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1.
Sci Rep ; 12(1): 13182, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35915212

RESUMO

Rapid non-invasive kidney-specific readouts are essential to maximizing the potential of microfluidic tissue culture platforms for drug-induced nephrotoxicity screening. Transepithelial electrical resistance (TEER) is a well-established technique, but it has yet to be evaluated as a metric of toxicity in a kidney proximal tubule (PT) model that recapitulates the high permeability of the native tissue and is also suitable for high-throughput screening. We utilized the PREDICT96 high-throughput microfluidic platform, which has rapid TEER measurement capability and multi-flow control, to evaluate the utility of TEER sensing for detecting cisplatin-induced toxicity in a human primary PT model under both mono- and co-culture conditions as well as two levels of fluid shear stress (FSS). Changes in TEER of PT-microvascular co-cultures followed a dose-dependent trend similar to that demonstrated by lactate dehydrogenase (LDH) cytotoxicity assays and were well-correlated with tight junction coverage after cisplatin exposure. Additionally, cisplatin-induced changes in TEER were detectable prior to increases in cell death in co-cultures. PT mono-cultures had a less differentiated phenotype and were not conducive to toxicity monitoring with TEER. The results of this study demonstrate that TEER has potential as a rapid, early, and label-free indicator of toxicity in microfluidic PT-microvascular co-culture models.


Assuntos
Cisplatino , Microfluídica , Cisplatino/metabolismo , Cisplatino/toxicidade , Impedância Elétrica , Humanos , Túbulos Renais Proximais/metabolismo , Junções Íntimas/metabolismo
2.
Artigo em Inglês | MEDLINE | ID: mdl-35955076

RESUMO

BACKGROUND: Rosinidin is a flavonoid anthocyanin pigmentation found in shrub flowers such as Catharanthus roseus and Primula rosea. The molecular docking studies predicted that rosinidin has adequate structural competency, making it a viable medicinal candidate for the treatment of a wide range of disorders. The current study intends to assess rosinidin nephroprotective efficacy against nephrotoxicity induced by cisplatin in rats. MATERIALS AND METHODS: Oral acute toxicity tests of rosinidin were conducted to assess potential toxicity in animals, and it was shown to be safe. The nephroprotective effect of rosinidin 10, and 20 mg/kg were tested in rats for 25 days with concurrent administration of cisplatin. Several biochemical parameters were measured to support enzymatic and non-enzymatic oxidative stress such as superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH). Likewise, changes in several non-protein-nitrogenous components and blood chemistry parameters were made to support the theory linked with the pathogenesis of chemical-induced nephrotoxicity. RESULTS: Cisplatin caused significant changes in biochemical, enzymatic, and blood chemistry, which rosinidin efficiently controlled. CONCLUSIONS: The present investigation linked rosinidin with nephroprotective efficacy in experimental models.


Assuntos
Antioxidantes , Cisplatino , Animais , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Cisplatino/toxicidade , Creatinina , Glutationa/metabolismo , Rim , Simulação de Acoplamento Molecular , Estresse Oxidativo , Ratos , Superóxido Dismutase/metabolismo
3.
Nutrients ; 14(14)2022 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-35889833

RESUMO

Acute kidney injury (AKI) describes a sudden loss of kidney function and is associated with a high mortality. Pediococcus acidilactici is a potent producer of bacteriocin and inhibits the growth of pathogens during fermentation and food storage; it has been used in the food industry for many years. In this study, the potential of P. acidilactici GKA4 (GKA4) to ameliorate AKI was investigated using a cisplatin-induced animal model. First, mice were given oral GKA4 for ten days and intraperitoneally injected with cisplatin on the seventh day to create an AKI mode. GKA4 attenuated renal histopathological alterations, serum biomarkers, the levels of inflammatory mediators, and lipid oxidation in cisplatin-induced nephrotoxicity. Moreover, GKA4 significantly decreased the expression of inflammation-related proteins and mitogen-activated protein kinase (MAPK) in kidney tissues. Eventually, GKA4 also increased the levels of related antioxidant enzymes and pathways. Consistently, sirtuin 1 (SIRT1) upregulated the level of autophagy-related proteins (LC3B, p62, and Beclin1). Further studies are needed to check our results and advance our knowledge of the mechanism whereby PI3K inhibition (wortmannin) reverses the effect of GKA4 on cisplatin-treated AKI. Taken together, GKA4 provides a therapeutic target with promising clinical potential after cisplatin treatment by reducing oxidative stress and inflammation via the MAPK, AMP-activated protein kinase (AMPK)/SIRT1/nuclear factor kappa B (NF-κB), and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) axes.


Assuntos
Injúria Renal Aguda , Pediococcus acidilactici , Proteínas Quinases Ativadas por AMP/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/prevenção & controle , Animais , Cisplatino/toxicidade , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo , Pediococcus acidilactici/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Sirtuína 1/genética , Sirtuína 1/metabolismo
4.
Theranostics ; 12(10): 4753-4766, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35832084

RESUMO

Rationale: Cisplatin nephrotoxicity is an important cause of acute kidney injury (AKI), limiting cisplatin application in cancer therapy. Growing evidence has suggested that genome instability, telomeric dysfunction, and DNA damage were involved in the tubular epithelial cells (TECs) damage in cisplatin-induced AKI (cAKI). However, the exact mechanism is largely unknown. Methods: We subjected miR-155-/- mice and wild-type controls, as well as HK-2 cells, to cAKI models. We assessed kidney function and injury with standard techniques. The cell apoptosis and DNA damage of TECs were evaluated both in vivo and in vitro. Telomeres were measured by the fluorescence in situ hybridization. Results: The expression level of miR-155 was upregulated in cAKI. Inhibition of miR-155 expression protected cisplatin-induced AKI both in vivo and in vitro. Compared with wild-type mice, miR-155-/- mice had reduced mortality, improved renal function and pathological damage after cisplatin intervention. Moreover, inhibition of miR-155 expression attenuated TECs apoptosis and DNA damage. These protective effects were caused by increasing expression of telomeric repeat binding factor 1 (TRF1) and cyclin-dependent kinase 12 (CDK12), thereby limiting the telomeric dysfunction and the genomic DNA damage in cAKI. Conclusion: We demonstrated that miR-155 deficiency could significantly attenuate pathological damage and mortality in cAKI through inhibition of TECs apoptosis, genome instability, and telomeric dysfunction, which is possibly regulated by the increasing expression of TRF1 and CDK12. This study will provide a new molecular strategy for the prevention of cAKI.


Assuntos
Injúria Renal Aguda , Dano ao DNA , MicroRNAs , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Injúria Renal Aguda/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Cisplatino/toxicidade , Células Epiteliais/efeitos dos fármacos , Instabilidade Genômica , Genômica , Hibridização in Situ Fluorescente , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Telômero/metabolismo
5.
Phytomedicine ; 104: 154331, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35878553

RESUMO

BACKGROUND: Cisplatin-induced cardiotoxicity severely limits its clinical application as an antitumor drug and increases the risk of cardiovascular disease. Icariin (ICA), the main flavonoid isolated from Epimedii Folium, has been demonstrated to have various beneficial effects on cardiovascular disease. However, the protective effect of ICA against cisplatin-induced cardiotoxicity remains unclear. PURPOSE: In present study, we explored the protective action of ICA against cisplatin-induced cardiotoxicity and its possible molecular mechanisms in vitro and in vivo. METHODS: Mice were intraperitoneally injected with cisplatin 4 mg/kg every other day for 7 times to establish myocardial injury model. ICA (15, 30 mg/kg) was administered to mice by gavage for 21 days. H9c2 cells were treated with ICA (3, 6, 12 µM) in the presence or absence of cisplatin (40 µM), and then cell viability, oxidative stress, apoptosis, and mitochondrial function were evaluated. RESULTS: Biochemical index detection and histopathological staining analysis showed that ICA had a good protective effect on cisplatin-induced cardiotoxicity. Cellular experiments showed that ICA inhibited cisplatin-induced oxidative stress in a dose-dependent manner by regulating the levels of glutathione peroxidase (GSH-Px), catalase (CAT), superoxide dismutase (SOD) and malondialdehyde (MDA). ICA could inhibit the expression of NF-κB and the secretion of inflammatory factors, thereby alleviating the inflammatory injury caused by cisplatin. In addition, ICA could alleviate cisplatin-induced myocardial injury by activating SIRT1 and PI3K/Akt signaling pathways and inhibiting MAPKs signaling pathway. CONCLUSION: These results suggest that ICA could attenuate cisplatin-induced cardiac injury by inhibiting oxidative stress, inflammation and apoptosis, laying a foundation for ICA to reduce chemotherapy-induced cardiotoxicity in clinical practice.


Assuntos
Doenças Cardiovasculares , Cisplatino , Animais , Apoptose , Cardiotoxicidade/etiologia , Cisplatino/toxicidade , Flavonoides , Camundongos , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo
6.
BMC Complement Med Ther ; 22(1): 179, 2022 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-35790919

RESUMO

BACKGROUND: Cisplatin (CisPT) is a chemotherapeutic that outcome in adverse effects including neurotoxicity. We examined the efficacy of hydaspica ethyl acetate extract (AHE) against CisPT-prompted neurotoxicity. METHODS: Group I: Distilled water; Group II: CisPT (12 mg/kg b.w. i.p) on the 13th day of treatment. Group III: received AHE (400 mg/kg b.w) orally for 16 days. Group IV and V received 200 and 400 mg/kg b.w AHE orally for 16 days while CisPT injection on day 13, respectively. Group VI: received Silymarin (100 mg/kg b.w) orally for 16 days and CP (12 mg/kg b.w., i.p.) on day 13. TNF-α, IL6, brain acetylcholinesterase activity (AChE), oxidative trauma markers, genotoxicity, antioxidant enzymes, and morphological alterations in cerebral hemispheres were inspected. RESULTS: AHE administration before CisPT considerably reduced both tissue TNF-α and IL 6 expressions compared to CisPT treated group in a dose-dependent manner. AHE treatment (400 mg/kg b.w) significantly ameliorated brain AChE activity. Brain tissue MDA, H2O2, and NO content were markedly (p < 0.001) elevated after CisPT inoculation while a noticeable (p < 0.001) diminution was observed in AHE treatment groups. AHE treatment significantly (p < 0.001) improved brain antioxidant defense in a dose-dependent manner. Furthermore, AHE efficiently recused CisPT to induce DNA damage in brain tissue as revealed by ladder assay and DNA fragmentation patterns. Histopathological findings revealed severe neurodegenerations in CisPT treated group, however, AHE treatment noticeably precluded morphological alterations and neuron damages induced by CisPT. CONCLUSION: A. hydaspica AHE extract may be provided as a prospective adjuvant that precludes CisPT-induced neurotoxicity due to its radical scavenging and antioxidant potential.


Assuntos
Acacia , Acetatos , Acetilcolinesterase , Animais , Antioxidantes/farmacologia , Encéfalo , Cisplatino/toxicidade , Citocinas , Dano ao DNA , Estresse Oxidativo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Estudos Prospectivos , Ratos , Ratos Sprague-Dawley , Roedores , Fator de Necrose Tumoral alfa
7.
Physiol Rep ; 10(12): e15348, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35748040

RESUMO

Obesity affects acute kidney injury (AKI) induced by various clinical settings, including transplantation and cisplatin-cancer therapy. However, the effect of short-term food intake change remains to be defined. Here, we investigated the effects of short-term high-fat diet intake and food restriction on cisplatin-induced AKI. Mice were fed either a high-fat diet (HFD) or a low-fat diet (LFD) for 11 days or were not fed for 40 hh (fasting), before cisplatin administration. Cisplatin-induced functional and structural damages to kidneys in both HFD- and LFD-fed mice, with greater damages in HFD-fed mice than LFD-fed mice. HFD decreased mitochondrial total glutathione (tGSH) level, along with increases in the plasma and kidney cholesterol levels. Cisplatin caused the increase of kidney cholesterol levels and oxidative stress, along with the decrease of mitochondrial tGSH levels. In addition, cisplatin-induced mitochondrial damage and apoptosis of tubular cells in both HFD- and LFD-fed mice. An increase of Fis1 (mitochondria fission 1 protein), whereas a decrease of Opa1 (mitochondria fusion 1 protein) occurred by cisplatin. These cisplatin effects were greater in HFD-fed mice than in LFD-fed mice. Administration of mitochondria-specific antioxidant treatment during HFD feeding inhibited these cisplatin-induced changes. Fasting for 40 h also significantly reduced the cisplatin-induced changes mentioned above. These data demonstrate that short-term HFD intake worsens cisplatin-induced oxidative stress by the reduction of mitochondrial tGSH, resulting in increased cisplatin-induced nephrotoxicity. These data newly indicate that the control of calorie intake, even for a short period, affects kidney susceptibility to injury. Although most studies described the effects of a long-term high-fat diet on the kidneys, in this study, we found that even if a high-fat diet was consumed for a short-term, physiological changes and mitochondria tGSH decrease in the kidneys, and consequently increased cisplatin-nephrotoxic susceptibility. These data suggest the association of calorie intake with kidney susceptibility to cisplatin.


Assuntos
Injúria Renal Aguda , Cisplatino , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Animais , Colesterol/metabolismo , Cisplatino/toxicidade , Dieta Hiperlipídica/efeitos adversos , Glutationa/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Dinâmica Mitocondrial
8.
Int J Clin Pract ; 2022: 6541026, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35685593

RESUMO

Objective: This study aimed to investigate the effects of gallic acid and silymarin against nephrotoxicity and hepatotoxicity caused by cisplatin. Materials and Methods: In the study, 56 Wistar Albino rats were equally divided into eight groups. Group 1 was the control group; group 2 was the group receiving cisplatin; group 3 was the group receiving cisplatin + gallic acid; group 4 was the group receiving cisplatin + silymarin; group 5 was the group receiving cisplatin + silymarin + gallic acid; group 6 was the group receiving silymarin; group 7 was the group receiving gallic acid; group 8 was the group receiving gallic acid + silymarin. AST, ALT, urea, creatinine, albumin, globulin, and total protein levels were measured at the end of the study. Superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), glutathione (GSH), and 8-hydroxy-2'-deoxyguanosine (8OH-dG) levels were measured in kidney and liver tissues. Additionally, histopathological evaluations of the tissues were also performed. Results: In kidney and liver tissues, cisplatin significantly increased MDA and 8-OHdG levels compared with treatment groups (p < 0.05). Silymarin-treated group significantly increased the SOD activity and GSH amount in the liver tissue compared with the cisplatin-treated group (p < 0.05). Gallic acid significantly increased CAT activity compared with the cisplatin-treated group (p < 0.05). It was determined that the cisplatin-treated group significantly decreased CAT and SOD activity compared with the control group (p > 0.05). Gallic acid showed a significant increase in CAT and SOD activity in kidney tissue compared with the cisplatin-treated group (p < 0.05). Conclusion: As a result, it was observed that gallic acid silymarin had a protective effect on cisplatin-induced nephrotoxic and hepatotoxic effects.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Silimarina , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Cisplatino/metabolismo , Cisplatino/toxicidade , Ácido Gálico/metabolismo , Ácido Gálico/farmacologia , Ácido Gálico/uso terapêutico , Glutationa/metabolismo , Glutationa/farmacologia , Humanos , Rim , Estresse Oxidativo , Ratos , Ratos Wistar , Silimarina/metabolismo , Silimarina/farmacologia , Superóxido Dismutase/metabolismo , Superóxido Dismutase/farmacologia
9.
Artigo em Inglês | MEDLINE | ID: mdl-35697282

RESUMO

Pharmaceuticals and personal care products are emerging environmental pollutants. Cisplatin, one of the most widely used platinum-based chemotherapeutic agents, has been found to contaminate aquatic environments. Using zebrafish embryos as a model, cisplatin was previously found to impair skin ionocytes and ion regulation. The purpose of this study was to further investigate how cisplatin damages ionocytes. Zebrafish embryos were exposed to cisplatin (0, 50, and 100 µM) for 96 h (4-100 h post-fertilization) and then stained with fluorescent dyes to reveal mitochondrial activity (rhodamine123), apoptosis (acridine orange), and oxidative stress (CellROX/MitoSOX) in ionocytes of living embryos. Results showed that cisplatin exposure decreased rhodamine 123-labeled ionocytes, induced oxidative stress in ionocytes, and promoted apoptosis in a concentration-dependent manner. Quantitative PCR analysis showed that mRNA levels of antioxidative genes (sod1, sod2, gpx1a, and cat) and an apoptotic gene (caps3a) were induced. In the time-course experiment at 96-98 h post-fertilization, cisplatin increased oxidative stress and apoptosis in ionocytes in a time-dependent manner. In conclusion, this study demonstrates that cisplatin exposure induces oxidative stress, mitochondrial damage, and apoptosis in ionocytes of zebrafish embryos.


Assuntos
Poluentes Químicos da Água , Peixe-Zebra , Animais , Apoptose/genética , Cisplatino/metabolismo , Cisplatino/toxicidade , Embrião não Mamífero/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo/genética , Poluentes Químicos da Água/metabolismo , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/genética
10.
Life Sci ; 304: 120677, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35654117

RESUMO

AIMS: In this study we evaluated the effect of pharmacological treatment with AnxA1-derived peptide Ac2-26 in an experimental model of toxicity induced by cisplatin. MAIN METHODS: Male rats were divided into Sham (control), Cisplatin (received intraperitoneal injections of 10 mg/kg/day of cisplatin for 3 days) and Ac2-26 (received intraperitoneal injections of 1 mg/kg/day of peptide, 15 min before cisplatin) groups. KEY FINDINGS: After 6 h of the last dose of cisplatin, an acute inflammatory response was observed characterized by a marked increase in the number of neutrophils and GM-CSF, IL-ß, IL-6, IL-10 and TNF-α plasma levels. These findings were associated with increased AnxA1 protein levels in liver and kidneys, as well as positive AnxA1/Fpr2 circulating leukocytes. Treatment with Ac2-26 produced higher levels of GM-CSF, corroborating the high numbers of neutrophils, and the anti-inflammatory cytokine IL-4. Ac2-26 preserved the morphology of liver structures and increased Fpr1 expression, preventing the damage caused by cisplatin. In the kidneys, Ac2-26 caused downregulation of renal Fpr1 and Fpr2 levels and abrogated the increased levels of the CLU and KIM-1 biomarkers of kidney damage induced by cisplatin. However, no effect of peptide treatment was detected in cisplatin-induced kidney morphology injury. SIGNIFICANCE: Despite activation of the anti-inflammatory AnxA1/Fpr axis during cisplatin administration, treatment with Ac2-26 did not efficiently prevent its deleterious effects on the liver and kidneys.


Assuntos
Anexina A1 , Animais , Anexina A1/química , Anexina A1/metabolismo , Anexina A1/farmacologia , Anti-Inflamatórios/farmacologia , Cisplatino/metabolismo , Cisplatino/toxicidade , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Rim/metabolismo , Fígado/metabolismo , Masculino , Peptídeos/química , Ratos
11.
Cells ; 11(9)2022 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-35563891

RESUMO

The immunophilin FKBP51, the angiomotin AmotL2, and the scaffoldin IQGAP1 are overexpressed in many types of cancer, with the highest increase in leucocytes from patients undergoing oxaliplatin chemotherapy. Inflammation is involved in the pathogenesis of nephrotoxicity induced by platinum analogs. Cilastatin prevents renal damage caused by cisplatin. This functional and confocal microscopy study shows the renal focal-segmental expression of TNFα after cisplatin administration in rats, predominantly of tubular localization and mostly prevented by co-administration of cilastatin. FKBP51, AmotL2 and IQGAP1 protein expression increases slightly with cilastatin administration and to a much higher extent with cisplatin, in a cellular- and subcellular-specific manner. Kidney tubule cells expressing FKBP51 show either very low or no expression of TNFα, while cells expressing TNFα have low levels of FKBP51. AmotL2 and TNFα seem to colocalize and their expression is increased in tubular cells. IQGAP1 fluorescence increases with cilastatin, cisplatin and joint cilastatin-cisplatin treatment, and does not correlate with TNFα expression or localization. These data suggest a role for FKBP51, AmotL2 and IQGAP1 in cisplatin toxicity in kidney tubules and in the protective effect of cilastatin through inhibition of dehydropeptidase-I.


Assuntos
Cilastatina , Cisplatino , Angiomotinas , Animais , Proteínas de Transporte/metabolismo , Cilastatina/metabolismo , Cilastatina/farmacologia , Cilastatina/uso terapêutico , Cisplatino/metabolismo , Cisplatino/toxicidade , Humanos , Ratos , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo
12.
Toxicol Lett ; 363: 27-35, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35561849

RESUMO

Cisplatin is an antineoplastic agent widely used, and no effective treatments capable of preventing cisplatin-induced ototoxicity and neurotoxicity in humans have yet been identified. This study evaluated the effect of the anti-inflammatory annexin A1 (AnxA1)-derived peptide Ac2-26 in a cisplatin-induced ototoxicity model. Wistar rats received intraperitoneal injections of cisplatin (10 mg/kg/day) for 3 days to induce hearing loss, and Ac2-26 (1 mg/kg) was administered 15 min before cisplatin administration. Control animals received an equal volume of saline. Hearing thresholds were measured by distortion product otoacoustic emissions (DPOAE) before and after treatments. Pharmacological treatment with Ac2-26 protected against cisplatin-induced hearing loss, as evidenced by DPOAE results showing similar signal-noise ratios between the control and Ac2-26-treated groups. These otoprotective effects of Ac2-26 were associated with an increased number of ganglion neurons compared with the untreated cisplatin group. Additionally, Ac2-26 treatment produced reduced immunoreactivity on cleaved caspase 3 and phosphorylated ERK levels in the ganglion neurons, compared to the untreated group, supporting the neuroprotective effects of the Ac2-26. Our results suggest that Ac2-26 has a substantial otoprotective effect in this cisplatin-induced ototoxicity model mediated by neuroprotection and the regulation of the ERK pathway.


Assuntos
Anexina A1 , Antineoplásicos , Perda Auditiva , Ototoxicidade , Animais , Anexina A1/farmacologia , Antineoplásicos/toxicidade , Cisplatino/toxicidade , Perda Auditiva/induzido quimicamente , Perda Auditiva/prevenção & controle , Emissões Otoacústicas Espontâneas , Ototoxicidade/prevenção & controle , Peptídeos/farmacologia , Ratos , Ratos Wistar
13.
Acta Cir Bras ; 37(2): e370208, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35507972

RESUMO

PURPOSE: The present study explored the role of melatonin in cisplatin-induced cardiac injury along with the possible role of brain-derived neurotrophic factor (BDNF) in melatonin-mediated effects. METHODS: Wistar rats were administered cisplatin (10 mg/kg), and cardiac injury was assessed by measuring the levels of cardiac troponin (cTnT) and lactate dehydrogenase (LDH-1).The extent of apoptosis was measured by measuring caspase-3 (pro-apoptotic) and Bcl-2 (anti-apoptotic) in hearts. The levels of BDNF, tumour necrosis factor α (TNF-α) and reduced glutathione were measured in heart. Melatonin (5 and 10 mg/kg) was administered for 15 days, and the role of BDNF was identified by co-administering BDNF inhibitor, ANA-12 (0.25 and 0.5 mg/kg). RESULTS: Melatonin attenuated cTnT and LDH-1 levels along with reduction in caspase-3 and increase in Bcl-2. It also increased cisplatin-induced decrease in BDNF, increase in TNF-α and decrease in reduced glutathione levels. Moreover, ANA-12 abolished the cardioprotective effects, anti-inflammatory and antioxidant effects of melatonin suggesting the role of BDNF in melatonin-mediated effects in cisplatin-induced cardiac injury. CONCLUSIONS: Melatonin is useful in cisplatin-induced cardiac injury, which may be due to an increase in BDNF, decrease in inflammation and increase in antioxidant activities.


Assuntos
Melatonina , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Apoptose , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Caspase 3/metabolismo , Cisplatino/toxicidade , Glutationa/metabolismo , Melatonina/farmacologia , Melatonina/uso terapêutico , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
14.
J Vis Exp ; (182)2022 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-35532272

RESUMO

Metals and metal-based compounds comprise multifarious pharmaco-active and toxicological xenobiotics. From heavy metal toxicity to chemotherapeutics, the toxicokinetics of these compounds have both historical and modern-day relevance. Zebrafish have become an attractive model organism in elucidating pharmaco- and toxicokinetics in environmental exposure and clinical translation studies. Although zebrafish studies have the benefit of being higher-throughput than rodent models, there are several significant constraints to the model. One such limitation is inherent in the waterborne dosing regimen. Water concentrations from these studies cannot be extrapolated to provide reliable internal dosages. Direct measurements of the metal-based compounds allow for a better correlation with compound-related molecular and biological responses. To overcome this limitation for metals and metal-based compounds, a technique was developed to digest zebrafish larval tissue after exposure and quantify metal concentrations within tissue samples by inductively coupled plasma mass spectrometry (ICPMS). ICPMS methods were used to determine the metal concentrations of platinum (Pt) from cisplatin and ruthenium (Ru) from several novel Ru-based chemotherapeutics in zebrafish tissue. Additionally, this protocol distinguished concentrations of Pt that were sequestered in the chorion of the larval compared with the zebrafish tissue. These results indicate that this method can be applied to quantitate the metal dose present in larval tissues. Further, this method may be adjusted to identify specific metals or metal-based compounds in a broad range of exposure and dosing studies.


Assuntos
Rutênio , Animais , Cisplatino/toxicidade , Larva , Espectrometria de Massas/métodos , Platina , Peixe-Zebra/fisiologia
15.
Sci Rep ; 12(1): 8125, 2022 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-35581281

RESUMO

Chemotherapy-induced peripheral neuropathy is a neurological complication that frequently occurs during chemotherapeutic intervention, resulting in damaged myelin sheath, motor weakness and/or sensory impairment. This study aims to investigate the therapeutic efficiency of low-intensity pulsed low-frequency ultrasound on cisplatin-induced peripheral neuropathy. Rats were randomly divided into five experimental groups as control, cisplatin administration, 10 mg/kg melatonin treatment after cisplatin administration, 1 MHz frequency 0.5 W/cm2 pulsed ultrasound treatment after cisplatin administration and 1 MHz frequency 1.5 W/cm2 pulsed ultrasound treatment after cisplatin administration. Chemical neuropathy was induced by the injection of 3 mg/kg/week of cisplatin (i.p.) for 5 weeks. Afterwards, melatonin and pulsed ultrasound treatments were applied for 15 consecutive days. Cisplatin administration resulted in a decrease in nociceptive pain perception and nerve conduction velocities together with a decrease in myelin thickness and diameters of axons and myelinated fibers, indicating a dysfunction and degeneration in sciatic nerves. In addition, cisplatin administration led to a decrease, in superoxide dismutase activity, and an increase in malondialdehyde and IL-1ß levels together with an increase in caspase-3 protein expression levels and a decrease in Bcl-2 and Parkin levels. The ultrasound treatments resulted in an increase in nociceptive pain perception and sciatic nerve conduction; led to a decrease in oxidative stress and inflammation, restored nerve degeneration and regulated apoptosis and mitophagy. Taken together, low-intensity pulsed low-frequency ultrasound was efficient in restoring the alterations attributable to cisplatin-induced peripheral neuropathy, and warrants further investigations.


Assuntos
Melatonina , Dor Nociceptiva , Doenças do Sistema Nervoso Periférico , Neuropatia Ciática , Animais , Cisplatino/metabolismo , Cisplatino/toxicidade , Melatonina/metabolismo , Dor Nociceptiva/metabolismo , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/terapia , Ratos , Ratos Wistar , Nervo Isquiático/metabolismo , Neuropatia Ciática/metabolismo , Ondas Ultrassônicas
16.
FASEB J ; 36(6): e22373, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35621716

RESUMO

Cisplatin is a widely used chemotherapeutic agent. However, its clinical utility is limited because of cisplatin-induced ototoxicity. Glutathione S-transferase (GST) was found to play a vital role in reducing cisplatin ototoxicity in mice. Deletion polymorphisms of GSTM1 and GSTT1, members of the GST family, are common in humans and are presumed to be associated with cisplatin-induced hearing impairment. However, the specific roles of GSTM1 and GSTT1 in cisplatin ototoxicity are not completely clear. Here, under cisplatin treatment, simultaneous deletion of Gstm1 and Gstt1 lead to a more profound hearing loss in CBA/CaJ mice (Gstm1/Gstt1-DKO) than in wild-type mice. The Gstm1/Gstt1-DKO mice, in which phase II detoxification genes were upregulated, exhibited more severe oxidative stress and higher outer hair cell apoptosis in the cochleae than the control mice. Thus, our study revealed that Gstm1 and Gstt1 protect auditory hair cells from cisplatin-induced ototoxicity in the CBA/CaJ mice, and genetic screening for GSTM1 and GSTT1 polymorphisms could help determine a standard cisplatin dose for cancer patients undergoing chemotherapy.


Assuntos
Cisplatino , Glutationa Transferase , Ototoxicidade , Animais , Cisplatino/toxicidade , Glutationa Transferase/genética , Humanos , Camundongos , Camundongos Endogâmicos CBA , Camundongos Endogâmicos , Ototoxicidade/etiologia , Ototoxicidade/genética , Ototoxicidade/prevenção & controle , Polimorfismo Genético
17.
Cell Stress Chaperones ; 27(4): 325-336, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35366755

RESUMO

Acute kidney injury (AKI) induced by cisplatin (cis-AKI) involves indicators such as inflammation and oxidative stress (OS) in proximal tubules, although its underlying mechanisms remain largely unknown so far. Exploration of the molecular mechanisms underlying cisplatin-induced AKI is of great significance for AKI prevention and also for preventing its progression into chronic kidney disease (CKD) or end-stage renal disease (ESRD). OS and ferroptosis are mutually causal; they finally lead to the regulatory cell injury and death induced by the accumulation of reactive oxygen species (ROS). GPX4 is critical not only in OS, but studies established as the key regulator of ferroptosis. In this context, the present study focused on determining the biological function of miR-214-3p in the cisplatin-induced ferroptosis of tubular epithelial cell (TEC) and the underlying molecular mechanism. The relationship between TEC ferroptosis and cisplatin-induced AKI was investigated in vitro and in vivo. Ferrostatin-1(Fer-1), an inhibitor of ferroptosis, was observed to confer a protective effect against the renal tubular injury and renal failure induced by cisplatin. MicroRNAs (miRNAs) regulate the genes that have important functions in the development of cis-AKI. In the present study, GPX4 was predicted as a target of miR-214-3p. Moreover, inhibiting miR-214-3p enhanced the expressions of GPX4 and SLC7A11 while decreasing the ACSL4 expression. Furthermore, miR-214-3p down-regulation protected against TEC death and renal tubule damage both in vitro and in vivo. According to these findings, inhibiting miR-214-3p would alleviate TEC ferroptosis in cis-AKI via GPX4.


Assuntos
Injúria Renal Aguda , Ferroptose , MicroRNAs , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/genética , Animais , Cisplatino/toxicidade , Túbulos Renais Proximais/metabolismo , Camundongos , MicroRNAs/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética
18.
J Biochem Mol Toxicol ; 36(7): e23075, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35451207

RESUMO

Cisplatin (Cis) is a chemotherapeutic agent that has many side effects. Neurotoxicity is one of the most important of these side effects. Oxidative stress and neuroinflammation are the best-known mechanisms in the pathogenesis of neurotoxicity development. In this study, we aimed to determine whether melatonin (Mel), with antioxidant and anti-inflammatory effects, is effective in preventing Cis-induced neurotoxicity. Forty-eight male Sprague-Dawley rats were divided into six groups (n = 8) as follows: control (0.9% NaCl), vehicle (5% ethanol), Cis (6 mg/kg), Cis (6 mg/kg) + vehicle (5% ethanol), Mel (20 mg/kg), and Cis (6 mg/kg) + Mel (20 mg/kg) groups. Cis was administered as a single dose on the 3rd day of the experiment while Mel was given for 5 days. All administrations were performed via intraperitoneal injection. After injections, T-maze, rotarod, and hot plate tests were performed to evaluate cognitive, motor, and sensory functions, respectively. Following sacrification oxidative stress markers, cholinergic function, and proinflammatory cytokines were studied from brain homogenates. Cis impaired cognitive function and motor performance in the Cis and Cis+Vehicle groups. The drug also increased oxidative stress in the brain. Mel significantly improved brain oxidant/antioxidant status and also decreased the overproduction of proinflammatory cytokines (superoxide dismutase activities in Cis+Vehicle and Cis+Mel groups: 104.55 ± 9.50 µU/mg protein vs. 150.13 ± 4.70 µU/mg protein, respectively, p < 0.05; tumor necrosis factor-α levels in Cis and Cis+Mel groups: 40 pg/ml vs. 20 pg/ml, respectively, p < 0.05). It seems that Mel can improve Cis neurotoxicity. For a more firm conclusion, further studies using Mel at different doses with larger groups should be performed.


Assuntos
Encéfalo , Cisplatino , Melatonina , Animais , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Cisplatino/toxicidade , Citocinas , Etanol , Masculino , Melatonina/farmacologia , Melatonina/uso terapêutico , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley
19.
Food Chem Toxicol ; 163: 112970, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35367536

RESUMO

The present study focused on the protective effects of melatonin against cisplatin-induced acute kidney injury in mice and its possible mechanism of action in relation to the major regulator of fatty acid oxidation (FAO), peroxidase proliferative receptor α (PPARα). The experiment consisted of the following four groups: vehicle control, cisplatin (15 mg/kg), cisplatin & melatonin (20 mg/kg/day), and melatonin (20 mg/kg/day). Concomitant administration of melatonin significantly ameliorated cisplatin-induced acute kidney injury in mice by decreasing serum levels of triglyceride, blood urea nitrogen and creatinine, reducing the number and size of lipid droplets in tubular epithelial cells, and decreasing the incidence of histopathological changes including tubular cell apoptosis. Moreover, melatonin administration protected kidney tissue by significantly upregulating the levels of PPARα reduced by cisplatin injection, resulting in increased FAO pathway-associated genes (PGC-1a, Acadm, Acat1, Acsm2, Acsm3, Bdh2, Echs and Pecr) as well as reducing protein levels of caspase-3, -9 and Bax. Melatonin not only partially modulated FAO via PPARα signaling, but also decreased cisplatin-induced apoptosis by inhibiting the caspase-3, -9 and Bax pathways. Our findings suggest that melatonin prevents cisplatin-induced acute kidney injury in mice, possibly by upregulating the expression of PPARα, resulting in enhanced FAO and anti-apoptotic properties.


Assuntos
Injúria Renal Aguda , Melatonina , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/prevenção & controle , Animais , Apoptose , Caspase 3/metabolismo , Cisplatino/metabolismo , Cisplatino/toxicidade , Ácidos Graxos/metabolismo , Feminino , Humanos , Hidroxibutirato Desidrogenase/metabolismo , Hidroxibutirato Desidrogenase/farmacologia , Rim , Masculino , Melatonina/farmacologia , Camundongos , PPAR alfa/genética , PPAR alfa/metabolismo , Proteína X Associada a bcl-2/metabolismo
20.
J Biochem Mol Toxicol ; 36(7): e23068, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35403300

RESUMO

Since the discovery of calbindin release into the urine during renal injury, there has been growing interest in the utility of this protein as a biomarker of nephrotoxicity. However, little is known about the intrarenal regulation of the release and expression of this calcium-regulating protein during kidney injury. We sought to characterize the time-dependent expression and excretion of the protein calbindin in the distal tubule in comparison to kidney injury molecule-1 (Kim-1), a protein in the proximal tubule, in mice treated with cisplatin. Urine, blood, and kidneys were collected from male C57BL/6 mice treated with vehicle or cisplatin (20 mg/kg ip). Urinary concentrations of calbindin and Kim-1 were elevated by 11.6-fold and 2.5-fold, respectively, within 2 days after cisplatin. Circulating creatinine and blood urea nitrogen levels increased in cisplatin-treated mice by 3 days, confirming the development of acute kidney injury. Time-dependent decreases in intrarenal calbindin protein were observed on Days 3 and 4 and a 200-fold upregulation of calbindin (CALB1) and KIM-1 messenger RNAs (mRNAs) was observed on Day 3. These data suggest that early loss of calbindin protein into the urine along with declines in renal calbindin levels initiates a compensatory induction of mRNA expression at later time points (Days 3 and 4). Understanding the regulation of calbindin during cisplatin nephrotoxicity further enhances its utility as a potential urinary biomarker of kidney damage. The results of the current study support the combined use of a proximal (Kim-1) and distal tubule (calbindin) marker to phenotype acute kidney injury secondary to cisplatin administration.


Assuntos
Injúria Renal Aguda , Antineoplásicos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Animais , Antineoplásicos/efeitos adversos , Biomarcadores/metabolismo , Calbindinas/metabolismo , Cisplatino/toxicidade , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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