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Cisplatin (Cis) is among the most powerful antineoplastic medications, nevertheless, its serious side effects; particularly nephrotoxicity designates a major concern. Previous studies reported that ezetimibe (Eze), a well-known antihyperlipidemic drug, exerts additional trivial pharmacological effects. In this work, we displayed Eze as an intriguing protective candidate in a cisplatin-induced nephrotoxicity rat model through AMPK activation. Eze (10 mg/kg, p.o.) was administered for two weeks and Cis (10 mg/kg, i.p.) was administered on the 10th day to induce nephrotoxicity in male Wistar rats. Treatment with Eze greatly augmented the phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) and the antioxidant regulator; nuclear factor erythroid 2-related factor 2 (Nrf2), thus, mitigating oxidative injury through induction of the antioxidant enzymes, such as heme oxygenase-1 (HO-1) and glutathione reductase (GR). As well, Eze relieved inflammation by reducing protein expression of thioredoxin-interacting protein (TXNIP) and nucleotide-binding domain-like receptor protein 3 (NLRP3), which led to a decrease in the release of caspase-1, in addition to, the inflammatory markers IL-18 and IL-1 ß. Besides, Eze ameliorated apoptosis in the renal cells through inhibiting the phosphorylated Apoptosis signal-regulating kinase-1(p-ASK1), caspase-3 and reducing Bax/Bcl2ratio. Correspondingly, histopathological examination corroborated the previous biochemical findings. Collectively, Eze exerts significant renal protection against Cis-induced nephrotoxicity via antioxidant, anti-inflammatory and anti-apoptotic pathways that are probably mediated, at least partly, via activating AMPK/Nrf2/HO-1 pathway and conquering both TXNIP/NLRP3 inflammasome and TXNIP/ASK1 signaling pathways. To confirm the protective effect of Eze via AMPK-activation, an AMPK-inhibitor, dorsomorphin (Dors), when co-administered with Eze abolished its protective effect.

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Cisplatin (CP) is a chemotherapeutic drug used to treat solid tumors. However, studies have revealed its nephrotoxic effect. Oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction are involved in CP-induced renal damage. Thus, preconditioning (hormetic effect) of ER stress is a strategy to prevent CP-induced renal damage. On the other hand, isoliquiritigenin (IsoLQ) is recognized as a flavonoid with antioxidant properties and an inducer of ER stress. Therefore, we evaluated the ER stress-inducing capacity of IsoLQ and its possible protective effect against CP-induced nephrotoxicity in adult male Wistar rats. The findings reflected that IsoLQ pretreatment might decrease renal damage by reducing plasma creatinine and blood urea nitrogen levels in animals with CP-induced nephrotoxicity. These may be associated with IsoLQ activating ER stress and unfolded protein response (UPR). We found increased messenger RNA levels of the ER stress marker glucose-related protein 78 kDa (GRP78). In addition, we also found that pretreatment with IsoLQ reduced the levels of CCAAT/enhancer-binding protein-homologous protein (CHOP) and X-box-binding protein 1 (XBP1) in the renal cortex, reflecting that IsoLQ can regulate the UPR and activation of the apoptotic pathway. Moreover, this preconditioning with IsoLQ of ER stress had oxidative stress-regulatory effects, as it restored the activity of glutathione peroxidase and glutathione reductase enzymes. Finally, IsoLQ modifies the protein expression of mitofusin 2 (Mfn-2) and voltage-dependent anion channel (VDAC). In conclusion, these data suggest that IsoLQ pretreatment has a nephroprotective effect; it could functionally regulate the ER and mitochondria and reduce CP-induced renal damage by attenuating hormesis-mediated ER stress.

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A newly synthesized nanoplatform of hyaluronic acid and chitosan nanoparticles (HA/CNPs) was applied to improve the therapeutic efficacy and protection of bone marrow mesenchymal stem cells (BM-MSCs) against cisplatin (CDDP)-induced nephrotoxicity in rats. CDDP administration causes significant increases in levels of serum creatinine (SCr), urea, and KIM-1 coupled with significant albumin level falls, as indicative of acute renal dysfunction. Moreover, the level of the antioxidant enzyme (GSH) was significantly decreased, while the levels of lipid peroxidation (MDA) and inflammatory (IL-6) and apoptotic (caspase-3) markers were significantly increased, indicating a decline in the kidney's antioxidant defense and increased inflammation. In contrast, when rats were pre-treated with either MSCs or MSCs-HA/CNPs before receiving CDDP, the levels of SCr, urea, KIM-1, MDA, IL-6, and caspase-3 were significantly decreased with simultaneous significant rises in GSH and albumin, impelling a great improvement in the antioxidant and anti-inflammatory defenses of the kidney as well as its functions. Intriguingly, MSCs-HA/CNPs were more effective against caspase-3 than MSCs alone, revealing the high anti-apoptotic capability of HA/CNPs. This finding suggests that HA/CNPs could effectively protect MSCs from oxidative stress and apoptosis and thus increase their stability and longevity.

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Backgrounds: Cisplatin is a commonly used chemotherapeutic agent in cancer treatment. However, its high nephrotoxicity limits its therapeutic application and efficacy. Cisplatin induces nephrotoxicity mainly through oxidative stress and inflammation. Reactive oxygen species (ROS) in the kidneys mainly arise from nicotinamide adenine dinucleotide phosphate (NADPH) oxidases 2 (NOX2), which is highly upregulated during ischemia-reperfusion injury and diabetes mellitus. However, its role in cisplatin-induced acute kidney injury (AKI) remains unknown. Methods: A 8-10-week-old NOX2 gene-knockout and wild-type mice were injected with 25 mg/kg cisplatin intraperitoneally for experiments. Results: We investigated the role of NOX2 in cisplatin-induced AKI and found that NOX2-mediated ROS production is a key inflammatory mediator of proximal tubular cell injury in cisplatin-induced AKI. NOX2 gene-knockout alleviated cisplatin-induced renal function decline, tubular injury score, kidney injury molecule-1(Kim-1) expression, and interleukin (IL)-6 and IL-1α levels with a reduction of ROS production. Moreover, in cisplatin-induced AKI, intercellular adhesion molecule 1 (ICAM-1) and the chemoattractant CXC ligand 1 (CXCL1) were highly expressed in association with neutrophil infiltration, which were all attenuated by deletion of NOX2. Conclusion: These data indicate that NOX2 aggravates cisplatin nephrotoxicity by promoting ROS-mediated tissue injury and neutrophil infiltration. Thus, appropriate targeting of NOX2/ROS pathway may minimize the risk of cisplatin-induced kidney injury in patients receiving cancer therapy.

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ETHNOPHARMACOLOGICAL RELEVANCE: Shenshuaifu Granule (SSF) is an in-hospital preparation approved by the Guangdong Food and Drug Administration of China. It has been clinically used against kidney diseases for more than 20 years with a definite curative effect. AIM OF THE STUDY: Cisplatin (CDDP) is a first-line chemotherapeutic drug in clinical practice, primarily excreted by the kidney with nephrotoxicity as a common side effect. Approximately 5-20% of cancer patients develop acute kidney injury (AKI) after chemotherapy; however, prevention and control strategies are currently unavailable. Therefore, it is important to identify safe and effective drugs that can prevent the nephrotoxicity of CDDP. SSF is an herbal formulation with 8 herbs, and has been used to protect the kidney in China. Nonetheless, its mechanism in relieving CDDP nephrotoxicity remains unclear. Therefore, this work attempt to prove that SSF can alleviate CDDP nephrotoxicity. We also explore its mechanism. MATERIALS AND METHODS: First, Thin Layer Chromatography (TLC) of a few herbs in SSF were performed for quality control. Several open-access databases were used to identify the active ingredients of SSF, their corresponding targets, and CDDP-induced nephrotoxicity targets. We performed Protein-Protein Interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Next, the results of network pharmacology were validated using CDDP-induced nephrotoxicity mouse models. Renal function in the mice was assessed by analyzing the levels of serum creatinine (Scr) and blood urea nitrogen (BUN). On the other hand, renal damage was assessed by determining the level of tubular injury and apoptotic cells using Periodic acid-Schiff (PAS) staining and Terminal Dutp Nick End-Labeling (TUNEL) staining, respectively. The expression of inflammatory and apoptotic-related targets including IL-1ß, IL-6, TNF-α, Cox-2, Bax, Bcl-2, Cleaved-caspase 3, and Cleaved-caspase 9 was determined using Western Blot (WB) and Immunohistochemistry (IHC). Furthermore, WB was used to analyze the expression of proteins associated with the TLR4/MyD88/NF-κB pathway in the kidneys of mice with CDDP-induced nephrotoxicity. Finally, molecular docking simulations were performed to evaluate the binding abilities between major active ingredients of SSF and core targets. RESULT: Through network pharmacology, we identified 127 active ingredients of SSF and their corresponding 134 targets. Additional screening identified 14 active ingredients and 17 targets for further analysis. In biological process (BP), the targets were enriched in inflammation and apoptosis, among others. In KEGG terms, they were enriched in apoptosis and NF-κB pathways. Animal experiments revealed that SSF significantly reduced the levels of Scr and BUN and prevented renal tubular damage in mice treated with CDDP. In addition, SSF inhibited inflammation and apoptosis by targeting the TLR4/MyD88/NF-κB pathway. Molecular docking revealed good binding capacities of active ingredients and core targets. CONCLUSION: In summary, the experimental findings were consistent with the network pharmacological predictions. SSF can inhibit inflammation and apoptosis by targeting the TLR4/MyD88/NF-κB pathway. Taken together, our data suggest that SSF is an alternative agent for the treatment of CDDP-induced nephrotoxicity.

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[This corrects the article DOI: 10.3389/fphar.2022.907133.].

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OBJECTIVE: Supporting data exists concerning short hydration to prevent cisplatin-induced nephrotoxicity. However, only a few studies exist. Further, data remains limited, comprising mostly retrospective data. Therefore, the study would like to evaluate the efficacy of short hydration using a prospective cohort study. MATERIALS AND METHODS: This is a prospective cohort non-randomized controlled study in patients receiving intermediate to high doses of cisplatin. Short hydration was set as the intervention arm, while conventional hydration was set as the controlled arm. The consecutive estimates glomerular filtration rates (eGFR) were compared at baseline, Week 3, Week 6, Week 9, Week 12, and Week 15 for both groups by using multilevel regression analysis with the random-effects model with double adjustment (propensity score and confounding adjustment) was used. The trial was registered with the Thai Registry of Clinical Trials, SHORTCIS ThaiClinicalTrials.org, number TCTR20210128002. RESULTS: 30 patients were registered. 14 were assigned to a short hydration group, while 16 were assigned to a conventional hydration group. The levels of consecutive eGFR of the group receiving short hydration were stable (regression coefficients 0.05), while the levels of consecutive eGFR of the group receiving conventional hydration were declined (regression coefficients -1.94). The multilevel regression analysis of consecutive eGFR between conventional group and short hydration group when adjusted for random-effects parameters and double adjustment were significantly different (p-value = 0.001). When analyzing the relationship of received short hydration, it could significantly reduce the risk of nephrotoxicity as well, i.e. acute kidney injury (odds ratio 0.06, 95%CI 0.003, 0.990, p-value 0.049). CONCLUSION: Short hydration was more efficient for preventing nephrotoxicity than conventional hydration protocols in patients receiving intermediate to high doses of cisplatin.

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Cisplatin (CP) is an antineoplastic agent used to treat solid tumors, that has high nephrotoxicity caused by physiologic, hemodynamic, and biochemical alterations. Some studies have shown that naturally derived bioactive compounds in CP-induced nephrotoxicity reduce the side effects of this antineoplastic drug. Pitaya is an endemic fruit from Mexico with a high bioactive compound content, including betalains and phenolic compounds, with reports of antioxidant and anti-inflammatory properties. In this study, the aim was to establish the effect of a pitaya juice concentrate (PJC) on CP-induced nephrotoxicity in Wistar male rats through the identification of metabolites, determination of its chemical composition and antioxidant activity, and evaluation of the protective effect of a PJC on CP-induced nephrotoxicity in rats. The PJC showed a high content of betanins with antioxidant activity by an oxygen radical absorbance capacity assay (1299.6 ± 2.80 Trolox equivalents/g). PJC was administered daily (400 mg day-1, p. o.) for 3 days before CP administration until the end of the experiment. On day four, rats were administered a single injection of CP (6 mg kg, i.p.-1) and sacrificed 72 h later. We observed that CP provoked renal dysfunction (1.0 ± 0.1 vs. 0.4 ± 0.07 serum creatinine levels), oxidative stress, a decrease in nitrate and nitrite (NO2¯/NO3¯) levels (0.1 ± 0.08 vs. 0.4 ± 0.3) and activation of apoptosis and immune responses in kidney tissue. In addition, CP treatment induced tubular damage threefold. PJC administration prevented renal dysfunction (0.5 ± 0.06 vs. 1.0 ± 0.1), normalized degenerative structural damage prevented the increase in lipoperoxidation levels (0.04 ± 0.01 vs. 0.2 ± 0.1) and reduced the apoptosis index by 2.5 in kidney tissue. However, it did not modify the immune response caused by CP. Furthermore, PJC treatment increased nuclear factor erythroid two related factors two protein levels two times and NO2¯/NO3¯ levels 22 times in kidney tissue, which may play a role in the renoprotective effect. In conclusion, the renoprotective effect of PJC on CP-induced nephrotoxicity was associated with the attenuation of dysfunction, structural damage, apoptosis activation, and oxidative stress and was related to changes in the tumor necrosis factor-alpha and renal nitric oxide (NO) pathways. The changes in the NO pathway may be involved in renal hemodynamics. Pitaya could be used as a functional food and therapeutic coadjuvant during CP treatments due to its high bioactive levels and renoprotective compounds.

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INTRODUCTION: Cisplatin is the widely used antineoplastic agent in managing cervical cancer despite nephrotoxicity being a major concern. In addition, there was a paucity of data about the degree of nephrotoxicity due to cisplatin in the study setting. Therefore, this study aimed to investigate the prevalence of cisplatin nephrotoxicity among cervical patients. METHODS: A retrospective cross-sectional study was conducted at the Cancer Treatment Centre of Kenyatta National Hospital among 100 cervical cancer patients treated with a cisplatin regimen. Simple random sampling was employed to the recruit medical record of patients. This study used a data abstraction tool to extract the patients' relevant socio-demographic and clinical characteristics. The data were analysed using Statistical Package for Social Sciences version 25.0 software. Frequency tables and figures were used to present the findings of the study. Binary logistic regression analysis was used to determine factors associated with cisplatin nephrotoxicity. RESULTS: The study showed a mean age of 52.09 ± 10.44 years. The prevalence rate of cisplatin-induced nephrotoxicity in cervical cancer patients was 45%. Of these patients, 36% and 9% patients had grade 1 and 2 nephrotoxicities, respectively. Comorbidities (crude odd's ratio (COR) = 3.05, 95% confidence interval [CI] = 1.3-7.02, p = 0.011), hypertension (COR = 3.0, 95% CI = 1.1-7.8, p = 0.03), and more than three cycles of cisplatin treatment (adjusted odd's ratio = 4.5, 95% CI = 1.19-17.0, p = 0.027) were significant factors of nephrotoxicity. CONCLUSION: The prevalence of cisplatin-induced nephrotoxicity among cervical cancer patients was high in the study setting. Comorbidities, number of cycles and types of comorbidities were significant factors associated with cisplatin nephrotoxicity.

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Purpose: Apoptosis plays a critical role in cisplatin-induced acute kidney injury (AKI) and is related to mitochondrial dysfunction. Magnesium lithospermate B (Mlb), one of the most important components of Salvia miltiorrhiza Bunge, is mainly used to treat cardiovascular diseases because of its anti-apoptotic effects. The mechanism underlying the protective effect of Mlb against cisplatin-induced AKI remains unclear. In this study, we investigated the protective effect of Mlb on mitochondrial function against apoptosis caused by cisplatin-induced renal injury. Methods: Renal injury induced by cisplatin in mouse renal tubular epithelial cells (mTECs) was measured by quantifying serum creatinine levels, mitochondrial morphology, cell viability, apoptosis, Dynamin-related protein 1(Drp1) expression, etc. The cells were then administered Mlb to determine its protective effects against cisplatin-induced AKI. Results: Mlb treatment significantly reduced serum creatinine levels and pathological injury of renal, inhibited the production of malondialdehyde, and reduced the depletion of superoxide dismutase. In addition, Mlb reduced Bax/Bcl2, cleaved caspase-3/caspase-3, and maintained mitochondrial integrity after AKI. Mlb administration also improved cell viability and reduced the percentage of apoptotic cells in vitro. Furthermore, Mlb reduced mitochondrial reactive oxygen species, improved mitochondrial membrane potential, and ameliorated mitochondrial morphological abnormalities by downregulating Drp1 expression. Conclusion: These results indicated that Mlb could protect the kidneys against cisplatin-induced apoptosis by alleviating mitochondrial dysfunction.

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Cisplatin is a widely used and potent anti-neoplastic agent, but severe and inescapable side effects in multiple normal tissues and organs limit its application, especially nephrotoxicity. Molecular mechanisms of cisplatin nephrotoxicity involve mitochondrial damage, oxidative stress, endoplasmic reticulum stress, inflammation, apoptosis, necroptosis, etc. Receptor of advanced glycation end products (RAGE) is a multiligand pattern recognition receptor, engaged in inflammatory signaling and mitochondrial homeostasis. Whether inhibition of RAGE alleviates cisplatin-induced nephropathy has not been investigated. Here, we revealed that RAGE deficiency attenuates cisplatin-induced acute nephrotoxicity, as evidenced by reduced apoptosis, inflammation, lipid accumulation, restored mitochondrial homeostasis and fatty acid oxidation in renal tubular epithelial cells (TECs). In vitro studies showed that, the RAGE-specific inhibitor FPS-ZM1 attenuated the cisplatin-induced decrease of cell viability and fatty acid oxidation in the normal rat renal TEC line NRK-52E cells. Taken together, RAGE knockout mitigated cisplatin-induced acute nephrotoxicity by inhibiting apoptosis, inflammation, and restoring fatty acid oxidation in TECs, suggesting that RAGE inhibition could be a therapeutic option for cisplatin-induced acute nephrotoxicity.

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Cisplatin (Cisp) is a widely distributed chemotherapeutic drug for cancers. Nephrotoxicity is one of the most common side effects of the use of this drug. Carvacrol (CV) is a common natural compound in essential oils and extracts of medicinal plants with potent in vivo and in vitro bioactivities. The work was extended to achieve the target of investigation of the protective potentialities of CV and its nanoemulsion as a cytoprotective drug against Cisp-induced nephrotoxicity in albino rats. CV-nanoemulsion was prepared by a hydrophilic surfactant polysorbate 80 (Tween 80) and deionized water. The TEM image of the particle distribution prepared nanoemulsion is mainly spherical in shape with particle size varying between 14 and 30 nm. Additionally, the Cisp administration caused the increasing of the levels of urea and creatinine in the blood and serum. These increasing of urea and creatinine levels caused consequently the turbulence of the oxidative stress as well as the rising of hs-CRP, IL-6, and TNF-α levels in the serum. Also, histopathological changes of the kidney tissue were observed. These changes back to normal by treatment with CV-nanoemulsion. Expression levels of nephrotoxicity-related genes including LGALS3, VEGF, and CAV1 in kidney tissue using qRT-PCR were measured. The results revealed that the expression of LGALS3, VEGF and CAV1 genes was highly significantly increased in only Cisp treated group when compared with other treated groups. While, these genes expressions were significantly decreased in Cisp + CV treated group when compared with Cisp treated rats (P < 0.001). In addition, there were no significant differences between Cisp + nano-CV treated group and both negative control and nanoemulsion alone groups but it was not significant. In addition, the Western blot of protein analysis results showed that the LGALS3 and CAV1 are highly expressed only in Cisp + CV treated group compared with other groups. There was no significant difference between Cisp + nano-CV treated animals and negative control for both mRNA and protein expression. Based on these results, CV was combined with calcium alginate; a more stable capsule is formed, allowing for the formation of a double wall in the microcapsule. These results supported the therapeutic effect of CV and its nano-emulsion as cytoprotective agents against Cisp nephrotoxicity.

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INTRODUCTION: Cisplatin, a chemotherapeutic drug, is widely used for the treatment of various malignant tumors with good effects. However, cisplatin-induced nephrotoxicity is a major dose-limiting factor and a significant adverse event. Mannitol is used to reduce cisplatin-induced nephrotoxicity, which is controversial. This study aimed to evaluate the efficacy and safety of a hydration regimen containing mannitol against cisplatin-induced nephrotoxicity through a meta-analysis. METHODS: Potential records from PubMed, EMBASE, Cochrane Library, and ClinicalTrials that met the inclusion criteria were included from inception to May 2021. Cochrane Collaboration tools were used to assess the risk of bias in the included studies. Jadad's and NOS scores were applied to assess the quality of randomized controlled trials (RCTs) and case-control studies. A random-effects model or fixed-effects model was used depending on the heterogeneity. Subgroup analyses were performed to evaluate the potential study characteristics. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were evaluated. RESULTS: Four RCTs and seven case-control studies involving 4168 patients were included. Pooled results showed that mannitol use could reduce the incidence of cisplatin-induced nephrotoxicity (OR = 0.66, 95% CI [0.45-0.97], p = 0.03), especially reducing grade 3 nephrotoxicity events according to CTCAE 4.0 (OR = 0.37,95% CI [0.16-0.84]). Moreover, mannitol use was not significantly associated with creatinine clearance, serum creatine, and electrolyte disturbance (p > 0.05). Gastrointestinal cancer (OR = 0.36, 95% CI [0.15-0.83], p = 0.02) and urinary tract cancer (OR = 0.32,95% CI [0.14-0.73], p = 0.007) may be more sensitive to mannitol, although the test for overall effect was significantly different (OR = 0.66, 95% CI [0.49-0.89], p = 0.007). For patients with diabetes and hypertension, mannitol may worsen renal function (OR = 1.80, 95% CI [1.18-2.72], p = 0.006; OR = 2.19, 95% CI [1.50, 3.19], p < 0.0001, respectively). Mannitol may have a better protective effect when doses of mannitol were ≥ 25 g (OR = 0.58, 95% CI [0.39-0.88], p = 0.01) and doses of cisplatin < 75 mg/m2 (OR = 0.59, 95% CI [0.36-0.94], p = 0.03). It revealed that mannitol use was likely to cause nausea or vomiting (OR = 1.86, 95% CI [1.20-2.89], p = 0.006). CONCLUSION: Current evidence revealed that mannitol was an effective and safe drug to reduce cisplatin-induced nephrotoxicity events, especially Grade 3 events. However, it may cause more nausea/vomiting events and deteriorate renal function in patients with diabetes or hypertension. We also found that mannitol had the best effect when mannitol was ≥ 25 g in total or cisplatin was < 75 mg/m2. Meanwhile, mannitol may have a better effect on gastrointestinal and urinary tract cancers. SYSTEMATIC REVIEW REGISTRATION: crd. york. ac. uk/PROSPERO, CRD 42021253990.

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BACKGROUND: N6-methyladenosine (m6A) is the most abundant modification known in mRNAs. It participates in a variety of physiological and pathological processes, such as metabolism, inflammation, and apoptosis. AIMS: To explore the mechanism of m6A in cisplatin-induced acute kidney injury (AKI) and berberine alleviation in mouse. METHODS: This study investigated the N6-methyladenosine (m6A) methylome of kidneys from three mouse groups: C57 mice (controls), those with CI-AKI (injury group, IG), and those pretreated with berberine (treatment group, TG). Methylated RNA Immunoprecipitation Next Generation Sequencing (MeRIP-seq) and RNA-seq were performed to identify the differences between the injury group and the control group (IvC) and between the treatment group and the injury group (TvI). Western blotting was performed to identify the protein levels of candidate genes. RESULTS: In IvC, differentially methylated genes (DMGs) were enriched in metabolic processes and cell death. In TvI, DMGs were enriched in tissue development. Several genes involved in important pathways related to CI-AKI showed opposite methylation and expression trends in the IvC and TvI comparisons. CONCLUSION: m6A plays an important role in cisplatin induced AKI and berberine may alleviate this process.

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Platinum-containing drugs (PtDs; e.g. cisplatin, carboplatin, and oxaliplatin) have been widely used as anticancer reagents against various cancers. However, treatment with these drugs results in undesirable adverse effects with unknown mechanisms. Herein, we found a strong correlation between the inhibitory effects of PtDs on cytosolic thioredoxin reductase (TXNRD1) and tissue injury. Of the PtDs tested, cisplatin was found to be the most effective inhibitory PtD against TXRND1, causing the severest kidney injury. The initial inhibition of TXNRD1 in the kidney resulted from cisplatin-induced transcriptional activation of Nrf2-regulated genes including Txnrd1. However, the antioxidant responses in the kidney did not reverse the cisplatin-induced oxidation process. Nephrotoxicity was accompanied with an increase of protein glutathionylation and a cellular thiol redox environment oxidation. These results suggest that the changes of the cellular thiol-dependent redox environment regulated by TXNRD1 is a major event in the adverse effects of cisplatin in kidney.

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Although cisplatin is one of the most effective agents against various pediatric cancers, it is sometimes difficult to manage due to its dose-limiting nephrotoxicity. Magnesium sulfate (Mg) showed a kidney-protective effect against cisplatin-induced nephrotoxicity (CIN) by regulating renal platinum accumulation both in vitro and in vivo, and the body of clinical data demonstrating the efficacy of this drug in adult cancer patients is increasing.In this open, multicenter, phase-2, randomized trial, patients under age 18 years who are scheduled to receive cisplatin-containing chemotherapy will be enrolled and randomly allocated either to an Mg supplementation arm in even-numbered chemotherapy courses (arm AB) or to another arm in odd-numbered courses (arm BA), with a 1:1 allocation. Analysis objects will be reconstructed into two groups depending on whether the chemotherapy course has Mg supplementation (group B) or not (group A). The primary endpoint is the proportion of chemotherapy courses resulting in elevated serum creatinine equal to or greater than 50% of the prechemotherapy value. For the secondary endpoints, various parameters for measuring kidney function, such as serum cystatin-C, B2M, L-FABP, NGAL, and urinary NAG in the two groups will be compared. A sample size based on alpha = 5% and 80% power requires at least 40 samples per group (ideally, 60 samples per group).If Mg demonstrates efficacy, a phase-3 study to confirm the prophylactic effect of Mg supplementation in both acute and chronic CIN will be developed using novel and better biomarkers. TRIAL REGISTRATION: UMIN-CTR (http://www.umin.ac.jp/icdr/index.html) Identifier UMIN000029215.

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The clinical use of cisplatin, which is a first-line anticancer agent, is highly restricted due to its adverse effects on kidneys that lead to nephrotoxicity. Therefore, some potential reno-protective substances have been used in combination with cisplatin to cope with nephrotoxicity. Due to its high antitumor activity and oxygen-carrying capacity, we investigated the molecular effects of squalene against cisplatin-induced oxidative stress and kidney damage in mice. Single dose of cisplatin (7 mg/kg) was given to male Balb/c mice. Squalene (100 mg/kg/day) was administered orogastrically to mice for 10 days. Following sacrification, molecular alterations were investigated as analysis of the levels of oxidative stress index (OSI), inflammatory cytokines and cell survival-related proteins in addition to histopathological examinations in mice kidney tissue. The level OSI and Interferon-gamma (IFN-γ) decreased in the cisplatin and squalene cotreated mice compared to cisplatin-treated mice. Squalene treatment also increased the activation of protein kinase B (AKT). Furthermore, cisplatin-induced inactivation of mammalian target of rapamycin (mTOR) and histopathological damages were reversed by squalene. It may be suggested that squalene ameliorated the cisplatin-induced histopathological damages in the kidney through activation of AKT/mTOR signaling pathway by regulating the balance of the redox system due to its antioxidative effect.

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Though historically known as a toxic gas, hydrogen sulfide (H2S) has displayed a new face as the third endogenous gaseous signaling molecule after nitric oxide (NO) and carbon monoxide (CO). Here in this review, we survey the role and therapeutic potential of H2S in cisplatin-induced nephrotoxicity. Specifically, reduction of H2S by cystathionine γ-lyase (CSE) downregulation upon cisplatin treatment may contribute to cisplatin-induced renal cell injury, possibly by augmentation of endogenous reactive oxygen species (ROS) production, while H2S donation may prevent subsequent renal dysfunction by inhibiting NADPH oxidase activation. Intriguingly, H2S slow-releasing compound GYY4137 seems to increase the anticancer activity of cisplatin, at least in several cancer cell lines, and this is probably due to its own anticancer effect. However, the efficacy of H2S donors in tumor-bearing animals remains to be tested in terms of renal protection and cancer inhibition after receiving cisplatin. Furthermore, accumulative evidence regarding usage of polysulfide, a novel H2S derived molecule, in the therapy of cisplatin-induced nephrotoxicity, was also summarized.

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Occurrence of oxidative stress is the principal cause of acute kidney injury induced by cisplatin. Mangiferin, a naturally occurring antioxidant molecule, is found to ameliorate several oxidative stress mediated pathophysiological conditions including cancer. Cisplatin induced cytotoxicity was measured in NKE cells by MTT assay and microscopic analysis. Induction of oxidative stress and regulation of proapoptotic molecules were subsequently investigated by using different spectrophotometric analyses, FACS and immunocytochemistry. Induction of nephrotoxicity was determined by analyzing different serum biomarkers and histological parameters in vivo using swiss albino mice. Activation of NF-κB mediated pro-inflammatory and caspase dependent signaling cascades were investigated by semi-quantitative RT-PCR and immunoblotting. Mangiferin was found to ameliorate cisplatin induced nephrotoxicity in vitro and in vivo by attenuating the induction of oxidative stress and upregulating Nrf-2 mediated pro-survival signaling cascades via the activation of PI3K. Additionally, mangiferin showed synergistic anticancer activity with cisplatin in cancer cell lines (MCF-7 and SKRC-45) and EAC cell induced solid tumor bearing experimental mice. The ameliorative effect of mangiferin is primarily attributed to its anti-oxidant and anti-inflammatory properties. It acts differentially in normal tissue cells and tumor cells by modulating different cell survival regulatory signaling molecules. For the first time, the study reveals a mechanistic basis of mangiferin action against cisplatin induced nephrotoxicity. Since Mangiferin shows synergistic anticancer activity with cisplatin, it can be considered as a promising drug candidate, to be used in combination with cisplatin.

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Magnesium (Mg) supplementation has previously been demonstrated to confer protective effects against nephrotoxicity induced by cisplatin. Parathyroid hormone (PTH) regulates Mg homeostasis. The aim of present study was to determine the protective effects of Mg supplementation against cisplatin-induced nephrotoxicity and its association with PTH levels in patients with esophageal squamous cell carcinoma (ESCC). A total of 55 patients with primary ESCC who received chemotherapy with high-dose cisplatin were examined. Mg was administered intravenously, and serum concentrations of PTH, parathyroid hormone-related protein (PTH-rP), creatinine and Mg were prospectively measured. Of the 55 patients, 37 received Mg supplementation. Post-chemotherapeutic creatinine concentrations were significantly increased in patients without Mg supplementation (P=0.01), with grade 1 and 2 increases of 22.2 and 5.6%, respectively, whereas these increases were suppressed by Mg supplementation (change in creatinine, P=0.21), with grade 1 and 2 increases of 8.1 and 0%, respectively. In addition, PTH and PTH-rP concentrations were high in 8 (14.5%) and 6 (10.9%) of all 55 patients, respectively. Alterations in creatinine concentrations (post-/pre-chemotherapy) due to chemotherapy were higher in patients with high levels of PTH regardless of Mg supplementation (P<0.01). Pre-therapeutic creatinine concentrations did not correlate with the alterations in creatinine concentrations due to chemotherapy. Intravenous Mg supplementation therefore conferred protective effects against cisplatin-induced nephrotoxicity in patients with ESCC. Furthermore, increases in PTH or PTH-rP may have influenced the extent of nephrotoxicity.