J . Yan and D . Li : Radioprotection 2024 , 59 ( 4 ), 287 – 295 291
Amini et al . evaluated the regulatory effect of Se-L-Met on the aforementioned genes and the protective effect to the lungs after local irradiation to the chest of rats . Results showed that the serum level of IL-4 increased markedly as well as the expression of IL4Ra1 , Duox1 and Duox2 after irradiation . The levels of IL4Ra1 , Duox1 and Duox2 were significantly upregulated after exposing to 15 Gy radiation and could be reversed by supplementation of Se-L-Met . Histopathological analysis also showed that Se-L-Met could markedly attenuate the filtration of macrophages and lymphocytes together with the vascular and alveolar thickening and fibrosis , during which the JAK1-STAT6 cascade induced by IL-4 stimulation may take a leading role ( Amini et al ., 2019 ).
Myriad evidences have proved that IR may lead to the increase of incidence of cardiovascular diseases ( Boerma et al ., 2016 ; Najafi et al ., 2018 ), including carotid and coronary artery disorders , blood supply impairment to heart muscles , pericarditis and atherosclerosis ( Stewart et al ., 2006 ). The chronic excretion of pro-fibrotic and proinflammatory cytokines plays an instrumental role in the aggravation of cardiovascular diseases after irradiation for the stimulation of chronic production of ROS during the progression of inflammation and fibrosis ( Farhood et al ., 2019 ). Joseph L . Unthank et al . demonstrated that a significant reduction of the endothelial cells in coronary arteries was observed in mice 4 months after TBI at 8.53 or 8.72 Gy of g radiation , and persisted through 18 months ( Unthank et al ., 2019 ). Amini et al . revealed that g radiation exposed locally to chest area of rats could lead to increased expression levels of IL4Ra1 , Duox1 and Duox2 , meanwhile treatment before and after 15 Gy g local radiation with the combination of curcumin and Se-L-Met could decrease the expression all three significantly . Among which the change of Duox1 level is most obvious for its expression reduced to lower than 2-fold in treated rats ( Amini et al ., 2018 ), indicating the potential of Se-L-Met together with curcumin to alleviate radiation-induced injuries ( Basnet and Skalko- Basnet , 2011 ).
4 Ebselen
Ebselen [ 2-phenyl-1,2-benzisoselenazol-3 ( 2H ) -one ] ( Eb ), a synthesized multifunctional lipid-soluble selenium-containing compound , is recognized as an inhibitor of TrxRs , could functionally simulate GPx to protect cells free from ROSinduced injuries thus demonstrating its significant radioprotective effect ( Briviba et al ., 1998 ; Cardoso et al ., 2017 ; Tak and Park 2009 ). Additionally , Eb also exhibits a broad range of biological activities , including anti-atherosclerotic , antiinflammatory , anti-SARS-CoV-2 , and anti-cancer properties ( Barchielli et al ., 2022 ; Thabet et al ., 2023 ).
Thabet et . al have demonstrated that Eb has anti-arthritic and radioprotective effects in an arthritic irradiated model ( Thabet et al ., 2023 ). Eb , by abating ROS , could enhance the antioxidant system thus reducing the peroxidation of serum and synovial tissue , meanwhile inhibit the activation of NOD-like receptor protein-3 ( NLRP-3 ), thereby impeding caspase-1 / IL-1b / receptor activator of nuclear factor kB ligand ( RANKL )/ nuclear factor-kB ( NF-kB ) pathway . Arthritic irradiated rats treated with Eb exhibited a superior ability to limit ROS comparing with rats without Eb , highlighting the protection of Eb against oxidative stress . Antioxidant system also exhibited a upregulation by activities of superoxide dismutase ( SOD ), catalase ( CAT ) and GPx , along with the level of glutathione ( GSH ) in serum and synovial in the Ebtreated group compared to the untreated group ( Thabet et al ., 2023 ). Recent experiments and studies have shown that the upregulation of NLRP3 inflammasome has a substantial impact on radiation damage , including oral mucositis , skin , lung , intestine and other systems ( Wei et al ., 2019 ). Considering the notable inhibition of the activation of NLRP3 that Eb manifests , it is possible that Eb could present a potential protective effect on different radiation-induced organ damages , however further studies both in vivo and in vitro are necessary to support this point .
Tewari et al . have demonstrated that Eb could positively regulate DNA damage repair response by restoring decreased expression of mismatch repair ( MMR ) proteins . In their study , showing no effect on either mutL homolog 1 ( MLH1 ) or mutS homolog 2 ( MSH2 ) expression in A172 cells , Eb could restore the decreased levels of them both in TNFa treated cells , meanwhile in T98G cells , the decreased level of MSH2 was also elevated . Knowing that Eb could abate the proinflammatory mediators as well as ROS from TNFa treated cells , along with its ability of increasing the expression of MMR protein , Eb may curtail the accumulation of genetic instability , indicating that Eb could act as radioprotector during glioma treatment , while further demonstration in future study is warranted ( Tewari et al ., 2009 ).
The pretreatment with 5 mM Eb for 2h significantly increased the viability of U937 cells exposed to 2 Gy g radiation comparing to the untreated cells and decreased the increased dihydroethidium ( DHE ) fluorescence ( Tak and Park , 2009 ). Eb pretreatment could significantly inhibit oxidative stress by decreasing the level of MDA which was 3 times higher after 20 Gy g radiation in untreated cells . The fluorescence probe studies , including 1,3-Bis ( diphenylphosphino ) propane ( DPPP ) for lipid peroxidation and 8-OH-dG for DNA damage in vivo and in vitro , demonstrated that Eb could protect DNA from oxidative damages induced by IR . In comparison with the untreated cells , the pretreatment of Eb could lessen the amount of apoptotic cells after 2 Gy g radiation . The induction of the mitochondria permeability transition ( MPT ) is related to the opening of large pores in the membranes of mitochondria , which takes an important role in apoptosis , during which ROS act as stimuli that change MPT , thus fluorescence probe JC-1 was chosen to observe the change of MPT . Results showed that the pretreatment of Eb could markedly suppress the disruption in the mitochondrial membrane potential induced by 2 Gy g radiation . While the oxidant-sensitive probe , DHR 123 was chosen to estimate the levels of intracellular peroxides in the mitochondria of U937 cells , and results showed that the pretreatment of 5 mM Eb could significantly reduce the mitochondrial fluorescence in comparison with the untreated cells , suggesting that Eb could protect mitochondria from oxidative damages . Male mice treated orally with Eb at 10 mg / kg per day for 2 weeks also manifested a significant protective effect on liver morphological changes after 8 Gy of TBI comparing to the control group treated with DMSO ( Tak and Park , 2009 ).