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1.
Toxicol Appl Pharmacol ; 454: 116242, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36108929

RESUMO

Nephrotoxicity is an important adverse effect of oxidative stress induced by hexavalent chromium [Cr(VI)]. The effect of ellagic acid, a dietary polyphenolic compound with potent antioxidant activity, was investigated in Cr(VI)-induced kidney injury. Six groups of male Wistar rats were treated intragastrically with vehicle or ellagic acid (15 and 30 mg/kg) for 10 days. On day 10, rats received saline or Cr(VI) (K2Cr2O7 15 mg/kg) subcutaneously. Cr(VI) significantly increased kidney weight, affected kidney function assessed by biomarkers in blood and urine (protein, creatinine and urea nitrogen), caused histological changes (tubular injury and glomerular capillary tuft damage), increased markers of oxidative stress and reduced the activity of antioxidant enzymes. In addition, Cr(VI) altered mitochondrial ultrastructure, impaired mitochondrial respiration, increased lipid peroxidation, and inhibited the function of mitochondrial enzymes. Pretreatment with ellagic acid (30 mg/kg) attenuated all the aforementioned alterations. Furthermore, we explored whether ellagic acid might regulate the tumor necrosis factor-alpha (TNF-α)/receptor-interacting protein kinase 3 (RIPK3) pathway, reducing Cr(VI)-induced tubular necrosis. Cr(VI) upregulated both TNF-α and RIPK3, but ellagic acid only decreased TNF-α levels, having no effect on RIPK3 content. Therefore, understanding the mechanisms through which Cr(VI) promotes necroptosis is crucial for future studies, in order to design strategies to mitigate kidney damage. In conclusion, ellagic acid attenuated Cr(VI)-induced renal alterations by preventing oxidative stress, supporting enzymatic activities, suppressing TNF-α, and preserving mitochondrial ultrastructure and function, most likely due to its antioxidant properties.


Assuntos
Antioxidantes , Fator de Necrose Tumoral alfa , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Biomarcadores/metabolismo , Cromo/metabolismo , Cromo/toxicidade , Creatinina , Ácido Elágico/metabolismo , Ácido Elágico/farmacologia , Rim , Masculino , Mitocôndrias/metabolismo , Nitrogênio/metabolismo , Estresse Oxidativo , Proteínas Quinases/metabolismo , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo , Ureia/metabolismo
2.
Ann Diagn Pathol ; 60: 151705, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33685748

RESUMO

The aim of this study was to investigate the expression of leptin (LEP) and its receptor (LEPR) in breast cancer tissue of postmenopausal women with different body mass indexes (BMI), as well as the relationship of this expression with the rate of recurrence free survival (RFS). Leptin and LEPR expression, determined by immunohistochemistry, were studied in breast cancer tissues of 154 patients. Qualitative and semi-quantitative analysis of protein expression was performed by the H-Score method, through the ImageJ's IHC Profiler software. Kaplan-Meier survival analysis and log-rank statistic were used to estimate RFS differences. Protein expression of LEP, was significantly higher in women with overweight or with obesity, when compared to women with normal BMI (P = 0.032 and P = 0.013, respectively). We also observed a significantly higher expression of LEPR in breast tumor cells of women with obesity (58.8%), when compared to women with normal BMI (32.7%) (P = 0.007). Five-year survival rate, regarding LEPR expression, was 82.4% when positive and 94% when negative (P = 0.024). In the Cox proportional-hazards regression model, LEPR expression represented a risk factor for disease recurrence after adjustment for confounding factors (HR = 4.67; 95% CI: 1.13-19.31; P = 0.033). In conclusion, postmenopausal women with obesity and breast cancer present higher LEP and LEPR expression in breast tumors, when compared to women with normal BMI. Independently from BMI, women with tumors LEPR positive have worst RFS, when compared to women with tumors LEPR negative.


Assuntos
Neoplasias da Mama , Leptina/metabolismo , Receptores para Leptina/metabolismo , Neoplasias da Mama/metabolismo , Feminino , Humanos , Recidiva Local de Neoplasia , Obesidade/complicações , Pós-Menopausa
3.
J Clin Pathol ; 2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083413

RESUMO

AIM: To analyse the fibronectin type III domain containing 5 (FNDC5)/irisin expression in tumour tissue of postmenopausal women presenting breast cancer and different body mass indexes (BMIs), proposing that obesity deregulates the expression of FNDC5/irisin at the breast tumour level. In addition, we investigated if different breast cancer cell lines are capable to synthesise this protein. METHODS: A total of 150 postmenopausal women (50 with a normal BMI, 50 presenting overweight and 50 having obesity) diagnosed with operable breast cancer were included. FNDC5/irisin expression was determined by immunohistochemistry or by immunocytochemistry. Qualitative analysis of protein expression was performed by the H-Score method, through ImageJ's IHC Profiler software. Statistical analyses were carried out using STATA V.14.0 (Texas, USA); p value<0.05 was accepted as statistically significant. Statistical power of the study was >80% with a p<0.05. RESULTS: FNDC5/irisin expression in breast cancer tissue of postmenopausal women with obesity was significantly increased when compared with FNDC5/irisin expression in women with a normal BMI (p=0.001). Furthermore, three breast cancer cell lines studied were capable to synthesise and express FNDC5/irisin, being the BT-474 cell line the one that exhibited the highest intensity of expression. CONCLUSIONS: Our results confirm that women with breast cancer and obesity exhibit an increased irisin expression in their tumorous tissue compared with women with breast cancer and normal BMI. Likewise, in vitro breast cancer cell lines have the capacity to synthesise and express FNDC5/irisin, without any extracellular stimuli, however the microenvironment surrounding these cells in vivo participates in its regulation.

4.
Biol Trace Elem Res ; 167(1): 130-45, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25774041

RESUMO

Hexavalent chromium [Cr(VI)] compounds are extremely toxic and carcinogenic. Despite the vast quantity of reports about Cr(VI) toxicity, the information regarding its effects when it is intraperitoneally (i.p.) administered is still limited. In contrast, it has been shown that curcumin prevents hepatotoxicity induced by a single intraperitoneal injection of 15 mg/kg body weight (b.w.) of potassium dichromate (K2Cr2O7). This study aims to evaluate oxidative stress markers, the activity of antioxidant enzymes, and the potential histological injury in brain, heart, lung, kidney, spleen, pancreas, stomach, and intestine from rats treated with a hepatotoxic dose of K2Cr2O7 (15 mg/kg b.w.), and the effect of curcumin pretreatment. Rats were divided into four groups: control, curcumin, K2Cr2O7, and curcumin+K2Cr2O7. At the end of the treatment, plasma and ascites fluid were collected and target organs were dissected out for biochemical and histological analysis. K2Cr2O7 induced hepatotoxicity but failed to induce in all the other studied organs either oxidative or histological injury, since levels of malondialdehyde (MDA), glutathione (GSH), and the activity of superoxide dismutase (SOD), catalase (CAT), and related GSH enzymes were unchanged. As expected, curcumin was safe. Lack of K2Cr2O7-induced toxicity in those target organs could be due to the following: (1) route of administration, (2) absorption through the portal circulation, (3) lower dose than needed, (4) short time of exposure, or (5) repeated doses are required to produce damage. Thus, the intraperitoneal injection of 15 mg/kg of K2Cr2O7, that is able to induce hepatotoxicity, was unable to induce histological and oxidative damage in other target organs.


Assuntos
Biomarcadores/metabolismo , Curcumina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Dicromato de Potássio/toxicidade , Análise de Variância , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Biomarcadores/sangue , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Catalase/metabolismo , Relação Dose-Resposta a Droga , Mucosa Gástrica/metabolismo , Injeções Intraperitoneais , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Intestinos/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Malondialdeído/sangue , Malondialdeído/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Tamanho do Órgão/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Pâncreas/patologia , Dicromato de Potássio/administração & dosagem , Ratos Wistar , Baço/efeitos dos fármacos , Baço/metabolismo , Baço/patologia , Estômago/efeitos dos fármacos , Estômago/patologia , Superóxido Dismutase/metabolismo
5.
Artigo em Inglês | MEDLINE | ID: mdl-23956771

RESUMO

Curcumin is a polyphenol derived from turmeric with recognized antioxidant properties. Hexavalent chromium is an environmental toxic and carcinogen compound that induces oxidative stress. The objective of this study was to evaluate the potential protective effect of curcumin on the hepatic damage generated by potassium dichromate (K2Cr2O7) in rats. Animals were pretreated daily by 9-10 days with curcumin (400 mg/kg b.w.) before the injection of a single intraperitoneal of K2Cr2O7 (15 mg/kg b.w.). Groups of animals were sacrificed 24 and 48 h later. K2Cr2O7-induced damage to the liver was evident by histological alterations and increase in the liver weight and in the activity of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and alkaline phosphatase in plasma. In addition, K2Cr2O7 induced oxidative damage in liver and isolated mitochondria, which was evident by the increase in the content of malondialdehyde and protein carbonyl and decrease in the glutathione content and in the activity of several antioxidant enzymes. Moreover, K2Cr2O7 induced decrease in mitochondrial oxygen consumption, in the activity of respiratory complex I, and permeability transition pore opening. All the above-mentioned alterations were prevented by curcumin pretreatment. The beneficial effects of curcumin against K2Cr2O7-induced liver oxidative damage were associated with prevention of mitochondrial dysfunction.

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