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1.
Life Sci ; 266: 118869, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33309722

RESUMO

AIM: Cisplatin (Cis) is widely used chemotherapeutic and has some serious side effects as nephrotoxicity. Phloretin (PH) and Phloridzin (PZ) are known their anti-oxidant anti-inflammatory effects. We aimed to examine the protective effects of PH and PZ on cisplatin-induced nephrotoxicity. MAIN METHODS: Totally, 48 Balb/C female mice were separated into eight groups (n = 6). First day, single dose of cisplatin (20 mg/kg intraperitoneal) was administered to induce toxicity. PH and PZ were given (50 and 100 mg/kg orally) to treatment groups during 3 days. After the experimental procedures serum renal function enzymes (BUN and Creatinine), oxidative parameters (SOD, GSH and MDA), nuclear agent NFKß, inflammatory cytokines (Tnf-α and IL1ß) and HSP70 expressions and histopathological assessments were analyzed. KEY FINDINGS: Serum enzymes, tissue cytokines and oxidative stress were increased after the Cis treatment. PH and PZ treatments normalized all parameters compared to Cis administrated group. After the treatments, SOD activities and GSH levels were increased while MDA levels were decreased. PH and PZ treatments decreased Tnf-α, IL1ß and NFKß mRNA expressions. Cis significantly increased the HSP70 expression while PH and PZ administrations significantly decreased. Similar the biochemical and molecular results, PH and PZ showed positive effects on tissue pathological parameters. Cisplatin cause a lot of abnormal structures as tubular and glomeruli damages on the kidney. SIGNIFICANCE: PH and PZ play important physiological roles in the prevention of nephrotoxicity. Antioxidant and anti-inflammatory effects of PH and PZ demonstrated visible protective effects in the cisplatin-induced nephrotoxicity model.


Assuntos
Cisplatino/toxicidade , Regulação da Expressão Gênica , Inflamação/tratamento farmacológico , Nefropatias/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Floretina/farmacologia , Florizina/farmacologia , Animais , Antineoplásicos/toxicidade , Feminino , Inflamação/patologia , Nefropatias/induzido quimicamente , Nefropatias/patologia , Testes de Função Renal , Camundongos , Camundongos Endogâmicos BALB C
2.
Life Sci ; 266: 118880, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33310039

RESUMO

AIMS: Cisplatin (CP) is an antineoplastic widely used in the treatment of various solid tumors, however, its clinical application is limited by nephrotoxicity. Here, we compared the impact of preconditioning with high-intensity interval training (HIIT) with continuous training of low (LIT) and moderate (MIT) intensity on innate immunity markers in female rats with CP-induced acute kidney injury. MATERIALS AND METHODS: The rats were divided into five groups (n = 7): saline control and sedentary (C + S); CP and sedentary (CP + S); CP and LIT (CP + LIT); CP and MIT (CP + MIT) and CP and HIIT (CP + HIIT). The training intensity was determined by a maximum running test. At the end of training, the rats received a single dose of CP (5 mg/kg), and 7 days later they were euthanized. We evaluated renal function parameters (serum creatinine, glomerular filtration rate and proteinuria), renal structure, macrophage tissue infiltration, immunolocalization of nuclear transcription factor kappa B (NF-κB), renal levels of tumor necrosis factor-alpha (TNF-α), interleukin 1ß (IL-1ß), and interleukin 6 (IL-6), and gene expression of monocyte chemoattractant protein-1 (MCP-1), toll-like receptor 4 (TLR4), and NF-κB in renal tissue. KEY FINDINGS: Although both MIT and HIIT attenuated the degree of renal injury, only the HIIT prevented changes in renal function. The three training protocols mitigated the increase in expression of all inflammatory markers, however, this effect was more pronounced in HIIT. SIGNIFICANCE: All training protocols promoted renoprotective actions, but HIIT was more effective in mitigating CP-induced acute kidney injury, in part by modulation of important markers of the innate immune response.


Assuntos
Biomarcadores/metabolismo , Cisplatino/toxicidade , Treinamento Intervalado de Alta Intensidade , Mediadores da Inflamação/metabolismo , Inflamação/tratamento farmacológico , Nefropatias/prevenção & controle , Condicionamento Físico Animal , Animais , Antineoplásicos/toxicidade , Feminino , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Nefropatias/induzido quimicamente , Nefropatias/patologia , Ratos , Ratos Wistar
3.
Mutat Res ; 856-857: 503232, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32928372

RESUMO

miR-34a has been identified as a tumor suppressor microRNA (miRNA) involved in the P53 network. Its expression levels correlate to carcinogenesis, which are generally lower in tumor tissue and higher in response to DNA damage. In this study, the response of miR-34a from exposure to genotoxic agents in human lymphoblastoid TK6 cells was evaluated to assess whether the expression of this miRNA could be used as an early indicator for genotoxic damage in mammalian cells. TK6 cells were treated with seven genotoxic agents with different mode-of-actions (cisplatin, N-ethyl-N-nitrosourea, etoposide, mitomycin C, methyl methanesulphonate, taxol, and X-ray radiation) and a non-genetic toxin (usnic acid) at different concentrations for four hours (except for X-rays) and the expression levels of miR-34a were measured 24 h after the beginning of the treatments. The expression levels of miR-34a were significantly increased by these genetic toxins in a dose-dependent manner, while no significant change in miRNA expression was found in the usnic acid-treated cells. These results suggest that miR-34a can respond to genotoxic insults sensitively; thus, miR-34a expression has the potential to be used to evaluate genotoxicity of agents.


Assuntos
Carcinogênese/genética , Dano ao DNA/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Carcinogênese/efeitos dos fármacos , Cisplatino/farmacologia , Cisplatino/toxicidade , Etilnitrosoureia/farmacologia , Etoposídeo/farmacologia , Etoposídeo/toxicidade , Genes Supressores de Tumor , Humanos , Mutagênicos/farmacologia , Mutagênicos/toxicidade
4.
Toxicol Lett ; 334: 36-43, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32941993

RESUMO

Cisplatin is a widely used chemotherapeutic agent. However, it is causing nephrotoxic side effects including a reduced glomerular filtration rate and acute kidney injury. Although kidneys can recover to an extent from the treatment, long-term damage is possible. While a lot of research is focusing on short-term effects, little is known about adverse metabolic effects in the process of recovery. In this study, male Han Wistar rats were dosed with a single intraperitoneal injection of 3 mg/kg cisplatin. Urine and kidney samples were harvested 3, 8 and 26 days after administration. Tubular injury was demonstrated through urinary biomarkers. Complementing this, mass spectrometry imaging gives insight on molecular alterations on a spatial level, thus making it well suited to analyze short- and long-term disturbances. Various metabolic pathways seem to be affected, as changes in a wide range of metabolites were observed between treated and control animals. Besides previously reported early changes in kidney metabolism, unprecedented long-term effects were detected including deviation in nucleotides, antioxidants, and phospholipids.


Assuntos
Antineoplásicos/toxicidade , Antioxidantes/metabolismo , Cisplatino/toxicidade , Metabolismo Energético/efeitos dos fármacos , Rim/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Injeções Intraperitoneais , Rim/metabolismo , Rim/patologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Masculino , Ratos Wistar , Fatores de Tempo
5.
Chem Biol Interact ; 331: 109233, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32991863

RESUMO

Cisplatin (cis-Dichlorodiammine platinum, CP), as the first-line chemotherapy drug of choice for many cancers such as urogenital system tumors and digestive tract tumors, also causes toxicity and side effects to the kidney. Previous studies have shown that Pulsatilla chinensis has significant anti-inflammatory and antioxidant activities, but the mechanism of cisplatin induced acute kidney injury (AKI) in vivo has not been thoroughly studied. The purpose of this study is to investigate the protective effect of pulchinenoside B4 (PB4), a representative and major component with a content of up to 10% in root of P. chinensis, on AKI induced by CP in mice. Our results indicated the significant protective effect of PB4 by evaluating renal function indicators, inflammatory factor levels and renal histopathological changes. In addition, PB4 may mainly act on NF-κB signaling pathway to reduce the levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) in the kidney after CP exposure, thus exerting anti-inflammatory activity. Furthermore, PB4 regulated MAPK signaling pathway and its downstream apoptotic factors to inhibit the occurrence of apoptosis, such as Bax, Bcl-2, caspase 3 and caspase 9. Notably, the activations of caspase 3 induced by cisplatin were strikingly reduced in PB4-treated mice. Therefore, the above evidence suggested that PB4 is a potential renal protectant with significant anti-inflammatory and anti-apoptotic effects.


Assuntos
Lesão Renal Aguda/patologia , Apoptose/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/veterinária , Animais , Cisplatino/toxicidade , Modelos Animais de Doenças , Interleucina-1beta/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Fosforilação , Substâncias Protetoras/química , Fator de Necrose Tumoral alfa/metabolismo
6.
Chem Biol Interact ; 330: 109234, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32860823

RESUMO

Cisplatin is an antineoplastic drug well recognized for its success in the battle against several types of cancer in adult, juvenile, and child populations. Meanwhile, this drug is also famous due to its serious side effects, such as hepatotoxicity. This study evaluated the hepatoprotective effectiveness of Diphenyl Diselenide (PhSe)2 and Ebselen in a model of cisplatin-induced toxicity in juvenile rats. Juvenile Wistar rats received a single intraperitoneal (i.p) injection of cisplatin (6 mg/kg) or saline solution, at postnatal day (PND) 21. Ebselen (11 mg/kg) or (PhSe)2 (12 mg/kg) was intragastrically (i.g) administered in rats from PND 21 to PND 25. At PND 26, the blood and liver were collected for the biochemistry assays. A single administration of cisplatin was enough to alter the makers of hepatic function (an increase of AST activity) and the blood lipid profile (an increase of cholesterol and triglycerides, TG). The cisplatin-induced metabolic disruption was demonstrated by the increase of hepatic glycogen and TG contents and hexokinase, glucose-6-phosphatase, and tyrosine aminotransferase activities; a decrease of citrate synthase activity and the levels of GLUT-2. Cisplatin-induced hepatic oxidative stress was characterized by an increase in reactive oxygen species, TBARS, protein carbonyl, and Nox levels as well as the decrease in NPSH levels. Ebselen and (PhSe)2 were effective against all alterations caused by this chemotherapy medication. The present findings highlight the (PhSe)2 and Ebselen similar hepatoprotective effectiveness against cisplatin-induced disruption of metabolic homeostasis and redox balance in juvenile rats.


Assuntos
Azóis/farmacologia , Derivados de Benzeno/farmacologia , Cisplatino/toxicidade , Homeostase/efeitos dos fármacos , Fígado/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Substâncias Protetoras/farmacologia , Animais , Lipídeos/sangue , Fígado/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos
7.
Life Sci ; 258: 118242, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32784056

RESUMO

AIMS: As the spermatogenesis process is targeted by cisplatin (Cis) that changes testicular morphology, alters sperm quality, and hence causes male infertility. This study investigated the possible therapeutic effects of l-carnitine (LC) on Cis impaired spermatogenesis's establishment during the prepubertal phase. MATERIALS AND METHODS: Ninety-six prepubertal Sprague Dawley male rats were divided into four groups. CONTROL GROUP: rats were injected with 0.9% saline solution intraperitoneally (i.p.). LC group: animals were injected for eight weeks, with 250 mg/kg/wk. LC (i.p.). Cis group: animals were injected with a single dose of 5 mg/kg Cis (i.p.). LC + Cis group: animals were pre-injected with LC 250 mg/kg 2 h before Cis injection. The rats were sacrificed at 37, 60, and 90 days old, and their testes were taken for biochemical, molecular, and histopathological studies. The motility, viability, morphology, and DNA fragmentation of sperm in adult rats were also measured. KEY FINDINGS: Group treated with LC and Cis showed an increase in antioxidant and hormonal activity compared to the Cis treated group in the pre and post-pubertal period. Moreover, there was an increase in sperm survival, motility, and DNA integrity. Furthermore, LC showed an increase in the anti-apoptotic and chromatin remodeling genes and a decrease in the pro-inflammatory genes. SIGNIFICANCE: LC could enhance the spermatogenesis process after exposure to Cis during the prepubertal phase by restoring the balance between reactive oxygen species and antioxidant activity, improving hormonal activity, sperm quality and DNA integrity, promoting protamination and blood-testis barrier integrity, and maintaining the testicular architecture.


Assuntos
Carnitina/farmacologia , Cisplatino/toxicidade , Infertilidade Masculina/prevenção & controle , Infertilidade Masculina/fisiopatologia , Maturidade Sexual/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Animais , Antineoplásicos/toxicidade , Carnitina/uso terapêutico , Infertilidade Masculina/induzido quimicamente , Masculino , Ratos , Ratos Sprague-Dawley , Maturidade Sexual/fisiologia , Motilidade Espermática/efeitos dos fármacos , Motilidade Espermática/fisiologia , Espermatogênese/fisiologia
8.
Environ Sci Pollut Res Int ; 27(35): 44412-44426, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32767013

RESUMO

Cisplatin (CP) is a highly effective chemotherapeutic agent against neoplasms, but its clinical utility is limited due to the side effects of its dose-dependent nephrotoxicity. Vitamin E (Vit E) and cod liver oil (CLO) are natural substances with chemoprotective effects. The present study was conducted to evaluate the protective effects of Vit E and/or CLO for CP-induced acute kidney injury (AKI) in rats. This study involved 40 mature male Wistar albino rats that were equally allocated into eight groups: Veh, Vit E, CLO, Vit E + CLO, CP, Vit E + CP, CLO + CP, and Vit E + CLO + CP. The co-administration of Vit E and CLO significantly ameliorated CP-induced elevations in serum creatinine (Cr), blood urea nitrogen (BUN), interleukin 1 beta (IL-1ß), and interleukin- 6 (IL-6). Further, rats that received Vit E and/or CLO showed significant decrease in malondialdehyde (MDA) and increases in superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels in renal tissues, compared to CP-intoxicated rats. Additionally, the treatment restored the normal histological architecture (except for few cast formations) and upregulated the immunostaining area% of aquaporin 3 (AQP3) and downregulated the immunostaining area% of Bcl2 associated X protein (BAX) and inducible nitric oxide synthase (iNOS). The observed effects were stronger in the combination treatment group. The obtained data revealed that Vit E and CLO co-administration protects against the CP-induced AKI more than monotherapy with Vit E or CLO.


Assuntos
Lesão Renal Aguda , Cisplatino , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/prevenção & controle , Animais , Antioxidantes/metabolismo , Cisplatino/toxicidade , Óleo de Fígado de Bacalhau/metabolismo , Rim/metabolismo , Masculino , Estresse Oxidativo , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Vitamina E/metabolismo , Vitamina E/farmacologia
9.
Environ Sci Pollut Res Int ; 27(33): 41540-41550, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32691312

RESUMO

Cisplatin is broadly used in the treatment of malignancies. However, the high incidence of nephrotoxicity following cisplatin use deters its clinical utility. Former studies have shown that the essential oils, obtained from Citrus limonia demonstrated significant anti-inflammatory and antioxidant effects. The aim of the current work was to evaluate the protective effects of Citrus limonia oil against cisplatin-induced nephrotoxicity. Thirty-two adult male mice were divided into four groups, eight mice each. The control group received distilled water, and the second group received a single intraperitoneal injection of cisplatin (20 mg/kg), while the third and fourth groups received cisplatin plus Citrus limonia oil at 100 or 200 mg/kg for 10 days, respectively. GC-MS analysis showed that the major components in Citrus limonia oil were D-limonene, 5-methyl-pentadecane, (n)-menthol, 3,7-dimethyl-(E)-2,6-octadienal, 3,7-dimethyl-2,6-octadienal, and nonadecane. Biochemical analysis showed that cisplatin intoxication was associated with significantly increased (p < 0.05) serum levels of urea and creatine and pro-inflammatory cytokines, as well as augmented renal tissue oxidative stress. Light microscopic examination showed loss of renal architecture, atrophied glomeruli, interstitial hemorrhage, dilated cortical tubules with cast formation, and excessive collagen production. Electron microscopic examination revealed compressed and karyorrhectic endothelial nuclei with chromatin condensation in the glomeruli, accumulation of mesangial matrix, and obliteration of glomerular blood capillaries. Co-administration of Citrus limonia oil attenuated these effects in renal histopathological, morphometric, and ultrastructural examinations, frequently in a dose-dependent manner. In conclusion, Citrus limonia oil can ameliorate the toxic effect of cisplatin on mice kidneys, probably through its antioxidant and anti-inflammatory effects.


Assuntos
Cisplatino , Citrus , Animais , Antioxidantes/metabolismo , Cisplatino/toxicidade , Creatinina/metabolismo , Rim/metabolismo , Masculino , Camundongos , Estresse Oxidativo
10.
J Craniofac Surg ; 31(5): e506-e509, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32541270

RESUMO

Cisplatin, a pharmacological agent widely used for treating many cancers, may cause serious side effects including ototoxicity, nephrotoxicity, and peripheral neuropathy. The present study aimed to investigate whether platelet-rich plasma (PRP) protects against cisplatin ototoxicity. Eight rats (16 ears) were divided into 2 groups: control group (4 rats, 8 ears) that received intratympanic saline and study group (4 rats, 8 ears) that received intratympanic PRP. Cisplatin (10 mg/day intraperitoneally) or vehicle was administered 2 times per day to the animals. Auditory brainstem responses were recorded preoperatively and postoperatively on day 4 and at week 3. The authors compared the morphological appearances of spiral ganglion cells and the organ of Corti and the density of spiral ganglion cells between treatment groups. The number of outer hair cells in the organ of Corti significantly decreased in the control group compared with that in the PRP group. Although no statistically significant difference was observed between the groups regarding ABR thresholds on day 4 (P = 0.083, a statistically significant difference was observed between groups at week 3 (P = 0.038). Our results suggest that PRP can prevent cisplatin-induced ototoxicity.


Assuntos
Antineoplásicos/toxicidade , Cisplatino/toxicidade , Ototoxicidade/prevenção & controle , Plasma Rico em Plaquetas , Animais , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Feminino , Ototoxicidade/etiologia , Ratos
11.
Toxicology ; 441: 152528, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32565124

RESUMO

Cisplatin (Cis) is an effective chemotherapeutic intervention against many cancer types. However, the oxidative stress-related toxicities associated with cancer cell resistance-induced dose scaling has limited its long-term use. In the present study, we explored the benefits of the antioxidant, tert-butylhydroquinone (tBHQ; 50 mg/kg b.w./day, for 14 days) against Cis single dose injection (7 mg/kg b.w., i.p on Day 8), on testicular toxicity of male Wistar rats. Cis triggered testicular and epididymal oxidative stress, testicular inflammation (upregulated NF-κB, TNF-α and IL-1ß mRNA levels, and downregulated IL-10 mRNA level), increased testicular apoptosis (increased Bax/Bcl2 and caspase-3 mRNA levels) and decreased testicular germ cells proliferation. Further, Cis decreased testicular steroidogenesis (decreased expression of StAR, CYP11A1, 3ß-HSD and 17ß-HSD mRNA and proteins) and decreased follicle stimulating hormone, luteinizing hormone and testosterone levels. Cis also decreased sperm count, motility, viability, normal morphology and Johnsen score. However, intervention with tBHQ significantly decreased oxidative stress by upregulating Nrf2 gene, suppressed inflammation, apoptosis and increased testicular germ cells proliferation. tBHQ also increased steroidogenesis and improved sperm parameters. Taken together, tBHQ improves steroidogenesis and spermatogenesis in Cis-intoxicated rats by improving antioxidant status, dampening inflammation and apoptosis, thus improving the proliferative capacity of spermatogenic cells.


Assuntos
Apoptose/efeitos dos fármacos , Cisplatino/toxicidade , Hidroquinonas/farmacologia , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Testículo/efeitos dos fármacos , Animais , Cisplatino/antagonistas & inibidores , Hormônio Foliculoestimulante/metabolismo , Hormônio Luteinizante/metabolismo , Masculino , Ratos , Ratos Wistar , Testículo/metabolismo , Testosterona/metabolismo
12.
Aquat Toxicol ; 223: 105495, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32371336

RESUMO

Platinum-based antineoplastic drugs (PBADs) enter the environment via hospital and municipal wastes as reactive and highly toxic molecules. Chlorella vulgaris is a freshwater microalgae and is used as an excellent aquatic model for toxicity assessment. In the present study, the toxicity of PBADs to C. vulgaris was investigated for better understanding of PBADs environmental toxicity. The algae were cultured in Bold´s Basal Medium (BBM) and exposed to different concentrations of PBADs for 48, 72 and 96 h. Then, cell proliferation, the synthesis of photosynthetic pigments, protein content, malondialdehyde (MDA) release and antioxidant potential were determined. IC50 s of cisplatin, carboplatin and oxaliplatin for 96 h of exposure were 106.2, 124.3 and 153.9 mg/L respectively. Cell proliferation, synthesis of chlorophyll a, chlorophyll b and algal protein content significantly decreased in a time and dose-dependent manner. The release of MDA to culture media significantly increased and antioxidant potential decreased. Cisplatin showed more toxic effects on C. vulgaris compared to carboplatin and oxaliplatin indicating its severe toxicity for marine organisms. PBADs induce their toxic effects in algal cells via the interaction with DNA, production of free radicals (such as reactive oxygen species), lipid peroxidation and cell wall damages. Due to these toxic effects of PBADs for various environmental organisms, there must be severe restriction on their release into the environment.


Assuntos
Antineoplásicos/toxicidade , Chlorella vulgaris/efeitos dos fármacos , Microalgas/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Antioxidantes/metabolismo , Carboplatina/toxicidade , Chlorella vulgaris/metabolismo , Clorofila/metabolismo , Clorofila A/metabolismo , Cisplatino/toxicidade , Água Doce/química , Peroxidação de Lipídeos/efeitos dos fármacos , Malondialdeído/metabolismo , Microalgas/metabolismo , Oxaliplatina/toxicidade , Fotossíntese/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
13.
Toxicol Lett ; 331: 1-10, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32428544

RESUMO

Cisplatin is a well-known and commonly used chemotherapeutic agent. However, cisplatin-induced ototoxicity limits its clinical use. Previous studies have shown an important role of reactive oxygen species (ROS) accumulation in the pathogenesis of cisplatin-induced ototoxicity. In many cell types, the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant response element (ARE) protect against oxidative stress by suppressing ROS. Here our results showed that cisplatin injury reduced Nrf2 expression and inhibited Nrf2 translocation in HEI-OC1 cells and Nrf2 activator tert-butylhydroquinone (TBHQ) rescued hair cells from cisplatin induced apoptosis by suppressing the total cellular ROS accumulation. Moreover, we found that decreased ROS accumulation induced by TBHQ didn't depend on mitochondrial derived ROS production, indicating that Nrf2 activation alleviated cisplatin induced oxidative stress and apoptosis through mitochondrial-independent ROS production. Therefore, we provide a potential strategy of prevention and treatment for cisplatin-induced ototoxicity by Nrf2 activation. In conclusion, Nrf2 activation protects auditory hair cells from cisplatin-induced ototoxicity through suppressing the total cellular ROS levels which arise from sources other than mitochondria.


Assuntos
Antineoplásicos/toxicidade , Cisplatino/toxicidade , Células Ciliadas Auditivas/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Ototoxicidade/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Células Ciliadas Auditivas/metabolismo , Hidroquinonas/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/genética , Ototoxicidade/patologia , Espécies Reativas de Oxigênio/metabolismo
14.
Sci Rep ; 10(1): 6568, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32300186

RESUMO

The function and susceptibility of various drugs are tested with renal proximal tubular epithelial cells; yet, replicating the morphology and kidneys function using the currently available in vitro models remains difficult. To overcome this difficulty, in the study presented in this paper, a device and a three-layer microfluidic chip were developed, which provides a simulated environment for kidney organs. This device includes two parts: (1) microfluidic drug concentration gradient generator and (2) a flow-temperature controlled platform for culturing of kidney cells. In chip study, renal proximal tubular epithelial cells (RPTECs) and peritubular capillary endothelial cells (PCECs) were screened with the drugs to assess the drug-induced nephrotoxicity. Unlike cells cultured in petri dishes, cells cultured in the microfluidic device exhibited higher performance in terms of both cell growth and drug nephrotoxicity evaluation. It is worth mentioning that a significant decrease in cisplatin-induced nephrotoxicity was found because of the intervention of cimetidine in the microfluidic device. In conclusion, the different in the cell performance between the microfluidic device and the petri dishes demonstrates the physiological relevance of the nephrotoxicity screening technology along with the microfluidic device developed in this study. Furthermore, this technology can also facilitate the development of reliable kidney drugs and serve as a useful and efficient test-bed for further investigation of the drug nephrotoxicity evaluation.


Assuntos
Avaliação Pré-Clínica de Medicamentos , Rim/patologia , Microfluídica , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/toxicidade , Técnicas de Cocultura , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Fluorescência , Humanos , Rim/efeitos dos fármacos , Membranas , Permeabilidade , Temperatura
15.
Sci Rep ; 10(1): 5798, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32242081

RESUMO

Cancer drug development has been riddled with high attrition rates, in part, due to poor reproducibility of preclinical models for drug discovery. Poor experimental design and lack of scientific transparency may cause experimental biases that in turn affect data quality, robustness and reproducibility. Here, we pinpoint sources of experimental variability in conventional 2D cell-based cancer drug screens to determine the effect of confounders on cell viability for MCF7 and HCC38 breast cancer cell lines treated with platinum agents (cisplatin and carboplatin) and a proteasome inhibitor (bortezomib). Variance component analysis demonstrated that variations in cell viability were primarily associated with the choice of pharmaceutical drug and cell line, and less likely to be due to the type of growth medium or assay incubation time. Furthermore, careful consideration should be given to different methods of storing diluted pharmaceutical drugs and use of DMSO controls due to the potential risk of evaporation and the subsequent effect on dose-response curves. Optimization of experimental parameters not only improved data quality substantially but also resulted in reproducible results for bortezomib- and cisplatin-treated HCC38, MCF7, MCF-10A, and MDA-MB-436 cells. Taken together, these findings indicate that replicability (the same analyst re-performs the same experiment multiple times) and reproducibility (different analysts perform the same experiment using different experimental conditions) for cell-based drug screens can be improved by identifying potential confounders and subsequent optimization of experimental parameters for each cell line.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais/normas , Concentração Inibidora 50 , Antineoplásicos/toxicidade , Bortezomib/toxicidade , Carboplatina/toxicidade , Sobrevivência Celular , Cisplatino/toxicidade , Dimetil Sulfóxido/normas , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Humanos , Células MCF-7 , Reprodutibilidade dos Testes
16.
Nephrol Dial Transplant ; 35(7): 1145-1156, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32240312

RESUMO

BACKGROUND: Activation of mitogen-activated protein kinase phosphatase-1 (MKP-1), a dual-specificity protein phosphatase, regulates mitogen-activated protein kinase signaling. C-Jun N-terminal kinase (JNK) and p38 are activated in cisplatin-induced renal injury. However, the change of MKP-1 expression in cisplatin-induced renal injury and the regulatory effect of sirtuin 2 (SIRT2), a nicotinamide adenine dinucleotide-dependent deacetylase, on MKP-1 remains unknown. METHODS: To address these issues, we used constitutional Sirt2 knockout (KO) mice, transgenic (TG) mice with increased expression of SIRT2 specifically in proximal tubular epithelial cellsand wild-type (WT) mice. Cisplatin nephrotoxicity was induced by intraperitoneal injection of cisplatin. RESULTS: MKP-1 expression in the kidney was decreased after cisplatin treatment. Cisplatin-induced downregulation of MKP-1 was reversed in Sirt2 KO mice kidney and further decreased in Sirt2 TG mice kidney. We observed similar phenomenon with SIRT2-knockdown or SIRT2-overexpressed tubular epithelial cells. Phosphorylation of p38 and JNK, a downstream signal pathway of MKP-1, increased in WT mice kidney following treatment with cisplatin. A decrease in SIRT2 suppressed cisplatin-induced phosphorylation of p38 and JNK in kidney and tubular epithelial cells. Overexpression of SIRT2 further increased phosphorylation of p38 and JNK in kidney and tubular epithelial cells. Acetylation of MKP-1 was significantly increased in SIRT2-knockdown cells and decreased in SIRT2-overexpressed cells after cisplatin stimulation. Sirt2 KO mice and Sirt2 TG mice showed amelioration and aggravation of renal injury, apoptosis, necroptosis and inflammation induced by cisplatin. CONCLUSION: Our data show that SIRT2 is associated with cisplatin-induced renal injury through regulation of MKP-1 expression.


Assuntos
Lesão Renal Aguda/patologia , Antineoplásicos/toxicidade , Cisplatino/toxicidade , Fosfatase 1 de Especificidade Dupla/metabolismo , Regulação da Expressão Gênica , Sirtuína 2/fisiologia , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/metabolismo , Animais , Apoptose , Fosfatase 1 de Especificidade Dupla/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação , Transdução de Sinais
17.
Braz. j. otorhinolaryngol. (Impr.) ; 86(2): 222-227, March-Apr. 2020. graf
Artigo em Inglês | LILACS | ID: biblio-1132576

RESUMO

Abstract Introduction: The use of electron microscopy in the study of the inner ear has allowed us to observe minute details of the hair cells, especially in ototoxicity studies; however, the preparation of this material is a difficult and delicate task. In an attempt to simplify the handling of these materials, two agents, toluidine blue and ethylenediamine tetra-acetic acid were tested, in addition to the elimination of osmium tetroxide during the preparation of albino guinea pig cochleae. We also tested the applicability of these methodologies in an ototoxicity protocol. Objective: To verify the quality of the images obtained with and without the use of ethylenediamine tetra-acetic acid, toluidine blue and osmium tetroxide in the preparation of cochleae of albino guinea pigs for the scanning electron microscopy. Methods: Three groups of cochleae were used. In Group 1, 10 cochleae were prepared with the usual methodology, dissecting the optical capsule without decalcification and using osmium tetroxide as a post-fixative agent. In Group 2, we prepared 10 cochleae decalcified with ethylenediamine tetra-acetic acid, injecting toluidine blue in the endolymphatic space to facilitate the identification of the organ of Corti. In Group 3, we used 4 cochleae of guinea pigs that received 3 doses of cisplatin (7.5 mg/kg, D1-D5-D6), two prepared according to the methodology used in Group 1 and two with that used in Group 2. Scanning electron microscopy images were obtained from the organ of Corti region of the basal turn of each cochlea. Results: The organ of Corti was more easily identified with the use of toluidine blue. The dissection of the cochlea was more accurate in the decalcified cochleae. The quality of the images and the preservation of the organ of Corti obtained with the two methodologies were similar. Conclusion: The proposed modifications resulted in images of similar quality as those observed using the traditional methodology.


Resumo Introdução: O emprego da microscopia eletrônica no estudo da orelha interna permitiu observar detalhes minuciosos das células ciliadas especialmente em estudos de ototoxicidade. Entretanto, o preparo desse material é trabalhoso e delicado. Para simplificar a manipulação desses materiais, testou-se o uso de dois agentes, azul de toluidina e ácido etilenodiamino tetra-acético, além da retirada do tetróxido de ósmio na preparação de cócleas de cobaias albinas. Testamos também a aplicabilidade dessas metodologias em um protocolo de ototoxicidade. Objetivo: Verificar a qualidade das imagens obtidas com e sem o uso de ácido etilenodiamino tetra-acético, azul de toluidina e tetróxido de ósmio na preparação de cócleas de cobaias albinas para a microscopia eletrônica de varredura. Método: Foram utilizados três grupos de cócleas. No Grupo 1 preparou-se 10 cócleas com a metodologia usual, dissecando a cápsula ótica sem descalcificac¸ão e utilizando tetróxido de ósmio como pós-fixador. No Grupo 2 preparamos 10 cócleas descalcificadas com ácido etilenodiamino tetra-acético, injetando azul de toluidina no espac¸o endolinfático para facilitar a identificação do órgão de Corti. No Grupo 3 utilizamos 4 cócleas de cobaias que receberam 3 doses de cisplatina (7,5 mg/kg, D1-D5-D6), duas preparadas com a metodologia do Grupo 1 e duas com a do Grupo 2. Foram obtidas imagens da microscopia eletrônica de varredura da região do órgão de Corti do giro basal de cada cóclea. Resultados: O órgão de Corti foi mais facilmente identificado com o azul de touidina. A dissecção da cóclea foi mais precisa nas cócleas descalcificadas A qualidade das imagens e a preservac¸ão do órgão de Corti obtidas com as duas metodologias foi similar. Conclusão: As modificações propostas resultaram em imagens de qualidade similar as observadas com o uso da metodologia tradicional.


Assuntos
Animais , Feminino , Cisplatino/toxicidade , Cóclea/efeitos dos fármacos , Cóclea/ultraestrutura , Órgão Espiral/efeitos dos fármacos , Órgão Espiral/ultraestrutura , Tetróxido de Ósmio/administração & dosagem , Cloreto de Tolônio/administração & dosagem , Microscopia Eletrônica de Varredura , Ácido Edético/administração & dosagem , Cobaias , Células Ciliadas Auditivas/efeitos dos fármacos , Células Ciliadas Auditivas/ultraestrutura
18.
Sci Rep ; 10(1): 4441, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32157166

RESUMO

The DNA damage response after kidney injury induces cell cycle arrest in renal tubular epithelial cells, resulting in the secretion of pro-fibrotic cytokines, thereby promoting interstitial fibrosis in a paracrine manner. Phosphorylation of ataxia-telangiectasia mutated (ATM) is the initial step in the DNA damage response and subsequent cell cycle arrest; however, the effects of ATM inhibition on the injured kidney have not been explored. Pharmacological ATM inhibition by KU55933 in cisplatin-treated mice did not ameliorate, but instead exacerbated cisplatin-induced DNA damage and tubular injury, thereby increasing mortality. Analysis of isolated tubular epithelia by FACS from bigenic SLC34a1-CreERt2; R26tdTomato proximal tubular-specific reporter mice revealed that KU55933 upregulated p53 and subsequent pro-apoptotic signaling in tubular epithelia of cisplatin-treated mice, leading to marked mitochondrial injury and apoptosis. In addition, KU55933 attenuated several DNA repair processes after cisplatin treatment, including single-strand DNA repair and Fanconi anemia pathways, suggesting that DNA repair after dual treatment of cisplatin and KU55933 was not sufficient to prevent the cisplatin-induced tubular injury. Our study suggested that ATM inhibition does not increase DNA repair after cisplatin-induced DNA damage and exacerbates tubular injury through the upregulation of p53-dependent pro-apoptotic signaling. Acute kidney injury must be carefully monitored when ATM inhibitors become available in clinical practice in the future.


Assuntos
Lesão Renal Aguda/etiologia , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Cisplatino/toxicidade , Morfolinas/farmacologia , Proteínas Mutantes/antagonistas & inibidores , Mutação , Pironas/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Animais , Antineoplásicos/toxicidade , Apoptose , Proteínas Mutadas de Ataxia Telangiectasia/genética , Pontos de Checagem do Ciclo Celular , Reparo do DNA , Camundongos , Fosforilação , Transdução de Sinais , Proteína Supressora de Tumor p53/genética
19.
Am J Physiol Renal Physiol ; 318(4): F971-F978, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32150447

RESUMO

Acute kidney injury (AKI) remains a major global healthcare problem, and there is a need to develop human-based models to study AKI in vitro. Toward this goal, we have characterized induced pluripotent stem cell-derived human kidney organoids and their response to cisplatin, a chemotherapeutic drug that induces AKI and preferentially damages the proximal tubule. We found that a single treatment with 50 µM cisplatin induces hepatitis A virus cellular receptor 1 (HAVCR1) and C-X-C motif chemokine ligand 8 (CXCL8) expression, DNA damage (γH2AX), and cell death in the organoids but greatly impairs organoid viability. DNA damage was not specific to the proximal tubule but also affected the distal tubule and interstitial cell populations. This lack of specificity correlated with low expression of proximal tubule-specific SLC22A2/organic cation transporter 2 (OCT2) for cisplatin. To improve viability, we developed a repeated low-dose regimen of 4 × 5 µM cisplatin over 7 days and found this caused less toxicity while still inducing a robust injury response that included secretion of known AKI biomarkers and inflammatory cytokines. This work validates the use of human kidney organoids to model aspects of cisplatin-induced injury, with the potential to identify new AKI biomarkers and develop better therapies.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Antineoplásicos/toxicidade , Cisplatino/toxicidade , Dano ao DNA , Túbulos Renais Proximais/efeitos dos fármacos , Organoides/efeitos dos fármacos , Lesão Renal Aguda/genética , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Antineoplásicos/metabolismo , Células Cultivadas , Cisplatino/metabolismo , Relação Dose-Resposta a Droga , Receptor Celular 1 do Vírus da Hepatite A/genética , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Histonas/metabolismo , Humanos , Interleucina-8/genética , Interleucina-8/metabolismo , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Transportador 2 de Cátion Orgânico/metabolismo , Organoides/metabolismo , Organoides/patologia , Fatores de Tempo
20.
Int. arch. otorhinolaryngol. (Impr.) ; 24(1): 47-52, Jan.-Mar. 2020. graf
Artigo em Inglês | LILACS | ID: biblio-1090559

RESUMO

Abstract Introduction Cisplatin damages the auditory system and is related to the generation of free radicals. Glutathione peroxidase is an endogenous free radicals remover. Objective To investigate the mechanisms involved in otoprotection by N-acetylcys- teine through the expression of glutathione peroxidase in outer hair cells from rats treated with cisplatin. Methods Male Wistar rats were intraperitoneally injected with cisplatin (8 mg/Kg) and/or received oral administration by gavage of N-acetylcysteine (300 mg/Kg) for 3 consecutive days. On the 4th day, the animals were euthanized and beheaded. The tympanic bullae were removed and prepared for scanning electron microscopy and Results Among the groups exposed to ototoxic doses of cisplatin, there was an increase in glutathione peroxidase immunostaining in two groups, the one exposed to cisplatin alone, and the group exposed to both cisplatin and N-acetylcysteine. Conclusion The expression of glutathione peroxidase in the outer hair cells of rats exposed to cisplatin showed the synthesis of this enzyme under cellular toxicity conditions.


Assuntos
Animais , Masculino , Acetilcisteína/uso terapêutico , Depuradores de Radicais Livres/uso terapêutico , Cisplatino/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Antineoplásicos/toxicidade , Acetilcisteína/metabolismo , Acetilcisteína/farmacologia , Microscopia Eletrônica de Varredura , Potenciais Evocados Auditivos do Tronco Encefálico , Depuradores de Radicais Livres/metabolismo , Depuradores de Radicais Livres/farmacologia , Imunofluorescência , Cisplatino/uso terapêutico , Ratos Wistar , Cóclea/anatomia & histologia , Cóclea/efeitos dos fármacos , Radicais Livres , Glutationa Peroxidase/metabolismo , Perda Auditiva Neurossensorial/prevenção & controle
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