Cancer is one of the world’s deadliest disease and the global impact of the disease increases on a yearly basis due to several factors including aging, population growth and socioeconomic development [1, 2]. The incidence of the disease cuts across all age groups and ethnicity, making it a major health issue [3]. Chemotherapy has significantly increased the life expectancy of cancer patients, especially in cases where the disease is detected early. However, most of the drugs used during chemotherapy have displayed major adverse effects due to the inability of the drugs to discriminate between cancer and normal cells, thus negatively impacting on the quality of life of cancer patients. Cisplatin is a frontline chemotherapeutic drug for treating a wide range of cancers. As a common cytostatic agent, CIS is administered to lungs, breast, testicular, ovarian, head and neck cancer patients [4, 5].

The negative effects of CIS on humans have been widely demonstrated in several previous studies. Considering existing literatures, although CIS is successfully used to kill cancer cells, it is a multi-organ toxic agent [4, 5]. Cisplatin induces gross nephrotoxicity, ototoxicity, neurotoxicity, reproductive and hepatotoxicity [6, 7]. CIS also induces the activation of several inflammatory and oxidative stress sensitivity pathways which further aggravates its multi organ toxicity [7, 8].

Organ degeneration under cisplatin insult takes place through multiple pathways, mostly linked to oxidative stress, inflammation and apoptosis, DNA damage and mitochondrial dysfunction [5, 9]. Experimental studies have shown that CIS can generate highly reactive oxygen species (ROS), which invariably leads to the accumulation of lipid peroxides, impaired respiratory chain in the mitochondria, suppression of antioxidant defence system, leading to oxidative stress [5, 10]. Additionally, oxidative stress induced by CIS could instigate the infiltration of inflammatory neutrophils, chemokines and cytokines which in turn aggravates the severity of organ damages [11, 12].

At present, there are no effective treatment for mitigating CIS induced toxicity, although several approaches have been proposed including using antioxidants such as vitamin E [13]. Based on the limitations of the available therapy, together with the unavoidable deteriorating effects of CIS therapy, there is an urgent need to find effective strategies against CIS-induced toxicity. Tiliacora triandra is an ever green medicinal plant of the Menispermaceae family, with several antioxidant compounds reported from the plant. The plant is native to several southeast Asian countries including Thailand, Laos and Vietnam [14, 15, 16]. Earlier studies have demonstrated its antioxidant and anti-inflammatory effects [14, 17, 18]. Studies have shown that T. triandra abrogated oxidative stress and inflammation, as well as improve antioxidant activity in the kidney, testes and brain [16, 17, 19]. Furthermore, our previous studies have illustrated that T. triandra alleviated CIS induced neurotoxicity [20, 21]. However, the protective effect of T. triandra in cisplatin-induced hepatorenal and testicular toxicity is yet to be explored. As such, this study investigated the influence of T. triandra on CIS-induced toxicity in the kidney, liver and testes of rats.

Although the emergency of platinum based anticancer drugs have provided great relief in the treatment of cancer, the prevalence of secondary side effects associated with these drugs is worrisome. Cisplatin is a frontline choice in anticancer treatment options. However, it has gained considerable attention due to its notable multi-organ toxicity associated with deleterious redox-inflammatory cascades in major body organs. Currently, research efforts aimed at mitigating CIS non-targeted organ toxicity are exploring natural products [23]. In our previous study and that of others, Tiliacora triandra demonstrated antioxidant and anti-inflammatory activities [17, 19], however its hepatorenal and testicular protective effects against CIS toxicity remains unknown. Therefore, we examined its effect on CIS-induced toxicity in the liver, testis and kidney of Wistar rats.

In the current study, the administration of CIS significantly retarded the body weight gain compared to that of normal control rats. Anticancer agents are known to perturb metabolism and cause loss of appetite. According to recent findings [24, 25], CIS induced loss of body weight which may be associated with reduced food intake and metabolic dysfunction. This was further corroborated by Fulco et al. [26] that CIS depressed metabolic activity of citrate synthase, an enzyme involved in citric acid cycle for energy production. Furthermore, CIS caused marked increases in kidney weight and coefficient, while the liver and testes weights appreciably decreased compared to the weight of organs in control rats. The weight changes could be associated with the CIS-induced degeneration of histological microstructures in the liver, kidney and testes. In contrast, TiTE obviously improved body weight gain, organ weight and its coefficient. This is consistent with earlier study showing the beneficial effect of TiTE on body and organ weight [17].

Biomarkers are reporters of tissue damage and they are usually considered in the treatment and management of diseases. In this study, serum BUN, creatinine and uric acid were considered as biomarkers of kidney damage; AST and ALT for liver injury, while serum levels of testosterone, LH and FSH were evaluated for testicular injury followed by characteristic histopathological analysis. CIS evidently inflicted damages on the liver and kidney as demonstrated by prominently increased serum levels of AST, ALT, BUN, creatinine and uric acid, respectively. It is well known that hepatic injury due to toxins compromises hepatic transport function and increases membrane permeability leading to leakage of marker enzymes, including ALT and AST from the hepatocytes [27, 28]. However, the marked increase in these enzymes in our study indicated the extent of CIS damage on the liver [28]. Renal injury and renal dysfunction are indicated by increased levels of serum BUN, uric acid and creatinine. This study revealed nephrotoxic damage induced by CIS characterized by considerable increases in serum uric acid, BUN and creatinine levels. Conceivably, CIS exposure might have adversely affected glomerular filtration and ultrafiltration underlying the accumulation of creatinine, BUN, and uric acid in the blood as shown in this study. Our results regarding hepatorenal damage induced by CIS agreed with reported hepatorenal damage induced by CIS in earlier studies [25, 26, 29, 30]. On the contrary, TiTE decreased alterations in serum hepatorenal biomarkers investigated in this study. The liver enzyme activities and serum uric acid, BUN and creatinine levels were prominently reduced compared to the CIS control group.

Furthermore, CIS impaired spermatogenesis with consequent diminution in epididymal sperm quality and endocrine balance in the current study. Emerging evidences have implicated CIS as a strong disruptor of reproductive homeostasis [24, 31, 32]. In the CIS-injected rats, the sperm count, motility and viability were considerably reduced compared to the normal healthy control. The spermato-toxic effect of CIS could be associated with significantly reduced levels of testosterone, FSH and LH. The role of testosterone in spermatogenesis is well established; it modulates the conversion of round spermatids into elongated spermatids in the spermatogenetic cycle. The reduced level of testosterone found in this study might resulted into too early detachment of round spermatids from Sertoli cells and seminal epithelium [33, 34]. The effect of CIS on hypothalamic–pituitary–gonadal axis may induce FSH deficit [35]. However, FSH deficit might adversely affect testicular Leydig cell steroidogenesis resulting in depressed testosterone synthesis. Altogether, the present observations suggested that sperm anomalies might be attributed to alterations in testosterone, FSH and LH in consistent with previous studies [36, 37, 38]. Interestingly, TiTE administration abrogated CIS-induced sperm abnormalities and restored levels of serum testosterone, FSH and LH compared to the CIS control group.

The well-reported pathogenesis of CIS toxicity is related to reactive oxygen species (ROS)mediated pathways, including oxidative injury and inflammatory perturbations [39, 40]. Redox impairment provokes oxidative stress and aberrant signalling for tissue injury. Previous studies have shown that CIS suppresses antioxidant defence mechanisms and consequently mediates peroxidative attack [5, 36, 39]. Herein, CIS injection depressed SOD, CAT and GPx activities, while the MDA level increased notably in the testes, kidney and liver. CIS generates ROS capable of deactivating SOD and CAT and increases the cellular utilization of GSH, leading to reduced cellular antioxidant enzyme activities and glutathione homeostasis [41]. The resultant oxidative milieu attacks lipid-laden bio-membranes to initiate lipid peroxidation, hence the increased level of MDA in our study. Thus, oxidative stress status occasioned by CIS attack on antioxidant apparatus damaged histological cytoarchitecture of the organs. We observed spermatogenic atrophy and degeneration of Sertoli cells in consistent with earlier reports [24, 40]. Interestingly, TiTE administration abrogated CIS-induced oxidative stress via significantly increasing SOD, CAT and GPx activities which consequently yielded prominent depreciation in MDA levels. Increased tissue antioxidant activities preserves enzymatic defence mechanism that mitigates oxidative stress. The histopathological alterations were also alleviated close to normal histology of the liver, kidney and testes. Studies have shown that medicinal plant extracts are reservoirs of antioxidant bioactive compounds that mediate scavenging of ROS and drug-induced toxicity in vivo [42]. Like TiTE in our study, extracts of medicinal plants have inhibited CIS-induced oxidative stress by upregulating cellular antioxidant machinery [30, 43, 44]. Song et al. [17] recently showed that TiTE counteracted oxidative stress in diabetic kidney and testicular impairment.

Several signaling pathways are triggered by oxidative stress status. Cisplatin activates ROS generation that provokes activation of transcription factors and apoptosis [45]. CIS activates nuclear factor-kappa B (NF-$\kappa$B), a transcription factor that stimulates the expression of proinflammatory cytokines, growth factor-related proliferation, adhesion molecules and survival genes [43]. In response to CIS toxicity in this study, the markedly elevated expression of NF-$\kappa$B promoted considerable increases in pro-inflammatory cytokines levels (IL-6, IL-1$\beta$ and TNF-$\alpha$). The elevated expression of NF-$\kappa$B indicates its activation and transcription by CIS-induced oxidative stress [25, 46]. Its nuclear translocation unlocks inflammatory gene expression underlying the cause for increased cytokine levels in this study. Furthermore, the integrated network of redox-inflammatory responses impairs mitochondrial integrity leading to the release of cytochrome C and caspases for execution of cytotoxic apoptosis [47]. In consistent with previous studies we found considerably elevated caspase-3 activity in the kidney, liver and testes [46]. This indicated apoptosis induced by CIS via redox imbalance and proinflammation. Among caspases, caspase-3 is the main executor of apoptosis triggering enzyme degradation, protein denaturation and cell death [48, 49]. Our findings herein confirmed suggestions in existing literatures that cytotoxic apoptosis and inflammatory responses play a mechanistic role in the pathophysiology of CIS-induced organ toxicity [29, 46, 50, 51]. Strikingly, TiTE significantly diminished NF-$\kappa$B and cytokine levels (IL-6, IL-1$\beta$ and TNF-$\alpha$). In agreement with our earlier finding showing the anti-inflammatory and antiapoptotic effect of TiTE [17, 20], TiTE inhibited CIS-induced pro-inflammation and apoptosis that chiefly mediate pathologies in several tissue injuries.

In conclusion, the results from this study suggested that TiTE exhibited hepatorenal and testicular protective effects against CIS induced toxicity primarily by preventing oxidative stress, improving antioxidant system, inhibiting inflammation and ameliorating endocrine deficits.

CW and OJO conceived and designed the study. XMZ, XZP and OJO conducted the experiments and analyzed the data. OJO and AF wrote the manuscript. All authors approved the final version of the manuscript.

The Institutional Ethics Committee approved the protocol for the animal experiment and all animal experimental procedures were performed in strict compliance with National Institute of Health for the care and use of laboratory animals.

Not applicable.

This research received no external funding.

The authors declare no conflict of interest.