Protective Effects of Biobran/MGN-3 Against Etoposide-Induced Immune Modulation and Hepatotoxicity in Male Rats

Ali M. Eldib; Heba E. Mostafa; Rania E. Mufti; Zayed M Alnefaie; Osman Suliman; Amr Eldardear; Faris M. Elmahdi; Ibrahim H. Babikir; Sara M. Altom; Mohamed S. El-Gerbed; Mamdooh H. Ghoneum; Sarah A. Almohammadi; Nafisah M. Alshamry; Asma O. Elkhalifa; Ibtihal N. Albalwai; Modhi A. Saleem; Heba S. Khalifa; Attalla F. El-kott; Hytham M. Abdelatif

doi:10.7324/JAPS.2025.228488

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Abstract

A variety of toxicities can result from treatment with chemotherapeutic drugs, including hepatotoxicity and impaired immunity. This study investigates the use of biobran as an adjuvant treatment against toxicity caused by the chemotherapy medication etoposide. 40 rats were divided into 4 groups to study the effects of etoposide (1 mg/kg body weight/day) and biobran (40 mg/kg body weight/day) over a duration of 6 weeks. Rats treated with etoposide exhibited elevated liver enzymes-aspartate aminotransferase and alanine aminotransferase indicating impaired liver function, decreased immunoglobulins M, G (IgM, IgG) revealing reduced immunoglobulin levels (IgM, IgG), indicating diminished antibody production, and elevated oxidative stress markers-malondialdehyde and nitric oxide compared to the control and biobran groups. Biobran supplementation in etoposide-treated rats partially mitigated these effects. In addition, etoposide decreased antioxidant markers-superoxide dismutase-catalase, and reduced glutathione, while biobran increased them significantly. Etoposide also increased the cytokines (IL-4, IL-6, IL-8, and IL-17) while decreased IL10, but biobran reversed these changes. Immunohistochemical analysis revealed elevated levels of pro-inflammatory cytokines-interleukin-1 beta-tumor necrosis factor-alpha and transforming growth factor-beta in etoposide-treated rats, which biobran restored to normal levels. Histopathological analysis also revealed liver damage in rats treated with etoposide, but not in those rats receiving biobran. Flow cytometry indicated that etoposide increased the activity of apoptotic markers caspase-3 and annexin, while Bcl-2 was decreased, effects that were reverted by biobran treatment. Results also showed that immune cell expressions of T cell surface molecules-CD4, CD8, and CD3 in etoposide-treated rats are mitigated by biobran. Collectively, the results of this research demonstrate that biobran can be an effective adjuvant agent to counter the toxic effects and immunological decline resulting from etoposide in cancer chemotherapy.

Keyword: Biobran etoposide immune modulation hepatotoxicity flow cytometry

Citation:

Eldib AM, Mostafa HE, Mufti RE, Alnefaie ZM, Suliman O, Eldardear A, Elmahdi FM, Babikir IH, Altom SM, El-Gerbed MS, Ghoneum MH, Almohammadi SA, Alshamry NM, Elkhalifa AO, Albalwai IN, Saleem MA, Khalifa HS, El-kott AF, Abdelatif HM. Protective Effects of Biobran/MGN-3 Against Etoposide-Induced Immune Modulation and Hepatotoxicity in Male Rats. J Appl Pharm Sci. 2025. Article in Press. http://doi.org/10.7324/JAPS.2025.228488

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1. Lee EM, Jiménez-Fonseca P, Galán-Moral R, Coca-Membribes S, Fernández-Montes A, Sorribes E, et al. Toxicities and quality of life during cancer treatment in advanced solid tumors. Curr Oncol. 2023;30(10):9205-16. https://doi.org/10.3390/curroncol30100665
2. Anand U, Dey A, Chandel AKS, Sanyal R, Mishra A, Pandey DK, et al. Cancer chemotherapy and beyond: current status, drug candidates, associated risks and progress in targeted therapeutics. Genes Dis. 2023;10(4):1367-401. https://doi.org/10.1016/j.gendis.2022.02.007
3. Money ME, Matthews CM, Tan-Shalaby J. Review of under-recognized adjunctive therapies for cancer. Cancers (Basel). 2022;14(19):4780. https://doi.org/10.3390/cancers14194780
4. Eskandari S, Barzegar A, Mahnam K. Absorption of daunorubicin and etoposide drugs by hydroxylated and carboxylated carbon nanotube for drug delivery: theoretical and experimental studies. J Biomol Struct Dyn. 2022;40(20):10057-64. https://doi.org/10.1080/07391102.2021.1938232
5. Fan YW, Liu MH, Xu TJ, Fan RY, Xiang J, Wu JQ, et al. Mechanism of etoposide resistance in small cell lung cancer and the potential therapeutic options. Med Oncol. 2025;42(5):167. https://doi.org/10.1007/s12032-025-02718-0
6. Reyhanoglu G, Tadi P. Etoposide. Treasure Island, FL: StatPearls Publishing; 2025.
7. Montecucco A, Zanetta F, Biamonti G. Molecular mechanisms of etoposide. EXCLI J. 2015;14:95-108.
8. Zhang W, Gou P, Dupret JM, Chomienne C, Rodrigues-Lima F. Etoposide, an anticancer drug involved in therapy-related secondary leukemia: enzymes at play. Transl Oncol. 2021;14(10):101169. https://doi.org/10.1016/j.tranon.2021.101169
9. Morsi RM, Mansour DS, Mousa AM. Ameliorative potential role of Rosmarinus officinalis extract on toxicity induced by etoposide in male albino rats. Braz J Biol. 2022;84:e258234. https://doi.org/10.1590/1519-6984.258234
10. Tran A, Housset C, Boboc B, Tourani JM, Carnot F, Berthelot P. Etoposide (VP 16-213) induced hepatitis. Report of three cases following standard-dose treatments. J Hepatol. 1991;12(1):36-9. https://doi.org/10.1016/0168-8278(91)90905-Q
11. Bailly C. Etoposide: a rider on the cytokine storm. Cytokine. 2023;168:156234. https://doi.org/10.1016/j.cyto.2023.156234
12. Ooi SL, McMullen D, Golombick T, Nut D, Pak SC. Evidence-based review of BioBran/MGN-3 arabinoxylan compound as a complementary therapy for conventional cancer treatment. Integr Cancer Ther. 2018;17(2):165-78. https://doi.org/10.1177/1534735417735379
13. Agrawal S, Agrawal A, Ghoneum M. Biobran/MGN-3, an arabinoxylan rice bran, exerts anti-COVID-19 effects and boosts immunity in human subjects. Nutrients. 2024;16(6):881. https://doi.org/10.3390/nu16060881
14. Spaggiari M, Dall'Asta C, Galaverna G, Del Castillo Bilbao MD. Rice bran by-product: from valorization strategies to nutritional perspectives. Foods. 2021;10(1):85. https://doi.org/10.3390/foods10010085
15. Badr El-Din NK, Abdel Fattah SM, Pan D, Tolentino L, Ghoneum M. Chemopreventive activity of MGN-3/Biobran against chemical induction of glandular stomach carcinogenesis in rats and its apoptotic effect in gastric cancer cells. Integr Cancer Ther. 2016;15(4):Np26- 34. https://doi.org/10.1177/1534735416642287
16. Ashrafujjaman M, Mahtab MA, Noor-E-Alam SM, Rahim MA, Das DC, Ahmed F, et al. Role of biobran (Arabinoxylan Rice Bran) on patients with advanced stage hepatocellular carcinoma. Euroasian J Hepatogastroenterol. 2023;13(2):84-8. https://doi.org/10.5005/jp-journals-10018-1407
17. Bryan LJ, Casulo C, Allen PB, Smith SE, Savas H, Dillehay GL, et al. Pembrolizumab added to ifosfamide, carboplatin, and etoposide chemotherapy for relapsed or refractory classic Hodgkin lymphoma: a multi-institutional phase 2 investigator-initiated nonrandomized clinical trial. JAMA Oncol. 2023;9(5):683-91. https://doi.org/10.1001/jamaoncol.2022.7975
18. Badr El-Din NK, Areida SK, Ahmed KO, Ghoneum M. Arabinoxylan rice bran (MGN-3/Biobran) enhances radiotherapy in animals bearing Ehrlich ascites carcinoma†. J Radiat Res. 2019;60(6):747- 58. https://doi.org/10.1093/jrr/rrz055
19. Moradi M, Hashemian MA, Faramarzi A, Goodarzi N, Hashemian AH, Cheraghi H, et al. Therapeutic effect of sodium alginate on bleomycin, etoposide and cisplatin (BEP)-induced reproductive toxicity by inhibiting nitro-oxidative stress, inflammation and apoptosis. Sci Rep. 2024;14(1):1565. https://doi.org/10.1038/s41598-024-52010-w
20. Gurina TS, Simms L. Histology, staining. Treasure Island, FL: StatPearls Publishing; 2025
21. Leow WQ, Chan AW, Mendoza PGL, Lo R, Yap K, Kim H. Non-alcoholic fatty liver disease: the pathologist's perspective. Clin Mol Hepatol. 2023;29(Suppl):S302-18. https://doi.org/10.3350/cmh.2022.0329
22. Huang XJ, Choi YK, Im HS, Yarimaga O, Yoon E, Kim HS. Aspartate aminotransferase (AST/GOT) and alanine aminotransferase (ALT/ GPT) detection techniques. Sensors (Basel). 2006;6(7):756-82. https://doi.org/10.3390/s6070756
23. Ueno T, Hirayama S, Ito M, Nishioka E, Fukushima Y, Satoh T, et al. Albumin concentration determined by the modified bromocresol purple method is superior to that by the bromocresol green method for assessing nutritional status in malnourished patients with inflammation. Ann Clin Biochem. 2013;50(Pt 6):576-84. https://doi.org/10.1177/0004563213480137
24. Mori L. Modified Jendrassik--Grof method for bilirubins adapted to the Abbott bichromatic analyzer. Clin Chem. 1978;24(10):1841-5. https://doi.org/10.1093/clinchem/24.10.1841
25. Vos JG, Buys J, Beekhof P, Hagenaars AM. Quantification of total IgM and IgG and specific IgM and IgG to a thymus-independent (LPS) and a thymus-dependent (tetanus toxoid) antigen in the rat by enzyme-linked immunosorbent assay (ELISA). Ann N Y Acad Sci. 1979;320:518-34. https://doi.org/10.1111/j.1749-6632.1979.tb13174.x
26. Arsenijevic D, Stojanovic B, Milovanovic J, Arsenijevic A, Simic M, Pergal M, et al. Hepatoprotective effect of mixture of dipropyl polysulfides in concanavalin A-induced hepatitis. Nutrients. 2021;13(3):1022. https://doi.org/10.3390/nu13031022
27. Luan X, Chen P, Li Y, Yuan X, Miao L, Zhang P, et al. TNF-α/IL-1β- licensed hADSCs alleviate cholestatic liver injury and fibrosis in mice via COX-2/PGE2 pathway. Stem Cell Res Ther. 2023;14(1):100. https://doi.org/10.1186/s13287-023-03342-3
28. de Souza Dantas Oliveira SH, de Souza Aarão TL, da Silva Barbosa L, Souza Lisbôa PG, Tavares Dutra CD, Margalho Sousa L, et al. Immunohistochemical analysis of the expression of TNF-alpha, TGF-beta, and caspase-3 in subcutaneous tissue of patients with HIV lipodystrophy syndrome. Microb Pathog. 2014;67-68:41-7. https://doi.org/10.1016/j.micpath.2014.02.004
29. Wlodkowic D, Skommer J, Darzynkiewicz Z. Flow cytometry-based apoptosis detection. Methods Mol Biol. 2009;559:19-32. https://doi.org/10.1007/978-1-60327-017-5_2
30. Bernardo I, Mancebo E, Aguiló I, Anel A, Allende LM, Guerra- Vales JM, et al. Phenotypic and functional evaluation of CD3+CD4- CD8- T cells in human CD8 immunodeficiency. Haematologica. 2011;96(8):1195-203. https://doi.org/10.3324/haematol.2011.041301
31. Elsaid AF, Shaheen M, Ghoneum M., biobran/MGN-3, an arabinoxylan rice bran, enhances NK cell activity in geriatric subjects: a randomized, double-blind, placebo-controlled clinical trial. Exp Ther Med. 2018;15(3):2313-20. https://doi.org/10.3892/etm.2018.5713
32. Badr El-Din NK, Ali DA, Othman R, French SW, Ghoneum M. Chemopreventive role of arabinoxylan rice bran, MGN-3/ Biobran, on liver carcinogenesis in rats. Biomed Pharmacother. 2020;126:110064. https://doi.org/10.1016/j.biopha.2020.110064
33. Mohammadzadeh S, Kiani A, Amiri M. Lycopene modulates hepatic toxicity and testicular injury induced by etoposide in male rats. F S Sci. 2023;4(1):30-35. https://doi.org/10.1016/j.xfss.2022.07.005
34. Tousson E, Bayomy MF, Ahmed AA. Rosemary extract modulates fertility potential, DNA fragmentation, injury, KI67 and P53 alterations induced by etoposide in rat testes. Biomed Pharmacother. 2018;98:769-74. https://doi.org/10.1016/j.biopha.2018.01.025
35. Ooi SL, Micalos PS, Pak SC. Modified rice bran Arabinoxylan by Lentinus edodes mycelial enzyme as an immunoceutical for health and aging-a comprehensive literature review. Molecules. 2023;28(17):6313. https://doi.org/10.3390/molecules28176313
36. Ooi SL, Pak SC, Micalos PS, Schupfer E, Lockley C, Park MH, et al. The health-promoting properties and clinical applications of rice bran Arabinoxylan modified with Shiitake mushroom enzyme-a narrative review. Molecules. 2021;26(9):2539. https://doi.org/10.3390/molecules26092539
37. Hsu FY, Yang SC, Suk FM, Shirakawa H, Chiu WC, Liao YJ. Dietary rice bran attenuates hepatic stellate cell activation and liver fibrosis in mice through enhancing antioxidant ability. J Nutr Biochem. 2024;125:109565. https://doi.org/10.1016/j.jnutbio.2023.109565
38. Li Z, Lin A, Gao Z, Jiang A, Xiong M, Song J, et al. B-cell performance in chemotherapy: unravelling the mystery of B-cell therapeutic potential. Clin Transl Med. 2024;14(7):e1761. https://doi.org/10.1002/ctm2.1761
39. Elsaid AF, Agrawal S, Agrawal A, Ghoneum M. Dietary supplementation with biobran/MGN-3 increases innate resistance and reduces the incidence of influenza-like illnesses in elderly subjects: a randomized, double-blind, placebo-controlled pilot clinical trial. Nutrients. 2021;13(11):4133. https://doi.org/10.3390/nu13114133
40. Koushki M, Khedri A, Aberomand M, Akbari Baghbani K, Mohammadzadeh G. Synergistic anti-cancer effects of silibinin-etoposide combination against human breast carcinoma MCF-7 and MDA-MB-231 cell lines. Iran J Basic Med Sci. 2021;24(9):1211-9.
41. Cao M, Lu H, Yan S, Pang H, Sun L, Li C, et al. Apatinib plus etoposide in pretreated patients with advanced triple-negative breast cancer: a phase II trial. BMC Cancer. 2023;23(1):463. https://doi.org/10.1186/s12885-023-10768-8
42. Zhao Z, Cheng W, Qu W, Wang K. Arabinoxylan rice bran (MGN-3/ Biobran) alleviates radiation-induced intestinal barrier dysfunction of mice in a mitochondrion-dependent manner. Biomed Pharmacother. 2020;124:109855. https://doi.org/10.1016/j.biopha.2020.109855
43. Vallejo MJ, Salazar L, Grijalva M. Oxidative stress modulation and ROS-mediated toxicity in cancer: a review on in vitro models for plant-derived compounds. Oxid Med Cell Longev. 2017;2017:4586068. https://doi.org/10.1155/2017/4586068
44. Noaman E, Badr El-Din NK, Bibars MA, Abou Mossallam AA, Ghoneum M. Antioxidant potential by arabinoxylan rice bran, MGN- 3/biobran, represents a mechanism for its oncostatic effect against murine solid Ehrlich carcinoma. Cancer Lett. 2008;268(2):348-59. https://doi.org/10.1016/j.canlet.2008.04.012
45. Jiang H, Geng D, Liu H, Li Z, Cao J. Co-delivery of etoposide and curcumin by lipid nanoparticulate drug delivery system for the treatment of gastric tumors. Drug Deliv. 2016;23(9):3665-73. https://doi.org/10.1080/10717544.2016.1217954
46. Yang M, Zhang CY. Interleukins in liver disease treatment. World J Hepatol. 2024;16(2):140-5. https://doi.org/10.4254/wjh.v16.i2.140
47. Zimmermann HW, Seidler S, Gassler N, Nattermann J, Luedde T, Trautwein C, et al. Interleukin-8 is activated in patients with chronic liver diseases and associated with hepatic macrophage accumulation in human liver fibrosis. PLoS One. 2011;6(6):e21381. https://doi.org/10.1371/journal.pone.0021381
48. Briukhovetska D, Dörr J, Endres S, Libby P, Dinarello CA, Kobold S. Interleukins in cancer: from biology to therapy. Nat Rev Cancer. 2021;21(8):481-99. https://doi.org/10.1038/s41568-021-00363-z
49. Keeney JTR, Ren X, Warrier G, Noel T, Powell DK, Brelsfoard JM, et al. Doxorubicin-induced elevated oxidative stress and neurochemical alterations in brain and cognitive decline: protection by MESNA and insights into mechanisms of chemotherapy-induced cognitive impairment ("chemobrain"). Oncotarget. 2018;9(54):30324-39. https://doi.org/10.18632/oncotarget.25718
50. Wang C, Zhang F, Cao Y, Zhang M, Wang A, Xu M, et al., Etoposide induces apoptosis in activated human hepatic stellate cells via ER stress. Sci Rep. 2016;6:34330. https://doi.org/10.1038/srep34330
51. Yang SH, Choi HG, Lim SJ, Lee MG, Kim SH. Effects of morin on the pharmacokinetics of etoposide in 7,12-dimethylbenz[a] anthracene-induced mammary tumors in female Sprague-Dawley rats. Oncol Rep. 2013;29(3):1215-23. https://doi.org/10.3892/or.2012.2201
52. Noormohammadi M, Ghorbani Z, Shahinfar H, Shidfar F. Is there any hepatic impact associated with rice bran arabinoxylan compound supplementation? A systematic review and dose-response meta-analysis of randomized controlled trials. Clin Nutr ESPEN. 2023;57:665-75. https://doi.org/10.1016/j.clnesp.2023.08.023
53. Cattrini C, Capaia M, Boccardo F, Barboro P. Etoposide and topoisomerase II inhibition for aggressive prostate cancer: data from a translational study. Cancer Treat Res Commun. 2020;25:100221. https://doi.org/10.1016/j.ctarc.2020.100221
54. Nakazawa A, Nakano N, Fukuda A, Sakamoto S, Imadome K, Kudo T, et al. Use of serial assessment of disease severity and liver biopsy for indication for liver transplantation in pediatric Epstein-Barr virus-induced fulminant hepatic failure. Liver Transpl. 2015;21(3):362-8. https://doi.org/10.1002/lt.24052
55. Ooi SL, Micalos PS, Kim J, Pak SC. Rice bran arabinoxylan compound as a natural product for cancer treatment - an evidence-based assessment of the effects and mechanisms. Pharm Biol. 2024;62(1):367-93. https://doi.org/10.1080/13880209.2024.2349042
56. Yu Y, Zhang J, Wang J, Sun B. The anti-cancer activity and potential clinical application of rice bran extracts and fermentation products. RSC Adv. 2019;9(31):18060-9. https://doi.org/10.1039/C9RA02439E
57. Ghoneum MH, El Sayed NS. Protective effect of biobran/MGN-3 against sporadic alzheimer's disease mouse model: possible role of oxidative stress and apoptotic pathways. Oxid Med Cell Longev. 2021;2021:8845064. https://doi.org/10.1155/2021/8845064
58. Ghoneum M, Agrawal S. Mgn-3/biobran enhances generation of cytotoxic CD8+ T cells via upregulation of dec-205 expression on dendritic cells. Int J Immunopathol Pharmacol. 2014;27(4):523-30. https://doi.org/10.1177/039463201402700408

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Eldib A M [PubMed] [Google Scholar ]

Mostafa H E [PubMed] [Google Scholar ]

Mufti R E [PubMed] [Google Scholar ]

Alnefaie Z M [PubMed] [Google Scholar ]

Suliman O [PubMed] [Google Scholar ]

Eldardear A [PubMed] [Google Scholar ]

Elmahdi F M [PubMed] [Google Scholar ]

Babikir I H [PubMed] [Google Scholar ]

Altom S M [PubMed] [Google Scholar ]

El-Gerbed M S [PubMed] [Google Scholar ]

Ghoneum M H [PubMed] [Google Scholar ]

Almohammadi S A [PubMed] [Google Scholar ]

Alshamry N M [PubMed] [Google Scholar ]

Elkhalifa A O [PubMed] [Google Scholar ]

Albalwai I N [PubMed] [Google Scholar ]

Saleem M A [PubMed] [Google Scholar ]

Khalifa H S [PubMed] [Google Scholar ]

El-kott A F [PubMed] [Google Scholar ]

Abdelatif H M [PubMed] [Google Scholar ]

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1. Lee EM, Jiménez-Fonseca P, Galán-Moral R, Coca-Membribes S, Fernández-Montes A, Sorribes E, et al. Toxicities and quality of life during cancer treatment in advanced solid tumors. Curr Oncol. 2023;30(10):9205-16. https://doi.org/10.3390/curroncol30100665

2. Anand U, Dey A, Chandel AKS, Sanyal R, Mishra A, Pandey DK, et al. Cancer chemotherapy and beyond: current status, drug candidates, associated risks and progress in targeted therapeutics. Genes Dis. 2023;10(4):1367-401. https://doi.org/10.1016/j.gendis.2022.02.007

3. Money ME, Matthews CM, Tan-Shalaby J. Review of under-recognized adjunctive therapies for cancer. Cancers (Basel). 2022;14(19):4780. https://doi.org/10.3390/cancers14194780

4. Eskandari S, Barzegar A, Mahnam K. Absorption of daunorubicin and etoposide drugs by hydroxylated and carboxylated carbon nanotube for drug delivery: theoretical and experimental studies. J Biomol Struct Dyn. 2022;40(20):10057-64. https://doi.org/10.1080/07391102.2021.1938232

5. Fan YW, Liu MH, Xu TJ, Fan RY, Xiang J, Wu JQ, et al. Mechanism of etoposide resistance in small cell lung cancer and the potential therapeutic options. Med Oncol. 2025;42(5):167. https://doi.org/10.1007/s12032-025-02718-0

6. Reyhanoglu G, Tadi P. Etoposide. Treasure Island, FL: StatPearls Publishing; 2025.

7. Montecucco A, Zanetta F, Biamonti G. Molecular mechanisms of etoposide. EXCLI J. 2015;14:95-108.

8. Zhang W, Gou P, Dupret JM, Chomienne C, Rodrigues-Lima F. Etoposide, an anticancer drug involved in therapy-related secondary leukemia: enzymes at play. Transl Oncol. 2021;14(10):101169. https://doi.org/10.1016/j.tranon.2021.101169

9. Morsi RM, Mansour DS, Mousa AM. Ameliorative potential role of Rosmarinus officinalis extract on toxicity induced by etoposide in male albino rats. Braz J Biol. 2022;84:e258234. https://doi.org/10.1590/1519-6984.258234

10. Tran A, Housset C, Boboc B, Tourani JM, Carnot F, Berthelot P. Etoposide (VP 16-213) induced hepatitis. Report of three cases following standard-dose treatments. J Hepatol. 1991;12(1):36-9. https://doi.org/10.1016/0168-8278(91)90905-Q

11. Bailly C. Etoposide: a rider on the cytokine storm. Cytokine. 2023;168:156234. https://doi.org/10.1016/j.cyto.2023.156234

12. Ooi SL, McMullen D, Golombick T, Nut D, Pak SC. Evidence-based review of BioBran/MGN-3 arabinoxylan compound as a complementary therapy for conventional cancer treatment. Integr Cancer Ther. 2018;17(2):165-78. https://doi.org/10.1177/1534735417735379

13. Agrawal S, Agrawal A, Ghoneum M. Biobran/MGN-3, an arabinoxylan rice bran, exerts anti-COVID-19 effects and boosts immunity in human subjects. Nutrients. 2024;16(6):881. https://doi.org/10.3390/nu16060881

14. Spaggiari M, Dall'Asta C, Galaverna G, Del Castillo Bilbao MD. Rice bran by-product: from valorization strategies to nutritional perspectives. Foods. 2021;10(1):85. https://doi.org/10.3390/foods10010085

15. Badr El-Din NK, Abdel Fattah SM, Pan D, Tolentino L, Ghoneum M. Chemopreventive activity of MGN-3/Biobran against chemical induction of glandular stomach carcinogenesis in rats and its apoptotic effect in gastric cancer cells. Integr Cancer Ther. 2016;15(4):Np26- 34. https://doi.org/10.1177/1534735416642287

16. Ashrafujjaman M, Mahtab MA, Noor-E-Alam SM, Rahim MA, Das DC, Ahmed F, et al. Role of biobran (Arabinoxylan Rice Bran) on patients with advanced stage hepatocellular carcinoma. Euroasian J Hepatogastroenterol. 2023;13(2):84-8. https://doi.org/10.5005/jp-journals-10018-1407

17. Bryan LJ, Casulo C, Allen PB, Smith SE, Savas H, Dillehay GL, et al. Pembrolizumab added to ifosfamide, carboplatin, and etoposide chemotherapy for relapsed or refractory classic Hodgkin lymphoma: a multi-institutional phase 2 investigator-initiated nonrandomized clinical trial. JAMA Oncol. 2023;9(5):683-91. https://doi.org/10.1001/jamaoncol.2022.7975

18. Badr El-Din NK, Areida SK, Ahmed KO, Ghoneum M. Arabinoxylan rice bran (MGN-3/Biobran) enhances radiotherapy in animals bearing Ehrlich ascites carcinoma†. J Radiat Res. 2019;60(6):747- 58. https://doi.org/10.1093/jrr/rrz055

19. Moradi M, Hashemian MA, Faramarzi A, Goodarzi N, Hashemian AH, Cheraghi H, et al. Therapeutic effect of sodium alginate on bleomycin, etoposide and cisplatin (BEP)-induced reproductive toxicity by inhibiting nitro-oxidative stress, inflammation and apoptosis. Sci Rep. 2024;14(1):1565. https://doi.org/10.1038/s41598-024-52010-w

20. Gurina TS, Simms L. Histology, staining. Treasure Island, FL: StatPearls Publishing; 2025

21. Leow WQ, Chan AW, Mendoza PGL, Lo R, Yap K, Kim H. Non-alcoholic fatty liver disease: the pathologist's perspective. Clin Mol Hepatol. 2023;29(Suppl):S302-18. https://doi.org/10.3350/cmh.2022.0329

22. Huang XJ, Choi YK, Im HS, Yarimaga O, Yoon E, Kim HS. Aspartate aminotransferase (AST/GOT) and alanine aminotransferase (ALT/ GPT) detection techniques. Sensors (Basel). 2006;6(7):756-82. https://doi.org/10.3390/s6070756

23. Ueno T, Hirayama S, Ito M, Nishioka E, Fukushima Y, Satoh T, et al. Albumin concentration determined by the modified bromocresol purple method is superior to that by the bromocresol green method for assessing nutritional status in malnourished patients with inflammation. Ann Clin Biochem. 2013;50(Pt 6):576-84. https://doi.org/10.1177/0004563213480137

24. Mori L. Modified Jendrassik--Grof method for bilirubins adapted to the Abbott bichromatic analyzer. Clin Chem. 1978;24(10):1841-5. https://doi.org/10.1093/clinchem/24.10.1841

25. Vos JG, Buys J, Beekhof P, Hagenaars AM. Quantification of total IgM and IgG and specific IgM and IgG to a thymus-independent (LPS) and a thymus-dependent (tetanus toxoid) antigen in the rat by enzyme-linked immunosorbent assay (ELISA). Ann N Y Acad Sci. 1979;320:518-34. https://doi.org/10.1111/j.1749-6632.1979.tb13174.x

26. Arsenijevic D, Stojanovic B, Milovanovic J, Arsenijevic A, Simic M, Pergal M, et al. Hepatoprotective effect of mixture of dipropyl polysulfides in concanavalin A-induced hepatitis. Nutrients. 2021;13(3):1022. https://doi.org/10.3390/nu13031022

27. Luan X, Chen P, Li Y, Yuan X, Miao L, Zhang P, et al. TNF-α/IL-1β- licensed hADSCs alleviate cholestatic liver injury and fibrosis in mice via COX-2/PGE2 pathway. Stem Cell Res Ther. 2023;14(1):100. https://doi.org/10.1186/s13287-023-03342-3

28. de Souza Dantas Oliveira SH, de Souza Aarão TL, da Silva Barbosa L, Souza Lisbôa PG, Tavares Dutra CD, Margalho Sousa L, et al. Immunohistochemical analysis of the expression of TNF-alpha, TGF-beta, and caspase-3 in subcutaneous tissue of patients with HIV lipodystrophy syndrome. Microb Pathog. 2014;67-68:41-7. https://doi.org/10.1016/j.micpath.2014.02.004

29. Wlodkowic D, Skommer J, Darzynkiewicz Z. Flow cytometry-based apoptosis detection. Methods Mol Biol. 2009;559:19-32. https://doi.org/10.1007/978-1-60327-017-5_2

30. Bernardo I, Mancebo E, Aguiló I, Anel A, Allende LM, Guerra- Vales JM, et al. Phenotypic and functional evaluation of CD3+CD4- CD8- T cells in human CD8 immunodeficiency. Haematologica. 2011;96(8):1195-203. https://doi.org/10.3324/haematol.2011.041301

31. Elsaid AF, Shaheen M, Ghoneum M., biobran/MGN-3, an arabinoxylan rice bran, enhances NK cell activity in geriatric subjects: a randomized, double-blind, placebo-controlled clinical trial. Exp Ther Med. 2018;15(3):2313-20. https://doi.org/10.3892/etm.2018.5713

32. Badr El-Din NK, Ali DA, Othman R, French SW, Ghoneum M. Chemopreventive role of arabinoxylan rice bran, MGN-3/ Biobran, on liver carcinogenesis in rats. Biomed Pharmacother. 2020;126:110064. https://doi.org/10.1016/j.biopha.2020.110064

33. Mohammadzadeh S, Kiani A, Amiri M. Lycopene modulates hepatic toxicity and testicular injury induced by etoposide in male rats. F S Sci. 2023;4(1):30-35. https://doi.org/10.1016/j.xfss.2022.07.005

34. Tousson E, Bayomy MF, Ahmed AA. Rosemary extract modulates fertility potential, DNA fragmentation, injury, KI67 and P53 alterations induced by etoposide in rat testes. Biomed Pharmacother. 2018;98:769-74. https://doi.org/10.1016/j.biopha.2018.01.025

35. Ooi SL, Micalos PS, Pak SC. Modified rice bran Arabinoxylan by Lentinus edodes mycelial enzyme as an immunoceutical for health and aging-a comprehensive literature review. Molecules. 2023;28(17):6313. https://doi.org/10.3390/molecules28176313

36. Ooi SL, Pak SC, Micalos PS, Schupfer E, Lockley C, Park MH, et al. The health-promoting properties and clinical applications of rice bran Arabinoxylan modified with Shiitake mushroom enzyme-a narrative review. Molecules. 2021;26(9):2539. https://doi.org/10.3390/molecules26092539

37. Hsu FY, Yang SC, Suk FM, Shirakawa H, Chiu WC, Liao YJ. Dietary rice bran attenuates hepatic stellate cell activation and liver fibrosis in mice through enhancing antioxidant ability. J Nutr Biochem. 2024;125:109565. https://doi.org/10.1016/j.jnutbio.2023.109565

38. Li Z, Lin A, Gao Z, Jiang A, Xiong M, Song J, et al. B-cell performance in chemotherapy: unravelling the mystery of B-cell therapeutic potential. Clin Transl Med. 2024;14(7):e1761. https://doi.org/10.1002/ctm2.1761

39. Elsaid AF, Agrawal S, Agrawal A, Ghoneum M. Dietary supplementation with biobran/MGN-3 increases innate resistance and reduces the incidence of influenza-like illnesses in elderly subjects: a randomized, double-blind, placebo-controlled pilot clinical trial. Nutrients. 2021;13(11):4133. https://doi.org/10.3390/nu13114133

40. Koushki M, Khedri A, Aberomand M, Akbari Baghbani K, Mohammadzadeh G. Synergistic anti-cancer effects of silibinin-etoposide combination against human breast carcinoma MCF-7 and MDA-MB-231 cell lines. Iran J Basic Med Sci. 2021;24(9):1211-9.

41. Cao M, Lu H, Yan S, Pang H, Sun L, Li C, et al. Apatinib plus etoposide in pretreated patients with advanced triple-negative breast cancer: a phase II trial. BMC Cancer. 2023;23(1):463. https://doi.org/10.1186/s12885-023-10768-8

42. Zhao Z, Cheng W, Qu W, Wang K. Arabinoxylan rice bran (MGN-3/ Biobran) alleviates radiation-induced intestinal barrier dysfunction of mice in a mitochondrion-dependent manner. Biomed Pharmacother. 2020;124:109855. https://doi.org/10.1016/j.biopha.2020.109855

43. Vallejo MJ, Salazar L, Grijalva M. Oxidative stress modulation and ROS-mediated toxicity in cancer: a review on in vitro models for plant-derived compounds. Oxid Med Cell Longev. 2017;2017:4586068. https://doi.org/10.1155/2017/4586068

44. Noaman E, Badr El-Din NK, Bibars MA, Abou Mossallam AA, Ghoneum M. Antioxidant potential by arabinoxylan rice bran, MGN- 3/biobran, represents a mechanism for its oncostatic effect against murine solid Ehrlich carcinoma. Cancer Lett. 2008;268(2):348-59. https://doi.org/10.1016/j.canlet.2008.04.012

45. Jiang H, Geng D, Liu H, Li Z, Cao J. Co-delivery of etoposide and curcumin by lipid nanoparticulate drug delivery system for the treatment of gastric tumors. Drug Deliv. 2016;23(9):3665-73. https://doi.org/10.1080/10717544.2016.1217954

46. Yang M, Zhang CY. Interleukins in liver disease treatment. World J Hepatol. 2024;16(2):140-5. https://doi.org/10.4254/wjh.v16.i2.140

47. Zimmermann HW, Seidler S, Gassler N, Nattermann J, Luedde T, Trautwein C, et al. Interleukin-8 is activated in patients with chronic liver diseases and associated with hepatic macrophage accumulation in human liver fibrosis. PLoS One. 2011;6(6):e21381. https://doi.org/10.1371/journal.pone.0021381

48. Briukhovetska D, Dörr J, Endres S, Libby P, Dinarello CA, Kobold S. Interleukins in cancer: from biology to therapy. Nat Rev Cancer. 2021;21(8):481-99. https://doi.org/10.1038/s41568-021-00363-z

49. Keeney JTR, Ren X, Warrier G, Noel T, Powell DK, Brelsfoard JM, et al. Doxorubicin-induced elevated oxidative stress and neurochemical alterations in brain and cognitive decline: protection by MESNA and insights into mechanisms of chemotherapy-induced cognitive impairment ("chemobrain"). Oncotarget. 2018;9(54):30324-39. https://doi.org/10.18632/oncotarget.25718

50. Wang C, Zhang F, Cao Y, Zhang M, Wang A, Xu M, et al., Etoposide induces apoptosis in activated human hepatic stellate cells via ER stress. Sci Rep. 2016;6:34330. https://doi.org/10.1038/srep34330

51. Yang SH, Choi HG, Lim SJ, Lee MG, Kim SH. Effects of morin on the pharmacokinetics of etoposide in 7,12-dimethylbenz[a] anthracene-induced mammary tumors in female Sprague-Dawley rats. Oncol Rep. 2013;29(3):1215-23. https://doi.org/10.3892/or.2012.2201

52. Noormohammadi M, Ghorbani Z, Shahinfar H, Shidfar F. Is there any hepatic impact associated with rice bran arabinoxylan compound supplementation? A systematic review and dose-response meta-analysis of randomized controlled trials. Clin Nutr ESPEN. 2023;57:665-75. https://doi.org/10.1016/j.clnesp.2023.08.023

53. Cattrini C, Capaia M, Boccardo F, Barboro P. Etoposide and topoisomerase II inhibition for aggressive prostate cancer: data from a translational study. Cancer Treat Res Commun. 2020;25:100221. https://doi.org/10.1016/j.ctarc.2020.100221

54. Nakazawa A, Nakano N, Fukuda A, Sakamoto S, Imadome K, Kudo T, et al. Use of serial assessment of disease severity and liver biopsy for indication for liver transplantation in pediatric Epstein-Barr virus-induced fulminant hepatic failure. Liver Transpl. 2015;21(3):362-8. https://doi.org/10.1002/lt.24052

55. Ooi SL, Micalos PS, Kim J, Pak SC. Rice bran arabinoxylan compound as a natural product for cancer treatment - an evidence-based assessment of the effects and mechanisms. Pharm Biol. 2024;62(1):367-93. https://doi.org/10.1080/13880209.2024.2349042

56. Yu Y, Zhang J, Wang J, Sun B. The anti-cancer activity and potential clinical application of rice bran extracts and fermentation products. RSC Adv. 2019;9(31):18060-9. https://doi.org/10.1039/C9RA02439E

57. Ghoneum MH, El Sayed NS. Protective effect of biobran/MGN-3 against sporadic alzheimer's disease mouse model: possible role of oxidative stress and apoptotic pathways. Oxid Med Cell Longev. 2021;2021:8845064. https://doi.org/10.1155/2021/8845064

58. Ghoneum M, Agrawal S. Mgn-3/biobran enhances generation of cytotoxic CD8+ T cells via upregulation of dec-205 expression on dendritic cells. Int J Immunopathol Pharmacol. 2014;27(4):523-30. https://doi.org/10.1177/039463201402700408