The Protective Effects of Silymarin on the Reproductive Toxicity: A
Comprehensive Review

doi:10.2174/0929867330666230130115332
摘要

生殖系统极易受到化疗药物、电离辐射、有毒重金属、化学物质等的伤害。这些有害刺激可诱导生殖器官的氧化损伤、细胞凋亡、炎症等机制，导致不同的生殖不良效应。研究表明，使用药用植物(中草药)可以有效地预防和治疗多种健康状况。水飞蓟素是一种从水飞蓟种子中提取的草药提取物。即使在相对较高的生理剂量值下，这种草药制剂也是无毒的，这表明它可以安全用于治疗各种疾病。水飞蓟素的肝、神经、心脏和肾保护作用已经被评估过。水飞蓟素具有抗氧化、抗凋亡、抗炎、抗纤维化、免疫调节和膜稳定等保护作用。本文就水飞蓟素对生殖毒性的保护作用的研究进展进行综述。并对水飞蓟素抗细胞毒性的分子机制进行了研究。此外，还讨论了水飞蓟素改进配方和给药系统的发现。
关键词: 生殖毒性，水飞蓟素，化疗，放疗，重金属，化学品。
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[1]
Wang, R.; Song, B.; Wu, J.; Zhang, Y.; Chen, A.; Shao, L. Potential adverse effects of nanoparticles on the reproductive system. Int. J. Nanomedicine,  2018, 13, 8487-8506.
 [http://dx.doi.org/10.2147/IJN.S170723] [PMID: 30587973]

[2]
Haghi-Aminjan, H.; Asghari, M.H.; Farhood, B.; Rahimifard, M.; Goradel, N.H.; Abdollahi, M. The role of melatonin on chemotherapy-induced reproductive toxicity. J. Pharm. Pharmacol.,  2018, 70(3), 291-306.
 [http://dx.doi.org/10.1111/jphp.12855] [PMID: 29168173]

[3]
Farhood, B.; Mortezaee, K.; Haghi-Aminjan, H.; Khanlarkhani, N.; Salehi, E.; Nashtaei, M.S.; Najafi, M.; Sahebkar, A. A systematic review of radiation-induced testicular toxicities following radiotherapy for prostate cancer. J. Cell. Physiol.,  2019, 234(9), 14828-14837.
 [http://dx.doi.org/10.1002/jcp.28283] [PMID: 30740683]

[4]
Pant, N.; Kumar, G.; Upadhyay, A.D.; Patel, D.K.; Gupta, Y.K.; Chaturvedi, P.K. Reproductive toxicity of lead, cadmium, and phthalate exposure in men. Environ. Sci. Pollut. Res. Int.,  2014, 21(18), 11066-11074.
 [http://dx.doi.org/10.1007/s11356-014-2986-5] [PMID: 24816463]

[5]
Patwa, J.; Sharma, A.; Flora, S.J.S. Arsenic, cadmium, and lead. In: Reproductive and Developmental Toxicology, 3rd ed; Gupta, R.C., Ed.; Academic Press: Cambridge, 2022; pp. 547-571.
 [http://dx.doi.org/10.1016/B978-0-323-89773-0.00029-1]

[6]
Emokpae, M.A.; Moronkeji, M.A. Comparison of sperm indices, selected markers of oxidative stress and sex hormones among males with primary and secondary infertility in Osogbo, Nigeria. J. Infertil. Reprod. Biol.,  2022, 10(1), 10-14.

[7]
Mortezaee, K.; Motallebzadeh, E.; Milajerdi, A.; Farhood, B.; Najafi, M.; Sahebkar, A. The effect of prostate cancer radiotherapy on testosterone level: A systematic review and meta-analysis. Anticancer. Agents Med. Chem.,  2020, 20(6), 636-642.
 [http://dx.doi.org/10.2174/1871520620666200128112558] [PMID: 31994469]

[8]
Bäckström, T.; Mählck, C.G.; Kjellgren, O. Progesterone as a possible tumor marker for “nonendocrine” ovarian malignant tumors. Gynecol. Oncol.,  1983, 16(1), 129-138.
 [http://dx.doi.org/10.1016/0090-8258(83)90018-5] [PMID: 6884825]

[9]
Bao, R.; Xu, P.; Wang, Y.; Wang, J.; Xiao, L.; Li, G.; Zhang, C. Bone marrow derived mesenchymal stem cells transplantation rescues premature ovarian insufficiency induced by chemotherapy. Gynecol. Endocrinol.,  2018, 34(4), 320-326.
 [http://dx.doi.org/10.1080/09513590.2017.1393661] [PMID: 29073798]

[10]
Ahmad Khan, M.S.; Ahmad, I. Chapter 1 - Herbal medicine: Current trends and future prospects. In: New Look to Phytomedicine; Ahmad Khan, M.S.; Ahmad, I.; Chattopadhyay, D., Eds.; Academic Press: Cambridge, 2019; pp. 3-13.

[11]
Ahmed, R.F.; Moussa, R.A.; Eldemerdash, R.S.; Zakaria, M.M.; Abdel-Gaber, S.A. Ameliorative effects of silymarin on HCl-induced acute lung injury in rats; role of the Nrf-2/HO-1 pathway. Iran. J. Basic Med. Sci.,  2019, 22(12), 1483-1492.
 [PMID: 32133068]

[12]
Schindler, H. Active substances in pharmaceutical plants; methods to determine plant tinctures; contributions to a supplementary issue of the homoiopathic pharmacopeia. Arzneimittelforschung,  1952, 2(6), 291-296.
 [PMID: 12977653]

[13]
Hahn, G.; Lehmann, H.D.; Kürten, M.; Uebel, H.; Vogel, G. On the pharmacology and toxicology of silymarin, an antihepatotoxic active principle from Silybum marianum (L.) Gaertn. Arzneimittelforschung,  1968, 18(6), 698-704.
 [PMID: 5755807]

[14]
Comelli, M.C.; Mengs, U.; Schneider, C.; Prosdocimi, M. Toward the definition of the mechanism of action of silymarin: Activities related to cellular protection from toxic damage induced by chemotherapy. Integr. Cancer Ther.,  2007, 6(2), 120-129.
 [http://dx.doi.org/10.1177/1534735407302349] [PMID: 17548791]

[15]
Ligeret, H.; Brault, A.; Vallerand, D.; Haddad, Y.; Haddad, P.S. Antioxidant and mitochondrial protective effects of silibinin in cold preservation–warm reperfusion liver injury. J. Ethnopharmacol.,  2008, 115(3), 507-514.
 [http://dx.doi.org/10.1016/j.jep.2007.10.024] [PMID: 18061382]

[16]
Ferenci, P.; Dragosics, B.; Dittrich, H.; Frank, H.; Benda, L.; Lochs, H.; Meryn, S.; Base, W.; Schneider, B. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J. Hepatol.,  1989, 9(1), 105-113.
 [http://dx.doi.org/10.1016/0168-8278(89)90083-4] [PMID: 2671116]

[17]
Abenavoli, L.; Milic, N. Silymarin for liver disease. In: Liver Pathophysiology; Muriel, P., Ed.; Academic Press: Boston, 2017; pp. 621-631.
 [http://dx.doi.org/10.1016/B978-0-12-804274-8.00045-X]

[18]
Gazák, R.; Walterová, D.; Kren, V. Silybin and silymarin--new and emerging applications in medicine. Curr. Med. Chem.,  2007, 14(3), 315-338.
 [http://dx.doi.org/10.2174/092986707779941159] [PMID: 17305535]

[19]
Subramanian, A.K.; Prabhakar, R.; Vikram, N.R.; Dinesh, S.S.; Rajeshkumar, S. In vitro anti-inflammatory activity of silymarin/hydroxyapatite/chitosan nanocomposites and its cytotoxic effect using brine shrimp lethality assay. J. Popul. Ther. Clin. Pharmacol.,  2022, 28(2), e71-e77.
 [PMID: 35044118]

[20]
Féher, J.; Lengyel, G. Silymarin in the prevention and treatment of liver diseases and primary liver cancer. Curr. Pharm. Biotechnol.,  2012, 13(1), 210-217.
 [http://dx.doi.org/10.2174/138920112798868818] [PMID: 21466434]

[21]
Singh, R.P.; Agarwal, R. Flavonoid antioxidant silymarin and skin cancer. Antioxid. Redox Signal.,  2002, 4(4), 655-663.
 [http://dx.doi.org/10.1089/15230860260220166] [PMID: 12230878]

[22]
Yu, H.C.; Chen, L.J.; Cheng, K.C.; Li, Y.X.; Yeh, C.H.; Cheng, J.T. Silymarin inhibits cervical cancer cell through an increase of phosphatase and tensin homolog. Phytother. Res.,  2012, 26(5), 709-715.
 [http://dx.doi.org/10.1002/ptr.3618] [PMID: 22016029]

[23]
Zhu, W.; Zhang, J.S.; Young, C.Y. Silymarin inhibits function of the androgen receptor by reducing nuclear localization of the receptor in the human prostate cancer cell line LNCaP. Carcinogenesis,  2001, 22(9), 1399-1403.
 [http://dx.doi.org/10.1093/carcin/22.9.1399] [PMID: 11532861]

[24]
Barros, T.M.B.; Lima, A.P.B.; Almeida, T.C.; Silva, G.N. Inhibition of urinary bladder cancer cell proliferation by silibinin. Environ. Mol. Mutagen.,  2020, 61(4), 445-455.
 [http://dx.doi.org/10.1002/em.22363] [PMID: 32078183]

[25]
Koltai, T.; Fliegel, L. Role of silymarin in cancer treatment: Facts, hypotheses, and questions. J. Evid. Based Integr. Med.,  2022, 27, 2515690X211068826.
 [http://dx.doi.org/10.1177/2515690X211068826]

[26]
Kim, S.H.; Choo, G.S.; Yoo, E.S.; Woo, J.S.; Lee, J.H.; Han, S.H.; Jung, S.H.; Kim, H.J.; Jung, J.Y. Silymarin inhibits proliferation of human breast cancer cells via regulation of the MAPK signaling pathway and induction of apoptosis. Oncol. Lett.,  2021, 21(6), 492.
 [http://dx.doi.org/10.3892/ol.2021.12753] [PMID: 33968208]

[27]
Wu, T.; Liu, W.; Guo, W.; Zhu, X. Silymarin suppressed lung cancer growth in mice via inhibiting myeloid-derived suppressor cells. Biomed. Pharmacother.,  2016, 81, 460-467.
 [http://dx.doi.org/10.1016/j.biopha.2016.04.039] [PMID: 27261626]

[28]
Testino, G.; Leone, S.; Ansaldi, F.; Borro, P. Silymarin and S-adenosyl-L-methionine (SAMe): Two promising pharmacological agents in case of chronic alcoholic hepathopathy. A review and a point of view. Minerva Gastroenterol. Dietol.,  2013, 59(4), 341-356.
 [PMID: 24212353]

[29]
Zholobenko, A.; Modriansky, M. Silymarin and its constituents in cardiac preconditioning. Fitoterapia,  2014, 97, 122-132.
 [http://dx.doi.org/10.1016/j.fitote.2014.05.016] [PMID: 24879900]

[30]
Vargas-Mendoza, N.; Madrigal-Santillán, E.; Morales-González, A.; Esquivel-Soto, J.; Esquivel-Chirino, C.; García-Luna Y González-Rubio, M.; Gayosso-de-Lucio, J.A.; Morales-González, J.A. Hepatoprotective effect of silymarin. World J. Hepatol.,  2014, 6(3), 144-149.
 [http://dx.doi.org/10.4254/wjh.v6.i3.144] [PMID: 24672644]

[31]
Surai, P. Silymarin as a natural antioxidant: An overview of the current evidence and perspectives. Antioxidants,  2015, 4(1), 204-247.
 [http://dx.doi.org/10.3390/antiox4010204] [PMID: 26785346]

[32]
Guzel, S.; Sahinogullari, Z.U.; Canacankatan, N.; Antmen, S.E.; Kibar, D.; Coskun Yilmaz, B. Potential renoprotective effects of silymarin against vancomycin-induced nephrotoxicity in rats. Drug Chem. Toxicol.,  2020, 43(6), 630-636.
 [http://dx.doi.org/10.1080/01480545.2019.1584208] [PMID: 30862206]

[33]
Taleb, A.; Ahmad, K.A.; Ihsan, A.U.; Qu, J.; Lin, N.; Hezam, K.; Koju, N.; Hui, L.; Qilong, D. Antioxidant effects and mechanism of silymarin in oxidative stress induced cardiovascular diseases. Biomed. Pharmacother.,  2018, 102, 689-698.
 [http://dx.doi.org/10.1016/j.biopha.2018.03.140] [PMID: 29604588]

[34]
Abd Eldaim, M.A.; Barakat, E.R.; Alkafafy, M.; Elaziz, S.A.A. Antioxidant and anti-apoptotic prophylactic effect of silymarin against lead-induced hepatorenal toxicity in rats. Environ. Sci. Pollut. Res. Int.,  2021, 28(41), 57997-58006.
 [http://dx.doi.org/10.1007/s11356-021-14722-8] [PMID: 34100211]

[35]
Ferraz, A.C.; Almeida, L.T.; da Silva Caetano, C.C.; da Silva Menegatto, M.B.; Souza Lima, R.L.; de Senna, J.P.N.; de Oliveira Cardoso, J.M.; Perucci, L.O.; Talvani, A.; Geraldo de Lima, W.; de Mello Silva, B.; Barbosa Reis, A.; de Magalhães, J.C.; Lopes de Brito Magalhães, C. Hepatoprotective, antioxidant, anti-inflammatory, and antiviral activities of silymarin against mayaro virus infection. Antiviral Res.,  2021, 194, 105168.
 [http://dx.doi.org/10.1016/j.antiviral.2021.105168] [PMID: 34437912]

[36]
Post-White, J.; Ladas, E.J.; Kelly, K.M. Advances in the use of milk thistle (Silybum marianum). Integr. Cancer Ther.,  2007, 6(2), 104-109.
 [http://dx.doi.org/10.1177/1534735407301632] [PMID: 17548789]

[37]
Hosseinabadi, T.; Lorigooini, Z.; Tabarzad, M.; Salehi, B.; Rodrigues, C.F.; Martins, N.; Sharifi-Rad, J. Silymarin antiproliferative and apoptotic effects: Insights into its clinical impact in various types of cancer. Phytother. Res.,  2019, 33(11), 2849-2861.
 [http://dx.doi.org/10.1002/ptr.6470] [PMID: 31407422]

[38]
Akbari-Kordkheyli, V.; Abbaszadeh-Goudarzi, K.; Nejati-Laskokalayeh, M.; Zarpou, S.; Khonakdar-Tarsi, A. The protective effects of silymarin on ischemia-reperfusion injuries: A mechanistic review. Iran. J. Basic Med. Sci.,  2019, 22(9), 968-976.
 [PMID: 31807239]

[39]
Soleimani, V.; Delghandi, P.S.; Moallem, S.A.; Karimi, G. Safety and toxicity of silymarin, the major constituent of milk thistle extract: An updated review. Phytother. Res.,  2019, 33(6), 1627-1638.
 [http://dx.doi.org/10.1002/ptr.6361] [PMID: 31069872]

[40]
Bijak, M. Silybin, a major bioactive component of milk thistle (Silybum marianum L. Gaernt.)-chemistry, bioavailability, and metabolism. Molecules,  2017, 22(11), 1942.
 [http://dx.doi.org/10.3390/molecules22111942] [PMID: 29125572]

[41]
Gillessen, A.; Schmidt, H.H.J. Silymarin as supportive treatment in liver diseases: A narrative review. Adv. Ther.,  2020, 37(4), 1279-1301.
 [http://dx.doi.org/10.1007/s12325-020-01251-y] [PMID: 32065376]

[42]
He, J.; Hou, S.; Lu, W.; Zhu, L.; Feng, J. Preparation, pharmacokinetics and body distribution of silymarin-loaded solid lipid nanoparticles after oral administration. J. Biomed. Nanotechnol.,  2007, 3(2), 195-202.
 [http://dx.doi.org/10.1166/jbn.2007.024]

[43]
Kesharwani, S.S.; Jain, V.; Dey, S.; Sharma, S.; Mallya, P.; Kumar, V.A. An overview of advanced formulation and nanotechnology-based approaches for solubility and bioavailability enhancement of silymarin. J. Drug Deliv. Sci. Technol.,  2020, 60, 102021.
 [http://dx.doi.org/10.1016/j.jddst.2020.102021]

[44]
Mokhtari Sangdehi, S.R.; Hajizadeh Moghaddam, A.; Ranjbar, M. Anti-apoptotic effect of silymarin-loaded chitosan nanoparticles on hippocampal caspase-3 and Bcl-2 expression following cerebral ischemia/reperfusion injury. Int. J. Neurosci.,  2021, 132(11), 1102-1109.
 [PMID: 33287594]

[45]
Yang, K.Y.; Hwang, H.; Yousaf, A.M.; Kim, D.W.; Shin, Y.J.; Bae, O.N.; Kim, Y.I.; Kim, J.O.; Yong, C.S.; Choi, H.G. Silymarin-loaded solid nanoparticles provide excellent hepatic protection: Physicochemical characterization and in vivo evaluation. Int. J. Nanomedicine,  2013, 8, 3333-3343.
 [PMID: 24039417]

[46]
Mombeini, M.; Saki, G.; Khorsandi, L.; Bavarsad, N. Effects of silymarin-loaded nanoparticles on HT-29 human colon cancer cells. Medicina (Kaunas),  2018, 54(1), 1-9.
 [http://dx.doi.org/10.3390/medicina54010001] [PMID: 30344232]

[47]
Nguyen, T.H.T.; Trinh, N.T.; Tran, H.N.; Tran, H.T.; Le, P.Q.; Ngo, D.N.; Tran-Van, H.; Van Vo, T.; Vong, L.B.; Nagasaki, Y. Improving silymarin oral bioavailability using silica-installed redox nanoparticle to suppress inflammatory bowel disease. J. Control. Release,  2021, 331, 515-524.
 [http://dx.doi.org/10.1016/j.jconrel.2020.10.042] [PMID: 33616078]

[48]
Ebrahimi-Zadehlou, P.; Najafpour, A.; Mohammadi, R. Assessments of regenerative potential of silymarin nanoparticles loaded into chitosan conduit on peripheral nerve regeneration: A transected sciatic nerve model in rat. Neurol. Res.,  2021, 43(2), 148-156.
 [http://dx.doi.org/10.1080/01616412.2020.1831341] [PMID: 33034534]

[49]
Rajnochová Svobodová, A.; Gabrielová, E.; Ulrichová, J.; Zálešák, B.; Biedermann, D.; Vostálová, J. A pilot study of the UVA-photoprotective potential of dehydrosilybin, isosilybin, silychristin, and silydianin on human dermal fibroblasts. Arch. Dermatol. Res.,  2019, 311(6), 477-490.
 [http://dx.doi.org/10.1007/s00403-019-01928-7] [PMID: 31079190]

[50]
Roubalová, L.; Dinkova-Kostova, A.T.; 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, 115-120.
 [http://dx.doi.org/10.1016/j.fitote.2017.04.012] [PMID: 28450126]

[51]
Hu, L.F.; Lan, H.R.; Li, X.M.; Jin, K.T. A systematic review of the potential chemoprotective effects of resveratrol on doxorubicin-induced cardiotoxicity: Focus on the antioxidant, antiapoptotic, and anti-inflammatory activities. Oxid. Med. Cell. Longev.,  2021, 2021, 2951697.
 [http://dx.doi.org/10.1155/2021/2951697] [PMID: 34471463]

[52]
McCord, J.M. The evolution of free radicals and oxidative stress. Am. J. Med.,  2000, 108(8), 652-659.
 [http://dx.doi.org/10.1016/S0002-9343(00)00412-5] [PMID: 10856414]

[53]
Lobo, V.; Patil, A.; Phatak, A.; Chandra, N. Free radicals, antioxidants and functional foods: Impact on human health. Pharmacogn. Rev.,  2010, 4(8), 118-126.
 [http://dx.doi.org/10.4103/0973-7847.70902] [PMID: 22228951]

[54]
Sosa, V.; Moliné, T.; Somoza, R.; Paciucci, R.; Kondoh, H.; LLeonart, M.E. Oxidative stress and cancer: An overview. Ageing Res. Rev.,  2013, 12(1), 376-390.
 [http://dx.doi.org/10.1016/j.arr.2012.10.004] [PMID: 23123177]

[55]
Arabzadeh, A.; Mortezazadeh, T.; Aryafar, T.; Gharepapagh, E.; Majdaeen, M.; Farhood, B. Therapeutic potentials of resveratrol in combination with radiotherapy and chemotherapy during glioblastoma treatment: A mechanistic review. Cancer Cell Int.,  2021, 21(1), 391.
 [http://dx.doi.org/10.1186/s12935-021-02099-0] [PMID: 34289841]

[56]
Sheikholeslami, S.; Aryafar, T.; Abedi-Firouzjah, R.; Banaei, A.; Dorri-Giv, M.; Zamani, H.; Ataei, G.; Majdaeen, M.; Farhood, B. The role of melatonin on radiation-induced pneumonitis and lung fibrosis: A systematic review. Life Sci.,  2021, 281, 119721.
 [http://dx.doi.org/10.1016/j.lfs.2021.119721] [PMID: 34146555]

[57]
Sheikholeslami, S.; Khodaverdian, S.; Dorri-Giv, M.; Mohammad Hosseini, S.; Souri, S.; Abedi-Firouzjah, R.; Zamani, H.; Dastranj, L.; Farhood, B. The radioprotective effects of alpha-lipoic acid on radiotherapy-induced toxicities: A systematic review. Int. Immunopharmacol.,  2021, 96, 107741.
 [http://dx.doi.org/10.1016/j.intimp.2021.107741] [PMID: 33989970]

[58]
Carnevali, S.; Petruzzelli, S.; Longoni, B.; Vanacore, R.; Barale, R.; Cipollini, M.; Scatena, F.; Paggiaro, P.; Celi, A.; Giuntini, C. Cigarette smoke extract induces oxidative stress and apoptosis in human lung fibroblasts. Am. J. Physiol. Lung Cell. Mol. Physiol.,  2003, 284(6), L955-L963.
 [http://dx.doi.org/10.1152/ajplung.00466.2001] [PMID: 12547733]

[59]
Xavier, J.; Farias, C.P.; Soares, M.S.P.; Silveira, G.d.O.; Spanevello, R.M.; Yonamine, M.; Gamaro, G.D.; Carvalho, H.W.d.; Cognato, G.d.P. Ayahuasca prevents oxidative stress in a rat model of depression elicited by unpredictable chronic mild stress. Arch. Clin. Psychiatry,  2021, 48, 90-98.

[60]
Salah Noori, R.; Abdul-RedhaIsmaiel, M. Relationship between oxidative stress and the blood iron concentration and antioxidant status in major ß-thalassemia in Iraq. Arch. Razi Inst.,  2022, 77(1), 187-198.
 [PMID: 35891728]

[61]
Varadhan, S.; Venkatachalam, R.; Perumal, S.M.; Ayyamkulamkara, S.S. Evaluation of oxidative stress parameters and antioxidant status in coronary artery disease patients. Arch. Razi Inst.,  2022, 77(2), 853-859.
 [PMID: 36284944]

[62]
Sangeetha, T.; Chen, Y.; Sasidharan, S. Oxidative stress and aging and medicinal plants as antiaging agents. J. Complement. Med. Res.,  2020, 11(3), 01.
 [http://dx.doi.org/10.5455/jcmr.2020.11.03.01]

[63]
Barjaktarovic, Z.; Schmaltz, D.; Shyla, A.; Azimzadeh, O.; Schulz, S.; Haagen, J.; Dörr, W.; Sarioglu, H.; Schäfer, A.; Atkinson, M.J.; Zischka, H.; Tapio, S. Radiation-induced signaling results in mitochondrial impairment in mouse heart at 4 weeks after exposure to X-rays. PLoS One,  2011, 6(12), e27811.
 [http://dx.doi.org/10.1371/journal.pone.0027811] [PMID: 22174747]

[64]
Kim, G.J.; Fiskum, G.M.; Morgan, W.F. A role for mitochondrial dysfunction in perpetuating radiation-induced genomic instability. Cancer Res.,  2006, 66(21), 10377-10383.
 [http://dx.doi.org/10.1158/0008-5472.CAN-05-3036] [PMID: 17079457]

[65]
Vaiserman, A.M.; Lushchak, O.V.; Koliada, A.K. Anti-aging pharmacology: Promises and pitfalls. Ageing Res. Rev.,  2016, 31, 9-35.
 [http://dx.doi.org/10.1016/j.arr.2016.08.004] [PMID: 27524412]

[66]
Dedon, P.C.; Tannenbaum, S.R. Reactive nitrogen species in the chemical biology of inflammation. Arch. Biochem. Biophys.,  2004, 423(1), 12-22.
 [http://dx.doi.org/10.1016/j.abb.2003.12.017] [PMID: 14989259]

[67]
Lushchak, V.I. Free radicals, reactive oxygen species, oxidative stress and its classification. Chem. Biol. Interact.,  2014, 224, 164-175.
 [http://dx.doi.org/10.1016/j.cbi.2014.10.016] [PMID: 25452175]

[68]
Niki, E. Biomarkers of lipid peroxidation in clinical material. Biochim. Biophys. Acta, Gen. Subj.,  2014, 1840(2), 809-817.
 [http://dx.doi.org/10.1016/j.bbagen.2013.03.020] [PMID: 23541987]

[69]
Mukherjee, K.; Venkatesh, M.; Venkatesh, P.; Saha, B.P.; Mukherjee, P.K. Effect of soy phosphatidyl choline on the bioavailability and nutritional health benefits of resveratrol. Food Res. Int.,  2011, 44(4), 1088-1093.
 [http://dx.doi.org/10.1016/j.foodres.2011.03.034]

[70]
Alanazi, A.M.; Fadda, L.; Alhusaini, A.; Ahmad, R.; Hasan, I.H.; Mahmoud, A.M. liposomal resveratrol and/or carvedilol attenuate doxorubicin-induced cardiotoxicity by modulating inflammation, oxidative stress and S100A1 in rats. Antioxidants,  2020, 9(2), 159.
 [http://dx.doi.org/10.3390/antiox9020159] [PMID: 32079097]

[71]
Yahyapour, R.; Motevaseli, E.; Rezaeyan, A.; Abdollahi, H.; Farhood, B.; Cheki, M.; Rezapoor, S.; Shabeeb, D.; Musa, A.E.; Najafi, M.; Villa, V. Reduction–oxidation (redox) system in radiation-induced normal tissue injury: Molecular mechanisms and implications in radiation therapeutics. Clin. Transl. Oncol.,  2018, 20(8), 975-988.
 [http://dx.doi.org/10.1007/s12094-017-1828-6] [PMID: 29318449]

[72]
Said, R.S.; Mohamed, H.A.; Kassem, D.H. Alpha-lipoic acid effectively attenuates ionizing radiation-mediated testicular dysfunction in rats: Crosstalk of NF-ĸB, TGF-β, and PPAR-ϒ pathways. Toxicology,  2020, 442, 152536.
 [http://dx.doi.org/10.1016/j.tox.2020.152536] [PMID: 32649955]

[73]
El-Dein, E.; Anees, L.M.; Aly, S.M.E. Effects of α-lipoic acid on γ-radiation and lindane-induced heart toxicity in rats. Pak. J. Zool.,  2016, 48(5), 1523-1529.

[74]
Kidd, P.M. Bioavailability and activity of phytosome complexes from botanical polyphenols: The silymarin, curcumin, green tea, and grape seed extracts. Altern. Med. Rev.,  2009, 14(3), 226-246.
 [PMID: 19803548]

[75]
Sheweita, S.A.; Al-Shora, S.; Hassan, M. Effects of benzo[a]pyrene as an environmental pollutant and two natural antioxidants on biomarkers of reproductive dysfunction in male rats. Environ. Sci. Pollut. Res. Int.,  2016, 23(17), 17226-17235.
 [http://dx.doi.org/10.1007/s11356-016-6934-4] [PMID: 27221463]

[76]
Müzes, G.; Deák, G.; Láng, I.; Nékám, K.; Niederland, V.; Fehér, J. Effect of silimarin (Legalon) therapy on the antioxidant defense mechanism and lipid peroxidation in alcoholic liver disease (double blind protocol). Orv. Hetil.,  1990, 131(16), 863-866.
 [PMID: 2345633]

[77]
Yardım, A.; Kucukler, S.; Özdemir, S.; Çomaklı, S.; Caglayan, C.; Kandemir, F.M.; Çelik, H. Silymarin alleviates docetaxel-induced central and peripheral neurotoxicity by reducing oxidative stress, inflammation and apoptosis in rats. Gene,  2021, 769, 145239.
 [http://dx.doi.org/10.1016/j.gene.2020.145239] [PMID: 33069805]

[78]
Winther, F.Ø. X-ray irradiation of the inner ear of the guinea pig. An electron microscopic study of the degenerating outer hair cells of the organ of Corti. Acta Otolaryngol.,  1970, 69(1-6), 61-76.
 [http://dx.doi.org/10.3109/00016487009123336] [PMID: 5446609]

[79]
Najafi, M.; Hooshangi Shayesteh, M.R.; Mortezaee, K.; Farhood, B.; Haghi-Aminjan, H. The role of melatonin on doxorubicin-induced cardiotoxicity: A systematic review. Life Sci.,  2020, 241, 117173.
 [http://dx.doi.org/10.1016/j.lfs.2019.117173] [PMID: 31843530]

[80]
Haghi-Aminjan, H.; Farhood, B.; Rahimifard, M.; Didari, T.; Baeeri, M.; Hassani, S.; Hosseini, R.; Abdollahi, M. The protective role of melatonin in chemotherapy-induced nephrotoxicity: A systematic review of non-clinical studies. Expert Opin. Drug Metab. Toxicol.,  2018, 14(9), 937-950.
 [http://dx.doi.org/10.1080/17425255.2018.1513492] [PMID: 30118646]

[81]
Lin, M.T.; Beal, M.F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature,  2006, 443(7113), 787-795.
 [http://dx.doi.org/10.1038/nature05292] [PMID: 17051205]

[82]
Choi, K.M.; Kang, C.M.; Cho, E.; Kang, S.; Lee, S.; Um, H.D. Ionizing radiation-induced micronucleus formation is mediated by reactive oxygen species that are produced in a manner dependent on mitochondria, Nox1, and JNK. Oncol. Rep.,  2007, 17(5), 1183-1188.
 [http://dx.doi.org/10.3892/or.17.5.1183] [PMID: 17390063]

[83]
Sekine, S.; Ichijo, H. Mitochondrial proteolysis: Its emerging roles in stress responses. Biochim. Biophys. Acta, Gen. Subj.,  2015, 1850(2), 274-280.
 [http://dx.doi.org/10.1016/j.bbagen.2014.10.012] [PMID: 25459516]

[84]
Rolo, A.; Oliveira, P.J.; Moreno, A.J.; Palmeira, C.M. Protection against post-ischemic mitochondrial injury in rat liver by silymarin or TUDC. Hepatol. Res.,  2003, 26(3), 217-224.
 [http://dx.doi.org/10.1016/S1386-6346(03)00108-6] [PMID: 12850694]

[85]
Dong, Y.; Tu, J.; Zhou, Y.; Zhou, X.; Xu, B.; Zhu, S.Y. Silybum marianum oil attenuates oxidative stress and ameliorates mitochondrial dysfunction in mice treated with D-galactose. Pharmacogn. Mag.,  2014, 10(37)(Suppl. 1), 92.
 [http://dx.doi.org/10.4103/0973-1296.127353] [PMID: 24914315]

[86]
Mortezaee, K.; Goradel, N.H.; Amini, P.; Shabeeb, D.; Musa, A.E.; Najafi, M.; Farhood, B. NADPH oxidase as a target for modulation of radiation response; implications to carcinogenesis and radiotherapy. Curr. Mol. Pharmacol.,  2019, 12(1), 50-60.
 [http://dx.doi.org/10.2174/1874467211666181010154709] [PMID: 30318012]

[87]
Lee, I.T.; Yang, C.M. Role of NADPH oxidase/ROS in pro-inflammatory mediators-induced airway and pulmonary diseases. Biochem. Pharmacol.,  2012, 84(5), 581-590.
 [http://dx.doi.org/10.1016/j.bcp.2012.05.005] [PMID: 22587816]

[88]
Ushio-Fukai, M. Compartmentalization of redox signaling through NADPH oxidase-derived ROS. Antioxid. Redox Signal.,  2009, 11(6), 1289-1299.
 [http://dx.doi.org/10.1089/ars.2008.2333] [PMID: 18999986]

[89]
Azmoonfar, R.; Amini, P.; Saffar, H.; Rezapoor, S.; Motevaseli, E.; Cheki, M.; Yahyapour, R.; farhood, B.; Nouruzi, F.; Khodamoradi, E.; Shabeeb, D.; Eleojo Musa, A.; Najafi, M. Metformin protects against radiation-induced pneumonitis and fibrosis and attenuates upregulation of dual oxidase genes expression. Adv. Pharm. Bull.,  2018, 8(4), 697-704.
 [http://dx.doi.org/10.15171/apb.2018.078] [PMID: 30607342]

[90]
Yahyapour, R.; Amini, P.; Saffar, H.; Rezapoor, S.; Motevaseli, E.; Cheki, M.; Farhood, B.; Nouruzi, F.; Shabeeb, D.; Eleojo Musa, A.; Najafi, M. Metformin protects against radiation-induced heart injury and attenuates the upregulation of dual oxidase genes following rat’s chest irradiation. Int. J. Mol. Cell. Med.,  2018, 7(3), 193-202.
 [PMID: 31565651]

[91]
Aliasgharzadeh, A.; Farhood, B.; Amini, P.; Saffar, H.; Motevaseli, E.; Rezapoor, S.; Nouruzi, F.; Shabeeb, D.H.; Eleojo Musa, A.; Mohseni, M.; Moradi, H.; Najafi, M. Melatonin attenuates upregulation of Duox1 and Duox2 and protects against lung injury following chest irradiation in rats. Cell J.,  2019, 21(3), 236-242.
 [PMID: 31210428]

[92]
Doehner, W.; Landmesser, U. Xanthine oxidase and uric acid in cardiovascular disease: Clinical impact and therapeutic options. Semin. Nephrol.,  2011, 31(5), 433-440.
 [http://dx.doi.org/10.1016/j.semnephrol.2011.08.007] [PMID: 22000650]

[93]
Harrison, R. Physiological roles of xanthine oxidoreductase. Drug Metab. Rev.,  2004, 36(2), 363-375.
 [http://dx.doi.org/10.1081/DMR-120037569] [PMID: 15237859]

[94]
Juarez, J.C.; Manuia, M.; Burnett, M.E.; Betancourt, O.; Boivin, B.; Shaw, D.E.; Tonks, N.K.; Mazar, A.P.; Doñate, F. Superoxide dismutase 1 (SOD1) is essential for H2O2 -mediated oxidation and inactivation of phosphatases in growth factor signaling. Proc. Natl. Acad. Sci. USA,  2008, 105(20), 7147-7152.
 [http://dx.doi.org/10.1073/pnas.0709451105] [PMID: 18480265]

[95]
Muthumani, M.; Prabu, S.M. Silibinin potentially attenuates arsenic-induced oxidative stress mediated cardiotoxicity and dyslipidemia in rats. Cardiovasc. Toxicol.,  2014, 14(1), 83-97.
 [http://dx.doi.org/10.1007/s12012-013-9227-x] [PMID: 24062023]

[96]
Pauff, J.M.; Hille, R. Inhibition studies of bovine xanthine oxidase by luteolin, silibinin, quercetin, and curcumin. J. Nat. Prod.,  2009, 72(4), 725-731.
 [http://dx.doi.org/10.1021/np8007123] [PMID: 19388706]

[97]
Najafi, M.; Mortezaee, K.; Rahimifard, M.; Farhood, B.; Haghi-Aminjan, H. The role of curcumin/curcuminoids during gastric cancer chemotherapy: A systematic review of non-clinical study. Life Sci.,  2020, 257, 118051.
 [http://dx.doi.org/10.1016/j.lfs.2020.118051] [PMID: 32634426]

[98]
Smaili, S.S.; Hsu, Y.T.; Carvalho, A.C.P.; Rosenstock, T.R.; Sharpe, J.C.; Youle, R.J. Mitochondria, calcium and pro-apoptotic proteins as mediators in cell death signaling. Braz. J. Med. Biol. Res.,  2003, 36(2), 183-190.
 [http://dx.doi.org/10.1590/S0100-879X2003000200004] [PMID: 12563519]

[99]
Fischer, T.W.; Zmijewski, M.A.; Wortsman, J.; Slominski, A. Melatonin maintains mitochondrial membrane potential and attenuates activation of initiator (casp-9) and effector caspases (casp-3/casp-7) and PARP in UVR-exposed HaCaT keratinocytes. J. Pineal Res.,  2008, 44(4), 397-407.
 [http://dx.doi.org/10.1111/j.1600-079X.2007.00542.x] [PMID: 18086147]

[100]
Jänicke, R.U.; Sprengart, M.L.; Wati, M.R.; Porter, A.G. Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J. Biol. Chem.,  1998, 273(16), 9357-9360.
 [http://dx.doi.org/10.1074/jbc.273.16.9357] [PMID: 9545256]

[101]
Gondo, H.K. The effect of spirulina on apoptosis through the caspase-3 pathway in a Preeclamptic Wistar rat model. J. Nat. Sci. Biol. Med.,  2021, 12(3), 280-284.

[102]
Herceg, Z.; Wang, Z.Q. Functions of poly(ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. Mutat. Res.,  2001, 477(1-2), 97-110.
 [http://dx.doi.org/10.1016/S0027-5107(01)00111-7] [PMID: 11376691]

[103]
Saldeen, J.; Tillmar, L.; Karlsson, E.; Welsh, N. Nicotinamide- and caspase-mediated inhibition of poly(ADP-ribose) polymerase are associated with p53-independent cell cycle (G2) arrest and apoptosis. Mol. Cell. Biochem.,  2003, 243(1/2), 113-122.
 [http://dx.doi.org/10.1023/A:1021651811345] [PMID: 12619896]

[104]
Chang, H.; Sander, C.S.; Müller, C.S.L.; Elsner, P.; Thiele, J.J. Detection of poly(ADP-ribose) by immunocytochemistry: A sensitive new method for the early identification of UVB- and H2O2-induced apoptosis in keratinocytes. Biol. Chem.,  2002, 383(3-4), 703-708.
 [http://dx.doi.org/10.1515/BC.2002.072] [PMID: 12033459]

[105]
Alvarez-Gonzalez, R.; Spring, H.; Müller, M.; Bürkle, A. Selective loss of poly(ADP-ribose) and the 85-kDa fragment of poly(ADP-ribose) polymerase in nucleoli during alkylation-induced apoptosis of HeLa cells. J. Biol. Chem.,  1999, 274(45), 32122-32126.
 [http://dx.doi.org/10.1074/jbc.274.45.32122] [PMID: 10542247]

[106]
Scovassi, A.I.; Denegri, M.; Donzelli, M.; Rossi, L.; Bernardi, R.; Mandarino, A.; Frouin, I.; Negri, C. Poly(ADP-ribose) synthesis in cells undergoing apoptosis: An attempt to face death before PARP degradation. Eur. J. Histochem.,  1998, 42(4), 251-258.
 [PMID: 10068897]

[107]
Farkas, B.; Magyarlaki, M.; Csete, B.; Nemeth, J.; Rabloczky, G.; Bernath, S.; Literáti Nagy, P.; Sümegi, B. Reduction of acute photodamage in skin by topical application of a novel PARP inhibitor. Biochem. Pharmacol.,  2002, 63(5), 921-932.
 [http://dx.doi.org/10.1016/S0006-2952(01)00929-7] [PMID: 11911844]

[108]
Sherif, I.O.; Al-Gayyar, M.M.H. Antioxidant, anti-inflammatory and hepatoprotective effects of silymarin on hepatic dysfunction induced by sodium nitrite. Eur. Cytokine Netw.,  2013, 24(3), 114-121.
 [http://dx.doi.org/10.1684/ecn.2013.0341] [PMID: 24225033]

[109]
Song, Z.; Song, M.; Lee, D.Y.W.; Liu, Y.; Deaciuc, I.V.; McClain, C.J. Silymarin prevents palmitate-induced lipotoxicity in HepG2 cells: Involvement of maintenance of Akt kinase activation. Basic Clin. Pharmacol. Toxicol.,  2007, 101(4), 262-268.
 [http://dx.doi.org/10.1111/j.1742-7843.2007.00116.x] [PMID: 17845508]

[110]
Kandemir, F.M.; Kucukler, S.; Caglayan, C.; Gur, C.; Batil, A.A.; Gülçin, İ. Therapeutic effects of silymarin and naringin on methotrexate-induced nephrotoxicity in rats: Biochemical evaluation of anti-inflammatory, antiapoptotic, and antiautophagic properties. J. Food Biochem.,  2017, 41(5), e12398.
 [http://dx.doi.org/10.1111/jfbc.12398]

[111]
Aghazadeh, S.; Amini, R.; Yazdanparast, R.; Ghaffari, S.H. Anti-apoptotic and anti-inflammatory effects of Silybum marianum in treatment of experimental steatohepatitis. Exp. Toxicol. Pathol.,  2011, 63(6), 569-574.
 [http://dx.doi.org/10.1016/j.etp.2010.04.009] [PMID: 20471811]

[112]
Patel, N.; Joseph, C.; Corcoran, G.B.; Ray, S.D. Silymarin modulates doxorubicin-induced oxidative stress, Bcl-xL and p53 expression while preventing apoptotic and necrotic cell death in the liver. Toxicol. Appl. Pharmacol.,  2010, 245(2), 143-152.
 [http://dx.doi.org/10.1016/j.taap.2010.02.002] [PMID: 20144634]

[113]
Katiyar, S.K.; Roy, A.M.; Baliga, M.S. Silymarin induces apoptosis primarily through a p53-dependent pathway involving Bcl-2/Bax, cytochrome c release, and caspase activation. Mol. Cancer Ther.,  2005, 4(2), 207-216.
 [http://dx.doi.org/10.1158/1535-7163.207.4.2] [PMID: 15713892]

[114]
Manna, S.K.; Mukhopadhyay, A.; Van, N.T.; Aggarwal, B.B. Silymarin suppresses TNF-induced activation of NF-kappa B, c-Jun N-terminal kinase, and apoptosis. J. Immunol.,  1999, 163(12), 6800-6809.
 [PMID: 10586080]

[115]
Shi, W.; Hou, X.; Bao, X.; Hou, W.; Jiang, X.; Ma, L.; Jiang, X.; Dong, L. Mechanism and protection of radiotherapy induced sensorineural hearing loss for head and neck cancer. BioMed Res. Int.,  2021, 2021, 3548706.
 [http://dx.doi.org/10.1155/2021/3548706] [PMID: 34970625]

[116]
McCubrey, J.A.; LaHair, M.M.; Franklin, R.A. Reactive oxygen species-induced activation of the MAP kinase signaling pathways. Antioxid. Redox Signal.,  2006, 8(9-10), 1775-1789.
 [http://dx.doi.org/10.1089/ars.2006.8.1775] [PMID: 16987031]

[117]
Kholodenko, B.N.; Birtwistle, M.R. Four-dimensional dynamics of MAPK information-processing systems. Wiley Interdiscip. Rev. Syst. Biol. Med.,  2009, 1(1), 28-44.
 [http://dx.doi.org/10.1002/wsbm.16] [PMID: 20182652]

[118]
Rodríguez-Berriguete, G.; Fraile, B.; Martínez-Onsurbe, P.; Olmedilla, G.; Paniagua, R.; Royuela, M. MAP kinases and prostate cancer. J. Signal Transduct.,  2012, 2012, 1-9.
 [http://dx.doi.org/10.1155/2012/169170] [PMID: 22046506]

[119]
Burotto, M.; Chiou, V.L.; Lee, J.M.; Kohn, E.C. The MAPK pathway across different malignancies: A new perspective. Cancer,  2014, 120(22), 3446-3456.
 [http://dx.doi.org/10.1002/cncr.28864] [PMID: 24948110]

[120]
Johnson, G.L.; Stuhlmiller, T.J.; Angus, S.P.; Zawistowski, J.S.; Graves, L.M. Molecular pathways: Adaptive kinome reprogramming in response to targeted inhibition of the BRAF-MEK-ERK pathway in cancer. Clin. Cancer Res.,  2014, 20(10), 2516-2522.
 [http://dx.doi.org/10.1158/1078-0432.CCR-13-1081] [PMID: 24664307]

[121]
Brown, L.; Benchimol, S. The involvement of MAPK signaling pathways in determining the cellular response to p53 activation: Cell cycle arrest or apoptosis. J. Biol. Chem.,  2006, 281(7), 3832-3840.
 [http://dx.doi.org/10.1074/jbc.M507951200] [PMID: 16330547]

[122]
Kim, E.J.; Kim, J.; Lee, M.Y.; Sudhanva, M.S.; Devakumar, S.; Jeon, Y.J. Silymarin inhibits cytokine-stimulated pancreatic beta cells by blocking the ERK1/2 pathway. Biomol. Ther. (Seoul),  2014, 22(4), 282-287.
 [http://dx.doi.org/10.4062/biomolther.2014.072] [PMID: 25143805]

[123]
Garg, A.D.; Kaczmarek, A.; Krysko, O.; Vandenabeele, P.; Krysko, D.V.; Agostinis, P. ER stress-induced inflammation: Does it aid or impede disease progression? Trends Mol. Med.,  2012, 18(10), 589-598.
 [http://dx.doi.org/10.1016/j.molmed.2012.06.010] [PMID: 22883813]

[124]
Kumar, R.; Banerjee, P.; Kumar, T.; Sarangi, S.C.; Meetei, U.D.; Devi, A.S. Anti-inflammatory potential of aqueous extract of elsoltzia stachyodes on experimental models of inflammation in rats. J. Nat. Sci. Biol. Med.,  2021, 12(1), 103-108.
 [http://dx.doi.org/10.4103/jnsbm.JNSBM_5_20]

[125]
Farhood, B.; Mortezaee, K.; Goradel, N.H.; Khanlarkhani, N.; Salehi, E.; Nashtaei, M.S.; Najafi, M.; Sahebkar, A. Curcumin as an anti-inflammatory agent: Implications to radiotherapy and chemotherapy. J. Cell. Physiol.,  2019, 234(5), 5728-5740.
 [http://dx.doi.org/10.1002/jcp.27442] [PMID: 30317564]

[126]
Jeong, B.K.; Song, J.H.; Jeong, H.; Choi, H.S.; Jung, J.H.; Hahm, J.R.; Woo, S.H.; Jung, M.H.; Choi, B.H.; Kim, J.H.; Kang, K.M. Effect of alpha-lipoic acid on radiation-induced small intestine injury in mice. Oncotarget,  2016, 7(12), 15105-15117.
 [http://dx.doi.org/10.18632/oncotarget.7874] [PMID: 26943777]

[127]
Waetzig, V.; Czeloth, K.; Hidding, U.; Mielke, K.; Kanzow, M.; Brecht, S.; Goetz, M.; Lucius, R.; Herdegen, T.; Hanisch, U.K. c-Jun N-terminal kinases (JNKs) mediate pro-inflammatory actions of microglia. Glia,  2005, 50(3), 235-246.
 [http://dx.doi.org/10.1002/glia.20173] [PMID: 15739188]

[128]
Lee, Y.B.; Schrader, J.W.; Kim, S.U. p38 MAP kinase regulates tnf-α production in human astrocytes and microglia by multiple mechanisms. Cytokine,  2000, 12(7), 874-880.
 [http://dx.doi.org/10.1006/cyto.2000.0688] [PMID: 10880231]

[129]
Yahyapour, R.; Amini, P.; Rezapour, S.; Cheki, M.; Rezaeyan, A.; Farhood, B.; Shabeeb, D.; Musa, A.E.; Fallah, H.; Najafi, M. Radiation-induced inflammation and autoimmune diseases. Mil. Med. Res.,  2018, 5(1), 9.
 [http://dx.doi.org/10.1186/s40779-018-0156-7] [PMID: 29554942]

[130]
Multhoff, G.; Molls, M.; Radons, J. Chronic inflammation in cancer development. Front. Immunol.,  2012, 2, 98.
 [http://dx.doi.org/10.3389/fimmu.2011.00098] [PMID: 22566887]

[131]
Zhang, Q.; Wu, L. In vitro and in vivo cardioprotective effects of curcumin against doxorubicin-induced cardiotoxicity: A systematic review. J. Oncol.,  2022, 2022, 1-16.
 [http://dx.doi.org/10.1155/2022/7277562] [PMID: 35237323]

[132]
Moutabian, H.; Ghahramani-Asl, R.; Mortezazadeh, T.; Laripour, R.; Narmani, A.; Zamani, H.; Ataei, G.; Bagheri, H.; Farhood, B.; Sathyapalan, T.; Sahebkar, A. The cardioprotective effects of nano-curcumin against doxorubicin-induced cardiotoxicity: A systematic review. Biofactors,  2022, 48(3), 597-610.
 [http://dx.doi.org/10.1002/biof.1823] [PMID: 35080781]

[133]
Min, A.K.; Kim, M.K.; Seo, H.Y.; Kim, H.S.; Jang, B.K.; Hwang, J.S.; Choi, H.S.; Lee, K.U.; Park, K.G.; Lee, I.K. Alpha-lipoic acid inhibits hepatic PAI-1 expression and fibrosis by inhibiting the TGF-β signaling pathway. Biochem. Biophys. Res. Commun.,  2010, 393(3), 536-541.
 [http://dx.doi.org/10.1016/j.bbrc.2010.02.050] [PMID: 20153726]

[134]
Shih, R.H.; Wang, C.Y.; Yang, C.M. NF-kappaB signaling pathways in neurological inflammation: A mini review. Front. Mol. Neurosci.,  2015, 8, 77.
 [http://dx.doi.org/10.3389/fnmol.2015.00077] [PMID: 26733801]

[135]
Saliou, C.; Rihn, B.; Cillard, J.; Okamoto, T.; Packer, L. Selective inhibition of NF-kappaB activation by the flavonoid hepatoprotector silymarin in HepG2. Evidence for different activating pathways. FEBS Lett.,  1998, 440(1-2), 8-12.
 [http://dx.doi.org/10.1016/S0014-5793(98)01409-4] [PMID: 9862414]

[136]
Lawrence, T. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb. Perspect. Biol.,  2009, 1(6), a001651.
 [http://dx.doi.org/10.1101/cshperspect.a001651] [PMID: 20457564]

[137]
Ramasamy, K.; Agarwal, R. Multitargeted therapy of cancer by silymarin. Cancer Lett.,  2008, 269(2), 352-362.
 [http://dx.doi.org/10.1016/j.canlet.2008.03.053] [PMID: 18472213]

[138]
Abdel-Raheem, I.T.; Khedr, N.F. Renoprotective effects of montelukast, a cysteinyl leukotriene receptor antagonist, against methotrexate-induced kidney damage in rats. Naunyn Schmiedebergs Arch. Pharmacol.,  2014, 387(4), 341-353.
 [http://dx.doi.org/10.1007/s00210-013-0949-x] [PMID: 24363042]

[139]
Trivedi, P.P.; Tripathi, D.N.; Jena, G.B. Hesperetin protects testicular toxicity of doxorubicin in rat: Role of NFκB, p38 and caspase-3. Food Chem. Toxicol.,  2011, 49(4), 838-847.
 [http://dx.doi.org/10.1016/j.fct.2010.12.005] [PMID: 21168534]

[140]
Al-Sadi, R.; Engers, J.; Haque, M.; King, S.; Al-Omari, D.; Ma, T.Y. Matrix Metalloproteinase-9 (MMP-9) induced disruption of intestinal epithelial tight junction barrier is mediated by NF-κB activation. PLoS One,  2021, 16(4), e0249544.
 [http://dx.doi.org/10.1371/journal.pone.0249544] [PMID: 33826658]

[141]
Pan, X.D.; Chen, X.C.; Zhu, Y.G.; Chen, L.M.; Zhang, J.; Huang, T.W.; Ye, Q.Y.; Huang, H.P. Tripchlorolide protects neuronal cells from microglia-mediated β-amyloid neurotoxicity through inhibiting NF-κB and JNK signaling. Glia,  2009, 57(11), 1227-1238.
 [http://dx.doi.org/10.1002/glia.20844] [PMID: 19170180]

[142]
Kandemir, F.M.; Yıldırım, S.; Kucukler, S.; Caglayan, C.; Darendelioğlu, E.; Dortbudak, M.B. Protective effects of morin against acrylamide-induced hepatotoxicity and nephrotoxicity: A multi-biomarker approach. Food Chem. Toxicol.,  2020, 138, 111190.
 [http://dx.doi.org/10.1016/j.fct.2020.111190] [PMID: 32068001]

[143]
Chen, F.; Castranova, V.; Shi, X.; Demers, L.M. New insights into the role of nuclear factor-kappaB, a ubiquitous transcription factor in the initiation of diseases. Clin. Chem.,  1999, 45(1), 7-17.
 [http://dx.doi.org/10.1093/clinchem/45.1.7] [PMID: 9895331]

[144]
Moutabian, H.; Majdaeen, M.; Ghahramani-Asl, R.; Yadollahi, M.; Gharepapagh, E.; Ataei, G.; Falahatpour, Z.; Bagheri, H.; Farhood, B. A systematic review of the therapeutic effects of resveratrol in combination with 5-fluorouracil during colorectal cancer treatment: With a special focus on the oxidant, apoptotic, and anti-inflammatory activities. Cancer Cell Int.,  2022, 22(1), 142.
 [http://dx.doi.org/10.1186/s12935-022-02561-7] [PMID: 35366874]

[145]
Raj, V.; Bhadauria, A.S.; Singh, A.K.; Kumar, U.; Rai, A.; Keshari, A.K.; Kumar, P.; Kumar, D.; Maity, B.; Nath, S.; Prakash, A.; Ansari, K.M.; Jat, J.L.; Saha, S. Novel 1,3,4-thiadiazoles inhibit colorectal cancer via blockade of IL-6/COX-2 mediated JAK2/STAT3 signals as evidenced through data-based mathematical modeling. Cytokine,  2019, 118, 144-159.
 [http://dx.doi.org/10.1016/j.cyto.2018.03.026] [PMID: 29580751]

[146]
Murakami, A.; Ohigashi, H. Targeting NOX, INOS and COX-2 in inflammatory cells: Chemoprevention using food phytochemicals. Int. J. Cancer,  2007, 121(11), 2357-2363.
 [http://dx.doi.org/10.1002/ijc.23161] [PMID: 17893865]

[147]
Goligorsky, M.S.; Brodsky, S.V.; Noiri, E. Nitric oxide in acute renal failure: NOS versus NOS. Kidney Int.,  2002, 61(3), 855-861.
 [http://dx.doi.org/10.1046/j.1523-1755.2002.00233.x] [PMID: 11849438]

[148]
Bubici, C.; Papa, S.; Dean, K.; Franzoso, G. Mutual cross-talk between reactive oxygen species and nuclear factor-kappa B: Molecular basis and biological significance. Oncogene,  2006, 25(51), 6731-6748.
 [http://dx.doi.org/10.1038/sj.onc.1209936] [PMID: 17072325]

[149]
Jafari, F.; Elyasi, S. Prevention of colistin induced nephrotoxicity: A review of preclinical and clinical data. Expert Rev. Clin. Pharmacol.,  2021, 14(9), 1113-1131.
 [http://dx.doi.org/10.1080/17512433.2021.1933436] [PMID: 34015235]

[150]
Hussain, S.A.; Jassim, N.A.; Numan, I.T.; Al-Khalifa, I.I.; Abdullah, T.A. Anti-inflammatory activity of silymarin in patients with knee osteoarthritis. A comparative study with piroxicam and meloxicam. Saudi Med. J.,  2009, 30(1), 98-103.
 [PMID: 19139781]

[151]
Hussain, S.A.; Mortada, A.H.; Jasim, N.A.; Gorial, F.I. Silibinin improves the effects of methotrexate in patients with active rheumatoid arthritis: Pilot clinical study. Oman Med. J.,  2016, 31(4), 263-269.
 [http://dx.doi.org/10.5001/omj.2016.52] [PMID: 27403238]

[152]
Zhao, F.; Shi, D.; Li, T.; Li, L.; Zhao, M. Silymarin attenuates paraquat-induced lung injury via Nrf2-mediated pathway in vivo and in vitro. Clin. Exp. Pharmacol. Physiol.,  2015, 42(9), 988-998.
 [http://dx.doi.org/10.1111/1440-1681.12448] [PMID: 26173462]

[153]
Morishima, C.; Shuhart, M.C.; Wang, C.C.; Paschal, D.M.; Apodaca, M.C.; Liu, Y.; Sloan, D.D.; Graf, T.N.; Oberlies, N.H.; Lee, D.Y.W.; Jerome, K.R.; Polyak, S.J. Silymarin inhibits in vitro T-cell proliferation and cytokine production in hepatitis C virus infection. Gastroenterology,  2010, 138(2), 671-681.e2, 681.e1-681.e2.
 [http://dx.doi.org/10.1053/j.gastro.2009.09.021] [PMID: 19782083]

[154]
De La Puerta, R.; Martinez, E.; Bravo, L.; Ahumada, M.C. Effect of silymarin on different acute inflammation models and on leukocyte migration. J. Pharm. Pharmacol.,  2011, 48(9), 968-970.
 [http://dx.doi.org/10.1111/j.2042-7158.1996.tb06014.x] [PMID: 8910865]

[155]
Trappoliere, M.; Caligiuri, A.; Schmid, M.; Bertolani, C.; Failli, P.; Vizzutti, F.; Novo, E.; Manzano, C.; Marra, F.; Loguercio, C.; Pinzani, M. Silybin, a component of sylimarin, exerts anti-inflammatory and anti-fibrogenic effects on human hepatic stellate cells. J. Hepatol.,  2009, 50(6), 1102-1111.
 [http://dx.doi.org/10.1016/j.jhep.2009.02.023] [PMID: 19398228]

[156]
Gharagozloo, M.; Velardi, E.; Bruscoli, S.; Agostini, M.; Di Sante, M.; Donato, V.; Amirghofran, Z.; Riccardi, C. Silymarin suppress CD4+ T cell activation and proliferation: Effects on NF-κB activity and IL-2 production. Pharmacol. Res.,  2010, 61(5), 405-409.
 [http://dx.doi.org/10.1016/j.phrs.2009.12.017] [PMID: 20056147]

[157]
Li, C.C.; Hsiang, C.Y.; Wu, S.L.; Ho, T.Y. Identification of novel mechanisms of silymarin on the carbon tetrachloride-induced liver fibrosis in mice by nuclear factor-κB bioluminescent imaging-guided transcriptomic analysis. Food Chem. Toxicol.,  2012, 50(5), 1568-1575.
 [http://dx.doi.org/10.1016/j.fct.2012.02.025] [PMID: 22386810]

[158]
Jin, Y.; Zhao, X.; Zhang, H.; Li, Q.; Lu, G.; Zhao, X. Modulatory effect of silymarin on pulmonary vascular dysfunction through HIF-1α-iNOS following rat lung ischemia-reperfusion injury. Exp. Ther. Med.,  2016, 12(2), 1135-1140.
 [http://dx.doi.org/10.3892/etm.2016.3370] [PMID: 27446333]

[159]
Arafa Keshk, W.; Zahran, S.M.; Katary, M.A.; Abd-Elaziz Ali, D. Modulatory effect of silymarin on nuclear factor-erythroid-2-related factor 2 regulated redox status, nuclear factor-κB mediated inflammation and apoptosis in experimental gastric ulcer. Chem. Biol. Interact.,  2017, 273, 266-272.
 [http://dx.doi.org/10.1016/j.cbi.2017.06.022] [PMID: 28648817]

[160]
Younis, N.N.; Shaheen, M.A.; Mahmoud, M.F. Silymarin preconditioning protected insulin resistant rats from liver ischemia-reperfusion injury: Role of endogenous H2S. J. Surg. Res.,  2016, 204(2), 398-409.
 [http://dx.doi.org/10.1016/j.jss.2016.04.069] [PMID: 27565076]

[161]
Zhu, Z.; Sun, G. Silymarin mitigates lung impairments in a rat model of acute respiratory distress syndrome. Inflammopharmacology,  2018, 26(3), 747-754.
 [http://dx.doi.org/10.1007/s10787-017-0407-3] [PMID: 29098546]

[162]
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]

[163]
Behranvand, N.; Nasri, F.; Zolfaghari Emameh, R.; Khani, P.; Hosseini, A.; Garssen, J.; Falak, R. Chemotherapy: A double-edged sword in cancer treatment. Cancer Immunol. Immunother.,  2022, 71(3), 507-526.
 [http://dx.doi.org/10.1007/s00262-021-03013-3] [PMID: 34355266]

[164]
Kaufmann, S.H.; Earnshaw, W.C. Induction of apoptosis by cancer chemotherapy. Exp. Cell Res.,  2000, 256(1), 42-49.
 [http://dx.doi.org/10.1006/excr.2000.4838] [PMID: 10739650]

[165]
Mesner, P.W., Jr; Budihardjo, I.I.; Kaufmann, S.H. Chemotherapy-induced apoptosis. Adv. Pharmacol.,  1997, 41, 461-499.
 [http://dx.doi.org/10.1016/S1054-3589(08)61069-8] [PMID: 9204156]

[166]
Woods, D.; Turchi, J.J. Chemotherapy induced DNA damage response. Cancer Biol. Ther.,  2013, 14(5), 379-389.
 [http://dx.doi.org/10.4161/cbt.23761] [PMID: 23380594]

[167]
Bagnyukova, T.V.; Serebriiskii, I.G.; Zhou, Y.; Hopper-Borge, E.A.; Golemis, E.A.; Astsaturov, I. Chemotherapy and signaling. Cancer Biol. Ther.,  2010, 10(9), 839-853.
 [http://dx.doi.org/10.4161/cbt.10.9.13738] [PMID: 20935499]

[168]
Malhotra, V.; Perry, M.C. Classical chemotherapy: Mechanisms, toxicities and the therapeutic window. Cancer Biol. Ther.,  2003, 2(Suppl. 1), 1-3.
 [http://dx.doi.org/10.4161/cbt.199] [PMID: 14508075]

[169]
Pang, B.; Qiao, X.; Janssen, L.; Velds, A.; Groothuis, T.; Kerkhoven, R.; Nieuwland, M.; Ovaa, H.; Rottenberg, S.; van Tellingen, O.; Janssen, J.; Huijgens, P.; Zwart, W.; Neefjes, J. Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin. Nat. Commun.,  2013, 4(1), 1908.
 [http://dx.doi.org/10.1038/ncomms2921] [PMID: 23715267]

[170]
Xiao, M.; Cai, J.; Cai, L.; Jia, J.; Xie, L.; Zhu, Y.; Huang, B.; Jin, D.; Wang, Z. Let-7e sensitizes epithelial ovarian cancer to cisplatin through repressing DNA double strand break repair. J. Ovarian Res.,  2017, 10(1), 24.
 [http://dx.doi.org/10.1186/s13048-017-0321-8] [PMID: 28376831]

[171]
Demaria, M.; O’Leary, M.N.; Chang, J.; Shao, L.; Liu, S.; Alimirah, F.; Koenig, K.; Le, C.; Mitin, N.; Deal, A.M.; Alston, S.; Academia, E.C.; Kilmarx, S.; Valdovinos, A.; Wang, B.; de Bruin, A.; Kennedy, B.K.; Melov, S.; Zhou, D.; Sharpless, N.E.; Muss, H.; Campisi, J. Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov.,  2017, 7(2), 165-176.
 [http://dx.doi.org/10.1158/2159-8290.CD-16-0241] [PMID: 27979832]

[172]
Alexandre, J.; Hu, Y.; Lu, W.; Pelicano, H.; Huang, P. Novel action of paclitaxel against cancer cells: Bystander effect mediated by reactive oxygen species. Cancer Res.,  2007, 67(8), 3512-3517.
 [http://dx.doi.org/10.1158/0008-5472.CAN-06-3914] [PMID: 17440056]

[173]
Gewirtz, D.A.; Holt, S.E.; Elmore, L.W. Accelerated senescence: An emerging role in tumor cell response to chemotherapy and radiation. Biochem. Pharmacol.,  2008, 76(8), 947-957.
 [http://dx.doi.org/10.1016/j.bcp.2008.06.024] [PMID: 18657518]

[174]
Gao, Y.; Chen, L.; Gu, W.; Xi, Y.; Lin, L.; Li, Y. Targeted nanoassembly loaded with docetaxel improves intracellular drug delivery and efficacy in murine breast cancer model. Mol. Pharm.,  2008, 5(6), 1044-1054.
 [http://dx.doi.org/10.1021/mp800072e] [PMID: 19434922]

[175]
Saxena, V.; Hussain, M.D. Polymeric mixed micelles for delivery of curcumin to multidrug resistant ovarian cancer. J. Biomed. Nanotechnol.,  2013, 9(7), 1146-1154.
 [http://dx.doi.org/10.1166/jbn.2013.1632] [PMID: 23909128]

[176]
Jiang, L.; Li, L.; He, B.; Pan, D.; Luo, K.; Yi, Q.; Gu, Z. Anti-cancer efficacy of paclitaxel loaded in pH triggered liposomes. J. Biomed. Nanotechnol.,  2016, 12(1), 79-90.
 [http://dx.doi.org/10.1166/jbn.2016.2123] [PMID: 27301174]

[177]
Higuchi, T.; Sugisawa, N.; Miyake, K.; Oshiro, H.; Yamamoto, N.; Hayashi, K.; Kimura, H.; Miwa, S.; Igarashi, K.; Bouvet, M.; Singh, S.R.; Tsuchiya, H.; Hoffman, R.M. The combination of olaratumab with doxorubicin and cisplatinum regresses a chemotherapy-resistant osteosarcoma in a patient-derived orthotopic xenograft mouse model. Transl. Oncol.,  2019, 12(9), 1257-1263.
 [http://dx.doi.org/10.1016/j.tranon.2019.06.002] [PMID: 31299622]

[178]
Ruiz-González, R.; Milán, P.; Bresolí-Obach, R.; Stockert, J.; Villanueva, A.; Cañete, M.; Nonell, S. Photodynamic synergistic effect of pheophorbide a and doxorubicin in combined treatment against tumoral cells. Cancers (Basel),  2017, 9(12), 18.
 [http://dx.doi.org/10.3390/cancers9020018] [PMID: 28218672]

[179]
Kartini, D.; Taher, A.; Panigoro, S.; Setiabudy, R.; Jusman, S.; Haryana, S.; Murdani, A.; Rustamadji, P.; Karisyah, A.; Rasyid, S. Melatonin effect on hypoxia inducible factor-1a and clinical response in patients with oral squamous cell carcinoma receiving neoadjuvant chemotherapy: A randomized controlled trial. J. Carcinog.,  2021, 20(1), 5.
 [http://dx.doi.org/10.4103/jcar.JCar_19_20] [PMID: 34429714]

[180]
Malekinejad, H.; Janbaz-Acyabar, H.; Razi, M.; Varasteh, S. Preventive and protective effects of silymarin on doxorubicin-induced testicular damages correlate with changes in c-myc gene expression. Phytomedicine,  2012, 19(12), 1077-1084.
 [http://dx.doi.org/10.1016/j.phymed.2012.06.011] [PMID: 22819302]

[181]
Janbaz-Acyabar, H.; Malekinejad, H.; Sadrrkhanlou, R.; Razi, M. P-40: Silymarin prevents and protects from the doxorubicin-induced oxidative stress in testis and improves sperm quality in rats. J. Int. J. Fertil. Steril.,  2012, 6(Suppl. 1), 61.

[182]
Kranti, V.; Mahesh, V.; Srinivas, P.; Ganesh, Y.; Godwin, A.; Lahkar, M. Evaluation of the protective effect of silymarin on doxorubicin induced chronic testicular toxicity in rats. Int. J. Pharm. Biol.,  2013, 4(1), 473-484.

[183]
Shafiei-Roudbari, S.K.; Malekinejad, H.; Janbaz-Aciabar, H.; Razi, M. Crosstalk between E2F1 and P53 transcription factors in doxorubicin-induced DNA damage: Evidence for preventive/protective effects of silymarin. J. Pharm. Pharmacol.,  2017, 69(9), 1116-1124.
 [http://dx.doi.org/10.1111/jphp.12745] [PMID: 28542928]

[184]
Afsar, T.; Razak, S.; khan, M.R.; Almajwal, A. Acacia hydaspica ethyl acetate extract protects against cisplatin-induced DNA damage, oxidative stress and testicular injuries in adult male rats. BMC Cancer,  2017, 17(1), 883.
 [http://dx.doi.org/10.1186/s12885-017-3898-9] [PMID: 29268699]

[185]
Ijaz, M.U.; Khan, M.A.; Yousaf, S.; Nasir, S.; Naz, H.; Anwar, H.; Younis, T.; Samad, A. Methanolic extract of Fraxinus xanthoxyloides attenuates cisplatin-induced reproductive toxicity in male albino rats. Pak. Vet. J.,  2020, 40, 489-493.

[186]
Abd El-Hameed, S.; Mahgoub, H.; Awadin, W.; Elshaieb, A. The in vivo ameliorative effect of silymarin on cisplatin-associated ovarian and testicular histopathological and biochemical alterations. Mansoura Veterin. Med. J.,  2021, 22(2), 65-71.
 [http://dx.doi.org/10.21608/mvmj.2021.56846.1025]

[187]
Turk, P.; Kuspinar, G.; Ozerkan, K.; Avci, B. Protective effect of silymarin on cyclophosphamide toxicity in ovarian tissue. Fertil. Steril.,  2016, 106(3), e125.
 [http://dx.doi.org/10.1016/j.fertnstert.2016.07.375]

[188]
Ford, E.C.; Terezakis, S. How safe is safe? Risk in radiotherapy. Int. J. Radiat. Oncol. Biol. Phys.,  2010, 78(2), 321-322.
 [http://dx.doi.org/10.1016/j.ijrobp.2010.04.047] [PMID: 20832662]

[189]
Baskar, R.; Lee, K.A.; Yeo, R.; Yeoh, K.W. Cancer and radiation therapy: Current advances and future directions. Int. J. Med. Sci.,  2012, 9(3), 193-199.
 [http://dx.doi.org/10.7150/ijms.3635] [PMID: 22408567]

[190]
Mortezaee, K.; Parwaie, W.; Motevaseli, E.; Mirtavoos-Mahyari, H.; Musa, A.E.; Shabeeb, D.; Esmaely, F.; Najafi, M.; Farhood, B. Targets for improving tumor response to radiotherapy. Int. Immunopharmacol.,  2019, 76, 105847.
 [http://dx.doi.org/10.1016/j.intimp.2019.105847] [PMID: 31466051]

[191]
Farhood, B.; Geraily, G.; Abtahi, S.M.M. A systematic review of clinical applications of polymer gel dosimeters in radiotherapy. Appl. Radiat. Isot.,  2019, 143, 47-59.
 [http://dx.doi.org/10.1016/j.apradiso.2018.08.018] [PMID: 30390500]

[192]
Bagheri, H.; Rabie Mahdavi, S.; Shekarchi, B.; Manouchehri, F.; Farhood, B. Measurement of the contralateral breast photon and thermal neutron doses in breast cancer radiotherapy: A comparison between physical and dynamic wedges. Radiat. Prot. Dosimetry,  2018, 178(1), 73-81.
 [http://dx.doi.org/10.1093/rpd/ncx076] [PMID: 28591863]

[193]
Sogwagwa, N; Davison, G; Khan, S; Solomon, W. P9. Correlation of radiation induced apoptosis with Bax and Bcl-2 protein expression. 2016, 32(Suppl. 2), 163.

[194]
Gao, W.; Liang, J.X.; Ma, C.; Dong, J.; Yan, Q. The protective effect of N-acetylcysteine on ionizing radiation induced ovarian failure and loss of ovarian reserve in female mouse. BioMed Res. Int.,  2017, 2017, 4176170.
 [http://dx.doi.org/10.1155/2017/4176170] [PMID: 28607932]

[195]
Prasad, S.K.; Bose, A.; Bhattacharjee, A.; Banerjee, O.; Singh, S.; Mukherjee, S.; Pal, S. Radioprotective effect of ethanolic extract of Alocasia indica on γ-irradiation-induced reproductive alterations in ovary and uterus. Int. J. Radiat. Biol.,  2019, 95(11), 1529-1542.
 [http://dx.doi.org/10.1080/09553002.2019.1642545] [PMID: 31314632]

[196]
Sheikhzadeh, P.D.; Khezerloo, D.; Mortezazadeh, T.; Farhood, B.; Seyfizadeh, N.; Pezhman, L. The effect of date palm seed extract as a new potential radioprotector in gamma-irradiated mice. J. Cancer Res. Ther.,  2019, 15(3), 517-521.
 [http://dx.doi.org/10.4103/jcrt.JCRT_1341_16] [PMID: 31169213]

[197]
Farhood, B.; Aliasgharzadeh, A.; Amini, P.; Saffar, H.; Motevaseli, E.; Rezapoor, S.; Nouruzi, F.; Shabeeb, D.; Eleojo Musa, A.; Ashabi, G.; Mohseni, M.; Moradi, H.; Najafi, M. Radiation-induced dual oxidase upregulation in rat heart tissues: Protective effect of melatonin. Medicina (Kaunas),  2019, 55(7), 317.
 [http://dx.doi.org/10.3390/medicina55070317] [PMID: 31252673]

[198]
Farhood, B.; Aliasgharzadeh, A.; Amini, P.; Rezaeyan, A.; Tavassoli, A.; Motevaseli, E.; Shabeeb, D.; Eleojo Musa, A.; Najafi, M. Mitigation of radiation-induced lung pneumonitis and fibrosis using metformin and melatonin: A histopathological study. Medicina (Kaunas),  2019, 55(8), 417.
 [http://dx.doi.org/10.3390/medicina55080417] [PMID: 31366142]

[199]
Amini, P.; Nodooshan, S.J.; Ashrafizadeh, M.; Eftekhari, S.M.; Aryafar, T.; Khalafi, L.; Musa, A.E.; Mahdavi, S.R.; Najafi, M.; Farhood, B. Resveratrol induces apoptosis and attenuates proliferation of MCF-7 cells in combination with radiation and hyperthermia. Curr. Mol. Med.,  2021, 21(2), 142-150.
 [http://dx.doi.org/10.2174/18755666MTA2dODEdz] [PMID: 32436827]

[200]
Farhood, B.; Hassanzadeh, G.; Amini, P.; Shabeeb, D.; Musa, A.E.; Khodamoradi, E.; Mohseni, M.; Aliasgharzadeh, A.; Moradi, H.; Najafi, M. Mitigation of radiation-induced gastrointestinal system injury using resveratrol or alpha-lipoic acid: A pilot histopathological study. Antiinflamm. Antiallergy Agents Med. Chem.,  2020, 19(4), 413-424.
 [http://dx.doi.org/10.2174/1871523018666191111124028] [PMID: 31713500]

[201]
Nodooshan, S.J.; Amini, P.; Ashrafizadeh, M.; Tavakoli, S.; Aryafar, T.; Khalafi, L.; Musa, A.E.; Mahdavi, S.R.; Najafi, M.; Ahmadi, A.; Farhood, B. Suberosin attenuates the proliferation of MCF-7 breast cancer cells in combination with radiotherapy or hyperthermia. Curr. Drug Res. Rev.,  2021, 13(2), 148-153.
 [http://dx.doi.org/10.2174/2589977512666201228104528] [PMID: 33371865]

[202]
Najafi, M.; Taeb, S.; Farhood, B.; Amini, P.; Nodooshan, S.J.; Ashrafizadeh, M.; Aliasgharzadeh, A.; Vakili, Z.; Tavakoli, S.; Aryafar, T.; Musa, A.E. Imperatorin attenuates proliferation of MCF-7 cells in combination with radiotherapy or hyperthermia. Curr. Radiopharm.,  2022, 15(3), 236-241.
 [http://dx.doi.org/10.2174/1874471015666220318122202] [PMID: 35306999]

[203]
Marzban, M.; Anjamshoa, M.; Jafari, P.; Masoumi, H.; Ahadi, R.; Fatehi, D. Effects of gamma rays on rat testis tissue according to the morphological parameters and immunohistochemistry: Radioprotective role of silymarin. Electron. Physician,  2017, 9(6), 4524-4532.
 [http://dx.doi.org/10.19082/4524] [PMID: 28848626]

[204]
Fatehi, D.; Mohammadi, M.; Shekarchi, B.; Shabani, A.; Seify, M.; Rostamzadeh, A. Radioprotective effects of Silymarin on the sperm parameters of NMRI mice irradiated with γ-rays. J. Photochem. Photobiol. B,  2018, 178, 489-495.
 [http://dx.doi.org/10.1016/j.jphotobiol.2017.12.004] [PMID: 29232573]

[205]
Duffus, J.H. “Heavy metals” a meaningless term? (IUPAC Technical Report). Pure Appl. Chem.,  2002, 74(5), 793-807.
 [http://dx.doi.org/10.1351/pac200274050793]

[206]
Verma, R.; Vijayalakshmy, K.; Chaudhiry, V. Detrimental impacts of heavy metals on animal reproduction: A review. J. Entomol. Zool. Stud.,  2018, 6, 27-30.

[207]
Appenroth, K-J. Definition of “heavy metals” and their role in biological systems. In: Soil heavy metals; Springer, 2010; pp. 19-29.
 [http://dx.doi.org/10.1007/978-3-642-02436-8_2]

[208]
Singh, R.; Gautam, N.; Mishra, A.; Gupta, R. Heavy metals and living systems: An overview. Indian J. Pharmacol.,  2011, 43(3), 246-253.
 [http://dx.doi.org/10.4103/0253-7613.81505] [PMID: 21713085]

[209]
Babula, P.; Adam, V.; Opatrilova, R.; Zehnalek, J.; Havel, L.; Kizek, R. Uncommon heavy metals, metalloids and their plant toxicity: A review. Organic farming, pest control remediation of soil pollutants. Environ. Chem. Lett.,  2009, 275-317.
 [http://dx.doi.org/10.1007/978-1-4020-9654-9_14]

[210]
Pizent, A.; Tariba, B.; Živković, T. Reproductive toxicity of metals in men. Arh. Hig. Rada Toksikol.,  2012, 63(Suppl. 1), 35-46.
 [PMID: 22548851]

[211]
Gashi, F.; Dreshaj, E.; Troni, N.; Maxhuni, A.; Laha, F. Determination of heavy metal contents in water of Llapi River (Kosovo). A case study of correlations coefficients. Eur. Chem. Bull.,  2020, 9(2), 43-47.
 [http://dx.doi.org/10.17628/ecb.2020.9.43-47]

[212]
Ogundele, L.T.; Adejoro, I.A.; Ayeku, P.O. Health risk assessment of heavy metals in soil samples from an abandoned industrial waste dumpsite in Ibadan, Nigeria. Environ. Monit. Assess.,  2019, 191(5), 290.
 [http://dx.doi.org/10.1007/s10661-019-7454-8] [PMID: 31001700]

[213]
Stohs, S.; Bagchi, D. Oxidative mechanisms in the toxicity of metal ions. Free Radic. Biol. Med.,  1995, 18(2), 321-336.
 [http://dx.doi.org/10.1016/0891-5849(94)00159-H] [PMID: 7744317]

[214]
Ivanova, J.; Gluhcheva, Y.; Tsanova, D.; Piskova, A.; Djaleva, R.; Mokresheva, S.; Kamenova, D.; Mitewa, M. On the effect of chelating agents and antioxidants on cadmium-induced organ toxicity. An overview. Eur. J. Chem.,  2013, 4(1), 74-84.
 [http://dx.doi.org/10.5155/eurjchem.4.1.74-84.739]

[215]
Pirhadi, M.; Shariatifar, N.; Bahmani, M.; Manouchehri, A. Heavy metals in wheat grain and its impact on human health: A mini-review. J. Chem. Health Risks,  2022, 12(3), 421-426.

[216]
Tomilola D, O. Effect of cadmium on female reproduction and treatment options. Res. J. Obstetr. Gynecol.,  2018, 11(1), 41-48.
 [http://dx.doi.org/10.3923/rjog.2018.41.48]

[217]
Renu, K.; Madhyastha, H.; Madhyastha, R.; Maruyama, M.; Vinayagam, S.; Valsala Gopalakrishnan, A. Review on molecular and biochemical insights of arsenic-mediated male reproductive toxicity. Life Sci.,  2018, 212, 37-58.
 [http://dx.doi.org/10.1016/j.lfs.2018.09.045] [PMID: 30267786]

[218]
Anyanwu, B.O.; Orisakwe, O.E. Current mechanistic perspectives on male reproductive toxicity induced by heavy metals. J. Environ. Sci. Health Part C Environ. Carcinog. Ecotoxicol. Rev.,  2020, 38(3), 204-244.
 [http://dx.doi.org/10.1080/26896583.2020.1782116] [PMID: 32648503]

[219]
Jones, R.; Mann, T.; Sherins, R. Peroxidative breakdown of phospholipids in human spermatozoa, spermicidal properties of fatty acid peroxides, and protective action of seminal plasma. Fertil. Steril.,  1979, 31(5), 531-537.
 [http://dx.doi.org/10.1016/S0015-0282(16)43999-3] [PMID: 446777]

[220]
Aitken, R.J.; Harkiss, D.; Buckingham, D. Relationship between iron-catalysed lipid peroxidation potential and human sperm function. Reproduction,  1993, 98(1), 257-265.
 [http://dx.doi.org/10.1530/jrf.0.0980257] [PMID: 8345470]

[221]
Liang, R.; Senturker, S.; Shi, X.; Bal, W.; Dizdarogluand, M.; Kasprzak, K.S. Effects of Ni(II) and Cu(II) on DNA interaction with the N-terminal sequence of human protamine P2: Enhancement of binding and mediation of oxidative DNA strand scission and base damage. Carcinogenesis,  1999, 20(5), 893-898.
 [http://dx.doi.org/10.1093/carcin/20.5.893] [PMID: 10334208]

[222]
Wellejus, A.; Poulsen, H.E.; Loft, S. Iron-induced oxidative DNA damage in rat sperm cells in vivo and in vitro. Free Radic. Res.,  2000, 32(1), 75-83.
 [http://dx.doi.org/10.1080/10715760000300081] [PMID: 10625219]

[223]
Chandel, M.; Jain, G. Toxic effects of transition metals on male reproductive system: A review. J. Environ. Occup. Sci.,  2014, 3(4), 204-213.
 [http://dx.doi.org/10.5455/jeos.20140929042630]

[224]
Bomhard, E.; Vogel, O.; Löser, E. Chronic effects on single and multiple oral and subcutaneous cadmium administrations on the testes of Wistar rats. Cancer Lett.,  1987, 36(3), 307-315.
 [http://dx.doi.org/10.1016/0304-3835(87)90024-3] [PMID: 3652031]

[225]
Couto-Moraes, R.; Felício, L.F.; de Oliveira, C.A.; Bernardi, M.M. Post-partum testosterone administration partially reverses the effects of perinatal cadmium exposure on sexual behavior in rats. Psychol. Neurosci.,  2012, 5(2), 221-229.
 [http://dx.doi.org/10.3922/j.psns.2012.2.13]

[226]
Ciarrocca, M.; Capozzella, A.; Tomei, F.; Tomei, G.; Caciari, T. Exposure to cadmium in male urban and rural workers and effects on FSH, LH and testosterone. Chemosphere,  2013, 90(7), 2077-2084.
 [http://dx.doi.org/10.1016/j.chemosphere.2012.10.060] [PMID: 23290941]

[227]
Kumar, S.; Sharma, A. Cadmium toxicity: Effects on human reproduction and fertility. Rev. Environ. Health,  2019, 34(4), 327-338.
 [http://dx.doi.org/10.1515/reveh-2019-0016] [PMID: 31129655]

[228]
Cheng, Y.; Zhang, J.; Wu, T.; Jiang, X.; Jia, H.; Qing, S.; An, Q.; Zhang, Y.; Su, J. Reproductive toxicity of acute Cd exposure in mouse: Resulting in oocyte defects and decreased female fertility. Toxicol. Appl. Pharmacol.,  2019, 379, 114684.
 [http://dx.doi.org/10.1016/j.taap.2019.114684] [PMID: 31325558]

[229]
Hatem, R.M.; Hussain, E.M. Selenium nanoparticles and silymarin to prevent lead acetate-induced toxicity on reproductive performance of male rats. J. Phys. Conf. Ser.,  2020, 1664(1), 012104.
 [http://dx.doi.org/10.1088/1742-6596/1664/1/012104]

[230]
AL-Naimi, R.A. The therapeutic effect of Silybum marianum on the lead acetate induced-reproductive toxicity in both gender laboratory rats. Wassit J Sci Med.,  2012, 5(1), 144-155.

[231]
Faraji, T.; Momeni, H.R.; Malmir, M. Protective effects of silymarin on testis histopathology, oxidative stress indicators, antioxidant defence enzymes and serum testosterone in cadmium-treated mice. Andrologia,  2019, 51(5), e13242.
 [http://dx.doi.org/10.1111/and.13242] [PMID: 30729546]

[232]
Etemadi, T.; Momeni, H.R.; Ghafarizadeh, A.A. Impact of silymarin on cadmium-induced apoptosis in human spermatozoa. Andrologia,  2020, 52(11), e13795.
 [http://dx.doi.org/10.1111/and.13795] [PMID: 32829504]

[233]
Enebeli, B.; Nwangwa, E.K.; Nwogueze, B.C.; Nzenegu, A.; Agbonifo-Chijiokwu, E.; Omeru, O.; Ebuwa, E.I. In vivo attenuation of alcohol- and cadmium chloride–induced testicular toxicity modulated by silymarin in male wistar rat. Biol. Trace Elem. Res.,  2022, 200(8), 3666-3676.
 [http://dx.doi.org/10.1007/s12011-021-02944-3] [PMID: 34761358]

[234]
Momeni, H.R.; Sepehri, H.; Yosefi, M. Effect of silymarin on plasma membrane and acrosome of sperm treated with aluminum chloride. J. Arak Univ. Med. Sci.,  2015, 18(4), 71-80.

[235]
Aghashahi, M.; Momeni, H.R.; Darbandi, N. Impact of aluminium toxicity on vital human sperm parameters-Protective effects of silymarin. Andrologia,  2020, 52(10), e13742.
 [http://dx.doi.org/10.1111/and.13742] [PMID: 33616990]

[236]
Eskandari, F.; Momeni, H.R. Silymarin protects plasma membrane and acrosome integrity in sperm treated with sodium arsenite. Int. J. Reprod. Biomed. (Yazd),  2016, 14(1), 47-52.
 [http://dx.doi.org/10.29252/ijrm.14.1.47] [PMID: 27141548]

[237]
Eskandari, F.; Momeni, H.R. Protective effect of silymarin on viability, motility and mitochondrial membrane potential of ram sperm treated with sodium arsenite. Int. J. Reprod. Biomed. (Yazd),  2016, 14(6), 397-402.
 [http://dx.doi.org/10.29252/ijrm.14.6.397] [PMID: 27525323]

[238]
Ali, W.; Khudair, A. AL-Masoudi EA: Ameliorative role of silymarin extracted from Silybum marianum seeds on nickel chloride induce changes in testicular functions in adult male rabbits. Basra J. Vet. Res.,  2015, 14, 135-144.
 [http://dx.doi.org/10.33762/bvetr.2015.99994]

[239]
Rahimi-Madiseh, M.; Mohammadi, M.; Hassanvand, A.; Ahmadi, R.; Shahmohammadi, M.; Rostamzadeh, A. Assessment of the toxicity effects of nicotine on sperm and IVF and the potential protective role of silymarin-an experimental study in mice. Middle East Fertil. Soc. J.,  2020, 25(1), 1-9.

[240]
Uera, R.B.; Paz-Alberto, A.M.; Sigua, G.C. Phytoremediation potentials of selected tropical plants for Ethidium bromide. Environ. Sci. Pollut. Res. Int.,  2007, 14(7), 505-509.
 [http://dx.doi.org/10.1065/espr2007.02.391] [PMID: 18062483]

[241]
Zhang, C.; Liu, L.; Wang, J.; Rong, F.; Fu, D. Electrochemical degradation of ethidium bromide using boron-doped diamond electrode. Separ. Purif. Tech.,  2013, 107, 91-101.
 [http://dx.doi.org/10.1016/j.seppur.2013.01.033]

[242]
AL-Fatlawi, H.G.; AL-Sa’aidi, J.A.; Al-Arak, J.K. Potential impact of silymarin in EtBr induced reprotoxicity in female rats. Ann. Rom. Soc. Cell Biol.,  2021, 15372-15382.

[243]
Abdulshaheed, H.G.; Al-Saaidi, J.A.; Al-Arak, J.K. Ovario-utero protective effect of silymarin in ethidium bromide treated female rats. Iraqi J. Vet. Sci.,  2021, 36(1), 213-211.
 [http://dx.doi.org/10.33899/ijvs.2021.129798.1688]

[244]
Sheweita, S. Drug-metabolizing enzymes: Mechanisms and functions. Curr. Drug Metab.,  2000, 1(2), 107-132.
 [http://dx.doi.org/10.2174/1389200003339117] [PMID: 11465078]

[245]
Owumi, S.E.; Popoola, O.; Otunla, M.T.; Okuu, U.A.; Najophe, E.S. Benzo-a-pyrene-induced reproductive toxicity was abated in rats co-treated with taurine. Toxin Rev.,  2022, 41(3), 846-859.
 [http://dx.doi.org/10.1080/15569543.2021.1949617]

[246]
Boström, C.E.; Gerde, P.; Hanberg, A.; Jernström, B.; Johansson, C.; Kyrklund, T.; Rannug, A.; Törnqvist, M.; Victorin, K.; Westerholm, R. Cancer risk assessment, indicators, and guidelines for polycyclic aromatic hydrocarbons in the ambient air. Environ. Health Perspect.,  2002, 110(110)(Suppl. 3), 451-488.
 [http://dx.doi.org/10.1289/ehp.110-1241197] [PMID: 12060843]

[247]
Chung, J.Y.; Kim, Y.J.; Kim, J.Y.; Lee, S.G.; Park, J.E.; Kim, W.R.; Yoon, Y.D.; Yoo, K.S.; Yoo, Y.H.; Kim, J.M. Benzo[a]pyrene reduces testosterone production in rat Leydig cells via a direct disturbance of testicular steroidogenic machinery. Environ. Health Perspect.,  2011, 119(11), 1569-1574.
 [http://dx.doi.org/10.1289/ehp.1003391] [PMID: 21737371]

[248]
Xu, A.; Wang, J.; Wang, H.; Sun, Y.; Hao, T. Protective effect of lycopene on testicular toxicity induced by Benzo[a]pyrene intake in rats. Toxicology,  2019, 427, 152301.
 [http://dx.doi.org/10.1016/j.tox.2019.152301] [PMID: 31568845]

[249]
Neal, M.S.; Zhu, J.; Foster, W.G. Quantification of benzo[a]pyrene and other PAHs in the serum and follicular fluid of smokers versus non-smokers. Reprod. Toxicol.,  2008, 25(1), 100-106.
 [http://dx.doi.org/10.1016/j.reprotox.2007.10.012] [PMID: 18065195]

[250]
Konieczna, A.; Rutkowska, A.; Rachoń, D. Health risk of exposure to bisphenol A (BPA). Rocz. Panstw. Zakl. Hig.,  2015, 66(1), 5-11.
 [PMID: 25813067]

[251]
Vandenberg, L.N.; Hauser, R.; Marcus, M.; Olea, N.; Welshons, W.V. Human exposure to bisphenol A (BPA). Reprod. Toxicol.,  2007, 24(2), 139-177.
 [http://dx.doi.org/10.1016/j.reprotox.2007.07.010] [PMID: 17825522]

[252]
Stoker, T.E.; Robinette, C.L.; Britt, B.H.; Laws, S.C.; Cooper, R.L. Prepubertal exposure to compounds that increase prolactin secretion in the male rat: Effects on the adult prostate. Biol. Reprod.,  1999, 61(6), 1636-1643.
 [http://dx.doi.org/10.1095/biolreprod61.6.1636] [PMID: 10570013]

[253]
Takao, T.; Nanamiya, W.; Nagano, I.; Asaba, K.; Kawabata, K.; Hashimoto, K. Exposure with the environmental estrogen bisphenol A disrupts the male reproductive tract in young mice. Life Sci.,  1999, 65(22), 2351-2357.
 [http://dx.doi.org/10.1016/S0024-3205(99)00502-0] [PMID: 10597890]

[254]
Huo, X.; Chen, D.; He, Y.; Zhu, W.; Zhou, W.; Zhang, J. Bisphenol-A and female infertility: A possible role of gene-environment interactions. Int. J. Environ. Res. Public Health,  2015, 12(9), 11101-11116.
 [http://dx.doi.org/10.3390/ijerph120911101] [PMID: 26371021]

[255]
Jang, H-Y.; Kong, H-S.; Choi, B-Y.; Shin, J-S.; Cheong, H-T.; Kim, J-T.; Park, I-C.; Park, C-K.; Yang, B-K. Protective effects of silymarin against the toxicity of bisphenol A (BPA) on boar sperm quality. J. Embryo Transf.,  2011, 26(4), 257-263.

[256]
Abo-Amer, A. Involvement of chromosomally-encoded genes in malathion utilization by Pseudomonas aeruginosa AA112. Acta Microbiol. Immunol. Hung.,  2007, 54(3), 261-277.
 [http://dx.doi.org/10.1556/amicr.54.2007.3.3] [PMID: 17896475]

[257]
Jalili, C.; Farzaei, M.H.; Roshankhah, S.; Salahshoor, M.R. Resveratrol attenuates malathion-induced liver damage by reducing oxidative stress. J. Lab. Physicians,  2019, 11(3), 212-219.
 [http://dx.doi.org/10.4103/JLP.JLP_43_19] [PMID: 31579256]

[258]
Selmi, S.; Rtibi, K.; Grami, D.; Sebai, H.; Marzouki, L. Malathion, an organophosphate insecticide, provokes metabolic, histopathologic and molecular disorders in liver and kidney in prepubertal male mice. Toxicol. Rep.,  2018, 5, 189-195.
 [http://dx.doi.org/10.1016/j.toxrep.2017.12.021] [PMID: 29854588]

[259]
Ali, R.I.; Ibrahim, M.A. Malathion induced testicular toxicity and oxidative damage in male mice: The protective effect of curcumin. Egypt. J. Forensic Sci.,  2018, 8(1), 1-13.

[260]
Choudhary, N.; Goyal, R.; Joshi, S.C. Effect of malathion on reproductive system of male rats. J. Environ. Biol.,  2008, 29(2), 259-262.
 [PMID: 18831386]

[261]
Ozsoy, A.Z.; Nursal, A.F.; Karsli, M.F.; Uysal, M.; Alici, O.; Butun, I.; Tas, U.; Delibas, I.B. Protective effect of intravenous lipid emulsion treatment on malathion-induced ovarian toxicity in female rats. Eur. Rev. Med. Pharmacol. Sci.,  2016, 20(11), 2425-2434.
 [PMID: 27338071]

[262]
Abo El-Atta, H.; Ahmed, D. Testicular dysfunction in malathion induced toxicity in male rats: Protective role of NAC and Silymarin. Mansoura J. Forensic Med. Clin. Toxicol.,  2020, 28(2), 33-45.

[263]
Unsal, V.; Cicek, M.; Sabancilar, İ. Toxicity of carbon tetrachloride, free radicals and role of antioxidants. Rev. Environ. Health,  2021, 36(2), 279-295.
 [http://dx.doi.org/10.1515/reveh-2020-0048] [PMID: 32970608]

[264]
Abdel Moneim, A.E. Prevention of carbon tetrachloride (CCl4)-induced toxicity in testes of rats treated with Physalis peruviana L. fruit. Toxicol. Ind. Health,  2016, 32(6), 1064-1073.
 [http://dx.doi.org/10.1177/0748233714545502] [PMID: 25147302]

[265]
Huo, H.Z.; Wang, B.; Liang, Y.K.; Bao, Y.Y.; Gu, Y. Hepatoprotective and antioxidant effects of licorice extract against CCl4-induced oxidative damage in rats. Int. J. Mol. Sci.,  2011, 12(10), 6529-6543.
 [http://dx.doi.org/10.3390/ijms12106529] [PMID: 22072903]

[266]
Hamid, A.K.; Ahmed, M.A.; Tayawi, H.M. Silymarin effect as an antioxidant to improve damages induced by CCl4 on some characteristics of male rats reproductive system. Tikrit J. Pure Sci.,  2018, 23(2), 60-65.
 [http://dx.doi.org/10.25130/tjps.23.2018.029]

[267]
Mally, A.; Solfrizzo, M.; Degen, G.H. Biomonitoring of the mycotoxin Zearalenone: Current state-of-the art and application to human exposure assessment. Arch. Toxicol.,  2016, 90(6), 1281-1292.
 [http://dx.doi.org/10.1007/s00204-016-1704-0] [PMID: 27034246]

[268]
Richard, J.L. Some major mycotoxins and their mycotoxicoses-An overview. Int. J. Food Microbiol.,  2007, 119(1-2), 3-10.
 [http://dx.doi.org/10.1016/j.ijfoodmicro.2007.07.019] [PMID: 17719115]

[269]
Zinedine, A.; Soriano, J.M.; Moltó, J.C.; Mañes, J. Review on the toxicity, occurrence, metabolism, detoxification, regulations and intake of zearalenone: An oestrogenic mycotoxin. Food Chem. Toxicol.,  2007, 45(1), 1-18.
 [http://dx.doi.org/10.1016/j.fct.2006.07.030] [PMID: 17045381]

[270]
Ahmad, B.; Shrivastava, V.K.; Saleh, R.; Henkel, R.; Agarwal, A. Protective effects of saffron against zearalenone-induced alterations in reproductive hormones in female mice (Mus musculus). Clin. Exp. Reprod. Med.,  2018, 45(4), 163-169.
 [http://dx.doi.org/10.5653/cerm.2018.45.4.163] [PMID: 30538946]

[271]
Pfeiffer, E.; Hildebrand, A.A.; Becker, C.; Schnattinger, C.; Baumann, S.; Rapp, A.; Goesmann, H.; Syldatk, C.; Metzler, M. Identification of an aliphatic epoxide and the corresponding dihydrodiol as novel congeners of zearalenone in cultures of Fusarium graminearum. J. Agric. Food Chem.,  2010, 58(22), 12055-12062.
 [http://dx.doi.org/10.1021/jf1022498] [PMID: 20977187]

[272]
Gao, X.; Xiao, Z.H.; Liu, M.; Zhang, N.Y.; Khalil, M.M.; Gu, C.Q.; Qi, D.S.; Sun, L.H. Dietary silymarin supplementation alleviates zearalenone-induced hepatotoxicity and reproductive toxicity in rats. J. Nutr.,  2018, 148(8), 1209-1216.
 [http://dx.doi.org/10.1093/jn/nxy114] [PMID: 30137478]

[273]
Mikaili, P.; Moloudizargari, M.; Aghajanshakeri, S. Treatment with topical nitroglycerine may promote the healing process of diabetic foot ulcers. Med. Hypotheses,  2014, 83(2), 172-174.
 [http://dx.doi.org/10.1016/j.mehy.2014.05.002] [PMID: 24880867]

[274]
Boland, B.B.; Alarcón, C.; Ali, A.; Rhodes, C.J. Monomethylated-adenines potentiate glucose-induced insulin production and secretion via inhibition of phosphodiesterase activity in rat pancreatic islets. Islets,  2015, 7(2), e1073435.
 [http://dx.doi.org/10.1080/19382014.2015.1073435] [PMID: 26404841]

[275]
Pourheydar, B.; Azarm, F.; Farjah, G.; Karimipour, M.; Pourheydar, M. Effect of silymarin and metformin on the sperm parameters and histopathological changes of testes in diabetic rats: An experimental study. Int. J. Reprod. Biomed. (Yazd),  2022, 19(12), 1091-1104.
 [http://dx.doi.org/10.18502/ijrm.v19i12.10060] [PMID: 35098011]

[276]
Loeken, M.R. A new role for pancreatic insulin in the male reproductive axis. Diabetes,  2012, 61(7), 1667-1668.
 [http://dx.doi.org/10.2337/db12-0539] [PMID: 22723275]

[277]
Schoeller, E.L.; Albanna, G.; Frolova, A.I.; Moley, K.H. Insulin rescues impaired spermatogenesis via the hypothalamic-pituitary-gonadal axis in Akita diabetic mice and restores male fertility. Diabetes,  2012, 61(7), 1869-1878.
 [http://dx.doi.org/10.2337/db11-1527] [PMID: 22522616]

[278]
Agbaje, I.M.; Rogers, D.A.; McVicar, C.M.; McClure, N.; Atkinson, A.B.; Mallidis, C.; Lewis, S.E.M. Insulin dependant diabetes mellitus: Implications for male reproductive function. Hum. Reprod.,  2007, 22(7), 1871-1877.
 [http://dx.doi.org/10.1093/humrep/dem077] [PMID: 17478459]

[279]
Jangir, R.; Jain, G. Diabetes mellitus induced impairment of male reproductive functions: A review. Curr. Diabetes Rev.,  2014, 10(3), 147-157.
 [http://dx.doi.org/10.2174/1573399810666140606111745] [PMID: 24919656]

[280]
Bacon, C.G.; Hu, F.B.; Giovannucci, E.; Glasser, D.B.; Mittleman, M.A.; Rimm, E.B. Association of type and duration of diabetes with erectile dysfunction in a large cohort of men. Diabetes Care,  2002, 25(8), 1458-1463.
 [http://dx.doi.org/10.2337/diacare.25.8.1458] [PMID: 12145250]

[281]
Ricci, G.; Catizone, A.; Esposito, R.; Pisanti, F.A.; Vietri, M.T.; Galdieri, M. Diabetic rat testes: Morphological and functional alterations. Andrologia,  2009, 41(6), 361-368.
 [http://dx.doi.org/10.1111/j.1439-0272.2009.00937.x] [PMID: 19891634]

[282]
Scarano, W.R.; Messias, A.G.; Oliva, S.U.; Klinefelter, G.R.; Kempinas, W.G. Sexual behaviour, sperm quantity and quality after short-term streptozotocin-induced hyperglycaemia in rats. Int. J. Androl.,  2006, 29(4), 482-488.
 [http://dx.doi.org/10.1111/j.1365-2605.2006.00682.x] [PMID: 16524366]

[283]
Grossmann, M. Low testosterone in men with type 2 diabetes: Significance and treatment. J. Clin. Endocrinol. Metab.,  2011, 96(8), 2341-2353.
 [http://dx.doi.org/10.1210/jc.2011-0118] [PMID: 21646372]

[284]
Hayoz, D.; Ziegler, T.; Brunner, H.R.; Ruiz, J. Diabetes mellitus and vascular lesions. Metabolism,  1998, 47(12)(Suppl. 1), 16-19.
 [http://dx.doi.org/10.1016/S0026-0495(98)90365-1] [PMID: 9867065]

[285]
Ghanbari, E.; Nejati, V.; Azadbakht, M. Protective effect of royal jelly against renal damage in streptozotocin induced diabetic rats. World J. Urol.,  2015, 9(28), 1258-1263.

[286]
Paul, R.; Mukkadan, J. Modulation of blood glucose, oxidative stress, and anxiety level by controlled vestibular stimulation in prediabetes. J. Nat. Sci. Biol. Med.,  2020, 11(2), 111-111.

[287]
Mohsen, I.H.; Jawad, M.A.; Kadhim, A.J.; Al-Terehi, M.N. The oxidative stress state in diabetes mellitus type 2 patients with different medications types. J. Chem. Health Risks,  2022, 12(3), 523-525.

[288]
Heidari Khoei, H.; Fakhri, S.; Parvardeh, S.; Shams Mofarahe, Z.; Ghasemnejad-Berenji, H.; Nazarian, H.; Baninameh, Z. Testicular toxicity and reproductive performance of streptozotocin-induced diabetic male rats: The ameliorating role of silymarin as an antioxidant. Toxin Rev.,  2019, 38(3), 223-233.
 [http://dx.doi.org/10.1080/15569543.2018.1444641]

[289]
Abed, N.M.; Hamza, F.Z.; Nuhair, R.S. Effect of silymarin on oxidative stress biomarker, lipid peroxidation and reproductive function of diabetic albino rats. Kufa J. Veterin. Med. Sci.,  2019, 10(1), 88-98.
 [http://dx.doi.org/10.36326/kjvs/2019/v10i13327]

[290]
Rastegarpanah, M.; Zarif-Yeganeh, M. Clinical role of silymarin in oxidative stress and infertility: A short review for pharmacy practitioners. J. Res. Pharm. Pract.,  2019, 8(4), 181-188.
 [http://dx.doi.org/10.4103/jrpp.JRPP_18_100] [PMID: 31956630]

[291]
Brown, J.; Farquhar, C. Endometriosis: An overview of cochrane reviews. Cochrane Database Syst. Rev.,  2014, 2014(3), CD009590.
 [PMID: 24610050]

[292]
Arosh, J.A.; Lee, J.; Balasubbramanian, D.; Stanley, J.A.; Long, C.R.; Meagher, M.W.; Osteen, K.G.; Bruner-Tran, K.L.; Burghardt, R.C.; Starzinski-Powitz, A.; Banu, S.K. Molecular and preclinical basis to inhibit PGE2 receptors EP2 and EP4 as a novel nonsteroidal therapy for endometriosis. Proc. Natl. Acad. Sci. USA,  2015, 112(31), 9716-9721.
 [http://dx.doi.org/10.1073/pnas.1507931112] [PMID: 26199416]

[293]
Giudice, L.C. Endometriosis. N. Engl. J. Med.,  2010, 362(25), 2389-2398.
 [http://dx.doi.org/10.1056/NEJMcp1000274] [PMID: 20573927]

[294]
Fritzer, N.; Tammaa, A.; Haas, D.; Oppelt, P.; Renner, S.; Hornung, D.; Wölfler, M.; Ulrich, U.; Hudelist, G. When sex is not on fire: A prospective multicentre study evaluating the short-term effects of radical resection of endometriosis on quality of sex life and dyspareunia. Eur. J. Obstet. Gynecol. Reprod. Biol.,  2016, 197, 36-40.
 [http://dx.doi.org/10.1016/j.ejogrb.2015.11.007] [PMID: 26704015]

[295]
Jouhari, S.; Mohammadzadeh, A.; Soltanghoraee, H.; Mohammadi, Z.; Khazali, S.; Mirzadegan, E.; Lakpour, N.; Fatemi, F.; Zafardoust, S.; Mohazzab, A.; Naderi, M.M. Effects of silymarin, cabergoline and letrozole on rat model of endometriosis. Taiwan. J. Obstet. Gynecol.,  2018, 57(6), 830-835.
 [http://dx.doi.org/10.1016/j.tjog.2018.10.011] [PMID: 30545536]

[296]
Mirzaei, N.; Jahanian Sadatmahalleh, S.; Rouholamin, S.; Nasiri, M. A randomized trial assessing the efficacy of Silymarin on endometrioma-related manifestations. Sci. Rep.,  2022, 12(1), 17549.
 [http://dx.doi.org/10.1038/s41598-022-22073-8] [PMID: 36266431]

[297]
Visser, J.A. The importance of metabolic dysfunction in polycystic ovary syndrome. Nat. Rev. Endocrinol.,  2021, 17(2), 77-78.
 [http://dx.doi.org/10.1038/s41574-020-00456-z] [PMID: 33318648]

[298]
Acién, P.; Quereda, F.; Matallín, P.; Villarroya, E.; López-Fernández, J.A.; Acién, M.; Mauri, M.; Alfayate, R. Insulin, androgens, and obesity in women with and without polycystic ovary syndrome: A heterogeneous group of disorders. Fertil. Steril.,  1999, 72(1), 32-40.
 [http://dx.doi.org/10.1016/S0015-0282(99)00184-3] [PMID: 10428145]

[299]
De Leo, V.; la Marca, A.; Petraglia, F. Insulin-lowering agents in the management of polycystic ovary syndrome. Endocr. Rev.,  2003, 24(5), 633-667.
 [http://dx.doi.org/10.1210/er.2002-0015] [PMID: 14570747]

[300]
Pasquali, R.; Gambineri, A.; Pagotto, U. Review article: The impact of obesity on reproduction in women with polycystic ovary syndrome. BJOG,  2006, 113(10), 1148-1159.
 [http://dx.doi.org/10.1111/j.1471-0528.2006.00990.x] [PMID: 16827825]

[301]
Taher, Md A.; Atia, Y.A.; Amin, M.K. Improving an ovulation rate in women with polycystic ovary syndrome by using silymarin. Iraqi J. Pharm Sci.,  2010, 19(2), 11-18.

[302]
Kayedpoor, P.; Mohamadi, S.; Karimzadeh-Bardei, L.; Nabiuni, M. Anti-inflammatory effect of silymarin on ovarian immunohistochemical localization of TNF-α associated with systemic inflammation in polycystic ovarian syndrome. Int. J. Morphol.,  2017, 35(2), 723-732.
 [http://dx.doi.org/10.4067/S0717-95022017000200054]

[303]
Agarwal, A.; Gupta, S.; Sharma, R.K. Role of oxidative stress in female reproduction. Reprod. Biol. Endocrinol.,  2005, 3(1), 28.
 [http://dx.doi.org/10.1186/1477-7827-3-28] [PMID: 16018814]

[304]
Jang, H.Y.; Park, I.C.; Yuh, I.S.; Cheong, H.T.; Kim, J.T.; Park, C.K.; Yang, B.K. Beneficial effects of silymarin against nitric oxide-induced oxidative stress on cell characteristics of bovine oviduct epithelial cell and developmental ability of bovine IVF embryos. J. Appl. Anim. Res.,  2014, 42(2), 166-176.
 [http://dx.doi.org/10.1080/09712119.2013.823864]

[305]
Moosavifar, N.; Mohammadpour, A.H.; Jallali, M.; Karimi, G.; Saberi, H. Evaluation of effect of silymarin on granulosa cell apoptosis and follicular development in patients undergoing in vitro fertilization. East. Mediterr. Health J.,  2010, 16(6), 642-645.
 [http://dx.doi.org/10.26719/2010.16.6.642] [PMID: 20799592]

[306]
Amawi, H.; Hussein, N.A.; Karthikeyan, C.; Manivannan, E.; Wisner, A.; Williams, F.E.; Samuel, T.; Trivedi, P.; Ashby, C.R., Jr.; Tiwari, A.K. HM015k, a Novel silybin derivative, multi-targets metastatic ovarian cancer cells and is safe in Zebrafish toxicity studies. Front. Pharmacol.,  2017, 8, 498.
 [http://dx.doi.org/10.3389/fphar.2017.00498] [PMID: 28824426]

[307]
Kosina, P.; Kren, V.; Gebhardt, R.; Grambal, F.; Ulrichová, J.; Walterová, D. Antioxidant properties of silybin glycosides. Phytother. Res.,  2002, 16(Suppl. 1), S33-S39.
 [http://dx.doi.org/10.1002/ptr.796] [PMID: 11933137]

[308]
Dobiasová, S.; Řehořová, K.; Kučerová, D.; Biedermann, D.; Káňová, K.; Petrásková, L.; Koucká, K.; Václavíková, R.; Valentová, K.; Ruml, T.; Macek, T.; Křen, V.; Viktorová, J. Multidrug resistance modulation activity of silybin derivatives and their anti-inflammatory potential. Antioxidants,  2020, 9(5), 455.
 [http://dx.doi.org/10.3390/antiox9050455] [PMID: 32466263]

[309]
Simánek, V.; Kubisch, J.; Sedmera, P.; Halada, P.; Gazák, R.; Skottová, N.; Kren, V. Chemoenzymatic preparation of oligoglycosides of silybin, the flavonolignan from Silybum marianum. Heterocycles,  2001, 54(2), 901-915.
 [http://dx.doi.org/10.3987/COM-00-S(I)89]

[310]
Škottová, N.; ŠVagera, Z.; Večeřa, R.; Urbánek, K.; Jegorov, A.; Šimánek, V. Pharmacokinetic study of iodine-labeled silibinins in rat. Pharmacol. Res.,  2001, 44(3), 247-253.
 [http://dx.doi.org/10.1006/phrs.2001.0854] [PMID: 11529693]

[311]
Plíšková, M.; Vondráček, J.; Křen, V.; Gažák, R.; Sedmera, P.; Walterová, D.; Psotová, J.; Šimánek, V.; Machala, M. Effects of silymarin flavonolignans and synthetic silybin derivatives on estrogen and aryl hydrocarbon receptor activation. Toxicology,  2005, 215(1-2), 80-89.
 [http://dx.doi.org/10.1016/j.tox.2005.06.020] [PMID: 16076518]

[312]
Pyszková, M.; Biler, M.; Biedermann, D.; Valentová, K.; Kuzma, M.; Vrba, J.; Ulrichová, J.; Sokolová, R.; Mojović, M.; Popović-Bijelić, A.; Kubala, M.; Trouillas, P.; Křen, V.; Vacek, J. Flavonolignan 2,3-dehydroderivatives: Preparation, antiradical and cytoprotective activity. Free Radic. Biol. Med.,  2016, 90, 114-125.
 [http://dx.doi.org/10.1016/j.freeradbiomed.2015.11.014] [PMID: 26582372]

[313]
Yang, L.X.; Huang, K.X.; Li, H.B.; Gong, J.X.; Wang, F.; Feng, Y.B.; Tao, Q.F.; Wu, Y.H.; Li, X.K.; Wu, X.M.; Zeng, S.; Spencer, S.; Zhao, Y.; Qu, J. Design, synthesis, and examination of neuron protective properties of alkenylated and amidated dehydro-silybin derivatives. J. Med. Chem.,  2009, 52(23), 7732-7752.
 [http://dx.doi.org/10.1021/jm900735p] [PMID: 19673490]

[314]
Barzaghi, N.; Crema, F.; Gatti, G.; Pifferi, G.; Perucca, E. Pharmacokinetic studies on IdB 1016, a silybin-phosphatidylcholine complex, in healthy human subjects. Eur. J. Drug Metab. Pharmacokinet.,  1990, 15(4), 333-338.
 [http://dx.doi.org/10.1007/BF03190223] [PMID: 2088770]

[315]
Abenavoli, L.; Capasso, R.; Milic, N.; Capasso, F. Milk thistle in liver diseases: Past, present, future. Phytother. Res.,  2010, 24(10), 1423-1432.
 [http://dx.doi.org/10.1002/ptr.3207] [PMID: 20564545]

[316]
Drouet, S.; Doussot, J.; Garros, L.; Mathiron, D.; Bassard, S.; Favre-Réguillon, A.; Molinié, R.; Lainé, É.; Hano, C. Selective synthesis of 3-O-palmitoyl-silybin, a new-to-nature flavonolignan with increased protective action against oxidative damages in lipophilic media. Molecules,  2018, 23(10), 2594.
 [http://dx.doi.org/10.3390/molecules23102594] [PMID: 30309022]

[317]
Abenavoli, L.; Izzo, A.A.; Milić, N.; Cicala, C.; Santini, A.; Capasso, R. Milk thistle (Silybum marianum): A concise overview on its chemistry, pharmacological, and nutraceutical uses in liver diseases. Phytother. Res.,  2018, 32(11), 2202-2213.
 [http://dx.doi.org/10.1002/ptr.6171] [PMID: 30080294]

[318]
Javed, S.; Kohli, K.; Ali, M. Reassessing bioavailability of silymarin. Altern. Med. Rev.,  2011, 16(3), 239-249.
 [PMID: 21951025]

[319]
Javed, S.; Kohli, K.; Ali, M. Patented bioavailability enhancement techniques of silymarin. Recent Pat. Drug Deliv. Formul.,  2010, 4(2), 145-152.
 [http://dx.doi.org/10.2174/187221110791184999] [PMID: 20156178]

[320]
Di Costanzo, A.; Angelico, R. Formulation strategies for enhancing the bioavailability of silymarin: The state of the art. Molecules,  2019, 24(11), 2155.
 [http://dx.doi.org/10.3390/molecules24112155] [PMID: 31181687]

[321]
Yousaf, A.M.; Malik, U.R.; Shahzad, Y.; Mahmood, T.; Hussain, T. Silymarin-laden PVP-PEG polymeric composite for enhanced aqueous solubility and dissolution rate: Preparation and in vitro characterization. J. Pharm. Anal.,  2019, 9(1), 34-39.
 [http://dx.doi.org/10.1016/j.jpha.2018.09.003] [PMID: 30740255]

[322]
Ibrahim, A.H.; Rosqvist, E.; Smått, J.H.; Ibrahim, H.M.; Ismael, H.R.; Afouna, M.I.; Samy, A.M.; Rosenholm, J.M. Formulation and optimization of lyophilized nanosuspension tablets to improve the physicochemical properties and provide immediate release of silymarin. Int. J. Pharm.,  2019, 563, 217-227.
 [http://dx.doi.org/10.1016/j.ijpharm.2019.03.064] [PMID: 30946894]

[323]
Liang, J.; Liu, Y.; Liu, J.; Li, Z.; Fan, Q.; Jiang, Z.; Yan, F.; Wang, Z.; Huang, P.; Feng, N. Chitosan-functionalized lipid-polymer hybrid nanoparticles for oral delivery of silymarin and enhanced lipid-lowering effect in NAFLD. J. Nanobiotechnol.,  2018, 16(1), 64.
 [http://dx.doi.org/10.1186/s12951-018-0391-9] [PMID: 30176941]

[324]
Yang, G.; Zhao, Y.; Feng, N.; Zhang, Y.; Liu, Y.; Dang, B. Improved dissolution and bioavailability of silymarin delivered by a solid dispersion prepared using supercritical fluids. Asian J. Pharmaceut. Sci.,  2015, 10(3), 194-202.
 [http://dx.doi.org/10.1016/j.ajps.2014.12.001]

[325]
Nasr, S.S.; Nasra, M.M.A.; Hazzah, H.A.; Abdallah, O.Y. Mesoporous silica nanoparticles, a safe option for silymarin delivery: Preparation, characterization, and in vivo evaluation. Drug Deliv. Transl. Res.,  2019, 9(5), 968-979.
 [http://dx.doi.org/10.1007/s13346-019-00640-3] [PMID: 31001719]

[326]
Nagi, A.; Iqbal, B.; Kumar, S.; Sharma, S.; Ali, J.; Baboota, S. Quality by design based silymarin nanoemulsion for enhancement of oral bioavailability. J. Drug Deliv. Sci. Technol.,  2017, 40, 35-44.
 [http://dx.doi.org/10.1016/j.jddst.2017.05.019]

[327]
Piazzini, V.; Rosseti, C.; Bigagli, E.; Luceri, C.; Bilia, A.; Bergonzi, M. Prediction of permeation and cellular transport of Silybum marianum extract formulated in a nanoemulsion by using PAMPA and Caco-2 cell models. Planta Med.,  2017, 83(14/15), 1184-1193.
 [http://dx.doi.org/10.1055/s-0043-110052] [PMID: 28472840]

[328]
Woo, J.S.; Kim, T.S.; Park, J.H.; Chi, S.C. Formulation and biopharmaceutical evaluation of silymarin using SMEDDS. Arch. Pharm. Res.,  2007, 30(1), 82-89.
 [http://dx.doi.org/10.1007/BF02977782] [PMID: 17328246]

[329]
El-Far, M.; Salah, N.; Essam, A.; Abd El-Azim, A.O.; El-Sherbiny, I.M. Silymarin nanoformulation as potential anticancer agent in experimental Ehrlich ascites carcinoma-bearing animals. Nanomedicine (Lond.),  2018, 13(15), 1865-1858.
 [http://dx.doi.org/10.2217/nnm-2017-0394] [PMID: 30136915]

[330]
Adhikari, M.; Arora, R. Nano-silymarin provides protection against γ-radiation-induced oxidative stress in cultured human embryonic kidney cells. Mutat. Res. Genet. Toxicol. Environ. Mutagen.,  2015, 792, 1-11.
 [http://dx.doi.org/10.1016/j.mrgentox.2015.08.006] [PMID: 26433256]

[331]
Azadpour, M.; Farajollahi, M.M.; Dariushnejad, H.; Varzi, A.M.; Varezardi, A.; Barati, M. Effects of synthetic silymarin-PLGA nanoparticles on M2 polarization and inflammatory cytokines in LPS-treated murine peritoneal macrophages. Iran. J. Basic Med. Sci.,  2021, 24(10), 1446-1454.
 [PMID: 35096304]
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DOI https://dx.doi.org/10.2174/0929867330666230130115332	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X
当代药物化学

水飞蓟素对生殖毒性的保护作用综述

摘要

Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.

Approaches to the Treatment of Chronic Inflammation

Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications

Chalcogen-modified nucleic acid analogues

当代药物化学

水飞蓟素对生殖毒性的保护作用综述

摘要

Call for Papers in Thematic Issues

Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.

Approaches to the Treatment of Chronic Inflammation

Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications

Chalcogen-modified nucleic acid analogues

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