Curcumin protects radiation-induced liver damage in rats through the NF-κB signaling pathway

In both human and animals, radiotherapy plays a role in controlling tumors, while its injuries to the liver, bone marrow and other tissues restrict the radiation dose to suppress tumors [1]. The effects of radiation on the liver are influenced by lifestyle factors, especially diet, alcohol and obesity [2]. Irradiation to the non-tumor part of the liver leads to cell damage, and is termed as radiation-induced liver damage (RILD) [3]. Radiation-induced liver damage (RILD) is histologically featured with venous obstruction, distortion of the lobular architecture, a loss of parenchymal hepatocytes sinusoidal congestions, as well as some clinical symptoms such as ascites, fatigue, and elevated liver enzymes [4]. Currently, no pharmacological therapy is obtainable to relieve RILD. So, it is essential to o identify the toxicity at an early stage using biomarkers or to develop approaches to minimize the toxicity. Natural products intake that is abundant in anti-oxidant phytochemicals is becoming a hot issue, and the products can be considered to be radioprotective in preventing ionizing radiation injury [5].

Curcumin is a phenolic compound extracted from the rhizomes of turmeric (Curcuma longa) [6], which is widely applied in clinical therapy due to its safety, tolerability, and cost-effectiveness [7]. A review has suggested that curcumin has therapeutic capabilities in various chronic diseases including diabetes, obesity, cancers, as well as cardiovascular, pulmonary, neurological and autoimmune diseases [8]. In recent years, curcumin has been revealed to protect against liver damage based on the clinical trials of human [9]. Also, curcumin is shown to alleviate the liver damage in some animal models of liver injury, and can be successfully used to treat with liver damage in human and animal models [10‐15]. For instance, a prior study has reported that curcumin decreases the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in serum of a model of liver damage in rats [13]. Oral administration of curcumin to BPA-exposed rats reverses the lipid peroxidation product contents, and enhances glutathione peroxidase (GPx) and glutathione S-transferase (GST), catalase (CAT), and superoxide dismutase (SOD) activities to against BPA-stimulated hepatotoxicity in rats [15].

Curcumin can exert its biological functions through a diverse range of molecular targets and signaling pathways such as β-catenin, p38 mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3), nuclear factor-κB (NF-κB), nuclear factor E2-related factor 2 (Nrf2), reactive oxygen species (ROS), cyclin D1, cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), glutathione, and tumor necrosis factor-α (TNF-α) [9]. It is reported that curcumin enables to retard the inflammatory mediators’ production partly via the inhibition of the Wnt/β-catenin and NF-κB pathways as well as nucleotide binding oligomerization domain-like receptor 3 (NLRP3) inflammasome activation [16]. NF-κB is essential in radioresistance together with induced radiosensitivity [17]. Curcumin shows its antioxidant and inhibitory effects against a diverse range of hepatic diseases through the NF-κB signaling pathway [18‐20]. Nanji et al. [20] supported that curcumin enables to prevent alcohol-induced liver disease in rats through modulation of the NF-κB signaling pathway. A review detailed the relationship between curcumin and radiotherapy, and addressed the radioprotection of curcumin [21]. Although many studies have focused on RILD for decades, it remains unclear for its inner mechanisms and effective treatments. Therefore, the current study aimed to inquiry into the capabilities and its mechanism of curcumin in rats with RILD.

Radiation-induced liver damage (RILD) usually occurs due to the radiotherapy of hepatocellular carcinoma, and it is a chronic or subacute liver damage in clinic [26, 27]. In addition, RILD severely restricts the reirradiation of hepatobiliary tumors and the elevation of the tumor radiotherapy dose [28, 29]. Curcumin, as a naturally-occurring phenolic compound [30], has been found to be significant in the suppression of tumorigenesis, oxidation, platelet aggregation, or inflammation [31]. Meanwhile, curcumin is demonstrated to have other protective roles against various diseases [32‐34]. The obtained results of this article indicate that curcumin treatment reliefs the liver damage caused by radiation through inhibiting the NF-κB signal pathway.

Oxidative stress has been considered a key causing factor of liver damage. The ionizing radiation-induced oxidative stress is caused by increased free radicals’ production which can attack different components in the cells, resulting in biochemical changes and macromolecule modifications [35, 36]. The protective effect of curcumin against oxidative stress was previously described both in vitro and in vivo [37]. For instance, curcumin can be used as a radio protective agent due to its ability to reduce oxidative stress and inhibit transcription of genes related to oxidative stress and inflammatory responses [38]. Most of the toxic effects of ionizing radiation to normal tissue are due to the generation of ROS which triggers formation of several reactive intermediates. To overcome such events, living cells are equipped with integrated endogenous enzymatic and antioxidant systems such as SOD, CAT, GPx and GSH [39]. In line with our findings, it is reported that curcumin pretreatment to γ-induced hepatocytes leads to reduced lipid peroxidation and alleviated anti-oxidant status, thereby hampering its damage to the hepatocytes [40]. Another study revealed that curcumin pretreatment protects against γ-irradiated damage through suppressing membrane lipids peroxidation and DNA strand break formation induced by free radicals [41]. In this study, it is found that curcumin protects liver functions and alleviates oxidative stress of rats from radiation damage through the changes of ALT, AST, ALP, LDH, MDA, TP, SOD, CAD and GSH levels.

Our study also suggests that curcumin contributes to the prevention of inflammation in rats with RILD. Inflammation induced by deleterious circumstances is the product of complex series of responses triggered by the immune system, and it also causes a wide range of physiological and pathological morbidities [42]. Changes of inflammation are indicated by the increase of pro-inflammatory cytokines such as IL-6, IL-1 and TNF-α, genes encoded by activation of NF-κB [43]. Curcumin alleviates inflammation in chronic diseases and regulates inflammatory and pro-inflammatory pathways related with most chronic diseases [44]. Curcumin was reported to be useful in management of inflammation in non-alcoholic fatty liver disease (NAFLD) [45]. Wang et al. [34] have proposed that post curcumin treatment alleviates the severity of arthritis and the histopathological changes, and decreases proinflammatory cytokines release in rats with collagen-induced arthritis [46]. This study finds that curcumin reduces inflammation in rats with RILD through suppression of TNF-α, IL-1β, and IL-6 secretion.

The in vitro and in vivo studies suggested that curcumin alleviates oxidative stress, inflammation in chronic diseases through the Nrf2-keap1 pathway, the production of TNF and the cell signaling mediated by TNF [43]. As previously described, the NF-κB pathway is depicted to be the most important pathway for curcumin-regulated oxidative stress [47, 48]. Curcumin induces cell death of liver cancer stem cells (CSCs) or exerts its therapeutic effects on hepatitis B virus infection by directly targeting the NF-κB pathway [49, 50]. In this study, it is shown that curcumin attenuates radiation-induced liver damage by blocking the NF-κB pathway. A previous study proved that NF-κB activation restricts the apoptotic response to radiation, which offers a mechanism for evading potential cytotoxicity and antiangiogenic effects of tumor microvasculature to radiation therapy [51]. In an article reported by He and his colleagues, curcumin is found to be beneficial in the prevention of inflammation and oxidative damage through activating the NF-κB pathway in the liver [52]. Curcumin has been revealed to down-regulate the NF-κB pathway activation, which is modulated by the decrease of IκB kinase and p-IκBα, thereby inhibiting proliferation and promoting apoptosis of cells [53]. Cao et al. [54] observed that NF-κB expression downregulated by curcumin is in line with its inhibition of the expression levels of proinflammatory cytokines, implying that curcumin modulates cytokine secretion through the NF-κB pathway. In addition, curcumin treatment has been demonstrated to decrease the pro-inflammatory cytokines, oxidative stress, and other chemokines in NASH mice, while NF-κB is attenuated by curcumin treatment in NASH [6]. This study further provides the detailed relationship between curcumin and the NF-κB pathway in RILD rats.

In summary, it is highlighted that curcumin treatment protects rats with RILD by reducing oxidative stress, inflammation as well as apoptosis via the modulation of the NF-κB pathway. Hence, curcumin administration before radiation therapy can be helpful to prevent hepatocyte damage.