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

Tita      Hariyanti; Ria      Margiana; Moaed   Emran   Al-Gazally; Indrajit      Patra; Ghaidaa   Raheem   Lateef Al-Awsi; Noora      Hameed; Dilrabo      Kayumova; Mohammad   Javed   Ansari; Larry   Miguel   Torres-Criollo; Yasser   Fakri   Mustafa; Razzagh      Abedi-Firouzjah; Bagher      Farhood
doi:10.2174/0929867330666230130115332
Abstract

The reproductive system is extremely vulnerable to chemotherapy drugs, ionizing radiation, toxic heavy metals, chemicals, and so on. These harmful stimuli are able to induce oxidative damage, apoptosis, inflammation, and other mechanisms in the reproductive organs, leading to different adverse reproductive effects. It was shown that using medicinal plants (medicinal herbs) can be an effective medication for the prevention and treatment of multiple health conditions. Silymarin is a medicinal herb extract, obtained from the seeds of Silybum marianum. This herbal agent is a nontoxic agent even at relatively high physiological dose values, which suggests that it is safe for use in the treatment of different diseases. The hepato-, neuro-, cardio- and nephro-protective effects of silymarin have been assessed previously. The protective activities of silymarin can point to anti-oxidant, anti-apoptotic, anti-inflammatory, anti-fibrotic, immunomodulatory, and membrane-stabilizing properties. In this review, we aim to summarize current studies on the protective potentials of silymarin against reproductive toxicity. The molecular mechanisms of silymarin protection against cellular toxicity are also studied. Moreover, the findings obtained from improved formulations and delivery systems of silymarin have been addressed.
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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
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Current Medicinal Chemistry

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