The liver and kidney are systems affected by chemotherapy drugs like cyclophosphamide. Acute and chronic exposure to some chemical agents result in nephrotoxicity and hepatotoxicity (Bhat, Kalthur, Padmashali, & Monappa, 2018). Inflammation is characterized by the protective response of the immune system against exogenous chemicals are metabolized and finally excreted by liver and kidney. In this process, pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-α), interleukins and mediators such as nitric oxide (NO) increase in the body and reactive oxygen species (ROS) are produced. Generation of ROS, including the hydroxyl radical (OH), hydrogen peroxide and superoxide anions or the reduction of antioxidant defense leads to oxidative stress, which plays a critical role in the development of liver and renal injury and even organ failure. Therefore, ROS scavengers and antioxidants that remove free radicals, moreover, anti-inflammatory herbal medicines (natural remedies) can protect against renal and liver dysfunction mediated by cyclophosphamide (Kocahan, Dogan, Erdemli, & Taskin, 2017; Zhai et al., 2018).
Many investigations have been done about the antioxidant, anti-inflammatory and immune-regulator role of saponins. Saponins reduce the produced free radicals, regulate the expression of antioxidant enzymes and eliminate the toxic effects of the industrial chemicals that lead to resolution of inflammation and return to hemostasis (Ma, Jiang, Yuan, Qiu, & Zhu, 2019; Yao et al., 2019). Therefore, in the present study, we hypothesized saponins with antioxidant and anti-inflammatory capacity able to inhibit liver and kidney toxicity due to the treatment with cyclophosphamide.
Our result in the current study indicated that exposure with CP significantly increased the serum levels of ALP, ALT, AST and BUN- Cr, suggesting a liver and renal dysfunction which was greatly decreased after saponin treatment. Saponin and co-administration of SP together with CP significantly reduced these parameters. Probably, antioxidant properties of saponin could be effective in the improvement of hepatic and renal function. On the other hand, histological evaluation showed that CP caused glomerular and tubular changes, as shown by glomerular atrophy, dilated bowman’s space, acute tubular necrosis and congestion. Saponin and CP plus SP attenuated the pathological changes in renal tissue caused by cyclophosphamide. Also, renal histological index was decreased by the saponin treatment. This cyto-protective effect of saponin may be due to its powerful antioxidant capacity (Hu et al., 2019).
In addition, cyclophosphamide resulted in the pathological changes in the hepatocytes, including acute triaditis and lymphocyte infiltration. As the administration of saponin and CP plus SP reduced the morphological changes of the liver tissues. Correspondingly, liver histological index was significantly decreased with the saponin treatment in the effective dose of 2.5 mg/kg. Probably, these protective effects of saponin may be due to potent anti-inflammatory and antioxidant properties (Wang, Xiang, Yi, & He, 2017), which were documented by the recovery and regeneration of pathological defects in the liver and renal structure.
The lipid peroxidation, as a free radical generating system, has been reported to be closely related to CP- induced tissue damages, and MDA is a good marker of the degree of lipid peroxidation (Mehraban et al., 2021). In the present experiment, the MDA levels were elevated and the activity of GPx, TAC and SOD were reduced by CP treatment. These data are consistent with previously published findings about the effects of CP on the organ toxicity (Duggina, Kalla, Varikasuvu, Bukke, & Tartte, 2015). The administration of CP led to oxidative stress, lipid peroxidation in renal and hepatic tissues and reduced antioxidant defenses. Increased oxidative stress is an important participant in the induced toxicity by CP. Therefore, compounds that can inhibit the production of free radicals will be of particular importance. Saponin has a more significant antioxidant effect, which our results confirmed that it decreased the amount of oxidative stress and subsequently lipid peroxidation and improved the antioxidant capacity. Thus documenting the ability of saponin’s dual function as both an enhancer of antioxidative enzyme defenses and a free radical scavenger.
Exposure to chemicals and drugs result in inflammation that is characterized by the protective response of the immune system against these agents. Pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-α), IL-1B and IL-6 increase in the body. Transcription of these interleukins are induced by an important protein in inflammatory process, NF-kB (Ginwala, Bhavsar, Chigbu, Jain, & Khan, 2019). Oxidative stress has been considered to be related with NF-kB. Actually, a vicious cycle has been suggested between the oxidative stress and NF-kB signaling pathway. Oxidative stress is crucial for the activation of the NF-kB cascade. On the other hand, the expression of NF-kB leads to the aggravation of free radical generation (Morgan & Liu, 2011).
Our results indicated that CP created a state of oxidative stress in kidney and liver tissues and then induced the production of pro-inflammatory cytokines such as NF-kB and IL-1B from these two organs which these findings are consistent with previous researches in this regard (Jnaneshwari et al., 2014). Usually, inhibition of inflammation is the most main actions in controlling the toxicity effect of these agents. The inflammatory conditions have been treated with the natural compounds. To prevent unwanted side effects of anti-inflammatory medicines, nonsteroidal anti-inflammatory drugs (NSAIDs), it is necessary to find out alternative anti-inflammatory agents with more efficacy than NSAIDs but with fewer side effects. Our findings demonstrated that saponin significantly could inhibit the production of inflammatory mediators induced by CP. Also, CP plus SP significantly reduced the NF-kB and IL-1B in kidney and liver tissues that were increased by CP. Probably, the high antioxidant and anti-inflammatory properties of saponin is responsible for ROS detoxification and inflammatory reduction.
In a nutshell, diagram 1 illustrates saponins-mediated hepato and renoprotection by the inhibition of oxidative stress.