The Effects and Safety of Silymarin on β-thalassemia in Children and Adolescents:
A Systematic Review based on Clinical Trial Studies

Nasim      Rahimi-Dehkordi; Saeid      Heidari-Soureshjani; Catherine   MT   Sherwin

doi:10.2174/0115748871305325240511122602

Note! Please note that this article is currently in the "Article in Press" stage and is not the final "Version of record". While it has been accepted, copy-edited, and formatted, however, it is still undergoing proofreading and corrections by the authors. Therefore, the text may still change before the final publication. Although "Articles in Press" may not have all bibliographic details available, the DOI and the year of online publication can still be used to cite them. The article title, DOI, publication year, and author(s) should all be included in the citation format. Once the final "Version of record" becomes available the "Article in Press" will be replaced by that.

Abstract

Background: β-thalassemia imposes significant complications on affected patients. Silymarin, a natural flavonoid complex, has potential therapeutic properties.

Objective: This systematic review aims to comprehensively evaluate the literature on the mechanistic effects of Silymarin on β-thalassemia outcomes in children and adolescents.

Methods: A systematic search of electronic databases, including MEDLINE/PubMed, Embase, Scopus, Cochrane Library, and Web of Science (WOS), was done to identify relevant clinical trials before January 2024. Various data were extracted, including study characteristics, outcomes measured (hematological parameters, oxidative stress markers, iron metabolism, and other outcomes), proposed mechanisms, and safety.

Results: By iron chelation effects, Silymarin can reduce reactive oxygen species (ROS) production, increase intracellular antioxidant enzyme glutathione (GSH), and insert antioxidant effects. It also attenuated inflammation through reduced tumor necrosis factor-alpha (TNF-α), transforming growth factor-β1 (TGF-β1), interferon-gamma (IFNγ), C-reactive protein (CRP), interleukin 6 (IL-6), IL-17, and IL-23 levels and increase in IL-4 and IL-10 levels. By reducing iron overload conditions, Silymarin indicates modulatory effects on immune abnormalities, inhibits red blood cell (RBC) hemolysis, increases RBC count, and minimizes the need for a transfusion. Moreover, it reduces myocardial and hepatic siderosis, improves liver function tests, and modifies abnormal enzymes, particularly for aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total bilirubin, and total protein levels. Silymarin also reduces iron overload, increases antioxidant and anti-inflammatory capacity in cardiomyocytes, and reveals antioxidant effects.

Conclusion: Silymarin indicates promising effects on various aspects of children and adolescents with β-thalassemia and has no serious side effects on the investigated dosage.

[1]
Bajwa H, Basit H. Thalassemia. StatPearls. Treasure Island, FL: StatPearls Publishing 2023.

[2]
Kattamis A, Forni GL, Aydinok Y, Viprakasit V. Changing patterns in the epidemiology of β-thalassemia. Eur J Haematol  2020; 105(6): 692-703.
 [http://dx.doi.org/10.1111/ejh.13512] [PMID: 32886826]

[3]
Sanchez-Villalobos M, Blanquer M, Moraleda JM, Salido EJ, Perez-Oliva AB. New insights into pathophysiology of β-thalassemia. Front Med  2022; 9: 880752.
 [http://dx.doi.org/10.3389/fmed.2022.880752] [PMID: 35492364]

[4]
Nienhuis AW, Nathan DG. Pathophysiology and clinical manifestations of the -thalassemias. Cold Spring Harb Perspect Med  2012; 2(12): a011726.
 [http://dx.doi.org/10.1101/cshperspect.a011726] [PMID: 23209183]

[5]
Hossain MJ, Islam MW, Munni UR, et al. Health-related quality of life among thalassemia patients in Bangladesh using the SF-36 questionnaire. Sci Rep  2023; 13(1): 7734.
 [http://dx.doi.org/10.1038/s41598-023-34205-9] [PMID: 37173392]

[6]
Eziefula C, Shah FT, Anie KA. Promoting adherence to iron chelation treatment in beta-thalassemia patients. Patient Prefer Adherence  2022; 16: 1423-37.
 [http://dx.doi.org/10.2147/PPA.S269352] [PMID: 35698633]

[7]
Ali S, Mumtaz S, Shakir HA, et al. Current status of beta-thalassemia and its treatment strategies. Mol Genet Genomic Med  2021; 9(12): e1788.
 [http://dx.doi.org/10.1002/mgg3.1788] [PMID: 34738740]

[8]
Taher AT, Cappellini MD. How I manage medical complications of β-thalassemia in adults. Blood  2018; 132(17): 1781-91.
 [http://dx.doi.org/10.1182/blood-2018-06-818187] [PMID: 30206117]

[9]
Farmakis D, Porter J, Taher A, Domenica Cappellini M, Angastiniotis M, Eleftheriou A. 2021 thalassaemia international federation guidelines for the management of transfusion-dependent thalassemia. HemaSphere  2022; 6(8): e732.
 [http://dx.doi.org/10.1097/HS9.0000000000000732] [PMID: 35928543]

[10]
Di Nicola M, Barteselli G, Dell’Arti L, Ratiglia R, Viola F. Functional and structural abnormalities in deferoxamine retinopathy: A review of the literature. BioMed Res Int  2015; 2015: 1-12.
 [http://dx.doi.org/10.1155/2015/249617] [PMID: 26167477]

[11]
Adibi A, Azin S, Behjat S. Therapeutic effects of deferoxamine and silymarin versus deferoxamine alone in β-thalassemia major based on findings of liver MRI. J Res Med Sci  2012; 1: 73-8.

[12]
Igbokwe IO, Igwenagu E, Igbokwe NA. Aluminium toxicosis: A review of toxic actions and effects. Interdiscip Toxicol  2019; 12(2): 45-70.
 [http://dx.doi.org/10.2478/intox-2019-0007] [PMID: 32206026]

[13]
Tanaka N, Kashiwada Y. Phytochemical studies on traditional herbal medicines based on the ethnopharmacological information obtained by field studies. J Nat Med  2021; 75(4): 762-83.
 [http://dx.doi.org/10.1007/s11418-021-01545-7] [PMID: 34255289]

[14]
Ekor M. The growing use of herbal medicines: Issues relating to adverse reactions and challenges in monitoring safety. Front Pharmacol  2014; 4: 177.
 [http://dx.doi.org/10.3389/fphar.2013.00177] [PMID: 24454289]

[15]
Satari A, Amini SA, Raeisi E, Lemoigne Y, Heidarian E. Synergetic impact of combined 5-fluorouracil and rutin on apoptosis in PC3 cancer cells through the modulation of P53 gene expression. Adv Pharm Bull  2019; 9(3): 462-9.
 [http://dx.doi.org/10.15171/apb.2019.055] [PMID: 31592435]

[16]
Alidoost F, Gharagozloo M, Bagherpour B, et al. Effects of silymarin on the proliferation and glutathione levels of peripheral blood mononuclear cells from β-thalassemia major patients. Int Immunopharmacol  2006; 6(8): 1305-10.
 [http://dx.doi.org/10.1016/j.intimp.2006.04.004] [PMID: 16782543]

[17]
Bencze-Nagy J, Strifler P, Horváth B, et al. Effects of dietary milk thistle (Silybum marianum) supplementation in ducks fed mycotoxin-contaminated diets. Vet Sci  2023; 10(2): 100.
 [http://dx.doi.org/10.3390/vetsci10020100] [PMID: 36851404]

[18]
Bai ZL, Tay V, Guo SZ, Ren J, Shu MG. Silibinin induced human glioblastoma cell apoptosis concomitant with autophagy through simultaneous inhibition of mTOR and YAP. BioMed Res Int  2018; 2018: 1-10.
 [http://dx.doi.org/10.1155/2018/6165192] [PMID: 29780826]

[19]
Darvishi-Khezri H, Kosaryan M, Karami H, et al. Can use of silymarin improve inflammatory status in patients with β-thalassemia major? A crossover, randomized controlled trial. Complement Med Res  2021; 28(2): 123-30.
 [http://dx.doi.org/10.1159/000509829] [PMID: 32971524]

[20]
Darvishi-Khezri H, Salehifar E, Kosaryan M, et al. The impact of silymarin on antioxidant and oxidative status in patients with β-thalassemia major: A crossover, randomized controlled trial. Complement Ther Med  2017; 35: 25-32.
 [http://dx.doi.org/10.1016/j.ctim.2017.08.007] [PMID: 29154063]

[21]
Gharagozloo M, Karimi M, Amirghofran Z. Immunomodulatory effects of silymarin in patients with β-thalassemia major. Int Immunopharmacol  2013; 16(2): 243-7.
 [http://dx.doi.org/10.1016/j.intimp.2013.04.016] [PMID: 23624215]

[22]
Salehifar E, Khezri HD, Kosaryan M. Silymarin therapy and improvement of cardiac outcome in patients with β-thalassemia major. J Res Pharm Pract  2016; 5(1): 74-5.
 [http://dx.doi.org/10.4103/2279-042X.176555] [PMID: 26985440]

[23]
Darvishi-Khezri H. Can silymarin ameliorate β-thalassemia major-induced osteopenia/osteoporosis? J Complement Integr Med  2022; 19(2): 471-2.
 [http://dx.doi.org/10.1515/jcim-2020-0111] [PMID: 34036762]

[24]
Moayedi Esfahani BAS, Reisi N, Mirmoghtadaei M. Evaluating the safety and efficacy of silymarin in β-thalassemia patients: A review. Hemoglobin  2015; 39(2): 75-80.
 [http://dx.doi.org/10.3109/03630269.2014.1003224] [PMID: 25643967]

[25]
Darvishi Khezri H, Salehifar E, Kosaryan M, Aliasgharian A, Jalali H, Hadian Amree A. Potential effects of silymarin and its flavonolignan components in patients with β -thalassemia major: A comprehensive review in 2015. Adv Pharmacol Sci  2016; 2016: 1-8.
 [http://dx.doi.org/10.1155/2016/3046373] [PMID: 26997953]

[26]
Hagag A, Elfatah M. Therapeutic value of silymarin as iron chelator in children with beta thalassemia with iron overload. J Leuk  2014; 2(1): 2-6.
 [http://dx.doi.org/10.4172/2329-6917.1000130]

[27]
Gharagozloo M, Moayedi B, Zakerinia M, et al. Combined therapy of silymarin and desferrioxamine in patients with β-thalassemia major: A randomized double-blind clinical trial. Fundam Clin Pharmacol  2009; 23(3): 359-65.
 [http://dx.doi.org/10.1111/j.1472-8206.2009.00681.x] [PMID: 19453758]

[28]
Hagag AA, Elfrargy MS, Gazar RA, El-Lateef AE. Therapeutic value of combined therapy with deferasirox and silymarin on iron overload in children with Beta thalassemia. Mediterr J Hematol Infect Dis  2013; 5(1): e2013065.
 [http://dx.doi.org/10.4084/mjhid.2013.065] [PMID: 24363880]

[29]
Moayedi B, Gharagozloo M, Esmaeil N, Maracy MR, Hoorfar H, Jalaeikar M. A randomized double-blind, placebo-controlled study of therapeutic effects of silymarin in β-thalassemia major patients receiving desferrioxamine. Eur J Haematol  2013; 90(3): 202-9.
 [http://dx.doi.org/10.1111/ejh.12061] [PMID: 23278124]

[30]
Balouchi S, Gharagozloo M, Esmaeil N, Mirmoghtadaei M, Moayedi B. Serum levels of TGFβ, IL-10, IL-17, and IL-23 cytokines in β-thalassemia major patients: The impact of silymarin therapy. Immunopharmacol Immunotoxicol  2014; 36(4): 271-4.
 [http://dx.doi.org/10.3109/08923973.2014.926916] [PMID: 24945737]

[31]
Hagag A, Elfaragy M, Elrifaey S, Abd El-Lateef A. Therapeutic value of combined therapy with deferiprone and silymarin as iron chelators in Egyptian children with beta thalassemia major. Infect Disord Drug Targets  2015; 15(3): 189-95.
 [http://dx.doi.org/10.2174/1871526515666150731113305] [PMID: 26239735]

[32]
Darvishi-Khezri H, Salehifar E, Kosaryan M, et al. Iron-chelating effect of silymarin in patients with β-thalassemia major: A crossover randomised control trial. Phytother Res  2018; 32(3): 496-503.
 [http://dx.doi.org/10.1002/ptr.5995] [PMID: 29235162]

[33]
Hamed EM, Meabed MH, Hussein RRS, Aly UF. Recent insight on improving the iron chelation efficacy of deferasirox by adjuvant therapy in transfusion dependent beta thalassemia children with sluggish response. Expert Opin Drug Metab Toxicol  2020; 16(3): 179-93.
 [http://dx.doi.org/10.1080/17425255.2020.1729353] [PMID: 32067512]

[34]
Eghbali A, Rahimi Afzal R, Hashemi M, Eghbali A, Taherkhanchi B, Bagheri B. A randomized, controlled study evaluating the effects of silymarin addition to deferasirox on the liver function of children with transfusion-dependent thalassemia. Iran J Ped Hematol Oncol  2021; 11(4): 7169.
 [http://dx.doi.org/10.18502/ijpho.v11i4.7169]

[35]
Reisi N, Esmaeil N, Gharagozloo M, Moayedi B. Therapeutic potential of silymarin as a natural iron-chelating agent in β-thalassemia intermedia. Clin Case Rep  2022; 10(1): e05293.
 [http://dx.doi.org/10.1002/ccr3.5293] [PMID: 35106163]

[36]
Needs T, Gonzalez-Mosquera LF, Lynch DT. Beta Thalassemia. StatPearls. Treasure Island, FL: StatPearls Publishing 2023.

[37]
Voon HPJ, Vadolas J. Controlling -globin: A review of -globin expression and its impact on -thalassemia. Haematologica  2008; 93(12): 1868-76.
 [http://dx.doi.org/10.3324/haematol.13490] [PMID: 18768527]

[38]
Mettananda S, Gibbons RJ, Higgs DR. α-Globin as a molecular target in the treatment of β-thalassemia. Blood  2015; 125(24): 3694-701.
 [http://dx.doi.org/10.1182/blood-2015-03-633594] [PMID: 25869286]

[39]
Oikonomidou PR, Rivella S. What can we learn from ineffective erythropoiesis in thalassemia? Blood Rev  2018; 32(2): 130-43.
 [http://dx.doi.org/10.1016/j.blre.2017.10.001] [PMID: 29054350]

[40]
Wontakal SN, Guo X, Smith C, et al. A core erythroid transcriptional network is repressed by a master regulator of myelo-lymphoid differentiation. Proc Natl Acad Sci USA  2012; 109(10): 3832-7.
 [http://dx.doi.org/10.1073/pnas.1121019109] [PMID: 22357756]

[41]
Abdalla MY, Fawzi M, Al-Maloul SR, El-Banna N, Tayyem RF, Ahmad IM. Increased oxidative stress and iron overload in Jordanian β-thalassemic children. Hemoglobin  2011; 35(1): 67-79.
 [http://dx.doi.org/10.3109/03630269.2010.544624] [PMID: 21250883]

[42]
Voskou S, Aslan M, Fanis P, Phylactides M, Kleanthous M. Oxidative stress in β-thalassaemia and sickle cell disease. Redox Biol  2015; 6: 226-39.
 [http://dx.doi.org/10.1016/j.redox.2015.07.018] [PMID: 26285072]

[43]
Fibach E, Dana M. Oxidative stress in β-thalassemia. Mol Diagn Ther  2019; 23(2): 245-61.
 [http://dx.doi.org/10.1007/s40291-018-0373-5] [PMID: 30484264]

[44]
Haghpanah S, Hosseini-Bensenjan M, Sayadi M, et al. Cytokine levels in patients with β-thalassemia major and healthy individuals: A systematic review and meta-analysis. Clin Lab  2022; 68(11/2022)
 [http://dx.doi.org/10.7754/Clin.Lab.2022.220142] [PMID: 36378002]

[45]
Caprari P, Profumo E, Massimi S, et al. Hemorheological profiles and chronic inflammation markers in transfusion-dependent and non-transfusion- dependent thalassemia. Front Mol Biosci  2023; 9: 1108896.
 [http://dx.doi.org/10.3389/fmolb.2022.1108896] [PMID: 36699704]

[46]
Wagener FADTG, Feldman E, de Witte T, Abraham NG. Heme induces the expression of adhesion molecules ICAM-1, VCAM-1, and E selectin in vascular endothelial cells. Exp Biol Med  1997; 216(3): 456-63.
 [http://dx.doi.org/10.3181/00379727-216-44197] [PMID: 9402154]

[47]
Peng HB, Libby P, Liao JK. Induction and stabilization of I kappa B alpha by nitric oxide mediates inhibition of NF-kappa B. J Biol Chem  1995; 270(23): 14214-9.
 [http://dx.doi.org/10.1074/jbc.270.23.14214] [PMID: 7775482]

[48]
Martinelli T, Whittaker A, Benedettelli S, Carboni A, Andrzejewska J. The study of flavonolignan association patterns in fruits of diverging Silybum marianum (L.) Gaertn. chemotypes provides new insights into the silymarin biosynthetic pathway. Phytochemistry  2017; 144: 9-18.
 [http://dx.doi.org/10.1016/j.phytochem.2017.08.013] [PMID: 28863306]

[49]
Koltai T, Fliegel L. Role of silymarin in cancer treatment: Facts, hypotheses, and questions. J Evid Based Integr Med  2022; 27: 2515690x211068826.

[50]
Xu F, Han C, Li Y, et al. The chemical constituents and pharmacological actions of Silybum marianum. Curr Nutr Food Sci  2019; 15(5): 430-40.
 [http://dx.doi.org/10.2174/1573401314666180327155745]

[51]
Gillessen A, Schmidt HHJ. Silymarin as supportive treatment in liver diseases: A narrative review. Adv Ther  2020; 37(4): 1279-301.
 [http://dx.doi.org/10.1007/s12325-020-01251-y] [PMID: 32065376]

[52]
Wadhwa K, Pahwa R, Kumar M, et al. Mechanistic insights into the pharmacological significance of silymarin. Molecules  2022; 27(16): 5327.
 [http://dx.doi.org/10.3390/molecules27165327] [PMID: 36014565]

[53]
Biedermann D, Vavříková E, Cvak L, Křen V. Chemistry of silybin. Nat Prod Rep  2014; 31(9): 1138-57.
 [http://dx.doi.org/10.1039/C3NP70122K] [PMID: 24977260]

[54]
Fatima T, Khan S, Khan MM, Kamran R, Uddin MW, Sohrab S. Oxidative stress in beta-thalassemia patients: Role of enzymatic and non-enzymatic modulators. Protein Pept Lett  2023; 30(12): 1030-7.
 [http://dx.doi.org/10.2174/0109298665246270231020062048] [PMID: 37953620]

[55]
Hirsch RE, Sibmooh N, Fucharoen S, Friedman JM. HbE/β-thalassemia and oxidative stress: The key to pathophysiological mechanisms and novel therapeutics. Antioxid Redox Signal  2017; 26(14): 794-813.
 [http://dx.doi.org/10.1089/ars.2016.6806] [PMID: 27650096]

[56]
Surai P. Silymarin as a natural antioxidant: An overview of the current evidence and perspectives. Antioxidants  2015; 4(1): 204-47.
 [http://dx.doi.org/10.3390/antiox4010204] [PMID: 26785346]

[57]
Zholobenko A, Modriansky M. Silymarin and its constituents in cardiac preconditioning. Fitoterapia  2014; 97: 122-32.
 [http://dx.doi.org/10.1016/j.fitote.2014.05.016] [PMID: 24879900]

[58]
Anthony K, Saleh M. Free radical scavenging and antioxidant activities of silymarin components. Antioxidants  2013; 2(4): 398-407.
 [http://dx.doi.org/10.3390/antiox2040398] [PMID: 26784472]

[59]
Serçe A, Toptancı BÇ, Tanrıkut SE, et al. Assessment of the antioxidant activity of silybum marianum extract and its protective effect against DNA oxidation, protein damage and lipid peroxidation. Food Technol Biotechnol  2016; 54(4): 455-61.
 [http://dx.doi.org/10.17113/ftb.54.04.16.4323] [PMID: 28115903]

[60]
Vargas-Mendoza N, Morales-González Á, Morales-Martínez M, et al. Flavolignans from silymarin as Nrf2 bioactivators and their therapeutic applications. Biomedicines  2020; 8(5): 122.
 [http://dx.doi.org/10.3390/biomedicines8050122] [PMID: 32423098]

[61]
Roubalová L, Dinkova-Kostova AT, Biedermann D, Křen V, Ulrichová J, Vrba J. Flavonolignan 2,3-dehydrosilydianin activates Nrf2 and upregulates NAD(P)H: quinone oxidoreductase 1 in Hepa1c1c7 cells. Fitoterapia  2017; 119: 115-20.
 [http://dx.doi.org/10.1016/j.fitote.2017.04.012] [PMID: 28450126]

[62]
Veisi S, Johari SA, Tyler CR, Mansouri B, Esmaeilbeigi M. Antioxidant properties of dietary supplements of free and nanoencapsulated silymarin and their ameliorative effects on silver nanoparticles induced oxidative stress in Nile tilapia (Oreochromis niloticus). Environ Sci Pollut Res Int  2021; 28(20): 26055-63.
 [http://dx.doi.org/10.1007/s11356-021-12568-8] [PMID: 33483926]

[63]
Banaee M, Impellitteri F, Multisanti CR, et al. Evaluating silymarin extract as a potent antioxidant supplement in diazinon-exposed rainbow trout: Oxidative stress and biochemical parameter analysis. Toxics  2023; 11(9): 737.
 [http://dx.doi.org/10.3390/toxics11090737] [PMID: 37755747]

[64]
Bresgen N, Eckl P. Oxidative stress and the homeodynamics of iron metabolism. Biomolecules  2015; 5(2): 808-47.
 [http://dx.doi.org/10.3390/biom5020808] [PMID: 25970586]

[65]
Jain M, Rivera S, Monclus EA, et al. Mitochondrial reactive oxygen species regulate transforming growth factor-β signaling. J Biol Chem  2013; 288(2): 770-7.
 [http://dx.doi.org/10.1074/jbc.M112.431973] [PMID: 23204521]

[66]
Khazaei R, Seidavi A, Bouyeh M. A review on the mechanisms of the effect of silymarin in milk thistle ( Silybum marianum ) on some laboratory animals. Vet Med Sci  2022; 8(1): 289-301.
 [http://dx.doi.org/10.1002/vms3.641] [PMID: 34599793]

[67]
Shahidi M, Vaziri F, Haerian A, et al. Proliferative and anti-inflammatory effects of resveratrol and silymarin on human gingival fibroblasts: A view to the future. J Dent  2017; 14(4): 203-11.
 [PMID: 29285030]

[68]
Kim BR, Seo HS, Ku JM, et al. Silibinin inhibits the production of pro-inflammatory cytokines through inhibition of NF-κB signaling pathway in HMC-1 human mast cells. Inflamm Res  2013; 62(11): 941-50.
 [http://dx.doi.org/10.1007/s00011-013-0640-1] [PMID: 24045679]

[69]
Kang JS, Jeon YJ, Kim HM, Han SH, Yang KH. Inhibition of inducible nitric-oxide synthase expression by silymarin in lipopolysaccharide-stimulated macrophages. J Pharmacol Exp Ther  2002; 302(1): 138-44.
 [http://dx.doi.org/10.1124/jpet.302.1.138] [PMID: 12065710]

[70]
Zheng W, Feng Z, Lou Y, et al. Silibinin protects against osteoarthritis through inhibiting the inflammatory response and cartilage matrix degradation in vitro and in vivo. Oncotarget  2017; 8(59): 99649-65.
 [http://dx.doi.org/10.18632/oncotarget.20587] [PMID: 29245931]

[71]
Ranjan S, Gautam A. Pharmaceutical prospects of Silymarin for the treatment of neurological patients: An updated insight. Front Neurosci  2023; 17: 1159806.
 [http://dx.doi.org/10.3389/fnins.2023.1159806] [PMID: 37274201]

[72]
Farmakis D, Giakoumis A, Polymeropoulos E, Aessopos A. Pathogenetic aspects of immune deficiency associated with beta-thalassemia. Med Sci Monit  2003; 9(1): RA19-22.
 [PMID: 12552254]

[73]
Gluba-Brzózka A, Franczyk B, Rysz-Górzyńska M, Rokicki R, Koziarska-Rościszewska M, Rysz J. Pathomechanisms of immunological disturbances in β-thalassemia. Int J Mol Sci  2021; 22(18): 9677.
 [http://dx.doi.org/10.3390/ijms22189677] [PMID: 34575839]

[74]
Walker EM Jr, Walker SM. Effects of iron overload on the immune system. Ann Clin Lab Sci  2000; 30(4): 354-65.
 [PMID: 11045759]

[75]
Tyrkalska SD, Pérez-Oliva AB, Rodríguez-Ruiz L, et al. Inflammasome regulates hematopoiesis through cleavage of the master erythroid transcription factor GATA1. Immunity  2019; 51(1): 50-63.e5.
 [http://dx.doi.org/10.1016/j.immuni.2019.05.005] [PMID: 31174991]

[76]
Mishra AK, Tiwari A. Iron overload in Beta thalassaemia major and intermedia patients. Maedica  2013; 8(4): 328-32.
 [PMID: 24790662]

[77]
Rivella S. Ineffective erythropoiesis and thalassemias. Curr Opin Hematol  2009; 16(3): 187-94.
 [http://dx.doi.org/10.1097/MOH.0b013e32832990a4] [PMID: 19318943]

[78]
Eid R, Arab NTT, Greenwood MT. Iron mediated toxicity and programmed cell death: A review and a re-examination of existing paradigms. Biochim Biophys Acta Mol Cell Res  2017; 1864(2): 399-430.
 [http://dx.doi.org/10.1016/j.bbamcr.2016.12.002] [PMID: 27939167]

[79]
Akhtar MN, Saeed R, Saeed F, et al. Silymarin: a review on paving the way towards promising pharmacological agent. Int J Food Prop  2023; 26(1): 2256-72.
 [http://dx.doi.org/10.1080/10942912.2023.2244685]

[80]
Imam M, Zhang S, Ma J, Wang H, Wang F. Antioxidants mediate both iron homeostasis and oxidative stress. Nutrients  2017; 9(7): 671.
 [http://dx.doi.org/10.3390/nu9070671] [PMID: 28657578]

[81]
Razavi BM, Karimi G. Protective effect of silymarin against chemical-induced cardiotoxicity. Iran J Basic Med Sci  2016; 19(9): 916-23.
 [PMID: 27803777]

[82]
Chaichompoo P, Qillah A, Sirankapracha P, et al. Abnormal red blood cell morphological changes in thalassaemia associated with iron overload and oxidative stress. J Clin Pathol  2019; 72(8): 520-4.
 [http://dx.doi.org/10.1136/jclinpath-2019-205775] [PMID: 31010830]

[83]
Altorjay I, Dalmi L, Sári B, Imre S, Balla G. The effect of silibinin (Legalon) on the the free radical scavenger mechanisms of human erythrocytes in vitro. Acta Physiol Hung  1992; 80(1-4): 375-80.
 [PMID: 1345204]

[84]
Zou CG, Agar NS, Jones GL. Oxidative insult to human red blood cells induced by free radical initiator AAPH and its inhibition by a commercial antioxidant mixture. Life Sci  2001; 69(1): 75-86.
 [http://dx.doi.org/10.1016/S0024-3205(01)01112-2] [PMID: 11411807]

[85]
Soltanian A, Mosallanejad B, Razi Jalali M, Najafzadeh Varzi H, Ghorbanpour M. Comparative evaluation of therapeutic effects of silymarin and hydrocortisone on clinical and hematological alterations, and organ injury (liver and heart) in a low-dose canine lipopolysaccharide-induced sepsis model. Vet Res Forum  2020; 11(3): 235-41.
 [PMID: 33133460]

[86]
Padeniya P, Ediriweera D, De Silva AP, Niriella M, Premawardhena A. The association between steatosis and liver damage in transfusion-dependent beta thalassaemia patients. Br J Haematol  2023; 200(4): 517-23.
 [http://dx.doi.org/10.1111/bjh.18492] [PMID: 36194160]

[87]
Cappellini MD, Cohen A, Eleftheriou A. Guidelines for the clinical management of thalassaemia. The Liver in Thalassaemia .  (2nd ed.), Nicosia (CY): Thalassaemia International Federation 2008.

[88]
Pinyopornpanish K, Tantiworawit A, Leerapun A, Soontornpun A, Thongsawat S. Secondary iron overload and the liver: A comprehensive review. J Clin Transl Hepatol  2023; 11(4): 932-41.
 [http://dx.doi.org/10.14218/JCTH.2022.00420] [PMID: 37408825]

[89]
Lee YY, Tee V. Role of silymarin in the management of deranged liver function in non-alcoholic steatohepatitis: A case report. Drugs Context  2023; 12: 1-5.
 [http://dx.doi.org/10.7573/dic.2023-2-10] [PMID: 37342459]

[90]
Pennell DJ, Udelson JE, Arai AE, et al. Cardiovascular function and treatment in β-thalassemia major: A consensus statement from the American Heart Association. Circulation  2013; 128(3): 281-308.
 [http://dx.doi.org/10.1161/CIR.0b013e31829b2be6] [PMID: 23775258]

[91]
Russo V, Melillo E, Papa AA, Rago A, Chamberland C, Nigro G. Arrhythmias and sudden cardiac death in beta-thalassemia major patients: Noninvasive diagnostic tools and early markers. Cardiol Res Pract  2019; 2019: 1-8.
 [http://dx.doi.org/10.1155/2019/9319832] [PMID: 31885907]

[92]
Walker M, Wood J. Cardiac complications in thalassaemia major. Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT) .  (3rd ed.), Nicosia (CY): Thalassaemia International Federation 2014.

[93]
Kumfu S, Chattipakorn SC, Chattipakorn N. Iron overload cardiomyopathy: Using the latest evidence to inform future applications. Exp Biol Med  2022; 247(7): 574-83.
 [http://dx.doi.org/10.1177/15353702221076397] [PMID: 35130741]

[94]
Kadoglou NPE, Panayiotou C, Vardas M, et al. A comprehensive review of the cardiovascular protective properties of silibinin/silymarin: A new kid on the block. Pharmaceuticals  2022; 15(5): 538.
 [http://dx.doi.org/10.3390/ph15050538] [PMID: 35631363]

[95]
Chung WS, Lin CL, Lin CL, Kao CH. Thalassaemia and risk of cancer: A population-based cohort study. J Epidemiol Community Health  2015; 69(11): 1066-70.
 [http://dx.doi.org/10.1136/jech-2014-205075] [PMID: 25922472]

[96]
Marsella M, Ricchi P. Thalassemia and hepatocellular carcinoma: Links and risks. J Blood Med  2019; 10: 323-34.
 [http://dx.doi.org/10.2147/JBM.S186362] [PMID: 31572038]

[97]
De Sanctis V, Soliman AT, Daar S, et al. A concise review on the frequency, major risk factors and surveillance of hepatocellular carcinoma (HCC) in β-thalassemias: Past, present and future perspectives and the ICET-A experience. Mediterr J Hematol Infect Dis  2020; 12(1): e2020006.
 [http://dx.doi.org/10.4084/mjhid.2020.006] [PMID: 31934316]

[98]
Fargion S, Valenti L, Fracanzani AL. Role of iron in hepatocellular carcinoma. Clin Liver Dis  2014; 3(5): 108-10.
 [http://dx.doi.org/10.1002/cld.350] [PMID: 30992900]

[99]
Paganoni R, Lechel A, Vujic Spasic M. Iron at the interface of hepatocellular carcinoma. Int J Mol Sci  2021; 22(8): 4097.
 [http://dx.doi.org/10.3390/ijms22084097] [PMID: 33921027]

[100]
Zhang C, Li H, Li J, Hu J, Yang K, Tao L. Oxidative stress: A common pathological state in a high-risk population for osteoporosis. Biomed Pharmacother  2023; 163: 114834.
 [http://dx.doi.org/10.1016/j.biopha.2023.114834] [PMID: 37163779]

[101]
Gaudio A, Morabito N, Catalano A, Rapisarda R, Xourafa A, Lasco A. Pathogenesis of thalassemia major-associated osteoporosis: A review with insights from clinical experience. J Clin Res Pediatr Endocrinol  2019; 11(2): 110-7.
 [http://dx.doi.org/10.4274/jcrpe.galenos.2018.2018.0074] [PMID: 29991466]

[102]
Voskaridou E, Terpos E. Pathogenesis and management of osteoporosis in thalassemia. Pediatr Endocrinol Rev  2008; 6 (Suppl. 1): 86-93.
 [PMID: 19337161]

[103]
Valizadeh N, Farrokhi F, Alinejad V, et al. Bone density in transfusion dependent thalassemia patients in Urmia, Iran. Iran J Ped Hematol Oncol  2014; 4(2): 68-71.
 [PMID: 25002928]

[104]
Kim JL, Kang SW, Kang MK, et al. Osteoblastogenesis and osteoprotection enhanced by flavonolignan silibinin in osteoblasts and osteoclasts. J Cell Biochem  2012; 113(1): 247-59.
 [http://dx.doi.org/10.1002/jcb.23351] [PMID: 21898547]

[105]
Kim JH, Kim K, Jin HM, et al. Silibinin inhibits osteoclast differentiation mediated by TNF family members. Mol Cells  2009; 28(3): 201-8.
 [http://dx.doi.org/10.1007/s10059-009-0123-y] [PMID: 19756392]

[106]
Seidlová-Wuttke D, Becker T, Christoffel V, Jarry H, Wuttke W. Silymarin is a selective estrogen receptor β (ERβ) agonist and has estrogenic effects in the metaphysis of the femur but no or antiestrogenic effects in the uterus of ovariectomized (ovx) rats. J Steroid Biochem Mol Biol  2003; 86(2): 179-88.
 [http://dx.doi.org/10.1016/S0960-0760(03)00270-X] [PMID: 14568570]

[107]
El-Shitany NA, Hegazy S, El-desoky K. Evidences for antiosteoporotic and selective estrogen receptor modulator activity of silymarin compared with ethinylestradiol in ovariectomized rats. Phytomedicine  2010; 17(2): 116-25.
 [http://dx.doi.org/10.1016/j.phymed.2009.05.012] [PMID: 19577454]

[108]
Mulrow C, Lawrence V, Jacobs B. Milk thistle: Effects on liver disease and cirrhosis and clinical adverse effects: Summary.  AHRQ Evidence Report Summaries.  Rockville (MD): Agency for Healthcare Research and Quality (US); 1998-2005 2000; p. 21.

[109]
Soleimani V, Delghandi PS, Moallem SA, Karimi G. Safety and toxicity of silymarin, the major constituent of milk thistle extract: An updated review. Phytother Res  2019; 33(6): 1627-38.
 [http://dx.doi.org/10.1002/ptr.6361] [PMID: 31069872]

[110]
Hawke RL, Schrieber SJ, Soule TA, et al. Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C. J Clin Pharmacol  2010; 50(4): 434-49.
 [http://dx.doi.org/10.1177/0091270009347475] [PMID: 19841158]

[111]
Doehmer J, Tewes B, Klein KU, Gritzko K, Muschick H, Mengs U. Assessment of drug–drug interaction for silymarin. Toxicol In Vitro  2008; 22(3): 610-7.
 [http://dx.doi.org/10.1016/j.tiv.2007.11.020] [PMID: 18249085]

[112]
Zhang W, Zhang Y, Wen C, Jiang X, Wang L. In vitro assessment of the effects of silybin on CYP2B6-mediated metabolism. Planta Med  2023; 89(13): 1195-203.
 [http://dx.doi.org/10.1055/a-2102-0648] [PMID: 37236224]

[113]
Faisal Z, Mohos V, Fliszár-Nyúl E, et al. Interaction of silymarin components and their sulfate metabolites with human serum albumin and cytochrome P450 (2C9, 2C19, 2D6, and 3A4) enzymes. Biomed Pharmacother  2021; 138: 111459.
 [http://dx.doi.org/10.1016/j.biopha.2021.111459] [PMID: 33706132]

[114]
Jančová P, Anzenbacherová E, Papoušková B, et al. Silybin is metabolized by cytochrome P450 2C8 in vitro. Drug Metab Dispos  2007; 35(11): 2035-9.
 [http://dx.doi.org/10.1124/dmd.107.016410] [PMID: 17670841]

[115]
Kawaguchi-Suzuki M, Frye RF, Zhu HJ, et al. The effects of milk thistle (Silybum marianum) on human cytochrome P450 activity. Drug Metab Dispos  2014; 42(10): 1611-6.
 [http://dx.doi.org/10.1124/dmd.114.057232] [PMID: 25028567]

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DOI https://dx.doi.org/10.2174/0115748871305325240511122602	Print ISSN 1574-8871
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