Radiation-Induced Dual Oxidase Upregulation in Rat Heart Tissues: Protective Effect of Melatonin

Abstract

Background: Radiation-induced heart injury can lead to increased risk of heart failure, attack, and ischemia. Some studies proposed IL-4 and IL-13 as two important cytokines that are involved in late effects of ionizing radiation. On the other hand, these cytokines may, through upregulation of Duox1 and Duox2, induce chronic oxidative stress, inflammation, and fibrosis. In this study, we evaluated the upregulation of Duox1 and Duox2 pathways in hearts following chest irradiation in rats and then detected possible attenuation of them by melatonin. Materials and Methods: Twenty male Wistar rats were divided into four groups: (1) control; (2) melatonin treated (100 mg/kg); (3) radiation (15 Gy gamma rays); (4) melatonin treated before irradiation. All rats were sacrificed after 10 weeks and their heart tissues collected for real-time PCR (RT-PCR), ELISA detection of IL-4 and IL-13, as well as histopathological evaluation of macrophages and lymphocytes infiltration. Results: Results showed an upregulation of IL-4, IL4ra1, Duox1, and Duox2. The biggest changes were for IL4ra1 and Duox1. Treatment with melatonin before irradiation could attenuate the upregulation of all genes. Melatonin also caused a reduction in IL-4 as well as reverse infiltration of inflammatory cells. Conclusion: Duox1 and Duox2 may be involved in the late effects of radiation-induced heart injury. Also, via attenuation of these genes, melatonin can offer protection against the toxic effects of radiation on the heart.

Oxidative Stress in Radiation-Induced Cardiotoxicity

“…The abnormal upregulation of these enzymes may lead to the destruction of normal function and the increase of oxidative damage [62]. Chronic oxidative stress and inflammation can lead to fibrosis and hypertrophy, which may undermine normal cardiac function and myocardial blood supply [63]. A study by Farhood et al in 2017 showed that irradiation increased the level of IL-4 but not the level of IL-13 in rats.…”

“…The results of real-time PCR showed that radiation induced the upregulation of IL4ra1 (IL-4 receptor), DUOX1, and DUOX2; the changes induced by IL4ra1 and DUOX1 were the most obvious [62]. In addition to DUOX1 and DUOX2, IL-4 can also induce the upregulation of TGF-β, a powerful stimulator of fibrosis [63]. As mentioned earlier, the activation of the TGF-β pathway mediates collagen synthesis, promotes tissue fibrosis, and plays an important role in late radiationinduced cardiac toxicity.…”

“…Vitamin E Amygdala, peanut, and sunflower seeds [70] Reduce the activity of NADPH oxidase and inhibit lipid peroxidation and downregulate NF-κB [19] Antioxidation, anti-inflammation, and a decline of the risk of coronary heart diseases [75,76] Silymarin Milk thistle [77] Stimulate the expression of Nrf2 and downregulate NF-κB [14] Suppression of oxidative stress and inflammation and antiatherosclerosis [14,80] Resveratrol Grapes and red wine [81,82] Reduce the uncoupling of NADPH oxidase and eNOS and upregulate antioxidant defense enzymes [81,82] Antioxidative and anti-inflammatory properties against cardiovascular diseases [81,82,85] Lycopene Tomatoes, watermelons, pink grapefruit, apricots, pink guava, and papaya [29] Scavenge singlet oxygen, nitrogen dioxide, sulfur, and sulfonyl-free radicals [25] Prevention of the oxidation of DNA, lipid, and proteins [25,86] Melatonin Cereals, olives, walnuts, tomatoes, pineapples, ginger, and beans [63] Donate two electrons directly and stimulate the enzymatic antioxidant system indirectly [26,91] Suppression of oxidative stress and prevention of RIHD [90,91] Hesperidin Oranges, lemons, grapes, and olive oil [30] Passivate NADPH oxidase and inhibit TGF-β1 mRNA expression [95] Inhibition of oxidative stress, cardiac hypertrophy, and cardiac remodeling [95,96] 9 Oxidative Medicine and Cellular Longevity process of lipid peroxidation. Therefore, Vit E can reduce the risk of coronary heart disease [14].…”

“…Melatonin is a natural hormone found in plants, such as cereals, olives, walnuts, tomatoes, pineapples, ginger, and beans. Melatonin has a strong radiation protection effect because of its strong antioxidant ability [63]. Different animal studies of melatonin in various physiologic and pharmacologic concentrations and representing a wide range of doses have shown that melatonin has very low toxicity [89].…”

Therapeutic effects of kaempferol affecting autophagy and endoplasmic reticulum stress

“…The history of traditional herb medicine dates back to a long time ago, however, during the recent decades owing to the considerable positive impacts of herbals (Aliasgharzadeh et al, ; Farhood et al, ; Mortezaee et al, ; Najafi et al, ; Shabeeb et al, ) and noticeable side effects of chemical drugs, much attention has been made in pharmacognosy (Farhood et al, , , , ; Najafi et al, ). In other words, the harmful effects of synthetic drugs lead to the substitution of natural compounds for the remediation of a number of disorders (Azmoonfar et al, ; Farhood et al, ; Kolivand et al, ; Shabeeb et al, ). It has been shown that natural compounds derived from fruits and vegetables have various biological and therapeutic activities such as anticancer, antidiabetic, antiobesity, anti‐inflammatory, and antioxidant (Amini et al, , ; Najafi et al, , ; Shabeeb et al, ).…”