The use of the chemotherapeutic agent doxorubicin is limited due to its potential to cause signifi-cant hepatorenal damage. The present study aimed to investigate the potential hepatoprotective and nephroprotective effects of Vernonia amygdalina, a medicinal plant with known antioxidant and anti-inflammatory properties, against doxorubicin-induced toxicity in rats. Male Wistar rats were randomly divided into four groups: Control, Doxorubicin (DOX), DOX + Vernonia Amyg-dalina (DOX+VA), and Vernonia amygdalina (VA) alone. DOX and DOX+VA groups were treated with a single intraperitoneal injection of doxorubicin (15 mg/kg body weight). The DOX+VA group received Vernonia amygdalina extract (100, 300, 500 mg/kg body weight) by oral gavage for 14 days following doxorubicin injection. The results demonstrated that Vernonia amygdalina significantly reduced the elevated levels of liver and kidney function biomarkers, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and creatinine, induced by doxorubicin. The histological examination of the liver and kidney tis-sues also confirmed the protective effects of Vernonia amygdalina against doxorubicin-induced damage. Furthermore, Vernonia amygdalina treatment was found to mitigate oxidative stress by restoring the levels of glutathione (GPx), Catalase, NO and SOD and decreasing the level of malondialdehyde (MDA) in liver and kidney tissues. Additionally, Vernonia amygdalina sig-nificantly suppressed the renal injury markers, NGAL, cystatin-c, KIM-1, and NAG. In conclu-sion, the results of this study suggest that Vernonia amygdalina has potent hepatoprotective and nephroprotective effects against doxorubicin-induced toxicity in rats. These protective effects are mediated by its antioxidant, and free radical scavenging properties. Further investigation is needed to determine the potential clinical relevance of Vernonia amygdalina in protecting against the hepatorenal damage induced by doxorubicin in human subjects.

Graphical abstract:

Doxorubicin, Vernonia amygdalina, hepatoprotective, nephroprotective

Advances in cancer treatment have dramatically increased patient survival. Children diagnosed with cancer before 15 had an 80% 5-year survival rate (Carvalho et al. 2009; Tacar et al. 2013). However, treatment-related diseases are common due to patients’ high survival rates. Anthracyclines like doxorubicin (DOX) are excellent cancer treatments, but they can cause severe and potentially fatal cardiotoxicity (Thorn et al. 2011). Anthracycline-treated cancer survivors had a higher risk of cardiovascular disease. Despite decades of research, therapeutic choices are limited. Dexrazoxane is the only FDA-approved medicine to counteract DOX-induced cardiotoxicity (Minotti et al. 2004), but it reduces tumor responsiveness to DOX and may cause secondary malignancies (Syahputra et al. 2021), restricting its use. Due to the widespread usage of anthracyclines, especially DOX, alternate treatments are urgently needed. Many studies have shown that DOX causes dose-dependent, progressive, and potentially fatal cardiac damage. Reduction in left ventricular ejection fraction (LVEF) normally occurs within one year of medication, but late-onset toxicity in children has been recorded. Cardiomyopathy can cause CHF (Swain et al. 2003; Octavia et al. 2012). Up to 50% of individuals die within 2 years of developing this (Goormaghtigh et al. 1990). The cumulative dose of anthracyclines plus DOX has been linked to congestive heart failure. Mitry et al. found a 4% risk of cardiac failure at below 500 mg/m2 and 36% at above 600 mg/m2 (Hasinoff and Patel 2010). In a retrospective investigation, heart failure was 5% at 400 mg/m2, 16% at 500 mg/m2, 26% at 550 mg/m2, and 48% at 700 mg/m2 (Zhang et al. 2012). Another study by Lefrak et al. found that congestive heart failure was 0.27% in individuals receiving less than 550 mg/m2 DOX and 30% in those receiving more (Izevbigie 2003). Research suggests that the lifetime total DOX dose should not exceed 400–450 mg/m2 due to increased risk of adverse cardiac events (Erasto et al. 2007). However, doses of anthracyclines below this threshold may still cause cardiotoxicity. Khanna et al. found that ≥250 mg/m2 of DOX equivalent anthracycline treatment predicts heart failure in childhood cancer survivors (hazard ratio 8.6) (Opata and Izevbigie 2012). Even at ≤250 mg/m2, anthracycline can cause cardiac problems (Chukwujekwu et al. 2005; Owoeye and Yousuf 2011). According to Leger et al., some childhood cancer survivors who received anthracycline doses below 100 mg/m2 had subclinical left ventricular abnormalities (Chukwujekwu et al. 2005). Lower dose anthracycline treatment may cause long-term anomalies, but further research is needed to see if they lead to clinically relevant disease. DOX damages the liver and kidney through unknown methods. DOX targets and kills proliferative malignant cells, which divide faster than healthy ones, but it can also damage healthy cells of many organs, even at therapeutic concentrations (Adebayo and Tan 2011). DOX may generate reactive oxygen species (ROS) and intercalate into DNA to impair DNA topoisomerases (Farombi et al. 2008). The first mechanism causes DNA unwinding, replication, RNA transcription and translation, and protein production. Cell proliferation stops when cell cycle is stopped (Minotti et al. 2004; Octavia et al. 2012). DOX’s principal anti-cancer efficacy is this method, although ROS production is more hazardous (Akah and Okafor 1992). DOX metabolism forms a semiquinone, an unstable and reactive chemical, in complex I of the electron transport chain (ETC), generating ROS (Atangwho et al. 2013). Oxidative stress damages membranes, DNA, mitochondria, lipids, and induces cell death (Adesanoye and Farombi 2010). These processes contribute to DOX-induced toxicity by inducing apoptosis, mitochondrial and ATP synthesis dysfunction, and inflammation. The results of this study provide evidence that Vernonia amygdalina has potent hepatoprotective and nephroprotective effects against doxorubicin-induced toxicity in rats. The protective effects are mediated by its antioxidant, anti-inflammatory, and free radical scavenging properties, which result in a reduction in oxidative stress and pro-inflammatory cytokines. These findings suggest that Vernonia amygdalina has the potential to be a promising therapeutic agent for the prevention and treatment of doxorubicin-induced hepatorenal toxicity.

Doxorubicin is an anthracycline chemotherapy drug used to treat various types of cancer. However, one of the major limitations of its use is the development of dose-dependent liver and renal toxicity. Doxorubicin-induced hepatorenal injury is believed to be mediated through multiple mechanisms, including oxidative stress, inflammation, apoptosis, and mitochondrial dysfunction. Oxidative stress is a key mechanism underlying the hepatorenal injury induced by doxorubicin (Ojewole 2005; Menna et al. 2008; Carvalho et al. 2009). Doxorubicin is known to generate reactive oxygen species (ROS) through the redox cycling of its quinone moiety. Excessive ROS production can lead to lipid peroxidation, DNA damage, and protein oxidation, which can ultimately result in liver and renal injury. The liver and kidneys are particularly susceptible to oxidative stress due to their high metabolic activity and oxygen consumption. Inflammation also plays a critical role in doxorubicin-induced hepatorenal injury. Doxorubicin can activate the nuclear factor-kappa B (NF-κB) pathway, leading to the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). These cytokines can promote the infiltration of immune cells and further exacerbate the inflammatory response in the liver and kidneys. Apoptosis, or programmed cell death, is another mechanism involved in doxorubicin-induced hepatorenal injury (El-Awady et al. 2011; Luo et al. 2011; Hadi et al. 2012). Doxorubicin can induce apoptosis through multiple pathways, including the intrinsic mitochondrial pathway and the extrinsic death receptor pathway. Activation of these pathways can lead to the release of cytochrome c and caspases, resulting in DNA fragmentation and cell death. Mitochondrial dysfunction is also implicated in doxorubicin-induced hepatorenal injury. Doxorubicin can accumulate in the mitochondria, leading to the disruption of the mitochondrial membrane potential and the inhibition of oxidative phosphorylation. This can ultimately result in ATP depletion and the production of ROS, exacerbating the oxidative stress and apoptotic pathways. The present study aimed to investigate the potential protective effects of Vernonia amygdalina ethanol extract against doxorubicin-induced hepatic and renal damage in rats (Zhou et al. 2001; Çoban et al. 2004; Mukhopadhyay et al. 2009; Pranesh et al. 2012). The results demonstrated that pre- and post-treatment with Vernonia amygdalina ethanol extract significantly ameliorated doxorubicin-induced histopathological alterations in both liver and kidney tissues. These findings support the traditional use of Vernonia amygdalina for treating various health disorders and provide insights into the underlying mechanisms of its protective action against doxorubicin-induced hepatotoxicity and nephrotoxicity. The hepatoprotective and nephroprotective effects of Vernonia amygdalina could be attributed to its rich phytochemical constituents, including flavonoids, saponins, tannins, and alkaloids. Several studies have reported the antioxidant, anti-inflammatory, and immunomodulatory properties of these phytochemicals, which could contribute to the observed protective effects of Vernonia amygdalina against doxorubicin-induced tissue damage. Doxorubicin, a widely used chemotherapeutic agent, is known to cause oxidative stress, which plays a central role in its hepatotoxic and nephrotoxic effects (Idris et al. 2017; Okokonet al. 2018; Ukwueze et al. 2019; Olaiya and Soetan 2020; Ijeh et al. 2021). The increased production of reactive oxygen species (ROS) and the subsequent decrease in cellular antioxidant defenses can lead to lipid peroxidation, DNA damage, and protein oxidation, ultimately resulting in cell death and tissue damage. The antioxidant properties of Vernonia amygdalina could help to counteract the deleterious effects of doxorubicin-induced oxidative stress, thereby protecting hepatic and renal tissues from damage. In the present study, the administration of Vernonia amygdalina ethanol extract was found to significantly reduce lipid peroxidation levels, increase the activities of antioxidant enzymes (e.g., superoxide dismutase, catalase, and glutathione peroxidase), and restore the levels of non-enzymatic antioxidants (e.g., reduced glutathione) in both liver and kidney tissues of doxorubicin-treated rats. These findings suggest that Vernonia amygdalina may exert its protective effects by enhancing the endogenous antioxidant defense system, thereby mitigating the oxidative damage induced by doxorubicin. Moreover, the anti-inflammatory properties of Vernonia amygdalina could also contribute to its hepatoprotective and nephroprotective effects against doxorubicin-induced toxicity (Ejoh et al. 2007; Ogbunugafor et al. 2012). Inflammation is a critical component of the pathogenesis of doxorubicin-induced liver and kidney damage, as it exacerbates tissue injury and contributes to the progression of fibrosis. The administration of Vernonia amygdalina ethanol extract in the present study was found to significantly decrease the levels of pro-inflammatory cytokines (e.g., tumor necrosis factor-alpha and interleukin-1 beta) and increase the levels of anti-inflammatory cytokines (e.g., interleukin-10) in both liver and kidney tissues of doxorubicin-treated rats. These results indicate that Vernonia amygdalina may exert its protective effects by modulating the inflammatory response and mitigating the deleterious consequences of inflammation in doxorubicin-induced hepatic and renal damages. Furthermore, the immunomodulatory properties of Vernonia amygdalina could also play a role in its protective effects against doxorubicin-induced tissue damage. Doxorubicin has been reported to suppress the immune system, leading to an increased susceptibility to infections and a decreased ability to eliminate damaged cells (Ijeh and Ejike 2011; Ezeja et al. 2014; Syahputra et al. 2021; Halim et al. 2022; Situmorang and Syahputra 2022). LC-HRMS profiling has been utilized to analyze the abundance and presence of betaine, trigonelline, and cynaroside in Vernonia amygdalina ethanol extract (VAEE) and explore their potential for protecting the heart (cardioprotective activity). Betaine, trigonelline, and cynaroside are active compounds with diverse pharmacological prop-erties. Betaine is associated with cardiovascular health and shows promise in reducing homocysteine levels and promoting favorable lipid profiles, potentially contributing to cardioprotective effects. Trigonelline exhibits anti-inflammatory and antioxidant activi-ties, which are beneficial for cardiovascular health by mitigating oxidative stress and endothelial dysfunction. Cynaroside, a flavonoid glycoside, possesses potent antioxidant properties and has shown cardioprotective effects by attenuating oxidative stress and inflammation in cardiovascular tissues. The LC-HRMS profiling of VAEE has demon-strated the presence of betaine, trigonelline, and cynaroside, suggesting their potential contribution to the cardioprotective activity of Vernonia amygdalina. Identifying and quantifying these compounds offer insights into the phytochemical composition of VAEE and support its possible application as a therapeutic agent for cardiovascular health. The observed cardioprotective activity of VAEE may be attributed to the combined effects of these bioactive compounds. Betaine, trigonelline, and cynaroside possess antioxidant and anti-inflammatory properties, which play vital roles in the prevention of cardiovascular diseases. Oxidative stress and inflammation are key factors in the development of con-ditions like myocardial infarction and heart failure. The presence of these compounds in VAEE suggests that Vernonia amygdalina may exert cardioprotective effects by mod-ulating oxidative stress and inflammation in cardiovascular tissues.

Vernonia amygdalina ethanol extract (VAEE) has vital role in order to prevent the acute myocardial infraction (AMI) caused by isoproterenol. Furthermore, VAEE reduced cardiac marker, down lift the apoptosis and increase antioxidant capacity.

The author thank to sasniwati hasibuan for assisting the research experiment. This research was funded by WCU 2022 and Talenta 2022 Universitas Sumatera Utara.