Cisplatin-induced Nephrotoxicity Research Articles

Effect of Ganoderma lucidum on Cisplatin-induced Nephrotoxicity and Gastrointestinal Toxicity.

Cancer remains a major global health challenge, with an estimated 10 million cancer-related deaths in 2020, hindering efforts to extend life expectancy. Cisplatin, an effective platinum-based chemotherapeutic agent used against various malignancies, has numerous side effects. Ganoderma lucidum is a traditional Chinese medicine with extensive historical use and proven biological activity. This study investigated the effects of G. lucidum on cisplatin-induced nephrotoxicity and gastrointestinal toxicity. RAW264.7 cells were treated with cisplatin, G. lucidum, or both. Cytotoxicity and antioxidant capacity were measured. Slc:ICR (ICR) mice were treated with cisplatin, G. lucidum, or both. The survival rate and physiological data were measured. G. lucidum suppressed cisplatin-induced cytotoxicity and apoptosis in RAW264.7 cells. G. lucidum suppressed cisplatin-induced nephrotoxicity and gastrointestinal toxicity via its antioxidant effects in ICR mice. The suppressive mechanism of G. lucidum may be mediated via its antioxidant effects. These findings indicate its potential to reduce the side effects of cisplatin.

Effects of ginsenoside Rh2 on cisplatin-induced nephrotoxicity in renal tubular epithelial cells by inhibiting endoplasmic reticulum stress.

Nephrotoxicity remains a major adverse reaction of the anticancer drug cisplatin (CDDP) chemotherapy, which is an important risk factor for chronic renal disease. Ginsenoside Rh2 from Panax ginseng has been shown to protect against CDDP-induced nephrotoxicity in vivo, but its pharmacological effect on renal tubular epithelial cells is not clearly understood. This study examined the molecular mechanisms underlying the nephroprotective effects of Rh2 on CDDP-induced HK-2 cells and acute kidney injury (AKI) mice. As a result of Rh2 treatment, CDDP-induced HK-2 cells showed increased cell viability and reduced lactate dehydrogenase release. Moreover, Rh2 ameliorated CDDP-induced mitochondrial membrane potential, increased antioxidant enzyme activities, and reduced pro-inflammatory cytokine expression to reduce damage. Rh2 inhibited apoptosis and enhanced the antioxidant capacity of HK-2 cells by reducing proteins associated with endoplasmic reticulum (ER) stress, as well as by attenuating tunicamycin-induced ER stress. In addition, treatment of CDDP-induced AKI mice with Rh2 substantially reduced blood urea nitrogen and serum creatinine levels, attenuated histological damage of kidney. Further, Rh2 also improved kidney function by inhibiting ER stress to support in vitro findings. These results consistently demonstrated that Rh2 protects renal tubular epithelial cells from CDDP-induced nephrotoxicity and apoptosis by restoring ER homeostasis, which might suggest a therapeutic potential and providing new insights into AKI alternative therapies.

Macrophage depletion protects against cisplatin-induced ototoxicity and nephrotoxicity.

Cisplatin is a widely used anticancer drug with notable side effects including ototoxicity and nephrotoxicity. Macrophages, the major resident immune cells in the cochlea and kidney, are important drivers of both inflammatory and tissue repair responses. To investigate the roles of macrophages in cisplatin-induced toxicities, we used PLX3397, a U.S. Food and Drug Administration-approved inhibitor of the colony-stimulating factor 1 receptor, to eliminate tissue-resident macrophages. Mice treated with cisplatin alone had considerable hearing loss (ototoxicity) and kidney injury (nephrotoxicity). Macrophage ablation resulted in significantly reduced hearing loss and had greater outer hair cell survival. Macrophage ablation also protected against cisplatin-induced nephrotoxicity, as evidenced by markedly reduced tubular injury and fibrosis. Mechanistically, our data suggest that the protective effect of macrophage ablation against cisplatin-induced ototoxicity and nephrotoxicity is mediated by reduced platinum accumulation in both the inner ear and the kidney. Together, our data indicate that ablation of tissue-resident macrophages represents an important strategy for mitigating cisplatin-induced ototoxicity and nephrotoxicity.

Protective and therapeutic effects of nobiletin against cisplatin-induced nephrotoxicity in rats

ABSTRACT Possible protective and therapeutic effects of nobiletin on kidney in a cisplatin-induced nephrotoxicity rat model were investigated. Forty male albino rats were divided into four groups: control, cisplatin (CIS), cisplatin+nobiletin (CIS+NOB), and nobiletin+cisplatin (NOB+CIS). At the end of the study, the rats were subjected to biochemical, histological and immunohistochemical analyzes. Compared to the control group, tGSH (p < 0.05) levels, and G6PD (p < 0.05) and GPx (p < 0.001) activities, were increased in the CIS group; while significant (p < 0.05) decreases occurred in the MDA and TOC levels. Histopathologically, the kidneys of the groups administered nobiletin (CIS+NOB, NOB+CIS) were significantly different from the CIS group, being closer to control group in terms of degeneration and hyaline cylinder formation in the tubules (p < 0.05). While dilatation in the tubules, protein-rich fluid and hyaline cylinder formation in the lumen were most common in the CIS group, a significant decrease (p < 0.05) of these parameters was seen in the nobiletin groups (CIS+NOB, NOB+CIS). This study suggests that nobiletin can be effective in preventing and ameliorating toxic effects of cisplatin on the kidney.

Is oral nano-curcumin formulation a safe and effective measure for preventing cisplatin-induced nephrotoxicity in cancer patients?

Nephrotoxicity is one of the most important complications in cancer patients under treatment with cisplatin-containing regimens. Curcumin, as the most important active component of Curcuma longa, is an antioxidant and anti-inflammatory compound. In this clinical trial, we assessed the preventive effect of nano-curcumin oral formulation against cisplatin-induced nephrotoxicity in cancer patients. In this triple-blind clinical trial 30 cancer patients on cisplatin were randomly included in the treatment group, receiving nano-curcumin 40 mg capsules (n = 15) or the placebo group (n = 15) twice a day during four chemotherapy courses. Kidney function was measured at the beginning of the study and then at the end of each course of chemotherapy. There was no significant difference in acute kidney injury occurrence rate and creatinine and blood urine nitrogen serum levels between the treatment and placebo groups at the end of each chemotherapy course (P value >0.05). Just at the end of the first course, the difference was close to significant (P = 0.055). We also found no difference in mortality and recurrence rate in an average 30-month follow-up. Nano-curcumin in the prescribed dose and duration was not effective in preventing cisplatin-induced nephrotoxicity in cancer patients in comparison with the placebo. Further studies with larger sample size using different doses and duration of nano-curcumin are recommended.

The Effects of Thymus Caramanicus Jalas Extract and Its Main Constituent Carvacrol Against Cisplatin-Induced Nephrotoxicity in Mice.

Cisplatin, an anti-cancer chemotherapy drug, has nephrotoxic effects. Thymus caramanicus Jalas (TCJ) has antioxidant effects due to its main components. In the current research, we assessed the impact of TCJ extract and its main compound on cisplatin-induced nephrotoxicity in mice. Forty-two male mice were used in the study. Depending on their group, the animals received saline, carvacrol (10 mg/kg), or TCJ extract (50, 100, and 150 mg/kg) for 10 days. On the fifth day, mice received cisplatin (7.5 mg/kg, i.p.). After 10 days, serum creatinine (Cr) and blood urea nitrogen (BUN) levels were measured. Additionally, malondialdehyde (MDA) and glutathione (GSH) contents, as well as the activity levels of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx), and total antioxidant capacity (TAC) were measured in the kidney tissues. The western blotting method was used to determine the kidney's expression of cleaved caspase-3, Bax, Bcl-2, nuclear factor kappa-B (NF-κB), and tumor necrosis factor-alpha (TNF-α). Kidney tissue damage score (KTDS) was assessed using the hematoxylin-eosin (H&E) staining method. Cisplatin significantly increased serum Cr, KTDS, MDA, BUN levels, NF-κB, TNF-α, cleaved caspase-3, and Bax protein expression in the cisplatin group compared to the control group (P < 0.01). Additionally, cisplatin significantly decreased the kidney tissue's TAC and GSH content, activity levels of SOD, catalase, and GPx indicators, and expression of Bcl-2 protein (P < 0.05). TCJ and carvacrol significantly ameliorated these indicators in the cisplatin + TCJ (150 mg/kg) and cisplatin + carvacrol (10 mg/kg) groups compared to the cisplatin group (P < 0.05). TCJ (150 mg/kg) and its main component, carvacrol, could somewhat reduce cisplatin-induced nephrotoxicity through their anti-inflammatory, antioxidant, and anti-apoptotic effects.

A Comparative Histological Study Between the Protective and the Therapeutic Effect of Probiotic on Cisplatin Induced Nephrotoxicity in Adult Male Albino Rat

Abstract Introduction Although cisplatin (CP) is one of the most effective chemotherapies, it is associated with significant nephrotoxicity (Acute kidney injury). Lactobacillus plantarum is often used as a probiotic on its own for its beneficial properties and anti-inflammatory activity. Aim to compare the protective and therapeutic role of probiotics on the microscopic structure of the kidney in a model of cisplatin-induced nephrotoxicity. Material and Methods thirty-five adult male albino rats weighing (200-220gm) were divided into 4 groups. Group I (control group), Group II (Cisplatin group): rats received intraperitoneal injection of CP (7.5 mg/kg) for 3 days. Group III (protective group): Rats received 1 mL of probiotic orally for 7 days. From the fifth day, the rats received intraperitoneal injections of CP (7.5mg/kg) for 3 days. Group IV (Therapeutic group): Rats received intraperitoneal injection of CP for 3 days. From the fourth day, the rats received probiotic L. plantarum orally at a dose of (1 mL/day) for 14 days. The concentration of probiotics in group III and group IV was 109 Colony forming units (CFU)/mL/100 g of body weight. Kidney specimens were proceeded for light microscopic examination, as well as Morphometrical and statistical analyses. Results H&amp;E-stained sections of Group II showed marked renal affection in which most glomeruli showed atrophy. Renal tubules were mostly distorted, necrotic, and degenerative with interstitial hemorrhage, congestion, and cellular infiltration. PAS-stained sections showed marked increased reaction in glomerular and tubular Basement membranes with an apparent loss of Brush borders of most of the PCTs. Masson`s trichrome-stained sections showed a marked increase in collagen fibers in renal interstitia mostly around blood vessels. Immunohistochemically stained sections showed a marked increase in positive cytoplasmic reaction to caspase -3 antibodies mostly in renal tubules. On the other hand, the renal structure of The protective group showed marked improvement which appeared nearly comparable to that of the control group while the therapeutic group showed minimal improvement. Conclusion The protective effect of probiotics on cisplatin-induced Acute Kidney Injury (Nephrotoxicity) was markedly better than the therapeutic effect as detected by microscopic, morphometric, and statistical studies.

Combined effect of naringin and adipose tissue-derived mesenchymal stem cell on cisplatin nephrotoxicity through Sirtuin1/Nrf-2/HO-1 signaling pathway: a promising nephroprotective candidate.

Cisplatin nephrotoxicity is a well-known emergency clinical condition caused by oxidative stress and inflammation. Naringin (NAR) is considered an antioxidant agent with renoprotective effects capable of removing reactive oxygen species. Adipose tissue-derived mesenchymal stem cells (AD-MSCs) are reported to have anti-inflammatory and antioxidant properties. The present research examined the renoprotective effect of the combination of NAR and AD-MSCs as opposed to each one alone on cisplatin-induced nephrotoxicity through SIRT-1/Nrf-2/HO-1 pathway. This study included five groups (n = 8 each) of male Sprague-Dawley rats (200 - 220g): sham, cisplatin: rats receiving cisplatin (6.5 mg/kg, i.p.) on the 4th day; NAR+cisplatin: rats pretreated with NAR (1 week, i.p.) + cisplatin on the 4th day; AD-MSCs: rats receiving AD-MSCs (1 × 106) by injection through the tail vein on the 5th day + cisplatin on the 4th day; and NAR+AD-MSCs+cisplatin. On the 8th day, the animals were anesthetized to obtain tissue and blood samples. Biochemical factors, inflammation, oxidative stress, and gene expression were explored. Cisplatin increased blood urea nitrogen, creatinine, inflammation, and oxidative stress. Moreover, mRNA expression of Sirtuin1, nuclear factor erythroid 2-related factor 2 (Nrf-2), and heme oxygenase-1 (HO-1) remarkably reduced. Furthermore, cisplatin led to a disturbance in kidney structure (glomerular atrophy, cell infiltrations, and tubular dysfunction) as confirmed by histology findings. However, NAR pretreatment, AD-MSC administration, or a combination of both significantly reversed these changes. Overall, when used together, NAR and AD-MSCs had stronger cisplatin-induced effects on kidney dysfunction by inhibiting inflammation, reducing oxidative stress, and increasing the Sirtuin1/Nrf-2/HO-1 pathway.

The Protective Effects of Curcumin Oil and Flaxseed Oil on Cisplatin-Induced Nephrotoxicity and Hepatotoxicity in Male Albino Rats

The Protective Effects of Curcumin Oil and Flaxseed Oil on Cisplatin-Induced Nephrotoxicity and Hepatotoxicity in Male Albino Rats

Analysis of the effectiveness of different schemes of supportive therapy in the prophylaxis of cisplatin-induced nephrotoxicity

Objective: To evaluate, in the scenario of rapid infusion, the effectiveness of the different regimens of supportive therapy employed in the prevention of nephrotoxicity and electrolyte depletion induced by cisplatin (CDDP). Methods: Data from patients who used CDDP weekly (30 to 40mg/m2) with an infusion time of 60-120 minutes were analyzed. The regimens evaluated were: saline solution (A), saline solution and mannitol (B), saline solution and magnesium (C) and saline solution with mannitol and magnesium (D). The following laboratory parameters were evaluated: creatinine (Cr), magnesium (Mg) sodium (Na) and potassium (K), and glomerular filtration rate (GFR). They were subsequently compiled in Microsoft Office Excel® and analyzed in Software R, using with analysis by means of descriptive statistics, developed in accordance with the recommendations of Strengthening the Reporting of Observational studies in Epidemiology (STROBE) statement. Results: The study population evaluated were 46 patients, who received 218 infusions of CDDP. It was observed that schemes A and B had a progressive decrease in Mg. Scheme B had decreased levels of K, Cr and increased Na. In the individual analysis of each cycle, the different schemes of supportive therapy in rapid infusion were equally effective in preventing nephrotoxicity and electrolyte depletion. The schemes used were evaluated for throughout CDDP administrations, the regimen C and D demonstrated efficacy in maintaining renal function throughout multiple administration of CDDP. Conclusion: In the analysis of cumulative doses, regimen C proved to be effective in preserving renal function throughout CDDP administrations. In the individual analysis of each cycle, regardless of the number of times CDDP was administered, protocols C and D, which contained Mg supplementation associated or not with mannitol, were equally effective in preventing nephrotoxicity.

β-Hydroxybutyrate Protects Against Cisplatin-Induced Renal Damage via Regulating Ferroptosis

Cisplatin is a particularly potent antineoplastic drug. However, its usefulness is restricted due to the induction of nephrotoxicity. More recent research has indicated that β-hydroxybutyrate (β-HB) protects against acute or chronic organ damage as an efficient healing agent. Nonetheless, the therapeutic mechanisms of β-HB in acute kidney damage caused by chemotherapeutic drugs remain unclear. Our study developed a model of cisplatin-induced acute kidney injury (AKI), which involved the administration of a ketogenic diet or β-HB. We analyzed blood urea nitrogen (BUN) and creatinine (Cr) levels in serum, and used western blotting and immunohistochemical staining to assess ferroptosis and the calcium/calmodulin-dependent kinase kinase 2 (Camkk2)/AMPK pathway. The mitochondrial morphology and function were examined. Additionally, we conducted in vivo and in vitro experiments using selective Camkk2 inhibitor or activator to investigate the protective mechanism of β-HB on cisplatin-induced AKI. Exogenous or endogenous β-HB effectively alleviated cisplatin-induced abnormally elevated levels of BUN and Cr and renal tubular necrosis in vivo. Additionally, β-HB reduced ferroptosis biomarkers and increased the levels of anti-ferroptosis biomarkers in the kidney. β-HB also improved mitochondrial morphology and function. Moreover, β-HB significantly attenuated cisplatin-induced cell ferroptosis and damage in vitro. Furthermore, western blotting and immunohistochemical staining indicated that β-HB may prevent kidney injury by regulating the Camkk2-AMPK pathway. The use of the Camkk2 inhibitor or activator verified the involvement of Camkk2 in the renal protection by β-HB. This study provided evidence of the protective effects of β-HB against cisplatin-induced nephrotoxicity and identified inhibited ferroptosis and Camkk2 as potential molecular mechanisms.

Comparison of preventive effects of combined furosemide and mannitol versus single diuretics, furosemide or mannitol, on cisplatin-induced nephrotoxicity

Cisplatin (CDDP)-induced nephrotoxicity is a common dose-limiting toxicity, and diuretics are often administered to prevent nephrotoxicity. However, the efficacy and optimal administration of diuretics in preventing CDDP-induced nephrotoxicity remain to be established. This study aimed to evaluate the efficacy of combining furosemide and mannitol to prevent CDDP-induced nephrotoxicity. This was a post-hoc analysis of pooled data from a multicenter, retrospective, observational study, including 396 patients who received one or two diuretics for CDDP-based chemotherapy, compared using propensity score matching. Multivariate logistic regression analyses were used to identify risk factors for nephrotoxicity. There was no significant difference in the incidence of nephrotoxicity between the two groups (22.2% vs. 28.3%, P = 0.416). Hypertension, CDDP dose ≥ 75 mg/m2, and no magnesium supplementation were identified as risk factors for nephrotoxicity, whereas the use of diuretics was not found to be a risk factor. The combination of furosemide and mannitol showed no advantage over a single diuretic in preventing CDDP-induced nephrotoxicity. The renal function of patients receiving CDDP-based chemotherapy (≥ 75 mg/m2) and that of those with hypertension should be carefully monitored. Magnesium supplementation is important for these patients.

Protopanaxadiol prevents cisplatin-induced acute kidney injury by regulating ferroptosis.

Acute kidney injury (AKI) caused by cisplatin (CDDP) is a complex, critical illness with no effective or specific treatment. The purpose of the study was to assess the protective effect of protopanaxadiol (PPD) on the kidneys in CDDP-induced AKI models and its possible mechanisms. In vitro, the protection of PPD was assessed in HK-2. KM mice were injected with CDDP to induce AKI models in vivo. The determination of blood urea nitrogen and serum creatinine (SCr) was performed, and pathological changes were examined by histopathological examination. Immunostaining and western blot analyses were used to analyze the expression levels of proteins. PPD can increase the viability of HK-2 cells damaged by CDDP, improve cell morphology, and alleviate the symptoms of AKI in mice. In addition, PPD can down-regulate the protein expression of TRF and up-regulate the protein expression of Ferritin heavy chain, Glutathione peroxidase 4, and ferroptosis suppressor protein 1 reduce the iron content in cells and kidney tissues, and restore the antioxidant defense system. PPD has an inhibitory effect on cisplatin-induced nephrotoxicity, which may be related to the inhibition of ferroptosis by regulating iron metabolism and lipid peroxidation.

Protective effect of magnesium preloading on cisplatin-induced nephrotoxicity: which dose is more suitable?

Cisplatin is a widely used and potent cytotoxic chemotherapy agent, but its nephrotoxicity is a significant limiting side effect. Various premedication approaches have been implemented to preserve renal function, including magnesium (Mg) preloading. However, the optimal Mg dosage is still unknown. Our study aimed to assess the protective effects of different Mg doses as premedication in cisplatin-based chemoradiotherapy for patients with local/locally advanced cervical and head-neck cancers. This retrospective, multicenter study involved premedication with saline infusion containing potassium chloride and magnesium sulfate (MgSO4) for all patients before cisplatin treatment. Patients were divided into two groups: 12 mEq MgSO4 (low-dose Mg preload group, low-Mg) and 24 mEq MgSO4 (high-dose Mg preload group, high-Mg). Renal function was evaluated using serum creatinine (sCr, mg/dl) and estimated glomerular filtration rate (eGFR, ml/min). Acute kidney injury (AKI) was defined per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Renal outcomes and efficacy were compared between the groups. In the low-Mg group (n = 159), sCr levels were significantly higher compared to baseline, various weeks during treatment, and at the 1st, 3rd, 6th, and 12th months post-treatment (p < 0.001). In the high-Mg group (n = 128), no significant changes were observed during treatment and at 1st, 3rd, and 12th months post-treatment (p > 0.05). A significant reduction in mean sCr level from baseline to 6 months was noted in the high-Mg group (p < 0.001). eGFR values are generally correlated with sCr levels. AKI occurred in 21 (13.2%) and 22 (17.7%) patients in the low-Mg and high-Mg groups, respectively (p = 0.292). There was no difference in progression-free or overall survival between the groups. We clearly demonstrated that saline hydration with 24 mEql MgSO4 supplementation before cisplatin treatment has a better renal protective effect than 12 mEql MgSO4 without reducing efficacy, especially in patients with local/local advanced cervical and head-neck cancer receiving cisplatin with concurrent radiotherapy.

An integrated view of cisplatin-induced nephrotoxicity, hepatotoxicity, and cardiotoxicity: characteristics, common molecular mechanisms, and current clinical management.

Cisplatin (CP) is a chemotherapy drug widely prescribed to treat various neoplasms. Although fundamental for the therapeutic action of the drug, its cytotoxic mechanisms trigger adverse effects in several tissues, such as the kidney, liver, and heart, which limit its clinical use. In this sense, studies point to an essential role of damage to nuclear and mitochondrial DNA associated with oxidative stress, inflammation, and apoptosis in the pathophysiology of tissue injuries. Due to the limitation of effective preventive and therapeutic measures against CP-induced toxicity, new strategies with potential cytoprotective effects have been studied. Therefore, this article is timely in reviewing the characteristics and main molecular mechanisms common to renal, hepatic, and cardiac toxicity previously described, in addition to addressing the main validated strategies for the current management of these adverse events in clinical practice. We also handle the main promising antioxidant substances recently presented in the literature to encourage the development of new research that consolidates their potential preventive and therapeutic effects against CP-induced cytotoxicity.

Empagliflozin protective effects against cisplatin-induced acute nephrotoxicity by interfering with oxidative stress and inflammation in Wistar rats.

Cisplatin (Cis) is a platinum-based antineoplastic drug used in various types of cancers. This drug can induce nephrotoxicity as a cause of acute kidney injury (AKI) by inducing oxidative stress and inflammation. Empagliflozin (Empa) is a newly developed inhibitor of sodium-glucose cotransporter-2 (SGLT2) approved as an antidiabetic medication for patients with type 2 diabetes mellitus. In addition to its blood glucose-lowering effect, Empa has been shown to exert anti-inflammatory and anti-oxidant properties. The current study aimed to investigate the protective effects of Empa on Cis-induced nephrotoxicity in rats. Male Wistar albino rats were divided into five groups, each of six rats: Sham group (received vehicle for 7 days), Control group (received vehicle for 7 days and Cis injection on day 2), Cis + Empa10 (received 10mg/kg Empa for 7 days and Cis injection on day 2), Cis + Empa30 (received 30mg/kg Empa for 7 days and Cis injection on day 2) and, Empa 30 (received 30mg/kg Empa for 7 days). One day after the last injection in each group, rats were weighed and then sacrificed to analyze the hematological, biochemical, and histological parameters. Cis markedly increased levels of inflammatory parameters such as renal tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and myeloperoxidase (MPO) activity. Notably, malondialdehyde (MDA), blood urea nitrogen (BUN), and creatinine levels were enhanced after Cis administration. Also, the chemotherapeutic agent significantly reduced antioxidant indicators such as renal catalase (CAT), glutathione peroxidase (GpX), and superoxide dismutase (SOD). Furthermore, histopathological examinations also revealed severe renal damage following Cis treatment which was improved by Empa administration. Empa treatment at both doses (10 mg/kg and 30 mg/kg) reversed Cis-induced changes in all the above renal parameters. In conclusion, Empa has protective effects on Cis-induced nephrotoxicity by inhibition of oxidative stress and inflammation.

Oleanolic Acid Acetate Alleviates Cisplatin-Induced Nephrotoxicity via Inhibition of Apoptosis and Necroptosis In Vitro and In Vivo.

Cisplatin is a widely used anti-cancer drug for treating solid tumors, but it is associated with severe side effects, including nephrotoxicity. Various studies have suggested that the nephrotoxicity of cisplatin could be overcome; nonetheless, an effective adjuvant drug has not yet been established. Oleanolic acid acetate (OAA), a triterpenoid isolated from Vigna angularis, is commonly used to treat inflammatory and allergic diseases. This study aimed to investigate the protective effects of OAA against cisplatin-induced apoptosis and necroptosis using TCMK-1 cells and a mouse model. In cisplatin-treated TCMK-1 cells, OAA treatment significantly reduced Bax and cleaved-caspase3 expression, whereas it increased Bcl-2 expression. Moreover, in a cisplatin-induced kidney injury mouse model, OAA treatment alleviated weight loss in the body and major organs and also relieved cisplatin-induced nephrotoxicity symptoms. RNA sequencing analysis of kidney tissues identified lipocalin-2 as the most upregulated gene by cisplatin. Additionally, necroptosis-related genes such as receptor-interacting protein kinase (RIPK) and mixed lineage kinase domain-like (MLKL) were identified. In an in vitro study, the phosphorylation of RIPKs and MLKL was reduced by OAA pretreatment in both cisplatin-treated cells and cells boosted via co-treatment with z-VAD-FMK. In conclusion, OAA could protect the kidney from cisplatin-induced nephrotoxicity and may serve as an anti-cancer adjuvant.

Nobiletin alleviates cisplatin-induced ototoxicity via activating autophagy and inhibiting NRF2/GPX4-mediated ferroptosis

Nobiletin, a citrus polymethoxy flavonoid with antiapoptotic and antioxidative properties, could safeguard against cisplatin-induced nephrotoxicity and neurotoxicity. Cisplatin, as the pioneer of anti-cancer drug, the severe ototoxicity limits its clinical applications, while the effect of nobiletin on cisplatin-induced ototoxicity has not been identified. The current study investigated the alleviating effect of nobiletin on cisplatin-induced ototoxicity and the underlying mechanisms. Apoptosis and ROS formation were evaluated using the CCK-8 assay, Western blotting, and immunofluorescence, indicating that nobiletin attenuated cisplatin-induced apoptosis and oxidative stress. LC3B and SQSTM1/p62 were determined by Western blotting, qPCR, and immunofluorescence, indicating that nobiletin significantly activated autophagy. Nobiletin promoted the nuclear translocation of NRF2 and the transcription of its target genes, including Hmox1, Nqo1, and ferroptosis markers (Gpx4, Slc7a11, Fth, and Ftl), thereby inhibiting ferroptosis. Furthermore, RNA sequencing analysis verified that autophagy, ferroptosis, and the NRF2 signaling pathway served as crucial points for the protection of nobiletin against ototoxicity caused by cisplatin. Collectively, these results indicated, for the first time, that nobiletin alleviated cisplatin-elicited ototoxicity through suppressing apoptosis and oxidative stress, which were attributed to the activation of autophagy and the inhibition of NRF2/GPX4-mediated ferroptosis. Our study suggested that nobiletin could be a prospective agent for preventing cisplatin-induced hearing loss.

Magnesium supplementation therapy to prevent cisplatin-induced acute nephrotoxicity in pediatric cancer: a randomized phase-2 trial.

The present study aimed to examine the effect of magnesium (Mg) supplementation on cisplatin-induced nephrotoxicity (CIN) in pediatric cancer patients. The present phase-2, open-label, multicenter, randomized controlled trial enrolled patients aged less than 20years who were scheduled to receive cisplatin-containing chemotherapy and randomly allocated them at a ratio of 1:1 to a Mg supplementation arm with even-numbered chemotherapy courses (arm AB) or another arm with odd-numbered courses (arm BA). Analysis objects were reconstructed into two groups depending on whether the chemotherapy course had Mg supplementation (group B) or not (group A). The primary outcome was the proportion of chemotherapy courses resulting in elevated serum creatinine per chemotherapy course. The secondary outcomes included efficacies evaluated using other biomarkers and the safety of the Mg supplementation. Twenty-eight patients were randomly allocated to either group (16 to arm AB and 12 to arm BA). The baseline characteristics of the groups were similar. There was no significant difference in the proportion of courses with increased serum creatinine between the groups (group A: 10% vs. group B: 6%; P = 0.465) nor was any significant difference observed in other biomarkers during any chemotherapy course. The Mg value during chemotherapy was significantly higher in group B than that in group A. No adverse events related to magnesium administration were observed. The study design, which treated a single chemotherapy course as a study object, failed to detect a statistically significant benefit of Mg supplementation for preventing CIN in pediatric cancer patients. JRCT ( https://jrct.niph.go.jp/ ) Identifier UMIN000029215 jRCTs031180251. UMIN-CTR ( http://www.umin.ac.jp/icdr/index.html ) Identifier UMIN000029215.

A combination of generated hydrogen sulfide and nitric oxide activity has a potentiated protectant effect against cisplatin induced nephrotoxicity

AimHydrogen sulfide and nitricoxide possess cytoprotective activity and in vivo, they are generated from exogenous sodium hydrosulfide and L-arginine respectively. Cisplatin is a major chemotherapeutic agent used to treat cancer and has a high incidence of nephrotoxicity as a side effect. The study aim was to explore the effects of NaHS and L-arginine or their combination on cisplatin induced nephrotoxicity in rats. MethodsWistar Kyoto rats were given a single intraperitoneal dose of cisplatin (5 mg/kg) followed either by NaHS (56 μmol/kg, i. p.), L-arginine (1.25 g/L in drinking water) or their combination daily for 28-days. Post-mortem plasma, urine and kidney samples were collected for biochemical assays and histopathological analysis. ResultsCisplatin decreased body weights and increased urinary output, while plasma creatinine and urea levels were elevated, but sodium and potassium concentrations were diminished. The renal function parameters, blood urea nitrogen and creatinine clearance, were raised and decreased respectively. Regarding markers of reactive oxygen species, plasma total superoxide dismutase was reduced, whereas malondiadehyde was augmented.Cisplatin also diminished plasma and urinary H2S as well as plasma NO, while NaHS and L-arginine counteracted this activity on both redox-active molecules. Cisplatin cotreatment with NaHS, and/or L-arginine exhibited a reversal of all other measured parameters. ConclusionIn current study, NaHS and L-arginine as monotherapy protected the rats from cisplatin-induced nephrotoxicity but the combination of both worked more effectively suggesting the augmented anti-inflammatory and antioxidative potential of test treatments when administered together.