Cisplatin-induced Renal Oxidative Stress Research Articles

Phytochemical profiling and nephroprotective potential of ethanolic leaf extract of Polyalthia longifolia against cisplatin-induced oxidative stress in rat model

Ethnopharmacological relevanceKidney problems are becoming more common globally and are considered a major health issue in the modern world with high mortality rate. Polyalthia longifolia (Sonn.) Thwaites is a tropical ethnomedicinal plant used to treat various diseases like diabetes, hypertension and urinary disorders and possess antioxidant and anti-inflammatory properties. Aim of the studyThis study aimed to investigate the phytochemical composition of 70% ethanolic leaf extract of Polyalthia longifolia (Sonn.) Thwaites (PL) and evaluates its nephroprotective effects against cisplatin-induced nephrotoxicity in Wistar rats. Materials and methodsThe leaves of PL were extracted with 70% ethanol and performed the phytochemical profiling using Liquid Chromatography–Mass Spectrometry (LC-MS). The nephroprotective effect of PL leaf extract was evaluated at three doses (150, 300 and 600 mg/kg, p.o.) for 14 days against cisplatin toxicity (16 mg/kg, i.p., once) in male Wistar rats. Body and kidney weight indices, kidney function markers and lipid profile markers in serum, and oxidative stress markers in kidney tissue were performed along with the histopathological analysis of kidney. ResultsThe LC-MS chromatograph confirmed the presence of various phytocompounds include N-Methylhernagine (aporphine alkaloid), 4-Acetamidobutanoic acid (gamma amino acid) and choline, etc. in the PL leaf extract. Exposure of cisplatin (16 mg/kg, i.p., once only) to the animals significantly elevated the levels of kidney functional markers (i.e. serum urea, uric acid, creatinine) and the lipid markers (triglyceride and total cholesterol) in blood circulation with depletion of serum albumin which were reversed by the therapy of PL leaf extract (150, 300 and 600 mg/kg) in dose-dependent manner. The altered level of body and kidney weight in cisplatin treated group was also restored by the therapy. PL leaf extract effectively improved the antioxidant defense system of kidney at all doses by restoring the levels of tissue glutathione, superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase with the dose-dependent reduction of lipid peroxidation against cisplatin-induced renal oxidative stress. The histopathological observations also showed the significant recovery in cellular morphology after PL treatment when compared to the cisplatin toxicity group. The highest dose 600 mg/kg of PL leaf extract showed more pronounced renal recovery (p < 0.001) followed by other two doses, which was similar to the silymarin treatment group (a reference drug) against nephrotoxicity. ConclusionThe results of this study revealed the nephroprotective effects of PL leaves against cisplatin-induced nephrotoxicity by reversing the level of biochemical markers and mitigating oxidative stress as well as improving the architecture of renal tissues. This renal protection by PL might be due to the synergistic effect of its phytoconstituents and antioxidant efficacy.

PROTECTIVE EFFICACY OF SILVER NANOPARTICLES SYNTHESIZED FROM SILYMARIN ON CISPLATIN INDUCED RENAL OXIDATIVE STRESS IN ALBINO RAT

Objective: This present study was carried out to evaluate the protective efficacy of silver nanoparticles synthesized from silymarin on cisplatin-induced renal oxidative stress in the albino rat.Methods: Silver nanoparticles of silymarin was characterized by particle size, UV-Visible, FTIR and XRD analysis. Albino rats were divided randomly into six groups of six animals each. Group I Normal rats were treated with an oral dose of distilled water for 15 d. Group II rats were treated with single i. p. dose of cisplatin (16 mg/kg) on day 1. Group III rats were treated only with oral dose of silymarin (50 mg/kg/d) for 15 d. Group IV rats were treated only with oral dose of silver nanoparticles of silymarin (50 mg/kg/d) for 15 d. Group V rats were treated with an oral dose of silymarin for 14 d after single i. p. dose of cisplatin on day 1. Group VI rats were treated with oral dose of silver nanoparticles of silymarin for 14 d after single i. p. dose of cisplatin on day 1. Collected blood samples and kidney tissue samples were used for biochemical, enzymatic antioxidant and histopathological studies in all groups.Results: The formation of silver nanoparticles of silymarin were confirmed by particle size, UV-Visible analysis, crystalline nature was confirmed by X-ray diffraction analysis, and active principles were confirmed by FTIR analysis. Biochemical results of silver nanoparticles of silymarin-treated groups showed the significant (p˂0.05) decrease in the level of creatinine, urea, and uric acid as compared to cisplatin-induced rats and The enzymatic antioxidants of silver nanoparticles of silymarin-treated groups showed the significant (p˂0.05) increase in the level of glutathione reductase and significant decrease in MDA level as compared to cisplatin-induced rats. Additionally, histopathological results of silver nanoparticles of silymarin-treated groups also confirmed that the ameliorative effect of silymarin nanoparticle against cisplatin-induced rats.Conclusion: From this research work, we have concluded that silver nanoparticles of silymarin protected the kidney of albino rats from the adverse effects caused by cisplatin.

Cisplatin-induced oxidative stress stimulates renal Fas ligand shedding

Acute kidney injury (AKI), a significant complication of cisplatin chemotherapy is associated with reactive oxygen species (ROS)-dependent renal cell death, but the cellular targets of ROS in cisplatin nephrotoxicity are not fully resolved. Here, we investigated cisplatin-induced oxidative renal damage and tested the hypothesis that ROS-dependent shedding of death activator Fas ligand (FasL) occurs in cisplatin nephropathy. We show that intraperitoneal injection of sulfobutyl ether-β-cyclodextrin (Captisol™)-solubilized cisplatin elevated the level of lipid peroxidation product malondialdehyde in mouse kidneys and urinary concentration of oxidative DNA damage biomarker 8-hydroxy-2′-deoxyguanosine. Cisplatin increased mouse kidney-to-body weight ratio and the plasma or urinary levels of predictive biomarkers of AKI, including creatinine, blood urea nitrogen, microalbumin, neutrophil gelatinase-associated lipocalin, and cystatin C. Histological analysis and dUTP nick end labeling of kidney sections indicated tubular injury and renal apoptosis, respectively in cisplatin-treated mice. Whereas the plasma concentration of soluble FasL (sFasL) was unaltered, urinary sFasL was increased ∼4-fold in cisplatin-treated mice. Real-time quantitative live-cell imaging and lactate dehydrogenase assay showed that cisplatin stimulated caspase 3/7 activation and cytotoxicity in a human proximal tubule epithelial cell line which were attenuated by inhibitors of the FasL/Fas system and poly [ADP-ribose] polymerase-1. Moreover, TEMPOL, an intracellular free radical scavenger mitigated cisplatin-induced renal oxidative stress and injury, AKI biomarker and urinary sFasL elevation, and proximal tubule cell death. Our findings indicate that cisplatin-induced oxidative stress triggers the shedding of membrane-bound FasL to sFasL in the kidney. We demonstrate that cisplatin elicits nephrotoxicity by promoting FasL/Fas-dependent oxidative renal tubular cell death.

Baicalein, a Bioflavonoid, Prevents Cisplatin-Induced Acute Kidney Injury by Up-Regulating Antioxidant Defenses and Down-Regulating the MAPKs and NF-κB Pathways.

Acute renal failure is a serious complication of the anticancer drug cisplatin. The potential role of baicalein, a naturally occurring bioflavonoid on cisplatin-induced renal injury is unknown. Here, we assessed the effect of baicalein against a murine model of cisplatin-induced acute renal failure and investigated the underlying possible mechanisms. Renal function, kidney histology, inflammation, oxidative stress, renal mitochondrial function, proteins involved in apoptosis, nuclear translocation of Nrf2 and effects on intracellular signaling pathways such as MAPKs, and NF-κB were assessed. Pretreatment with baicalein ameliorated the cisplatin-induced renal oxidative stress, apoptosis and inflammation and improved kidney injury and function. Baicalein inhibited the cisplatin-induced expression of iNOS, TNF-α, IL-6 and mononuclear cell infiltration and concealed redox-sensitive transcription factor NF-κB activation via reduced DNA-binding activity, IκBα phosphorylation and p65 nuclear translocation in kidneys. Further studies demonstrated baicalein markedly attenuated cisplatin-induced p38 MAPK, ERK1/2 and JNK phosphorylation in kidneys. Baicalein also restored the renal antioxidants and increased the amount of total and nuclear accumulation of Nrf2 and downstream target protein, HO-1 in kidneys. Moreover, baicalein preserved mitochondrial respiratory enzyme activities and inhibited cisplatin-induced apoptosis by suppressing p53 expression, Bax/Bcl-2 imbalance, cytochrome c release and activation of caspase-9, caspase-3 and PARP. Our findings suggest that baicalein ameliorates cisplatin-induced renal damage through up-regulation of antioxidant defense mechanisms and down regulation of the MAPKs and NF-κB signaling pathways.

Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro

IntroductionAdministration of bone marrow mesenchymal stem cells (MSCs) or secreted microvesicles improves recovery from acute kidney injury (AKI). However, the potential roles and mechanisms are not well understood. In the current study, we focused on the protective effect of exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-ex) on cisplatin-induced nephrotoxicity in vivo and in vitro.MethodsWe constructed cisplatin-induced AKI rat models. At 24 h after treatment with cisplatin, hucMSC-ex were injected into the kidneys via the renal capsule; human lung fibroblast (HFL-1)-secreted exosomes (HFL-1-ex) were used as controls. All animals were killed at day 5 after administration of cisplatin. Renal function, histological changes, tubular apoptosis and proliferation, and degree of oxidative stress were evaluated. In vitro, rat renal tubular epithelial (NRK-52E) cells were treated with or without cisplatin and after 6 h treated with or without exosomes. Cells continued to be cultured for 24 h, and were then harvested for western blotting, apoptosis and detection of degree of oxidative stress.ResultsAfter administration of cisplatin, there was an increase in blood urea nitrogen (BUN) and creatinine (Cr) levels, apoptosis, necrosis of proximal kidney tubules and formation of abundant tubular protein casts and oxidative stress in rats. Cisplatin-induced AKI rats treated with hucMSC-ex, however, showed a significant reduction in all the above indexes. In vitro, treatment with cisplatin alone in NRK-52E cells resulted in an increase in the number of apoptotic cells, oxidative stress and activation of the p38 mitogen-activated protein kinase (p38MAPK) pathway followed by a rise in the expression of caspase 3, and a decrease in cell multiplication, while those results were reversed in the hucMSCs-ex-treated group. Furthermore, it was observed that hucMSC-ex promoted cell proliferation by activation of the extracellular-signal-regulated kinase (ERK)1/2 pathway.ConclusionsThe results in the present study indicate that hucMSC-ex can repair cisplatin-induced AKI in rats and NRK-52E cell injury by ameliorating oxidative stress and cell apoptosis, promoting cell proliferation in vivo and in vitro. This suggests that hucMSC-ex could be exploited as a potential therapeutic tool in cisplatin-induced nephrotoxicity.

Crocin attenuates cisplatin-induced renal oxidative stress in rats

Reactive oxygen species (ROS) and oxidative damage are the most important factors in cisplatin-induced acute renal failure. This study examined the protective effects of crocin against cisplatin-induced renal oxidative stress in rat. Animals were divided into five groups (n=6). Group 1 received normal saline (2ml/day, i.p.). Group 2 received a single dose of cisplatin (5mg/kg, i.p.). Groups 3–5 received crocin (100, 200, and 400mg/kg, i.p., respectively) for four consecutive days beginning 1-h before a single dose of cisplatin (5mg/kg) on day 1. On day 5, blood samples were drawn and kidneys were removed for histopathological, biochemical and RT-PCR examinations. Twenty four hours urinary chemistries were measured. Blood urea and creatinine and urinary glucose and protein concentrations in crocin-treated groups were significantly lower compared to the cisplatin-treated group. Histopathological studies showed massive damage in the S3 segment of proximal tubules in cisplatin-treated group but not in crocin-treated groups. Crocin treatment resulted in a significant reduction in malondialdehyde (MDA) concentration and produced a significant elevation in total thiol and glutathione peroxidase concentrations. There was a significant elevation in the mRNA expression of glutathione peroxidase in crocin-treated groups. The results suggest that crocin attenuates cisplatin-induced renal oxidative stress in rats.

The protective effect of royal jelly against cisplatin-induced renal oxidative stress in rats

The aim of this study was to investigate the effects of royal jelly on cisplatin-induced nephrotoxicity and oxidative stress in rats. Adult male Wistar albino rats were randomly divided into eight groups: the control, cisplatin, royal jelly, and royal jelly plus cisplatin groups. Biochemical and histopathological methods were utilized for evaluation of the nephrotoxicity. Blood was collected and analyzed for blood urea nitrogen (BUN), alanine aminotransferase, aspartate aminotransferase, triglyceride, total cholesterol, uric acid, total bilirubin, and total protein levels. The kidney samples were stored for the measurement of malondialdehyde (MDA), glutathione peroxidase (GSHPx), superoxide dismutase (SOD), and catalase (CAT) activities and processed for histopathological examinations. Administration of cisplatin to rats induced a marked renal failure, characterized with a significant increase in serum BUN and uric acid concentrations, and they had higher kidney MDA and lower GSH-Px, SOD, and CAT activities. In the groups that were administered RJ in association with CP, improvement was observed in some oxidative stress parameters and certain other biochemical parameters, pre-treatment with RJ being more effective. The CP-induced changes in histopathologic findings of kidneys were partially reversed by treatment with royal jelly. The results provide further insight into the mechanisms of CP-induced nephrotoxicity and confirm the antioxidant potential of royal jelly.

Effect of Camel’s Milk on Cisplatin-Induced Nephrotoxicity in Swiss Albino Mice

Problem statement: Nephrotoxicity is a major complication and a dose limiting factor for cisplatin therapy. Cisplatin mediated nephrotoxicity is remarkably documented by reactive oxygen species. Camel's milk has good nutritive value, antigenotoxic and anticytotoxic effects. The aim of the present study was to assess the protective effect of camel's milk against Cisplatin-induced renal oxidative stress in mice. Approach: Forty mal Swiss albino mice were randomly divided into four groups (n = 10). Group I, control group. Group II was received cisplatin (12 mg kg-1) for 5 alternate days. Group III was received camel's milk (33 mL kg-1) for consecutive 30 days. Group IV was received camel's milk (33 mL kg-1) for consecutive 30 days before administration of Cisplatin. Results: Cisplatin-induced oxidative stress was indicated by increased level of tissue Malondialdehyde (MDA), serum creatinine and urea, decreased the concentration of reduced Glutathione (GSH), Vitamin C (Vit. C) and Vitamin E (Vit. E) and decreased both activities and gene expression of Superoxid Dismutase (SOD), Catalase (CAT), Glutathione Raductase (GR) and Glutathione Peroxidase (GPx). Camel's milk reduced these biochemical changes and counteracted the deleterious effects of cisplatin Conclusion: The present study demonstrated the renoprotective potential of camel's milk against cisplatin-induced oxidative stress and renal dysfunction in mice. Hence, camel's milk has a potential to be used as therapeutic adjuvant in cisplatin nephrotoxicity.

Antioxidant effect of carnosine pretreatment on cisplatin-induced renal oxidative stress in rats

Cisplatin mediated nephrotoxicity is remarkably documented by reactive oxygen species. Carnosine is a naturally occurring dipeptide and has a scavenging property. The aim of present study was to assess the lipid peroxidation and antioxidant enzymes in association with oxidative stress in cisplatin -treated and 10 subsequent doses of carnosine-pretreated rats. 24 male Albino Wistar rats, were randomly divided into four groups (n=6). Group I remains untreated; Group II received Cisplatin (3 mg / kg) for 5 alternate days; Group III received Carnosine (10 mg / kg) for consecutive 10 days; Group IV received Carnosine (10 mg / kg) before administration of Cisplatin (3 mg / kg). The effects of carnosine on cisplatin-induced nephrotoxicity were evaluated by plasma creatinine, urea, malondialdehyde, nitrate; kidney tissue malondialdehyde, 4-HNE, superoxide dismutase and catalase activities. Cisplatin-induced oxidative stress was indicated by increased level of tissue MDA, 4-HNE and decreased level of tissue GSH, SOD and Catalase. Marked elevation of kidney weight and reduced body weight and pathological changes in kidney tissues were also observed in Cisplatin-treated rats. Carnosine reduced these pathological changes and counteracted the deleterious effects of cisplatin. The results divulge the beneficial effect of Carnosine pretreatment with cisplatin in experimental rat model.