RESUMEN

Cisplatin-induced renal tubular injury largely restricts the wide-spread usage of cisplatin in the treatment of malignancies. Identifying the key signaling pathways that regulate cisplatin-induced renal tubular injury is thus clinically important. PARVB, a focal adhesion protein, plays a crucial role in tumorigenesis. However, the function of PARVB in kidney disease is largely unknown. To investigate whether and how PARVB contributes to cisplatin-induced renal tubular injury, a mouse model (PARVB cKO) was generated in which PARVB gene was specifically deleted from proximal tubular epithelial cells using the Cre-LoxP system. In this study, we found depletion of PARVB in proximal tubular epithelial cells significantly attenuates cisplatin-induced renal tubular injury, including tubular cell death and inflammation. Mechanistically, PARVB associates with transforming growth factor-ß-activated kinase 1 (TAK1), a central regulator of cell survival and inflammation that is critically involved in mediating cisplatin-induced renal tubular injury. Depletion of PARVB promotes cisplatin-induced TAK1 degradation, inhibits TAK1 downstream signaling, and ultimately alleviates cisplatin-induced tubular cell damage. Restoration of PARVB or TAK1 in PARVB-deficient cells aggravates cisplatin-induced tubular cell injury. Finally, we demonstrated that PARVB regulates TAK1 protein expression through an E3 ligase ITCH-dependent pathway. PARVB prevents ITCH association with TAK1 to block its ubiquitination. Our study reveals that PARVB deficiency protects against cisplatin-induced tubular injury through regulation of TAK1 signaling and indicates targeting this pathway may provide a novel therapeutic strategy to alleviate cisplatin-induced kidney damage.

Asunto(s)

Cisplatino , Quinasas Quinasa Quinasa PAM , Ratones Noqueados , Transducción de Señal , Cisplatino/efectos adversos , Cisplatino/toxicidad , Animales , Quinasas Quinasa Quinasa PAM/metabolismo , Quinasas Quinasa Quinasa PAM/genética , Transducción de Señal/efectos de los fármacos , Ratones , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/patología , Túbulos Renales Proximales/efectos de los fármacos , Humanos , Ratones Endogámicos C57BL , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Antineoplásicos/farmacología , Antineoplásicos/efectos adversos , Túbulos Renales/patología , Túbulos Renales/metabolismo , Túbulos Renales/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales

RESUMEN

Cisplatin is a common anticancer drug, but its frequent nephrotoxicity limits its clinical use. Small GTP-binding protein GDP dissociation stimulator (smgGDS), a small GTPase chaperone protein, was considerably downregulated during cisplatin-induced acute kidney injury (CDDP-AKI), especially in renal tubular epithelial cells. SmgGDS-knockdown mice was established and found that smgGDS knockdown promoted CDDP-AKI, as demonstrated by an increase in serum creatine, blood urea nitrogen levels and the appearance of tubular patterns. RNA sequencing suggested that protein kinase RNA-like ER kinase (PERK), which bridges mitochondria-associated ER membranes, was involved in smgGDS knockdown following CDDP-AKI, and then identified that smgGDS knockdown increased phosphorylated-PERK in vivo and in vitro. Furthermore, we confirmed that smgGDS deficiency aggravated apoptosis and ER stress in vivo and in vitro. And the ER stress inhibitor 4-Phenylbutyric acid and the inhibition of PERK phosphorylation mitigated smgGDS deficiency-induced ER stress related apoptosis following cisplatin treatment, while the eIF2α phosphorylation inhibitor could not reverse the smgGDS deficiency accelerated cell death. Furthermore, the over-expression of smgGDS could reverse the ER stress and apoptosis caused by CDDP. Overall, smgGDS regulated PERK-dependent ER stress and apoptosis, thereby influencing renal damage. This study identified a target for diagnosing and treating cisplatin-induced acute kidney injury.

Asunto(s)

Lesión Renal Aguda , Cisplatino , Estrés del Retículo Endoplásmico , eIF-2 Quinasa , Cisplatino/efectos adversos , Cisplatino/toxicidad , Animales , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Lesión Renal Aguda/genética , eIF-2 Quinasa/metabolismo , eIF-2 Quinasa/genética , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ratones , Masculino , Apoptosis/efectos de los fármacos , Ratones Endogámicos C57BL , Antineoplásicos/efectos adversos , Antineoplásicos/toxicidad , Fosforilación

RESUMEN

Neurotoxicity is characterized by the accumulation of harmful chemicals such as heavy metals and drugs in neural tissue, resulting in subsequent neuronal death. Among chemicals platinum-based cancer drugs are frequently used due to their antineoplastic effects, but this drug is also known to cause a wide range of toxicities, such as neurotoxicity. The nuclear-factor-erythroid 2-related factor-2 (NRF2) is crucial in combating oxidative stress and maintaining cellular homeostasis. This study thoroughly explores the protective effects of extracellular vesicles derived from NRF2 gene overexpressed neural progenitor cells (NEVs) on cisplatin-induced neurotoxicity. Therefore, extracellular vesicles derived from neural progenitor cells were isolated and characterized. The Cisplatin neurotoxicity dose was 75 µM in mature, post-mitotic neurons. 1.25 µM of tert-butyl hydroquinone that induces NRF2/ARE pathway was used as the positive control. The effects of extracellular vesicles (EVs) were investigated using functional and molecular assays such as PCR and protein-based assays. Here, we observed that NEVs dose-dependently protected post-mitotic neuron cells in response to cisplatin. The study also examined whether the effect was EV-induced by limiting EV biogenesis. The molecular basis of preventive treatment was established. When pre-administered, 1×108 particles/ml of NEVs maintained antioxidant and detoxifying gene and protein expression levels similar to control cell levels. Furthermore, NEVs reduced both cellular and mitochondrial ROS levels and preserved mitochondrial membrane potential. In addition, Catalase and SOD levels were found higher in NEV-treated cells compared to cisplatin control. The findings in NRF2-based protection of cisplatin-induced neurotoxicity may provide further evidence for the relationship between EVs and inhibition of neuronal stress through the NRF2/ARE pathway, increasing the understanding of neuroprotective responses and the development of gene-engineered EV therapy options for peripheral neuropathy or other neurodegenerative diseases. This is the first study in the literature to investigate the neutralizing potency of NRF2 overexpressed neural EVs against cisplatin-induced neurotoxicity.

Asunto(s)

Antineoplásicos , Cisplatino , Vesículas Extracelulares , Factor 2 Relacionado con NF-E2 , Células-Madre Neurales , Transducción de Señal , Cisplatino/toxicidad , Factor 2 Relacionado con NF-E2/metabolismo , Vesículas Extracelulares/efectos de los fármacos , Vesículas Extracelulares/metabolismo , Animales , Antineoplásicos/toxicidad , Antineoplásicos/farmacología , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Transducción de Señal/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Síndromes de Neurotoxicidad/prevención & control , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/etiología , Elementos de Respuesta Antioxidante/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Células Cultivadas

RESUMEN

Nephrotoxicity, including electrolytic disorders and acute kidney injury (AKI), limits the clinical dosage and utility of platinated antineoplastics such as cisplatin. Cisplatin nephrotoxicity embodies a tubulopathy involving the medullary S2 and S3 segments of the proximal and the distal tubules. Higher dosage extends damage over the cortical S1 segment and intensifies overall injury. However, the standard diagnosis based on plasma creatinine as well as novel injury biomarkers lacks enough pathophysiological specificity. Further granularity in the detection of renal injury would help understand the implications of individual damage patterns needed for personalized patient handling. In this article, we studied the association of urinary ganglioside GM2 activator protein (GM2AP) with the patterns of tubular damage produced by 5 and 10 mg/kg cisplatin in rats. Our results show that GM2AP appears in the urine only following damage to the cortical segment of the proximal tubule. The information provided by GM2AP is not redundant with but distinct and complementary to that provided by urinary neutrophil gelatinase-associated lipocalin (NGAL). Similarly, treatment with 150 mg/kg/day gentamicin damages the renal cortex and increases GM2AP urinary excretion; whereas renal ischemia, which does not affect the cortex, has no effect on GM2AP. Because of the key role of the cortical proximal tubule in renal function, we contend GM2AP as a potential diagnostic biomarker to stratify AKI patients according to the underlying damage and follow their evolution and prognosis. Prospectively, urinary GM2AP may help grade the severity of platinated antineoplastic nephrotoxicity by forming part of a non-invasive liquid biopsy.

Asunto(s)

Lesión Renal Aguda , Antineoplásicos , Biomarcadores , Cisplatino , Proteína Activadora de G (M2) , Corteza Renal , Cisplatino/toxicidad , Animales , Masculino , Ratas , Biomarcadores/orina , Antineoplásicos/toxicidad , Corteza Renal/efectos de los fármacos , Corteza Renal/patología , Corteza Renal/metabolismo , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/patología , Lesión Renal Aguda/orina , Gentamicinas/toxicidad , Ratas Sprague-Dawley , Lipocalina 2/orina , Índice de Severidad de la Enfermedad

RESUMEN

Mangiferin(MGF) exhibits crucial biological roles, including antioxidant and anti-inflammatory functions. However, how to clearly elucidate the functioning mechanism of MGF for inhibiting cisplatin-induced hearing loss requires in-depth investigation. In this work, we aimed at gaining insight into how MGF functions as the protective agent against cisplatin-triggered ototoxicity using various assays. The variation for reactive oxygen species (ROS) concentrations was determined with MitoSOX-Red and 2',7'-Dichlorodihydrofluorescein diacetate staining (DCFH-DA). The protective function and corresponding mechanism of MGF in hair cell survival in the House Ear Institute-Organ of Corti (HEI-OC1) cell line were assessed using RNA sequencing (RNA-Seq). Our findings demonstrated that MGF significantly alleviated cisplatin-induced injury to hair cells in vitro, encompassing cell lines and cochlear explants, as well as in vivo models, including C57BL/6 J mice and zebrafish larvae. Mechanistic studies revealed that MGF reversed the increased accumulation of ROS and inhibited cell apoptosis through mitochondrial-mediated intrinsic pathway. Moreover, real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting data indicated MGF protected against cisplatin-mediated ototoxicity via the mitogen-activated protein kinase pathway (MAPK). These findings demonstrated MGF has significant potential promise in combating cisplatin-induced ototoxicity, offering a foundation for expanded investigation into therapeutic approaches for auditory protection.

Asunto(s)

Apoptosis , Cisplatino , Células Ciliadas Auditivas , Pérdida Auditiva Sensorineural , Ratones Endogámicos C57BL , Ototoxicidad , Especies Reactivas de Oxígeno , Xantonas , Pez Cebra , Cisplatino/toxicidad , Cisplatino/efectos adversos , Animales , Ototoxicidad/prevención & control , Especies Reactivas de Oxígeno/metabolismo , Ratones , Pérdida Auditiva Sensorineural/inducido químicamente , Pérdida Auditiva Sensorineural/tratamiento farmacológico , Pérdida Auditiva Sensorineural/metabolismo , Pérdida Auditiva Sensorineural/prevención & control , Pérdida Auditiva Sensorineural/patología , Apoptosis/efectos de los fármacos , Xantonas/farmacología , Xantonas/uso terapéutico , Células Ciliadas Auditivas/efectos de los fármacos , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Antioxidantes/farmacología

RESUMEN

Cisplatin-induced nephrotoxicity restricts its clinical use against solid tumors. The present study elucidated the pharmacological effects of Renogrit, a plant-derived prescription medicine, using cisplatin-induced human renal proximal tubular (HK-2) cells and Caenorhabditis elegans. Quantification of phytochemicals in Renogrit was performed on HPTLC and UHPLC platforms. Renogrit was assessed in vitro in HK-2 cells post-exposure to clinically relevant concentration of cisplatin. It was observed that renoprotective properties of Renogrit against cisplatin-induced injury stem from its ability to regulate renal injury markers (KIM-1, NAG levels; NGAL mRNA expression), redox imbalance (ROS generation; GST levels), and mitochondrial dysfunction (mitochondrial membrane potential; SKN-1, HSP-60 expression). Renogrit was also found to modulate apoptosis (EGL-1 mRNA expression; protein levels of p-ERK, p-JNK, p-p38, c-PARP1), necroptosis (intracellular calcium accumulation; RIPK1, RIPK3, MLKL mRNA expression), mitophagy (lysosome population; mRNA expression of PINK1, PDR1; protein levels of p-PINK1, LC3B), and inflammation (IL-1ß activity; protein levels of LXR-α). More importantly, Renogrit treatment did not hamper normal anti-proliferative effects of cisplatin as observed from cytotoxicity analysis on MCF-7, A549, SiHa, and T24 human cancer cells. Taken together, Renogrit could be a potential clinical candidate to mitigate cisplatin-induced nephrotoxicity without compromising the anti-neoplastic properties of cisplatin.

Asunto(s)

Apoptosis , Caenorhabditis elegans , Cisplatino , Mitofagia , Cisplatino/efectos adversos , Cisplatino/toxicidad , Animales , Humanos , Mitofagia/efectos de los fármacos , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular , Extractos Vegetales/farmacología , Túbulos Renales/efectos de los fármacos , Túbulos Renales/metabolismo , Túbulos Renales/patología , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Antineoplásicos/efectos adversos , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/patología

RESUMEN

Chemotherapy-induced premature ovarian insufficiency (CIPOI) triggers gonadotoxicity in women undergoing cancer treatment, leading to loss of ovarian reserves and subfertility, with no effective therapies available. In our study, fecal microbiota transplantation in a cisplatin-induced POI mouse model reveals that a dysbiotic gut microbiome negatively impacts ovarian health in CIPOI. Multi-omics analyses show a significant decrease in Limosilactobacillus reuteri and its catabolite, ß-resorcylic acid , in the CIPOI group in comparison to healthy controls. Supplementation with L. reuteri or ß-RA mitigates cisplatin-induced hormonal disruptions, morphological damages, and reductions in follicular reserve. Most importantly, ß-RA pre-treatment effectively preserves oocyte function, embryonic development, and fetus health, thereby protecting against chemotherapy-induced subfertility. Our results provide evidence that ß-RA suppresses the nuclear accumulation of sex-determining region Y-box 7, which in turn reduces Bcl-2-associated X activation and inhibits granulosa cell apoptosis. These findings highlight the therapeutic potential of targeting the gut-ovary axis for fertility preservation in CIPOI.

Asunto(s)

Cisplatino , Limosilactobacillus reuteri , Ovario , Insuficiencia Ovárica Primaria , Femenino , Animales , Cisplatino/efectos adversos , Cisplatino/toxicidad , Ratones , Insuficiencia Ovárica Primaria/inducido químicamente , Insuficiencia Ovárica Primaria/patología , Ovario/efectos de los fármacos , Ovario/patología , Ovario/metabolismo , Microbioma Gastrointestinal/efectos de los fármacos , Apoptosis/efectos de los fármacos , Trasplante de Microbiota Fecal , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Ratones Endogámicos C57BL , Antineoplásicos/toxicidad , Antineoplásicos/efectos adversos , Células de la Granulosa/efectos de los fármacos , Células de la Granulosa/metabolismo , Modelos Animales de Enfermedad , Infertilidad

RESUMEN

HYPOTHESIS: Memantine, an N -methyl- d -aspartate receptor antagonist, is widely used to treat Alzheimer's disease and has been found to have potential neuroprotective effects. In this study, we evaluated the protective effects of memantine against cisplatin-induced ototoxicity. BACKGROUND: Cisplatin is a widely used anticancer drug for various cancers; however, its use is limited by its side effects, including ototoxicity. Several drugs have been developed to reduce cisplatin toxicity. In this study, we treated cisplatin-damaged cochlear hair cells with memantine and evaluated its protective effects. METHOD: House Ear Institute Organ of Corti 1 (HEI-OC1) cells and cochlear explants were treated with cisplatin or memantine. Cell viability, apoptotic patterns, reactive oxygen species (ROS) production, Bcl-2/caspase-3 activity, and cell numbers were measured to evaluate the anti-apoptotic and antioxidative effects of memantine. RESULT: Memantine treatment significantly improved cell viability and reduced cisplatin-induced apoptosis in auditory cells. Bcl-2/caspase-3 activity was also significantly increased, suggesting anti-apoptotic effects against cisplatin-induced ototoxicity. CONCLUSION: Our results suggest that memantine protects against cisplatin-induced ototoxicity in vitro, providing a potential new strategy for preventing hearing loss in patients undergoing cisplatin chemotherapy.

Asunto(s)

Antineoplásicos , Apoptosis , Supervivencia Celular , Cisplatino , Memantina , Ototoxicidad , Especies Reactivas de Oxígeno , Memantina/farmacología , Cisplatino/toxicidad , Cisplatino/efectos adversos , Animales , Ototoxicidad/prevención & control , Apoptosis/efectos de los fármacos , Antineoplásicos/toxicidad , Antineoplásicos/efectos adversos , Supervivencia Celular/efectos de los fármacos , Ratones , Especies Reactivas de Oxígeno/metabolismo , Células Ciliadas Auditivas/efectos de los fármacos , Células Ciliadas Auditivas/patología , Caspasa 3/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Fármacos Neuroprotectores/farmacología , Órgano Espiral/efectos de los fármacos , Órgano Espiral/patología , Cóclea/efectos de los fármacos , Cóclea/patología , Antagonistas de Aminoácidos Excitadores/farmacología , Línea Celular

RESUMEN

Cisplatin (CDDP) often leads to kidney impairment, limiting its effectiveness in cancer treatment. The lack of mitophagy in proximal tubules exacerbates this issue. Hence, targeting SIRT-3 and PGC1-α shows promise in mitigating CDDP-induced kidney damage. The potential renoprotective effects of linagliptin, however, remain poorly understood. This study represents the first exploration of linagliptin's impact on CDDP-induced kidney impairment in rats, emphasizing its potential role in mitophagic pathways. The experiment involved four rat groups: Group (I) received saline only, Group (II) received a single intraperitoneal injection of CDDP at 6 mg/kg. Groups (III) and (IV) received linagliptin at 6 and 10 mg/kg p.o., respectively, seven days before CDDP administration, continuing for an additional four days. Various parameters, including renal function tests, oxidative stress, TNF-α, IL-1ß, IL-6, PGC-1α, FOXO-3a, p-ERK1, and the gene expression of SIRT-3 and P62 in renal tissue, were assessed. Linagliptin improved renal function, increased antioxidant enzyme activity, and decreased IL-1ß, TNF-α, and IL-6 expression. Additionally, linagliptin significantly upregulated PGC-1α and PINK-1/Parkin-2 expression while downregulating P62 expression. Moreover, linagliptin activated FOXO-3a and SIRT-3, suggesting a potential enhancement of mitophagy. Linagliptin demonstrated a positive impact on various factors related to kidney health in the context of CDDP-induced impairment. These findings suggest a potential role for linagliptin in improving cancer treatment outcomes. Clinical trials are warranted to further investigate and validate its efficacy in a clinical setting.

Asunto(s)

Cisplatino , Linagliptina , Mitofagia , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Ubiquitina-Proteína Ligasas , Animales , Linagliptina/farmacología , Cisplatino/toxicidad , Mitofagia/efectos de los fármacos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Masculino , Ratas , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Sirtuina 3/metabolismo , Sirtuina 3/genética , Proteínas Quinasas/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Ratas Wistar , Antineoplásicos/toxicidad , Estrés Oxidativo/efectos de los fármacos , Enfermedades Renales/inducido químicamente , Enfermedades Renales/prevención & control , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Sirtuinas

RESUMEN

Cisplatin is a chemotherapeutic agent widely used to treat solid tumors. However, it can also be highly ototoxic, resulting in high-frequency hearing loss. Cisplatin causes degeneration of hair cells (HCs) and spiral ganglion neurons (SGNs) in the inner ear, which are essential components of the hearing process and cannot be regenerated in mammals. As the affected cells primarily die by apoptosis, we tested several anti-apoptotic small molecules to protect these cells from drug-induced toxicity. We found that the general caspase inhibitor Emricasan could significantly counteract the toxic effects of cisplatin in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells, phoenix auditory cells, and primary SGNs. Importantly, the anti-cytotoxic effect in neuronal cells was even more pronounced than the effect of sodium thiosulfate (STS), which is currently the only approved prevention option for cisplatin-induced ototoxicity. Finally, we tested the protective effect of Emricasan treatment in the context of another ototoxic drug, i.e., the aminoglycoside antibiotic neomycin, and again found a significant increase in cell viability when the cultures were co-treated with Emricasan. These results suggest a promising strategy to prevent ototoxicity in patients by temporarily blocking the apoptotic pathway when applying cisplatin or aminoglycoside antibiotics. KEY MESSAGES: Anti-apoptotic small molecules can reduce cisplatin-induced toxicity. Emricasan can effectively exert its anti-apoptotic effect on cochlear cells. Strong protection from cisplatin- and neomycin-induced cytotoxicity with Emricasan. Sodium thiosulfate and Emricasan provide similar protective effects to cisplatin-treated cells. Emricasan is more potent than sodium thiosulfate in reducing neomycin-induced cytotoxicity.

Asunto(s)

Inhibidores de Caspasas , Cisplatino , Neomicina , Cisplatino/efectos adversos , Cisplatino/toxicidad , Cisplatino/farmacología , Animales , Neomicina/farmacología , Neomicina/toxicidad , Inhibidores de Caspasas/farmacología , Ratones , Apoptosis/efectos de los fármacos , Cóclea/efectos de los fármacos , Cóclea/citología , Supervivencia Celular/efectos de los fármacos , Células Ciliadas Auditivas/efectos de los fármacos , Ganglio Espiral de la Cóclea/efectos de los fármacos , Ototoxicidad/etiología , Ototoxicidad/prevención & control , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Línea Celular , Células Cultivadas

RESUMEN

Acute kidney injury (AKI) is a worldwide public health problem with high morbidity and mortality. Cisplatin is a widely used chemotherapeutic agent for treating solid tumors, but the induction of AKI restricts its clinical application. In this study, the effect of cisplatin on the expression of organic ion transporters was investigated through in vivo and in vitro experiments. Targeted metabolomics techniques were used to measure the levels of selected endogenous substances in serum. Transmission electron microscopy was used to observe the microstructure of renal tubular epithelial cells. Our results show that the toxicity of cisplatin on HK-2 cells or HEK-293 cells was time- and dose-dependent. Administration of cisplatin decreased the expression of OAT1/3 and OCT2 and increased the expression of MRP2/4. Mitochondrial damage induced by cisplatin lead to renal tubular epithelial cell injury. In addition, administration of cisplatin resulted in significant changes in endogenous substance levels in serum, including amino acids, carnitine, and fatty acids. These serum amino acids and metabolites (α-aminobutyric acid, proline, and alanine), carnitines (tradecanoylcarnitine, hexanylcarnitine, octanoylcarnitine, 2-methylbutyroylcarnitine, palmitoylcarnitine, and linoleylcarnitine) and fatty acids (9E-tetradecenoic acid) represent endogenous substances with diagnostic potential for cisplatin-induced AKI.

Asunto(s)

Lesión Renal Aguda , Cisplatino , Cisplatino/toxicidad , Humanos , Animales , Células HEK293 , Masculino , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Antineoplásicos/toxicidad , Transportadores de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico/genética , Transportador 2 de Cátion Orgánico/metabolismo , Transportador 2 de Cátion Orgánico/genética , Proteínas de Transporte de Catión Orgánico/metabolismo , Proteínas de Transporte de Catión Orgánico/genética , Carnitina/análogos & derivados , Carnitina/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo

RESUMEN

Different organs respond differently to cisplatin (CDDP)-induced toxicity. Oleuropein (OLE) is a natural phenolic antioxidant. The purpose of this study was to determine the potential protective effect of OLE against CDDP-induced ototoxicity by evaluating expression of genes associated with deoxyribonucleic acid (DNA) damage and repair in cochlear cells. House Ear Institute-Organ of Corti 1 (HEI-OC1) cells were treated using CDDP, OLE, and OLE-CDDP. The water-soluble tetrazolium salt assay was used for monitoring cell viability. Deoxyribonucleic acid damage in cells due to the CDDP, OLE, and combination treatments was determined using a flow-cytometric kit. The change in the expression of 84 genes associated with CCDP, OLE, and OLE-CDDP treatments that induced DNA damage was tested using the reverse transcription polymerase chain reaction array. Changes ≥3-fold were considered significant. House Ear Institute-Organ of Corti 1 cell viability was significantly reduced by CDDP. The OLE-CDDP combination restored the cell viability. Cisplatin increased the H2AX ratio, while OLE-CDDP combination decreased it. Some of the DNA damage-associated genes whose expression was upregulated with CDDP were downregulated with OLE-CDDP, while the expression of genes such as Gadd45g and Rev1 was further downregulated. The expression of DNA repair-related Abl1, Dbd2, Rad52, and Trp53 genes was downregulated with CDDP, whereas their expression was upregulated with OLE-CDDP treatment. In cochlear cells, the OLE-CDDP combination downregulated DNA damage-associated gene expression relative to that upregulated mainly by CDDP. The results revealed that OLE has a potential protective effect on CDDP-induced ototoxicity in cochlear cells by altering the expression of DNA damage-related genes.

Asunto(s)

Supervivencia Celular , Cisplatino , Cóclea , Daño del ADN , Glucósidos Iridoides , Ototoxicidad , Cisplatino/toxicidad , Glucósidos Iridoides/farmacología , Daño del ADN/efectos de los fármacos , Animales , Cóclea/efectos de los fármacos , Cóclea/metabolismo , Cóclea/patología , Supervivencia Celular/efectos de los fármacos , Ototoxicidad/prevención & control , Ratones , Iridoides/farmacología , Antineoplásicos/toxicidad , Antioxidantes/farmacología , Humanos , Línea Celular , Expresión Génica/efectos de los fármacos

RESUMEN

With the postponement of female reproductive age and the higher incidence of cancer in young people, fertility preservation has become increasingly important in childbearing age. Chemotherapy during pregnancy is crucial for maternal cancer treatments and fetal outcomes. It is a need to further study ovarian damage caused by chemotherapy drug combinations and long-term effects on offspring development, and a detailed understanding of side effects of chemotherapy drugs. In this study, chemotherapy drug combinations significantly impacted on ovarian function, especially epirubicin/cyclophosphamide (EC) combination led to an unbalance in the development of the left and right ovary. Exposure to EC and cisplatin/paclitaxel (TP) increased the number of progenitor follicles while decreased the count of antral follicles and corpora luteum. As to the estrus cycle, EC exposure resulted in a longer estrus period and diestrus period, while TP exposure only extended the diestrus period. EC and TP affected steroid biosynthesis by reducing the expression of SF1 and P450arom.γ-H2AX was detected in both EC and TP exposure groups. As to the impact on the offspring from 4T1 tumor-bearing pregnant mice injected with EC, no significant difference was observed in the physical and neurological development compared to the control, but the ovarian weights, estrus cycles of the offspring were significantly different. Chemotherapy drug combinations exhibit ovarian toxicity, not only causing direct damage on the follicle cells but also disrupting steroid biosynthesis. The reproductive system of offspring from maternal tumor-bearing mice exposed to chemotherapy drugs was observed disorder, but the concrete mechanism still needs further exploration.

Asunto(s)

Cisplatino , Ciclofosfamida , Epirrubicina , Ovario , Femenino , Animales , Ciclofosfamida/toxicidad , Ciclofosfamida/efectos adversos , Embarazo , Ovario/efectos de los fármacos , Cisplatino/efectos adversos , Cisplatino/toxicidad , Epirrubicina/efectos adversos , Epirrubicina/toxicidad , Paclitaxel/efectos adversos , Paclitaxel/toxicidad , Ratones , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ratones Endogámicos BALB C , Antineoplásicos/efectos adversos , Antineoplásicos/toxicidad

RESUMEN

Calcitriol as a biologically active form of vitamin D3 has beneficial effects on all body systems. This vitamin has a potent neuroprotective effect via several independent mechanisms against brain insults induced by anticancer drugs. The present study was designed to examine the neuroprotective effects of calcitriol against neurotoxicity induced by cisplatin. Induction of neurotoxicity was done with cisplatin administration (5 mg/kg/week) for 5 successive weeks in male Wistar rats. The neuroprotective influence of calcitriol supplementation (100ng/kg/day for 5 weeks) was assessed through behavioral, electrophysiological, and molecular experiments. Cisplatin administration impaired spatial learning and memory and decreased prefrontal brain-derived neurotrophic factor (BDNF). Peripheral sensory neuropathy was induced through cisplatin administration. Cisplatin also reduced the amplitudes of the compound action potential of sensory nerves in electrophysiological studies. Cisplatin treatment elevated MDA levels and reduced anti-oxidant (SOD and GPx) enzymes. Pro-inflammatory cytokines (IL-1ß and TNF-α) and metalloproteinase-2 and 9 (MMP-2/9) were augmented through treatment with cisplatin. Learning and memory impairments along with BDNF changes caused by cisplatin were amended with calcitriol supplementation. Reduced sensory nerve conduction velocity in the cisplatin-treated group was improved by calcitriol. Calcitriol partially improved redox imbalance and diminished the pro-inflammatory cytokines and MMP-2/9 levels. Our findings showed that calcitriol supplementation can relieve cisplatin-induced peripheral neurotoxicity. Calcitriol can be regarded as a promising new neuroprotective agent.

Asunto(s)

Calcitriol , Cisplatino , Metaloproteinasa 2 de la Matriz , Metaloproteinasa 9 de la Matriz , Fármacos Neuroprotectores , Estrés Oxidativo , Ratas Wistar , Animales , Cisplatino/toxicidad , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Metaloproteinasa 2 de la Matriz/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Metaloproteinasa 9 de la Matriz/metabolismo , Calcitriol/farmacología , Calcitriol/uso terapéutico , Antineoplásicos/toxicidad , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Síndromes de Neurotoxicidad/tratamiento farmacológico , Síndromes de Neurotoxicidad/metabolismo

RESUMEN

Acute kidney injury (AKI) is one of the most serious complications of cisplatin anticancer therapies. Cilastatin is a highly promising nephroprotective agent to eventually enter clinical use, but its biochemical mechanism is still not fully understood. We have employed an untargeted metabolomics approach based on capillary electrophoresis mass spectrometry (CE-MS) analysis of serum and urine from an in vivo rat model, to explore the metabolic pathways involved in cisplatin-induced AKI and cilastatin nephroprotection. A total of 155 and 76 identified metabolites were found to be significantly altered during cisplatin treatment in urine and serum, respectively. Most of these altered metabolites were either partially or totally recovered by cilastatin and cisplatin co-treatment. The main metabolic pathways disturbed by cisplatin during AKI involved diverse amino acids metabolism and biosynthesis, tricarboxylic acids (TCA) cycle, nicotinate and nicotinamide metabolism, among others. Cilastatin was proved to protect diverse cisplatin-altered pathways involving metabolites related to immunomodulation, inflammation, oxidative stress and amino acid metabolism in proximal tubules. However, cisplatin-altered mitochondrial metabolism (especially, the energy-producing TCA cycle) remained largely unprotected by cilastatin, suggesting an unresolved mitochondrial direct damage. Multivariate analysis allowed effective discrimination of cisplatin-induced AKI and cilastatin renoprotection based on metabolic features. A number of potential serum and urine biomarkers could also be foreseen for cisplatin-induced AKI detection and cilastatin nephroprotection.

Asunto(s)

Lesión Renal Aguda , Cilastatina , Cisplatino , Metabolómica , Animales , Cisplatino/efectos adversos , Cisplatino/toxicidad , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/prevención & control , Metabolómica/métodos , Masculino , Cilastatina/farmacología , Ratas , Antineoplásicos , Redes y Vías Metabólicas/efectos de los fármacos , Ratas Sprague-Dawley

RESUMEN

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.

Asunto(s)

Lesión Renal Aguda , Cisplatino , Estrés del Retículo Endoplásmico , Células Epiteliales , Ginsenósidos , Túbulos Renales , Ginsenósidos/farmacología , Cisplatino/efectos adversos , Cisplatino/toxicidad , Estrés del Retículo Endoplásmico/efectos de los fármacos , Animales , Ratones , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Túbulos Renales/efectos de los fármacos , Túbulos Renales/patología , Túbulos Renales/metabolismo , Humanos , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/patología , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/tratamiento farmacológico , Masculino , Línea Celular , Apoptosis/efectos de los fármacos , Ratones Endogámicos C57BL

RESUMEN

PURPOSE: The present study investigated the nephron-testicular protective effects of sesamin against cisplatin (CP)-induced acute renal and testicular injuries. METHODS: Thirty-two male Wistar rats were allocated to receive carboxymethylcellulose (0.5%, as sesamin vehicle), CP (a single i.p. 5 mg/kg dose), CP plus sesamin at 10 or 20 mg/kg orally for 10 days. RESULTS: Data analysis showed significant increases in serum urea, creatinine, interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α), as well as renal and testicular tissue malondialdehyde and nitric-oxide concentrations in CP-intoxicated rats in comparison to control animals. On the contrary, rats treated with CP only exhibited significantly lower (p < .05) serum testosterone, tissue glutathione, and activities of endogenous antioxidant enzymes compared to control rats. Histopathologically examining CP-intoxicated rats' tissues using H&E and PAS stains showed atrophied glomeruli, interstitial inflammatory cells, atypic tubular epithelium with focal apoptosis, and reduced mucopolysaccharide content. Further, immunohistochemical staining of the same group revealed an increase in p53 and cyclooxygenase-II (Cox-II) expression in renal and testicular tissues. Treatment with sesamin alleviated almost all the changes mentioned above in a dose-dependent manner, with the 20 mg/kg dose restoring several parameters' concentrations to normal ranges. CONCLUSIONS: In brief, sesamin could protect the kidneys and testes against CP toxicity through its antioxidant, anti-inflammatory, and anti-apoptotic effects.

Asunto(s)

Antiinflamatorios , Antioxidantes , Apoptosis , Cisplatino , Dioxoles , Riñón , Lignanos , Ratas Wistar , Testículo , Animales , Masculino , Lignanos/farmacología , Lignanos/uso terapéutico , Cisplatino/toxicidad , Cisplatino/efectos adversos , Ratas , Dioxoles/farmacología , Antioxidantes/farmacología , Testículo/efectos de los fármacos , Testículo/patología , Testículo/metabolismo , Apoptosis/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Antiinflamatorios/farmacología , Estrés Oxidativo/efectos de los fármacos , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/patología , Lesión Renal Aguda/metabolismo , Antineoplásicos/toxicidad

RESUMEN

OBJECTIVE: Cisplatin, a widely used anticancer agent, induces hepatotoxicity alongside organ damage. Understanding Cisplatin's toxicity mechanism and developing preventive measures are crucial. Our study explores Myricetin, a flavonoid, for its protective effects against Cisplatin-induced hepatotoxicity. METHODS: In our study, a total of 32 Wistar albino male rats were utilized, which were categorized into four distinct groups: Control, Myricetin, Cisplatin, and Myricetin+Cisplatin. For the histological assessment of hepatic tissues, hematoxylin-eosin and periodic acid Schiff staining were employed, alongside immunohistochemical measurements of TNF-α, interleukin-17, and interleukin-6 immunoreactivity. Additionally, aspartate transaminase and alanine transaminase values were examined by biochemical analysis. RESULTS: In the histological evaluation of the tissues, a normal healthy cell structure and a strong periodic acid Schiff (+) reaction were observed in the hepatocyte cells in the tissues of the Control and Myricetin groups, while intense eosinophilia, minimal vacuolization, congestion, and sinusoidal expansions were observed in the hematoxylin-eosin stainings, and a decrease in the positive reaction in the periodic acid Schiff staining was observed in the Cisplatin group. Consistent with these histological findings, an increase in TNF-α, interleukin-17, and interleukin-6 expressions (p<0.0001) and a concomitant increase in aspartate transaminase and alanine transaminase values were observed in the Cisplatin group. In the group protected by Myricetin, a significant improvement was observed in all these histological and biochemical values. CONCLUSION: Cisplatin induces notable histopathological alterations in the liver. In this context, Myricetin exhibits the potential to alleviate Cisplatin-induced damage by modulating histological parameters and biochemical processes.

Asunto(s)

Alanina Transaminasa , Antineoplásicos , Aspartato Aminotransferasas , Enfermedad Hepática Inducida por Sustancias y Drogas , Cisplatino , Flavonoides , Interleucina-6 , Ratas Wistar , Factor de Necrosis Tumoral alfa , Animales , Flavonoides/farmacología , Flavonoides/uso terapéutico , Cisplatino/toxicidad , Masculino , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Antineoplásicos/efectos adversos , Antineoplásicos/toxicidad , Interleucina-6/análisis , Interleucina-6/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Ratas , Interleucina-17/metabolismo , Inmunohistoquímica

RESUMEN

Background: Cisplatin (CIS) is a broad-spectrum anticancer drug, with cytotoxic effects on either malignant or normal cells. We aimed to evaluate the hepatotoxicity in rats caused by CIS and its amelioration by the co-administration of either curcumin or resveratrol. Materials and Methods: Forty adult male rats divided into four equal groups: (control group): rats were given a saline solution (0.9%) once intraperitoneally, daily for the next 28 days; (cisplatin group): rats were given a daily oral dose of saline solution (0.9%) for 28 days after receiving a single dose of cisplatin (3.3 mg/kg) intraperitoneally for three successive days; (CIS plus curcumin/resveratrol groups): rats received the same previous dose of cisplatin (3.3 mg/kg) daily for three successive days followed by oral administration of either curcumin/resveratrol solution at a dose of (20 mg/kg) or (10 mg/kg) consequently daily for 28 days. Different laboratory tests (ALT, AST, ALP, bilirubin, oxidative stress markers) and light microscopic investigations were done. Results: Administration of CIS resulted in hepatotoxicity in the form of increased liver enzymes, oxidative stress markers; degenerative and apoptotic changes, the co-administration of CIS with either curcumin or resveratrol improved hepatotoxicity through improved microscopic structural changes, reduction in liver enzymes activity, decreased oxidative stress markers, improved degenerative, and apoptotic changes in liver tissues. Conclusion: Co-administration of either curcumin or resveratrol with cisplatin treatment could ameliorate hepatotoxicity caused by cisplatin in rats via anti-inflammatory and oxidative stress-apoptotic pathways.

Asunto(s)

Apoptosis , Enfermedad Hepática Inducida por Sustancias y Drogas , Cisplatino , Curcumina , Estrés Oxidativo , Resveratrol , Animales , Resveratrol/farmacología , Resveratrol/administración & dosificación , Cisplatino/toxicidad , Cisplatino/administración & dosificación , Curcumina/farmacología , Curcumina/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Masculino , Ratas , Apoptosis/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/toxicidad , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Antioxidantes/farmacología , Antioxidantes/administración & dosificación , Estilbenos/administración & dosificación , Estilbenos/farmacología , Estilbenos/uso terapéutico , Antiinflamatorios/farmacología , Antiinflamatorios/administración & dosificación , Ratas Wistar

RESUMEN

Cisplatin is a widely used chemotherapy drug for the treatment of various cancers. However, although cisplatin is effective in targeting cancer cells, it has severe side effects including skeletal muscle atrophy. In this study, we aimed to characterize the role of Dihydromyricetin in cisplatin-induced muscle atrophy in mice. 5-week-old male C57BL/6 mice were treated with Dihydromyricetin for 14 days orally followed by in intraperitoneally cisplatin administration for 6 days. Gastrocnemius muscles were isolated for the following experiments. Antioxidative stress were determined by peroxidative product malondialdehyde (MDA) and antioxidants superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities. Quadriceps muscle mass and grip strength were significantly restored by Dihydromyricetin in a dose-dependent manner. Moreover, muscle fibers were improved in Dihydromyricetin treated group. Excessive skeletal muscle E3 ubiquitin-protein ligases in cisplatin group were significantly repressed by Dihydromyricetin treatment. Dihydromyricetin significantly reduced oxidative stress induced by cisplatin by decreasing MDA level and restored SOD and GPx activities. In addition, ferroptosis was significantly reduced by Dihydromyricetin characterized by reduced iron level and ferritin heavy chain 1 and improved Gpx4 level. The present study demonstrated that Dihydromyricetin attenuated cisplatin-induced muscle atrophy by reducing skeletal muscle E3 ubiquitin-protein ligases, oxidative stress, and ferroptosis.

Asunto(s)

Cisplatino , Ferroptosis , Flavonoles , Ratones Endogámicos C57BL , Atrofia Muscular , Estrés Oxidativo , Animales , Masculino , Flavonoles/farmacología , Flavonoles/uso terapéutico , Atrofia Muscular/inducido químicamente , Atrofia Muscular/patología , Atrofia Muscular/metabolismo , Atrofia Muscular/prevención & control , Atrofia Muscular/tratamiento farmacológico , Ferroptosis/efectos de los fármacos , Cisplatino/toxicidad , Ratones , Estrés Oxidativo/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Músculo Esquelético/metabolismo , Antineoplásicos/toxicidad , Antioxidantes/farmacología