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1.
Antioxidants (Basel) ; 13(1)2023 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-38275623

RESUMO

Neuroblastoma (NB) is a paediatric cancer with noteworthy heterogeneity ranging from spontaneous regression to high-risk forms that are characterised by cancer relapse and the acquisition of drug resistance. The most-used anticancer drugs exert their cytotoxic effect by inducing oxidative stress, and long-term therapy has been demonstrated to cause chemoresistance by enhancing the antioxidant response of NB cells. Taking advantage of an in vitro model of multidrug-resistant (MDR) NB cells, characterised by high levels of glutathione (GSH), the overexpression of the oncoprotein BMI-1, and the presence of a mutant P53 protein, we investigated a new potential strategy to fight chemoresistance. Our results show that PTC596, an inhibitor of BMI-1, exerted a high cytotoxic effect on MDR NB cells, while PRIMA-1MET, a compound able to reactivate mutant P53, had no effect on the viability of MDR cells. Furthermore, both PTC596 and PRIMA-1MET markedly reduced the expression of epithelial-mesenchymal transition proteins and limited the clonogenic potential and the cancer stemness of MDR cells. Of particular interest is the observation that PTC596, alone or in combination with PRIMA-1MET and etoposide, significantly reduced GSH levels, increased peroxide production, stimulated lipid peroxidation, and induced ferroptosis. Therefore, these findings suggest that PTC596, by inhibiting BMI-1 and triggering ferroptosis, could be a promising approach to fight chemoresistance.

2.
Antioxidants (Basel) ; 11(8)2022 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-36009331

RESUMO

Alterations of redox homeostasis leads to a condition of resilience known as hormesis that is due to the activation of redox-sensitive pathways stimulating cell proliferation, growth, differentiation, and angiogenesis. Instead, supraphysiological production of reactive oxygen species (ROS) exceeds antioxidant defence and leads to oxidative distress. This condition induces damage to biomolecules and is responsible or co-responsible for the onset of several chronic pathologies. Thus, a dietary antioxidant supplementation has been proposed in order to prevent aging, cardiovascular and degenerative diseases as well as carcinogenesis. However, this approach has failed to demonstrate efficacy, often leading to harmful side effects, in particular in patients affected by cancer. In this latter case, an approach based on endogenous antioxidant depletion, leading to ROS overproduction, has shown an interesting potential for enhancing susceptibility of patients to anticancer therapies. Therefore, a deep investigation of molecular pathways involved in redox balance is crucial in order to identify new molecular targets useful for the development of more effective therapeutic approaches. The review herein provides an overview of the pathophysiological role of ROS and focuses the attention on positive and negative aspects of antioxidant modulation with the intent to find new insights for a successful clinical application.

3.
Antioxidants (Basel) ; 10(5)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067625

RESUMO

Heme oxygenase 1 (HO-1) plays a key role in cell adaptation to stressors through the antioxidant, antiapoptotic, and anti-inflammatory properties of its metabolic products. For these reasons, in cancer cells, HO-1 can favor aggressiveness and resistance to therapies, leading to poor prognosis/outcome. Genetic polymorphisms of HO-1 promoter have been associated with an increased risk of cancer progression and a high degree of therapy failure. Moreover, evidence from cancer biopsies highlights the possible correlation between HO-1 expression, pathological features, and clinical outcome. Indeed, high levels of HO-1 in tumor specimens often correlate with reduced survival rates. Furthermore, HO-1 modulation has been proposed in order to improve the efficacy of antitumor therapies. However, contrasting evidence on the role of HO-1 in tumor biology has been reported. This review focuses on the role of HO-1 as a promising biomarker of cancer progression; understanding the correlation between HO-1 and clinical data might guide the therapeutic choice and improve the outcome of patients in terms of prognosis and life quality.

4.
Antioxidants (Basel) ; 10(5)2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33924765

RESUMO

Cancer stem cells (CSCs) are a limited cell population inside a tumor bulk characterized by high levels of glutathione (GSH), the most important antioxidant thiol of which cysteine is the limiting amino acid for GSH biosynthesis. In fact, CSCs over-express xCT, a cystine transporter stabilized on cell membrane through interaction with CD44, a stemness marker whose expression is modulated by protein kinase Cα (PKCα). Since many chemotherapeutic drugs, such as Etoposide, exert their cytotoxic action by increasing reactive oxygen species (ROS) production, the presence of high antioxidant defenses confers to CSCs a crucial role in chemoresistance. In this study, Etoposide-sensitive and -resistant neuroblastoma CSCs were chronically treated with Etoposide, given alone or in combination with Sulfasalazine (SSZ) or with an inhibitor of PKCα (C2-4), which target xCT directly or indirectly, respectively. Both combined approaches are able to sensitize CSCs to Etoposide by decreasing intracellular GSH levels, inducing a metabolic switch from OXPHOS to aerobic glycolysis, down-regulating glutathione-peroxidase-4 activity and stimulating lipid peroxidation, thus leading to ferroptosis. Our results suggest, for the first time, that PKCα inhibition inducing ferroptosis might be a useful strategy with which to fight CSC chemoresistance.

5.
Oxid Med Cell Longev ; 2019: 7346492, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31341534

RESUMO

Chemoresistance is due to multiple factors including the induction of a metabolic adaptation of tumor cells. In fact, in these cells, stress conditions induced by therapies stimulate a metabolic reprogramming which involves the strengthening of various pathways such as glycolysis, glutaminolysis and the pentose phosphate pathway. This metabolic reprogramming is the result of a complex network of mechanisms that, through the activation of oncogenes (i.e., MYC, HIF1, and PI3K) or the downregulation of tumor suppressors (i.e., TP53), induces an increased expression of glucose and/or glutamine transporters and of glycolytic enzymes. Therefore, in order to overcome chemoresistance, it is necessary to develop combined therapies which are able to selectively and simultaneously act on the multiple molecular targets responsible for this adaptation. This review is focused on highlighting the role of MYC in modulating the epigenetic redox changes which are crucial in the acquisition of therapy resistance.


Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-myc/biossíntese , Resistencia a Medicamentos Antineoplásicos , Genes myc , Glicólise , Humanos , Neoplasias/genética , Oxirredução , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo
6.
J Feline Med Surg ; 21(6): 465-474, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30015556

RESUMO

OBJECTIVES: Cats are commonly affected by chronic kidney disease (CKD). Many reactive carbonyl intermediates and end products originating from the oxidative stress pathways are recognised as uraemic toxins and may play a role in CKD progression. The aim of the present study is to confirm whether carbonyl end-product formation is higher in cats affected by CKD and to assess whether an angiotensin-converting enzyme inhibitor (ACEi) might affect these hallmarks. METHODS: Twenty-two cats were divided into three groups: a control group (CG), cats with CKD and cats with CKD treated with an ACEi. Serum levels of pentosidine, carboxymethyllysine, advanced oxidation protein products, malondialdehyde, methylglyoxal and hexanoyl-lysine were measured. In addition, biochemical parameters and systolic blood pressure were evaluated. After checking for normality, comparisons between groups were performed followed by multiple comparison tests. P values ⩽0.05 were considered significant. Correlations between concentrations of the considered biomarkers and of the other metabolic parameters were investigated. RESULTS: Advanced oxidation protein products, malondialdehyde and hexanoyl-lysine concentrations were significantly higher in CKD and ACEi-treated groups compared with the CG ( P <0.05). Carboxymethyllysine increased in the ACEi-treated group when compared with the CG, whereas intermediate values of these biomarkers were found in the CKD group ( P <0.05). The ACEi-treated group showed the highest values of carboxymethyllysine, advanced oxidation protein products and hexanoyl-lysine. By contrast, the CKD group had the highest concentration of malondialdehyde. No statistically significant difference was found in the levels of pentosidine or methylglyoxal. End products correlated with creatinine and urea and with each other. CONCLUSIONS AND RELEVANCE: Significantly high concentrations of both intermediate and end products of carbonyl/oxidative stress were detected in CKD cats. This is the first study to have concurrently taken into account several uraemic toxins and biochemical parameters in cats affected by CKD.


Assuntos
Produtos da Oxidação Avançada de Proteínas/sangue , Estresse Oxidativo/fisiologia , Insuficiência Renal Crônica , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Arginina/análogos & derivados , Arginina/sangue , Biomarcadores/sangue , Gatos , Lisina/análogos & derivados , Lisina/sangue , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/veterinária , Ureia
7.
Sci Rep ; 8(1): 13762, 2018 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-30213983

RESUMO

Drug resistance is the major obstacle in successfully treating high-risk neuroblastoma. The aim of this study was to investigate the basis of etoposide-resistance in neuroblastoma. To this end, a MYCN-amplified neuroblastoma cell line (HTLA-230) was treated with increasing etoposide concentrations and an etoposide-resistant cell line (HTLA-ER) was obtained. HTLA-ER cells, following etoposide exposure, evaded apoptosis by altering Bax/Bcl2 ratio. While both cell populations shared a homozygous TP53 mutation encoding a partially-functioning protein, a mono-allelic deletion of 13q14.3 locus, where the P53 inducible miRNAs 15a/16-1 are located, and the consequent miRNA down-regulation were detected only in HTLA-ER cells. This event correlated with BMI-1 oncoprotein up-regulation which caused a decrease in p16 tumor suppressor content and a metabolic adaptation of HTLA-ER cells. These results, taken collectively, highlight the role of miRNAs 15a/16-1 as markers of chemoresistance.


Assuntos
Etoposídeo/farmacologia , MicroRNAs/genética , Neuroblastoma/tratamento farmacológico , Proteína Supressora de Tumor p53/genética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/genética , Neuroblastoma/patologia
8.
Oncotarget ; 7(43): 70715-70737, 2016 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-27683112

RESUMO

Neuroblastoma, a paediatric malignant tumor, is initially sensitive to etoposide, a drug to which many patients develop chemoresistance. In order to investigate the molecular mechanisms responsible for etoposide chemoresistance, HTLA-230, a human MYCN-amplified neuroblastoma cell line, was chronically treated with etoposide at a concentration that in vitro mimics the clinically-used dose. The selected cells (HTLA-Chr) acquire multi-drug resistance (MDR), becoming less sensitive than parental cells to high doses of etoposide or doxorubicin. MDR is due to several mechanisms that together contribute to maintaining non-toxic levels of H2O2. In fact, HTLA-Chr cells, while having an efficient aerobic metabolism, are also characterized by an up-regulation of catalase activity and higher levels of reduced glutathione (GSH), a thiol antioxidant compound. The combination of such mechanisms contributes to prevent membrane lipoperoxidation and cell death. Treatment of HTLA-Chr cells with L-Buthionine-sulfoximine, an inhibitor of GSH biosynthesis, markedly reduces their tumorigenic potential that is instead enhanced by the exposure to N-Acetylcysteine, able to promote GSH synthesis.Collectively, these results demonstrate that GSH and GSH-related responses play a crucial role in the acquisition of MDR and suggest that GSH level monitoring is an efficient strategy to early identify the onset of drug resistance and to control the patient's response to therapy.


Assuntos
Antioxidantes/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glutationa/metabolismo , Neuroblastoma/tratamento farmacológico , Inibidores da Topoisomerase II/farmacologia , Acetilcisteína/farmacologia , Apoptose/efeitos dos fármacos , Butionina Sulfoximina/farmacologia , Catalase/metabolismo , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Inibidores Enzimáticos/farmacologia , Etoposídeo/farmacologia , Etoposídeo/uso terapêutico , Humanos , Peróxido de Hidrogênio/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Inibidores da Topoisomerase II/uso terapêutico , Regulação para Cima
9.
Oxid Med Cell Longev ; 2016: 6235641, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27418953

RESUMO

Reactive oxygen species (ROS) and their products are components of cell signaling pathways and play important roles in cellular physiology and pathophysiology. Under physiological conditions, cells control ROS levels by the use of scavenging systems such as superoxide dismutases, peroxiredoxins, and glutathione that balance ROS generation and elimination. Under oxidative stress conditions, excessive ROS can damage cellular proteins, lipids, and DNA, leading to cell damage that may contribute to carcinogenesis. Several studies have shown that cancer cells display an adaptive response to oxidative stress by increasing expression of antioxidant enzymes and molecules. As a double-edged sword, ROS influence signaling pathways determining beneficial or detrimental outcomes in cancer therapy. In this review, we address the role of redox homeostasis in cancer growth and therapy and examine the current literature regarding the redox regulatory systems that become upregulated in cancer and their role in promoting tumor progression and resistance to chemotherapy.


Assuntos
Antioxidantes/metabolismo , Homeostase , Neoplasias/patologia , Neoplasias/terapia , Animais , Carcinogênese/metabolismo , Carcinogênese/patologia , Ensaios Clínicos como Assunto , Humanos , Oxirredução , Espécies Reativas de Oxigênio/metabolismo
10.
Biofactors ; 42(1): 80-92, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26669587

RESUMO

Macrophages play a crucial role in atherosclerosis progression. Classically activated M1 macrophages have been found in rupture-prone atherosclerotic plaques whereas alternatively activated macrophages, M2, localize in stable plaque. Macrophage accumulation of cholesterol and of its oxidized derivatives (oxysterols) leads to the formation of foam cells, a hallmark of atherosclerotic lesions. In this study, the effects of oxysterols in determining the functional polarization of human macrophages were investigated. Monocytes, purified from peripheral blood mononuclear cells of healthy donors, were differentiated into macrophages (M0) and treated with an oxysterol mixture, cholesterol, or ethanol, every 4 H for a total of 4, 8, and 12 H. The administration of the compounds was repeated in order to maintain the levels of oxysterols constant throughout the treatment. Compared with ethanol treatment, the oxysterol mixture decreased the surface expression of CD36 and CD204 scavenger receptors and reduced the amount of reactive oxygen species whereas it did not affect either cell viability or matrix metalloprotease-9 activity. Moreover, the oxysterol mixture increased the expression of both liver X receptor α and ATP-binding cassette transporter 1. An enhanced secretion of the immunoregulatory cytokine IL-10 accompanied these events. The results supported the hypothesis that the constant levels of oxysterols and, in particular, of 27-hydroxycholesterol stimulate macrophage polarization toward the M2 immunomodulatory functional phenotype, contributing to the stabilization of atherosclerotic plaques.


Assuntos
Aterosclerose/tratamento farmacológico , Hidroxicolesteróis/administração & dosagem , Macrófagos/efeitos dos fármacos , Placa Aterosclerótica/tratamento farmacológico , Transportadores de Cassetes de Ligação de ATP/biossíntese , Aterosclerose/metabolismo , Aterosclerose/patologia , Antígenos CD36/metabolismo , Polaridade Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colesterol/administração & dosagem , Colesterol/metabolismo , Etanol/administração & dosagem , Humanos , Interleucina-10/metabolismo , Receptores X do Fígado , Macrófagos/metabolismo , Metaloproteinase 9 da Matriz/biossíntese , Monócitos/efeitos dos fármacos , Receptores Nucleares Órfãos/biossíntese , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Espécies Reativas de Oxigênio/metabolismo , Receptores Depuradores Classe A/metabolismo
11.
Free Radic Biol Med ; 89: 91-8, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26391462

RESUMO

Hyperglycemia and diabetes are associated with endothelial cell dysfunction arising from enhanced oxidative injury, leading to the progression of diabetic vascular pathologies. The redox-sensitive transcription factor nuclear factor-E2-related factor 2 (Nrf2) is a master regulator of antioxidant genes, such as heme oxygenase-1 (HO-1), involved in cellular defenses against oxidative stress. We have investigated the pathways involved in high glucose-induced activation of HO-1 in endothelial cells and examined the molecular mechanisms underlying cytoprotection. Elevated d-glucose increased intracellular generation of reactive oxygen species (ROS), leading to nuclear translocation of Nrf2 and HO-1 expression in bovine aortic endothelial cells, with no changes in cell viability. Superoxide scavenging and inhibition of endothelial nitric oxide synthase (eNOS) abrogated upregulation of HO-1 expression by elevated glucose. Inhibition of HO-1 increased the sensitivity of endothelial cells to high glucose-mediated damage, while addition of bilirubin restored cell viability. Our findings establish that exposure of endothelial cells to high glucose leads to activation of endogenous antioxidant defense genes via the Nrf2/ARE pathway. Upregulation of HO-1 provides cytoprotection against high glucose-induced oxidative stress through the antioxidant properties of bilirubin. Modulation of the Nrf2 pathway in the early stages of diabetes may thus protect against sustained damage by hyperglycemia during progression of the disease.


Assuntos
Aorta/citologia , Bilirrubina/farmacologia , Citoproteção , Endotélio Vascular/citologia , Glucose/toxicidade , Heme Oxigenase-1/metabolismo , Animais , Antioxidantes/farmacologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Apoptose/efeitos dos fármacos , Western Blotting , Bovinos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Ensaio de Desvio de Mobilidade Eletroforética , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/genética , Espécies Reativas de Oxigênio , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Edulcorantes/toxicidade
12.
Biochim Biophys Acta ; 1842(4): 613-22, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24380881

RESUMO

High-risk neuroblastoma (NB) is characterized by the development of chemoresistance, and bortezomib (BTZ), a selective inhibitor of proteasome, has been proposed in order to overcome drug resistance. Considering the involvement of the nuclear factor-erythroid-derived 2-like 2 (Nrf2) and heme oxygenase-1 (HO-1) in the antioxidant and detoxifying ability of cancer cells, in this study we have investigated their role in differently aggressive NB cell lines treated with BTZ, focusing on the modulation of HO-1 to improve sensitivity to therapy. We have shown that MYCN amplified HTLA-230 cells were slightly sensitive to BTZ treatment, due to the activation of Nrf2 that led to an impressive up-regulation of HO-1. BTZ-treated HTLA-230 cells down-regulated p53 and up-regulated p21, favoring cell survival. The inhibition of HO-1 activity obtained by Zinc (II) protoprophyrin IX (ZnPPIX) was able to significantly increase the pro-apoptotic effect of BTZ in a p53- and p21-independent way. However, MYCN non-amplified SH-SY5Y cells showed a greater sensitivity to BTZ in relation to their inability to up-regulate HO-1. Therefore, we have shown that HO-1 inhibition improves the sensitivity of aggressive NB to proteasome inhibition-based therapy, suggesting that HO-1 up-regulation can be used as a marker of chemoresistance in NB. These results open up a new scenario in developing a combined therapy to overcome chemoresistance in high-risk neuroblastoma.


Assuntos
Antineoplásicos/farmacologia , Ácidos Borônicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Heme Oxigenase-1/fisiologia , Neuroblastoma/tratamento farmacológico , Pirazinas/farmacologia , Bortezomib , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/análise , Heme Oxigenase-1/análise , Heme Oxigenase-1/antagonistas & inibidores , Humanos , Proteína Proto-Oncogênica N-Myc , Fator 2 Relacionado a NF-E2/fisiologia , Neuroblastoma/enzimologia , Neuroblastoma/patologia , Proteínas Nucleares/análise , Proteínas Oncogênicas/análise , Risco , Regulação para Cima
13.
Clin Chem Lab Med ; 52(1): 117-20, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23612599

RESUMO

BACKGROUND: The histopathological hallmarks in Alzheimer's disease (AD) include neuronal cell death, formation of amyloid plaques and neurofibrillary tangles. Glycoxidation plays a crucial role in AD pathogenesis, as pentosidine and Nε- carboxymethyl-lysine (CML), were detected in AD hallmarks, and in vivo cerebrospinal fluid (CSF). However, the definitive role of AGEs in the neuropathology of AD is inconclusive. The aim of this preliminary study was to assess the level of pentosidine in CSF of patients affected by neurological disorders, including probable AD, in order to assess the feasibility of AGEs detection in CSF and to explore pentosidine as a potential biomarker in AD. METHODS: Twenty-five patients diagnosed with AD (NINCDS ADRDA criteria) and different neurological disorders were enrolled. Diabetic patients were excluded. Pentosidine, CML, amyloid ß1-42 were assessed by high performance liquid chromatography (HPLC) by Odetti modified method,and by sandwich ELISA respectively. RESULTS: Our data showed the presence of pentosidine in all CSF samples, a significant increase in CSF pentosidine levels with age (p<0.05) and a significant decreased concentration of pentosidine in four AD subjects (p<0.01), after normalization to CSF protein concentration. CONCLUSIONS: The study showed that AGEs concentration in CSF might benefit from age correction, at least for pentosidine, originally addressing a potential systemic age-dependent AGEs accumulation. The significant decrease of CSF pentosidine in AD, even in 4 patients, might conceive that different AGEs inform specific types of neurodegeneration, depending on oxidative stress levels, blood - brain barrier permeability, brain localization and systemic risk factors.


Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Arginina/análogos & derivados , Lisina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Arginina/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Cromatografia Líquida de Alta Pressão , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Lisina/líquido cefalorraquidiano , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano
14.
Oxid Med Cell Longev ; 2013: 972913, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23766865

RESUMO

Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and disturbances in GSH homeostasis are involved in the etiology and progression of many human diseases including cancer. While GSH deficiency, or a decrease in the GSH/glutathione disulphide (GSSG) ratio, leads to an increased susceptibility to oxidative stress implicated in the progression of cancer, elevated GSH levels increase the antioxidant capacity and the resistance to oxidative stress as observed in many cancer cells. The present review highlights the role of GSH and related cytoprotective effects in the susceptibility to carcinogenesis and in the sensitivity of tumors to the cytotoxic effects of anticancer agents.


Assuntos
Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Glutationa/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Animais , Glutationa/biossíntese , Humanos , Neoplasias/tratamento farmacológico
15.
Int J Mol Sci ; 14(6): 10694-709, 2013 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-23702842

RESUMO

The aim of this work was to evaluate the ability of oxidative and glycative stressors to modify properties of human serum albumin (HSA) by analyzing markers of glycation (pentosidine) and oxidation (advanced oxidative protein products (AOPPs)) and assessing fluorescence and circular dichroism. HSA was incubated for up to 21 days with ribose, ascorbic acid (AA) and diethylenetriamine pentacetate (DTPA) in various combinations in order to evaluate influences of these substances on the structure of HSA. Ribose was included as a strong glycative molecule, AA as a modulator of oxidative stress, and DTPA as an inhibitor of metal-catalyzed oxidation. Ribose induced a significant increase in pentosidine levels. AA and DTPA prevented the accumulation of pentosidine, especially at later time points. Ribose induced a mild increase in AOPP formation, while AA was a strong inducer of AOPP formation. Ribose, in combination with AA, further increased the formation of AOPP. DTPA prevented the AA-induced generation of AOPP. Ribose was also a potent inducer of fluorescence at 335nm ex/385nm em, which is typical of pentosidine. AA and DTPA prevented this fluorescence. Circular dichroism showed complex results, in which AA and DTPA were strong modifiers of the percentages of the alpha-helical structure of HSA, while ribose affected the structure of HSA only at later time points.


Assuntos
Estresse Oxidativo , Albumina Sérica/química , Albumina Sérica/metabolismo , Acetatos/farmacologia , Arginina/análogos & derivados , Arginina/farmacologia , Ácido Ascórbico/farmacologia , Dicroísmo Circular , Fluorescência , Glicosilação/efeitos dos fármacos , Humanos , Lisina/análogos & derivados , Lisina/farmacologia , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estrutura Secundária de Proteína
16.
J Alzheimers Dis ; 36(2): 303-9, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23609761

RESUMO

People affected by dementia experienced decreased life expectancy with a 2-4 times higher risk of death at a given age compared to non-demented people. Dementia represents a major cost to health care and society in the Western world and, particularly in Italy, is projected to become a high-resource demanding chronic disease. The present study aimed to estimate the average survival rate of a group of community dwelling elderly affected by dementia in Italy, and to assess the predictive variables associated with survival length. This retrospective study collected the data of patients (n = 290) who died from 2008 to 2012. The data were extracted from a cohort of over 2,000 patients from three outpatient Dementia Clinics of Genoa (Italy). Demographic data and other clinical parameters listed in the patients' clinical records were collected. The mean survival rate after dementia diagnosis was 3.3 ± 0.1 years, lower compared to the age-matched healthy population. The survival rate of these patients showed a significant correlation with age (n = 290; r = -0.16: p < 0.006), with the cognitive status (n = 285; r = 0.16: p < 0.007), with education (n = 204; r = 0.23: p < 0.001), with comorbidity (n = 138; r = -0.41: p < 0.0001), with depressive mood (n = 74; r = 0.44: p < 0.0001), and with the functional status (ADL: n = 242, r = 0.29: p < 0.0001; IADL: n = 243; r = 0.25: p < 0.0001). Multivariate regression revealed age, gender, and functional status as the main determinants informing patient survival. The study provides interesting and reliable data on the pivotal value of early dementia diagnosis in predicting longer survival and addresses comprehensive geriatric assessment, which encompasses most of the predictive variables provided by the study, as a remarkable tool in estimating life expectancy of patients with dementia.


Assuntos
Demência/epidemiologia , Demência/mortalidade , Transtornos da Memória/epidemiologia , Transtornos da Memória/mortalidade , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Itália/epidemiologia , Modelos Logísticos , Estudos Longitudinais , Masculino , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica , Características de Residência , Taxa de Sobrevida
17.
Exp Mol Pathol ; 94(1): 270-6, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22771309

RESUMO

Malondialdehyde (MDA), a major lipid peroxidation product, spontaneously binds to, and modifies proteins. In vivo, proteins are physiologically exposed to micromolar MDA concentrations for long periods. In order to mimic this process in vitro, protein modification is often performed by short exposure to millimolar MDA concentrations, also in order to generate antigenic structures for antibody production. However, in our study, spectrophotometric and fluorimetric characteristics, electrophoretic migration, susceptibility to trypsin digestion and reactivity to antibodies indicated substantial differences between albumin incubated with millimolar MDA concentrations for a short period of time and albumin incubated with micromolar MDA concentrations for a long period of time. Therefore, our study showed that short incubation of albumin with millimolar MDA concentrations does not mimic the consequences of albumin exposure to long incubation with micromolar MDA concentrations. This casts doubts on the real possibility that antibodies, elicited with proteins modified with millimolar MDA concentrations for a short period, could detect all MDA-modified proteins in vivo. Moreover, natural antibodies against albumin, modified with micromolar MDA concentrations, have been detected in the serum of healthy blood donors, which appears to justify the existence of these kinds of modified proteins in vivo.


Assuntos
Anticorpos/imunologia , Malondialdeído/química , Proteínas/metabolismo , Soroalbumina Bovina/química , Soroalbumina Bovina/imunologia , Western Blotting , Eletroforese , Ensaio de Imunoadsorção Enzimática , Peroxidação de Lipídeos , Malondialdeído/metabolismo , Proteínas/imunologia , Soroalbumina Bovina/metabolismo , Espectrofotometria , Triptases
18.
Int J Mol Med ; 29(5): 899-905, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22344537

RESUMO

Diabetes-induced glutathione (GSH) decrease is usually ascribed to GSH oxidation. Here we investigate, in streptozotocin-treated rats, if impairment of GSH synthesis contributes to GSH decrease in diabetic liver, and if antioxidant treatments can provide protection. Diabetic rats were divided into 3 groups: untreated diabetic rats (UD); N-acetyl-cysteine (NAC)-treated diabetic rats; taurine (TAU)-treated diabetic rats; a group of non-streptozotocin-treated rats was used as control (CTR). All rats were sacrificed at 40 weeks of age. Diabetes induced hepatic glutathione decrease, but oxidized glutathione (GSSG) did not increase significantly. Accumulations of cysteine and cysteinyl-glycine in UD suggest respectively decreased glutathione synthesis and increased loss through the plasma membrane with subsequent degradation. Decreased expression of γ-glutamyl-cysteine synthetase in UD is consistent with repressed GSH synthesis. Moreover, diabetes caused increase of GSSG/GSH ratio and induction of heme oxygenase-1, both signs of oxidative stress. Supplementation with NAC or TAU resulted in amelioration of glutathione levels, probably depending on antioxidant activity, more efficient glutathione synthesis and decreased GSH loss and degradation. In conclusion, impaired synthesis and increased loss and degradation of GSH appear to contribute to a decrease in GSH levels in diabetic liver. NAC and TAU are able to partially protect from oxidative stress and GSH decrease, while enhancing GSH synthesis and restricting GSH loss.


Assuntos
Acetilcisteína/uso terapêutico , Antioxidantes/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Glutationa/metabolismo , Fígado/metabolismo , Taurina/uso terapêutico , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Dissulfeto de Glutationa/metabolismo , Heme Oxigenase-1/metabolismo , Fígado/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Estreptozocina
19.
Free Radic Biol Med ; 52(2): 488-96, 2012 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-22142473

RESUMO

Cancer cell survival is known to be related to the ability to counteract oxidative stress, and glutathione (GSH) depletion has been proposed as a mechanism to sensitize cells to anticancer therapy. However, we observed that GI-ME-N cells, a neuroblastoma cell line without MYCN amplification, are able to survive even if GSH-depleted by l-buthionine-(S,R)-sulfoximine (BSO). Here, we show that in GI-ME-N cells, BSO activates Nrf2 and up-regulates heme oxygenase-1 (HO-1). Silencing of Nrf2 restrained HO-1 induction by BSO. Inhibition of HO-1 and silencing of Nrf2 or HO-1 sensitized GI-ME-N cells to BSO, leading to reactive oxygen/nitrogen species overproduction and decreasing viability. Moreover, targeting the Nrf2/HO-1 axis sensitized GI-ME-N cells to etoposide more than GSH depletion. Therefore, we have provided evidence that in GI-ME-N cells, the Nrf2/HO-1 axis plays a crucial role as a protective factor against cellular stress, and we suggest that the inhibition of Nfr2/HO-1 signaling should be considered as a central target in the clinical battle against neuroblastoma.


Assuntos
Butionina Sulfoximina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Glutationa/deficiência , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Etoposídeo/farmacologia , Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Glutamato-Cisteína Ligase/antagonistas & inibidores , Glutamato-Cisteína Ligase/metabolismo , Glutationa/metabolismo , Heme Oxigenase-1/antagonistas & inibidores , Heme Oxigenase-1/genética , Humanos , Neuroblastoma , Estresse Oxidativo , Protoporfirinas/farmacologia , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo
20.
Dig Liver Dis ; 43(10): 814-22, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21737367

RESUMO

INTRODUCTION: The incidence of small-for-size-liver-syndrome after liver transplantation and extended liver resection may be reduced by portal flow modulation. However, many aspects of the small-for-size-liver-syndrome pathogenesis are still unclear. In this experimental study we evaluated the early effects of portal flow modulation after 80% hepatic resection in rats. MATERIALS AND METHODS: Rats were randomised in: sham operation (G1), conventional hepatic resection (G2), splenectomy and hepatic resection (G3), splenic transposition followed by hepatic resection after three weeks (G4). Six hours after operation, oxygen saturation of hepatic vein blood, glutathione, and standard liver markers were measured from hepatic venous blood. Glutathione measurement and histopatological examination were performed in the remnant liver. RESULTS: Total bilirubin and liver glutathione did not show differences between groups. Aspartate aminotransferase and alanine aminotransferase significantly increased in G2-G4 groups. Blood glutathione and oxygen saturation of hepatic vein blood were lower in G2 than in other groups. A gradient of micro-vesicular degeneration was more severe in G2 compared with G3 and G4. Apoptosis, hemorrhagic necrosis, mitochondrial damage and leucocyte adhesion were evident in G2. CONCLUSION: The portal flow modulation induced by splenectomy or splenic transposition was effective in limiting early damage after extended liver resection.


Assuntos
Hepatectomia/efeitos adversos , Fígado/patologia , Fígado/fisiopatologia , Tamanho do Órgão/fisiologia , Sistema Porta/fisiopatologia , Alanina Transaminase/sangue , Análise de Variância , Animais , Apoptose , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Glutationa/metabolismo , Fígado/metabolismo , Circulação Hepática/fisiologia , Masculino , Necrose , Oxigênio/sangue , Ratos , Esplenectomia
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