soy diet and L-arginine in cyclosporin-A-induced osteopenia in rats. Pharmacol Toxicol 2001; 88: 16-19.
27. Jugdaohsingh R. Silicon and bone health. J Nutr Health Aging 2007; 11: 99-110.
28. Seaborn CD, Nielsen FH. Silicon deprivation decreases collagen formation in wounds and bone, and ornithine transaminase enzyme activity in liver. Biol Trace Elem Res, 2002; 89: 251-261.
29. Juturu V, Ferry D, Komorowski JR. United States Patent: Arginine slicate inositol complex and use thereof. United States Patent, 2009.
30. Sahin K, Onderci M, Sahin N, et al. Dietary arginine silicate inositol complex improves bone mineralization in quail. Poult Sci 2006; 85: 486-492.
31. Onderci M, Sahin N, Sahin K, et al. Dietary arginine silicate inositol complex during the late laying period of quail at different environmental temperatures. Br Poult Sci 2006; 47: 209-215.
32. Erten F, Tuzcu M, Orhan C, et al. Mango ginger supplementation may protect bone damage induced by methotrexate in rats. Acta Poloniae Pharmaceutica - Drug Research 2019; 76: 305-312.
33. Hair JF, Black WC, Babin BJ, et al. Multivariate Data Analysis. 7th Edition, Prentice Hall: Pearson Education Upper Saddle River, 2014.
34. Corrie PG. Cytotoxic chemotherapy: Clinical aspects. Medicine 2008; 36: 24-28.
35. Verweij J, de Jonge MJA. Achievements and future of chemotherapy. Eur J Cancer 2000; 36: 1479-1487.
36. Lee AMC, Shandala T, Soo PP, et al. Effects of resveratrol supplementation on methotrexate chemotherapy-induced bone loss. Nutrients 2017; 9: 1-15.
37. Park KG. The immunological and metabolic effects of L- arginine in human cancer. Proc Nutr Soc 1993;52:387- 401.
38. Schwarz K, Milne DB. Growth promoting effects of silicon in rats. Nature 1972; 239: 333-334.
39. Carlisle EM. Silicon: a possible factor in bone calcification. Science 1970; 167: 279-780.
40. Proctor SD, Kelly SE, Vine DF. Metabolic effects of a novel silicate inositol complex of the nitric oxide precursor arginine in the obese insulin-resistant JCR: LA-cp rat. Metabolism 2007; 56: 1318-1325.
41. Sahin N, Onderci M, Balci TA, et al. The effect of soy isoflavones on egg quality and bone mineralisation during the late laying period of quail. Br Poult Sci, 2007; 48: 363- 369.
42. Armagan I, Bayram D, Candan IA, et al. Effects of pentoxifylline and alpha lipoic acid on methotrexate- induced damage in liver and kidney of rats. Environ. Toxicol. Pharmacol 2015; 39: 1122-1131.
43. Ali N, Rashid S, Nafees S, et al. Protective effect of chlorogenic acid against methotrexate induced oxidative stress, inflammation and apoptosis in rat liver: an experimental approach. Chem Biol Interact 2017; 272: 80- 91.
44. Mehrzadi S, Fatemi I, Esmaeilizadeh M, et al. Hepatoprotective effect of berberine against methotrexate induced liver toxicity in rats. Biomedicine & Pharmacotherapy 2018; 97: 233-239.
45. Lin Y, Sheng M, Weng Y, et al. Berberine protects against ischemia/reperfusion injury after orthotopic liver transplantation via activating Sirt1/FoxO3alpha induced autophagy. Biochem Biophys Res Commun 2017; 483: 885-891.
46. Hussan F, Ibraheem NG, Kamarudin TA, et al. Curcumin protects against ovariectomy-induced bone changes in rat model. Evid Based Complement Alternat Med 2012; 2012: 1-7.
47. Raisz LG. Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J Clin Invest 2005; 115: 3318- 3325.
48. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003; 423: 337-342.
49. Rachner TD, Kasimir-Bauer S, Göbel A., et al. Prognostic value of RANKL/OPG serum levels and disseminated tumor cells in non-metastatic breast cancer. Clin Cancer Res 2018; 1: 1-22.
50. Russo C, Lazzaro V, Gazzaruso C, et al. Proinsulin C- peptide modulates the expression of ERK1/2, type I collagen and RANKL in human osteoblast-like cells (Saos-2). Molecular and Cellular Endocrinology 2017; 442: 134-141.
51. Nabai L, Kilani RT, Aminuddin F, et al. Methotrexate modulates the expression of MMP-1 and type 1 collagen in dermal fibroblast. Mol Cell Biochem 2015; 409: 213- 224