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1.
J Spinal Cord Med ; : 1-7, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32223592

RESUMO

Context: Both copper and betanin have been implicated as having significant bioactivity against ischemic damage in a variety of experimental and clinical settings. The aim of this study is to investigate whether betanin and copper have any protective effect on spinal cord in an ischemia-reperfusion (I/R) model in rats.Design: Spraque-Dawley rats were used in four groups: Sham group (n = 7), control group (laparotomy and cross-clamping of aorta, n = 7), betanin treatment group (dosage of 100 mg/kg of betanin administered intraperitoneally (i.p.) 60 min before laparotomy, n = 7), copper sulfate treatment group (administered copper sulfate i.p. at a dose of 0.1 mg/kg/day for 7 days before laparotomy, n = 7). Malondialdehyde (MDA), glutathione (GSH) levels, myeloperoxidase (MPO) and superoxide dismutase (SOD) activity were measured. Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay was also performed to evaluate apoptosis.Setting: Kafkas University, Faculty of Medicine, Kars, Turkey.Results: I/R injury was successfully demonstrated with the surgical model. Betanin and copper treatment significantly decreased MDA levels, MPO activity and the number of apoptotic cells in the spinal cord. Betanin and copper treatment significantly increased GSH levels. Copper treatment significantly increased SOD activity, whereas betanin was not as effective. Apoptotic cells were significantly decreased in both treatment groups.Conclusion: I/R injury of the spinal cord can be successfully demonstrated by aortic clamping in this surgical model. Betanin/Copper sulphate has ameliorative effects against operative I/R injury. Low toxicity of those agents makes them ideal targets for clinical research for this purpose.

2.
J Invest Surg ; : 1-6, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31509033

RESUMO

Objective: The aim of this study is to determine protective/modulatory effects of betanin in a femoral artery vasospasm model in rats. Materials and Methods: Sprague-Dawley rats were divided into three groups. Group 1: sham (n = 7), group 2: vasospasm model only (n = 7), group 3: postoperative betanin treatment in the vasospasm model (n = 7). 100 mg/kg betanin was administered orally to group 3 for 7 days, postoperatively. Peripheral blood malondialdehyde (MDA) and nitric oxide (NO) levels were measured for the quantification of oxidative stress, lumen diameter and wall thickness of femoral artery segments were determined to assess vasodilator effects of betanin. Results: Femoral artery vasospasm formation significantly increased both MDA (13.54 ± 3.09 mmol/mL) and NO levels (0.61 ± 0.06 µmol/mL) relative to the sham (9.07 ± 1.09 and 0.48 ± 0.1, respectively). Upon betanin administration, both MDA and NO approached baseline levels (9.95 ± 0.92 and 0.5 ± 0.06, respectively). Pathological examination of lumen diameter and wall thickness of the femoral arteries also revealed that betanin administration resulted in significant increase in lumen diameter when compared to vasospasm group (614.15 ± 245.77 versus 117.40 ± 46.19 µm) and decrease in wall thickness (64.68 ± 14.13 versus 96.73 ± 9.20 µm). Conclusion: Betanin was shown to have protective effect against oxidative stress in a peripheral artery vasospasm model in rats. It may also have a role in mitigating maladaptive changes in arterial structure, as shown in pathological examination.

3.
J Enzyme Inhib Med Chem ; 34(1): 789-798, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30871382

RESUMO

In this study, we investigated whether jervine (J) could prevent gastrointestinal (GI) side effects of abdominopelvic radiotherapy (RT) in Wistar-Albino female rats. Rats were divided into five groups: control (C), J only (J), J administered at 5 mg/kg/days for 7 days, RT only (RT), J before RT (J + RT), J administered for seven days before RT, J both before and after RT (J + RT + J), and J administered for 7 days before RT and after RT for 3 days. The weights of rats were measured on the 1st, 7th, and 10th days of the study. Rats were sacrificed to obtain tissues from the liver and intestine, which was followed by taking blood samples intracardially. In addition, the tissues were stained with pyruvate dehydrogenase (PDH) immunohistochemically. In our study, J supplementation markedly reduced weight loss, and histopathological, immunohistochemical, biochemical results suggest that J had a protective effect on GI toxicity following RT.


Assuntos
Fármacos Gastrointestinais/uso terapêutico , Lesões por Radiação/patologia , Lesões por Radiação/prevenção & controle , Alcaloides de Veratrum/uso terapêutico , Animais , Fármacos Gastrointestinais/química , Fármacos Gastrointestinais/farmacologia , Ratos , Ratos Wistar , Alcaloides de Veratrum/química , Alcaloides de Veratrum/farmacologia
4.
Int J Vitam Nutr Res ; : 1-7, 2019 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-30747610

RESUMO

The aim of this study was to investigate the effects of boric acid (BA) and borax (BX) on live weight and obesity associated molecules including leptin, L-carnitine, insulin-like growth factor 1 (IGF-I), and heat shock proteins 70 (HSP70) in rats fed with high-fat diet. A total of 60 rats were equally allocated as ND (normal diet), HF (high-fat diet), HF+BA, HF+BX, ND+BX, ND+BA. Body weight increases in HF+BA (85 g) and HF+BX (86 g) were significantly lower (p<0.05) compared to HF group (126 g). Boron treatment decreased serum L-carnitine level in high-fat diet (HF+BA 11.12 mg/L, HF+BX 10.51 mg/L, p<0.05) compared to HF group (15.57 mg/L), while no change was observed in groups ND+BA (7.55 mg/L) and ND+BX (7.57 mg/L) compared to group ND (8.29 mg/L). Neither BA nor BX supplementation in ND and HF groups altered the serum levels of HSP70 and leptin. BA and BX supplementation in rats fed HF resulted in a significant reduction in live weight. Boron compounds altered L-carnitine and IGF-1 levels in rats. These results indicate that boron compounds are beneficial in the treatment of obesity as well as in the prevention of high-fat diet-induced weight increase. Alterations in serum L-carnitine and IGF-1 levels in boron treated rats also indicate possible role of boron compounds in energy metabolism in response to high fat diet.

5.
Adv Med Sci ; 63(2): 296-300, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29803118

RESUMO

PURPOSE: Barrett's esophagus is one of the main risk factors for increased incidence of esophageal adenocarcinoma. In this study, we studied protein expression levels and cellular localizations of MUC-1, MUC-2, MUC-5AC, CK7, and cytoplasmic p27 to assess the relationship between the expression of each of these proteins and the disease progression on endoscopic biopsies. MATERIALS AND METHODS: Immunohistochemical analyses were performed using antibodies produced against MUC-1, MUC-2, MUC-5AC, CK7, and p27. Endoscopic specimens of esophageal mucosa were obtained from 72 patients who underwent esophagectomy for Barrett's esophagus, metaplasia, dysplasia, or esophageal adenocarcinoma developed from Barrett's esophagus. RESULTS: Multilayer squamous epithelium showed only MUC-1 positivity in the EAC group while MUC-2 and MUC-5AC staining could not be detected in this group. Strong and diffused membranous or cytoplasmic staining of CK7 was observed at squamous, ductal, surface columnar and/or glandular epithelium. c-p27 staining was diffused and moderate in the cellular membranes observed in all groups except for esophageal epithelial metaplasia without intestinal metaplasia. Additionally, weakly focal cytoplasmic staining in squamous epithelium of p27 in EAC was detected. CONCLUSIONS: Barrett's esophagus, which has a heterogeneous epithelium, might yield different diagnosis based on endoscopic evaluation and immunohistological investigation. Thus, the use of MUC1, p27, and CK7 might strengthen the truthful diagnosis. MUC-1, CK7, and c-p27 immunostaining can be used as the predictive markers for esophageal cancer progression from Barrett's esophagus.


Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Esôfago de Barrett/metabolismo , Esôfago de Barrett/patologia , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Queratina-7/metabolismo , Mucina-1/metabolismo , Mucina-2/metabolismo , Citoplasma/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos
6.
Anticancer Res ; 38(2): 647-654, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29374686

RESUMO

BACKGROUND/AIM: Sirtuins (SIRTs) play crucial roles in various signaling pathways that modulate differentiation and proliferation. We sought to elucidate the role of SIRTs in differentiation and proliferation of human neuroblastoma (NB). MATERIALS AND METHODS: NB cells were treated with nicotinamide (NAM), a non-specific SIRT inhibitor, SIRT-targeted short hairpin RNAs, and retinoic acid to assess cell growth and differentiation. RESULTS: SIRTs are involved in proliferation and differentiation using NAM in BE(2)-C cells. Specifically, SIRT6 knockdown in BE(2)-C cells reduced cell proliferation, induced neurite extension, corresponding with induction of p21CIP1 expression and G1 cell-cycle arrest. These effects were rescued by forced re-overexpression of SIRT6. SIRT6 expression was reduced in differentiated human NB sections, and RA-induced differentiation in BE(2)-C cells. CONCLUSION: SIRTs have important oncogenic properties in NB beyond its established functions in aging and genome stability. SIRT6 may represent a novel target for developing future therapeutics for the treatment of aggressive NBs.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Neuroblastoma/tratamento farmacológico , Neuroblastoma/metabolismo , Sirtuínas/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Técnicas de Silenciamento de Genes , Humanos , Neuroblastoma/patologia , Niacinamida/farmacologia , RNA Interferente Pequeno/farmacologia , Sirtuínas/genética , Tretinoína/administração & dosagem , Tretinoína/farmacologia
7.
Sci Rep ; 7(1): 5569, 2017 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-28717230

RESUMO

Advanced colorectal cancer (CRC) remains a critical health care challenge worldwide. Various TGF-ß superfamily members are important in colorectal cancer metastasis, but their signaling effects and predictive value have only been assessed in isolation. Here, we examine cross-regulation and combined functions of the two most prominent TGF-ß superfamily members activin and TGF-ß in advanced colorectal cancer. In two clinical cohorts we observed by immune-based assay that combined serum and tissue activin and TGF-ß ligand levels predicts outcome in CRC patients and is superior to single ligand assessment. While TGF-ß growth suppression is independent of activin, TGF-ß treatment leads to increased activin secretion in colon cancer cells and TGF-ß induced cellular migration is dependent on activin, indicating pathway cross-regulation and functional interaction in vitro. mRNA expression of activin and TGF-ß pathway members were queried in silico using the TCGA data set. Coordinated ligand and receptor expression is common in solid tumors for activin and TGF-ß pathway members. In conclusion, activin and TGF-ß are strongly connected signaling pathways that are important in advanced CRC. Assessing activin and TGF-ß signaling as a unit yields important insights applicable to future diagnostic and therapeutic interventions.


Assuntos
Ativinas/genética , Ativinas/metabolismo , Neoplasias Colorretais/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Ativinas/sangue , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Masculino , Estadiamento de Neoplasias , Prognóstico , Transdução de Sinais , Análise de Sobrevida , Fator de Crescimento Transformador beta/sangue , Regulação para Cima
8.
Oncotarget ; 8(23): 37377-37393, 2017 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-28418896

RESUMO

Colorectal cancer (CRC) remains a common and deadly cancer due to metastatic disease. Activin and TGFB (TGFß) signaling are growth suppressive pathways that exert non-canonical pro-metastatic effects late in CRC carcinogenesis. We have recently shown that activin downregulates p21 via ubiquitination and degradation associated with enhanced cellular migration independent of SMADs. To investigate the mechanism of metastatic activin signaling, we examined activated NFkB signaling and activin ligand expression in CRC patient samples and found a strong correlation. We hypothesize that activation of the E3 ubiquitin ligase MDM2 by NFkB leads to p21 degradation in response to activin treatment. To dissect the link between activin and pro-carcinogenic NFkB signaling and downstream targets, we found that activin but not TGFB induced activation of NFkB leading to increased MDM2 ubiquitin ligase via PI3K. Further, overexpression of wild type p65 NFkB increased MDM2 expression while the NFkB inhibitors NEMO-binding domain (NBD) and Bay11-7082 blocked the activin-induced increase in MDM2. In conclusion, in colon cancer cell migration, activin utilizes NFkB to induce MDM2 activity leading to the degradation of p21 in a PI3K dependent mechanism. This provides new mechanistic knowledge linking activin and NFkB signaling in advanced colon cancer which is applicable to targeted therapeutic interventions.


Assuntos
Ativinas/metabolismo , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Neoplasias Colorretais/metabolismo , NF-kappa B/metabolismo , Carcinogênese , Linhagem Celular Tumoral , Movimento Celular , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , NF-kappa B/genética , Nitrilos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Transdução de Sinais , Sulfonas/farmacologia , Ubiquitina-Proteína Ligases/metabolismo
9.
Bull Environ Contam Toxicol ; 97(2): 191-7, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27329111

RESUMO

Mussel samples were collected monthly between October-2010 and October-2011 from four stations (Bosphorus, Bandirma, Gelibolu, Tekirdag) in the Marmara Sea. Two consecutive months' samples were homogenized and combined as a single group for analysis. Mussel samples were analyzed for Organochlorine pesticides (OCPs); (total-DDT, total-HCH, Endrin, α-Endosulfan, ß-Endosulfan, Heptachlor) and Polychlorinated biphenyls (PCBs); (PCB 28, PCB 52, PCB 138, PCB 153, and PCB 180). All analyses were done according to Eurofins house method in ERGO Laboratory in Germany. Concentrations of α-endosulfan and heptachlor in mussel tissues were below method detection limits. The annual average OCPs concentrations among the stations ranged between 0.02 and 1.45 ng/g (wet weight), 1.9-99.75 ng/g (lipid weight) whereas the annual average PCBs concentrations among the stations ranged between 0.03 and 0.40 ng/g (wet weight), 1.71-26.48 ng/g (lipid weight), respectively. There was no relation between fat content of mussels and residues of the contaminants. PCB 138 and PCB 153 were the most predominant PCBs, while total-DDT and total-HCH were the most predominant OCPs in the mussels. Total-DDT concentrations were higher compared to total-HCH and PCBs isomers. Measured levels were below the national and international committees' and institutions' limits for human consumption and protection of aquatic biota.


Assuntos
Monitoramento Ambiental , Hidrocarbonetos Clorados/metabolismo , Mytilus/metabolismo , Praguicidas/metabolismo , Bifenilos Policlorados/metabolismo , Poluentes Químicos da Água/metabolismo , Animais , Endossulfano/análise , Endossulfano/metabolismo , Alemanha , Heptacloro/análise , Heptacloro/metabolismo , Hidrocarbonetos Clorados/análise , Praguicidas/análise , Bifenilos Policlorados/análise , Poluentes Químicos da Água/análise
10.
Sci Rep ; 6: 26273, 2016 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-27197561

RESUMO

BRCA1-associated RING domain protein 1 (BARD1) stabilizes BRCA1 protein by forming a heterodimeric RING-RING complex, and impacts function of BRCA1, including homologous recombination (HR) repair. Although colon cancer cells usually express wild type BRCA1, presence of an oncogenic BARD1 splice variant (SV) in select cancers may render BRCA1 dysfunctional and allow cells to become sensitive to HR targeting therapies. We previously reported association of loss of full-length (FL) BARD1 with poor prognosis in colon cancer as well as expression of various BARD1 SVs with unknown function. Here we show that loss of BARD1 function through the expression of a BARD1 SV, BARD1ß, results in a more malignant phenotype with decreased RAD51 foci formation, reduced BRCA1 E3 ubiquitin ligase activity, and decreased nuclear BRCA1 protein localization. BARD1ß sensitizes colon cancer cells to poly ADP ribose polymerase 1 (PARP-1) inhibition even in a FL BRCA1 background. These results suggest that expression of BARD1ß may serve as a future biomarker to assess suitability of colon cancers for HR targeting with PARP-1 inhibitors in treatment of advanced colon cancer.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteína BRCA1/genética , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Recombinação Homóloga , Humanos , Irinotecano/farmacologia , Irinotecano/uso terapêutico , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Processamento de Proteína , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
11.
Cancer Res ; 76(13): 3802-12, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27197174

RESUMO

Sirtuins participate in sensing nutrient availability and directing metabolic activity to match energy needs with energy production and consumption. However, the pivotal targets for sirtuins in cancer are mainly unknown. In this study, we identify the M2 isoform of pyruvate kinase (PKM2) as a critical target of the sirtuin SIRT2 implicated in cancer. PKM2 directs the synthesis of pyruvate and acetyl-CoA, the latter of which is transported to mitochondria for use in the Krebs cycle to generate ATP. Enabled by a shotgun mass spectrometry analysis founded on tissue culture models, we identified a candidate SIRT2 deacetylation target at PKM2 lysine 305 (K305). Biochemical experiments including site-directed mutants that mimicked constitutive acetylation suggested that acetylation reduced PKM2 activity by preventing tetramerization to the active enzymatic form. Notably, ectopic overexpression of a deacetylated PKM2 mutant in Sirt2-deficient mammary tumor cells altered glucose metabolism and inhibited malignant growth. Taken together, our results argued that loss of SIRT2 function in cancer cells reprograms their glycolytic metabolism via PKM2 regulation, partially explaining the tumor-permissive phenotype of mice lacking Sirt2 Cancer Res; 76(13); 3802-12. ©2016 AACR.


Assuntos
Neoplasias da Mama/patologia , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Glucose/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Recidiva Local de Neoplasia/patologia , Sirtuína 2/fisiologia , Hormônios Tireóideos/química , Hormônios Tireóideos/metabolismo , Acetilação , Animais , Western Blotting , Neoplasias da Mama/metabolismo , Proliferação de Células , Feminino , Imunofluorescência , Glicólise , Humanos , Técnicas Imunoenzimáticas , Camundongos , Camundongos Knockout , Recidiva Local de Neoplasia/metabolismo , Estadiamento de Neoplasias , Prognóstico , Análise Serial de Tecidos , Células Tumorais Cultivadas
12.
Mol Cancer ; 14: 182, 2015 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-26497569

RESUMO

BACKGROUND: Understanding cell signaling pathways that contribute to metastatic colon cancer is critical to risk stratification in the era of personalized therapeutics. Here, we dissect the unique involvement of mitogenic pathways in a TGFß or activin-induced metastatic phenotype of colon cancer. METHOD: Mitogenic signaling/growth factor receptor status and p21 localization were correlated in primary colon cancers and intestinal tumors from either AOM/DSS treated ACVR2A (activin receptor 2) -/- or wild type mice. Colon cancer cell lines (+/- SMAD4) were interrogated for ligand-induced PI3K and MEK/ERK pathway activation and downstream protein/phospho-isoform expression/association after knockdown and pharmacologic inhibition of pathway members. EMT was assessed using epithelial/mesenchymal markers and migration assays. RESULTS: In primary colon cancers, loss of nuclear p21 correlated with upstream activation of activin/PI3K while nuclear p21 expression was associated with TGFß/MEK/ERK pathway activation. Activin, but not TGFß, led to PI3K activation via interaction of ACVR1B and p85 independent of SMAD4, resulting in p21 downregulation. In contrast, TGFß increased p21 via MEK/ERK pathway through a SMAD4-dependent mechanism. While activin induced EMT via PI3K, TGFß induced EMT via MEK/ERK activation. In vivo, loss of ACVR2A resulted in loss of pAkt, consistent with activin-dependent PI3K signaling. CONCLUSION: Although activin and TGFß share growth suppressive SMAD signaling in colon cancer, they diverge in their SMAD4-independent pro-migratory signaling utilizing distinct mitogenic signaling pathways that affect EMT. p21 localization in colon cancer may determine a dominant activin versus TGFß ligand signaling phenotype warranting further validation as a therapeutic biomarker prior to targeting TGFß family receptors.


Assuntos
Ativinas/metabolismo , Neoplasias do Colo/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Receptores de Activinas Tipo II/genética , Receptores de Activinas Tipo II/metabolismo , Ativinas/genética , Animais , Western Blotting , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Imuno-Histoquímica , Imunoprecipitação , Técnicas In Vitro , Camundongos , Camundongos Knockout , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/genética
13.
Free Radic Biol Med ; 76: 163-172, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25152236

RESUMO

Pyruvate dehydrogenase E1α (PDHA1) is the first component enzyme of the pyruvate dehydrogenase (PDH) complex that transforms pyruvate, via pyruvate decarboxylation, into acetyl-CoA that is subsequently used by both the citric acid cycle and oxidative phosphorylation to generate ATP. As such, PDH links glycolysis and oxidative phosphorylation in normal as well as cancer cells. Herein we report that SIRT3 interacts with PDHA1 and directs its enzymatic activity via changes in protein acetylation. SIRT3 deacetylates PDHA1 lysine 321 (K321), and a PDHA1 mutant mimicking a deacetylated lysine (PDHA1(K321R)) increases PDH activity, compared to the K321 acetylation mimic (PDHA1(K321Q)) or wild-type PDHA1. Finally, PDHA1(K321Q) exhibited a more transformed in vitro cellular phenotype compared to PDHA1(K321R). These results suggest that the acetylation of PDHA1 provides another layer of enzymatic regulation, in addition to phosphorylation, involving a reversible acetyllysine, suggesting that the acetylome, as well as the kinome, links glycolysis to respiration.


Assuntos
Lisina/metabolismo , Neoplasias/enzimologia , Processamento de Proteína Pós-Traducional , Piruvato Desidrogenase (Lipoamida)/metabolismo , Ácido Pirúvico/metabolismo , Sirtuína 3/metabolismo , Acetilação , Western Blotting , Proliferação de Células , Imunofluorescência , Glucose/metabolismo , Glicólise , Humanos , Imunoprecipitação , Ácido Láctico/metabolismo , Lisina/química , Neoplasias/patologia , Oxirredução , Fosforilação Oxidativa , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Células Tumorais Cultivadas
14.
Bull Environ Contam Toxicol ; 90(5): 542-51, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23328894

RESUMO

Toxic metal (Hg, Cd, Pb, Cu and Zn) concentrations of small-medium bluefish, anchovy and sardine in Istanbul, Turkey, were determined using inductively coupled plasma-mass spectrometry (ICP-MS) throughout 1 year. The concentrations of pollutants were found to vary according to season and species. Estimates of weekly intake levels of the metals were calculated and compared to recommended safe limits for fish consumption by humans. The levels of Cd, Pb, Cu and Zn in the fillets of all species resulted in estimates of weekly intake levels that were lower than the recommended safe limits. The concentrations of Hg of small bluefish in September, of medium bluefish in June and September, of anchovy in March, and of sardine in August and September resulted in estimates of weekly intake levels that were higher than the recommended safe limits for human consumption.


Assuntos
Exposição Ambiental/análise , Metais/metabolismo , Perciformes/metabolismo , Poluentes Químicos da Água/metabolismo , Animais , Exposição Ambiental/estatística & dados numéricos , Contaminação de Alimentos/estatística & dados numéricos , Humanos , Alimentos Marinhos/estatística & dados numéricos , Turquia
15.
Transl Cancer Res ; 1(1): 15-21, 2012 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-22943040

RESUMO

One long standing observation in clinical oncology is that age increase is the single most statistically significant factor/variable that predicts for the incidence of solid tumors. This observation suggests that the cellular and molecular processes and mechanisms that direct an organism's life span may be used to determine the clinical connection between aging and carcinogenesis. In this regard, the genes that impact upon longevity have been characterized in S. cerevisiae and C. elegans, and the human homologs include the Sirtuin family of protein deacetylases. We have recently shown that the primary cytoplasmic sirtuin, Sirt2 appears to meet the criteria as a legitimate tumor suppressor protein. Mice genetically altered to delete Sirt2 develop gender-specific tumorigenesis, with females primarily developing mammary tumors, and males developing multiple different types of gastrointestinal malignancies. Furthermore human tumors, as compared to normal samples, displayed significant decreases in SIRT2 levels suggesting that SIRT2 may also be a human tumor suppressor.

16.
Free Radic Biol Med ; 53(4): 828-33, 2012 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-22732184

RESUMO

Mitochondrial oxidative metabolism is the major site of ATP production as well as a significant source of reactive oxygen species (ROS) that can cause damage to critical biomolecules. It is well known that mitochondrial enzymes that scavenge ROS are targeted by stress responsive proteins to maintain the fidelity of mitochondrial function. Manganese superoxide dismutase (MnSOD) is a primary mitochondrial ROS scavenging enzyme, and in 1983 Irwin Fridovich proposed an elegant chemical mechanism/model whereby acetylation directs MnSOD enzymatic activity. He christened it the "electrostatic repulsion model." However, the biochemical and genetic mechanism(s) determining how acetylation directs activity and the reasons behind the evolutionarily conserved need for several layers of transcriptional and posttranslational MnSOD regulation remain unknown. In this regard, we and others have shown that MnSOD is regulated, at least in part, by the deacetylation of specific conserved lysines in a reaction catalyzed by the mitochondrial sirtuin, Sirt3. We speculate that the regulation of MnSOD activity by lysine acetylation via an electrostatic repulsion mechanism is a conserved and critical aspect of MnSOD regulation necessary to maintain mitochondrial homeostasis.


Assuntos
Sirtuína 3/fisiologia , Superóxido Dismutase/metabolismo , Acetilação , Animais , Eletroquímica , Homeostase , Humanos , Mitocôndrias/enzimologia , Mitocôndrias/metabolismo , Ligação Proteica , Processamento de Proteína Pós-Traducional , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Sirtuína 3/química , Superóxido Dismutase/química
17.
Int J Mol Sci ; 12(9): 6226-39, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22016654

RESUMO

One fundamental observation in cancer etiology is that the rate of malignancies in any mammalian population increases exponentially as a function of age, suggesting a mechanistic link between the cellular processes governing longevity and carcinogenesis. In addition, it is well established that aberrations in mitochondrial metabolism, as measured by increased reactive oxygen species (ROS), are observed in both aging and cancer. In this regard, genes that impact upon longevity have recently been characterized in S. cerevisiae and C. elegans, and the human homologs include the Sirtuin family of protein deacetylases. Interestingly, three of the seven sirtuin proteins are localized into the mitochondria suggesting a connection between the mitochondrial sirtuins, the free radical theory of aging, and carcinogenesis. Based on these results it has been hypothesized that Sirt3 functions as a mitochondrial fidelity protein whose function governs both aging and carcinogenesis by modulating ROS metabolism. Sirt3 has also now been identified as a genomically expressed, mitochondrial localized tumor suppressor and this review will outline potential relationships between mitochondrial ROS/superoxide levels, aging, and cell phenotypes permissive for estrogen and progesterone receptor positive breast carcinogenesis.


Assuntos
Carcinogênese/metabolismo , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 3/metabolismo , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Regulação Enzimológica da Expressão Gênica , Humanos , Modelos Biológicos , Sirtuína 3/genética
18.
Aging (Albany NY) ; 3(2): 102-7, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21386137

RESUMO

A fundamental observation in biology is that mitochondrial function, as measured by increased reactive oxygen species (ROS), changes significantly with age, suggesting a potential mechanistic link between the cellular processes governing longevity and mitochondrial metabolism homeostasis. In addition, it is well established that altered ROS levels are observed in multiple age-related illnesses including carcinogenesis, neurodegenerative, fatty liver, insulin resistance, and cardiac disease, to name just a few. Manganese superoxide dismutase (MnSOD) is the primary mitochondrial ROS scavenging enzyme that converts superoxide to hydrogen peroxide, which is subsequently converted to water by catalase and other peroxidases. It has recently been shown that MnSOD enzymatic activity is regulated by the reversible acetylation of specific, evolutionarily conserved lysine(s) in the protein. These results, suggest for the first time, that the mitochondria contain bidirectional post-translational signaling networks, similar to that observed in the cytoplasm and nucleus, and that changes in lysine acetylation alter MnSOD enzymatic activity. In addition, these new results demonstrate that the mitochondrial anti-aging or fidelity / sensing protein, SIRT3, responds to changes in mitochondrial nutrient and/or redox status to alter the enzymatic activity of specific downstream targets, including MnSOD that adjusts and/or maintains ROS levels as well as metabolic homeostatic poise.


Assuntos
Metabolismo Energético , Estresse Oxidativo , Superóxido Dismutase/metabolismo , Acetilação , Animais , Homeostase , Humanos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 3/metabolismo , Superóxido Dismutase/genética
19.
Mol Cell ; 40(6): 893-904, 2010 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-21172655

RESUMO

Genetic deletion of the mitochondrial deacetylase sirtuin-3 (Sirt3) results in increased mitochondrial superoxide, a tumor-permissive environment, and mammary tumor development. MnSOD contains a nutrient- and ionizing radiation (IR)-dependent reversible acetyl-lysine that is hyperacetylated in Sirt3⁻/⁻ livers at 3 months of age. Livers of Sirt3⁻/⁻ mice exhibit decreased MnSOD activity, but not immunoreactive protein, relative to wild-type livers. Reintroduction of wild-type but not deacetylation null Sirt3 into Sirt3⁻/⁻ MEFs deacetylated lysine and restored MnSOD activity. Site-directed mutagenesis of MnSOD lysine 122 to an arginine, mimicking deacetylation (lenti-MnSOD(K122-R)), increased MnSOD activity when expressed in MnSOD⁻/⁻ MEFs, suggesting acetylation directly regulates function. Furthermore, infection of Sirt3⁻/⁻ MEFs with lenti-MnSOD(K122-R) inhibited in vitro immortalization by an oncogene (Ras), inhibited IR-induced genomic instability, and decreased mitochondrial superoxide. Finally, IR was unable to induce MnSOD deacetylation or activity in Sirt3⁻/⁻ livers, and these irradiated livers displayed significant IR-induced cell damage and microvacuolization in their hepatocytes.


Assuntos
Sequência Conservada , Evolução Molecular , Lisina/metabolismo , Estresse Oxidativo , Sirtuína 3/metabolismo , Superóxido Dismutase/metabolismo , Acetilação , Animais , Arginina/metabolismo , Linhagem Celular , Camundongos , Mutagênese Sítio-Dirigida , Sirtuína 3/deficiência , Sirtuína 3/genética
20.
J Med Food ; 13(6): 1524-31, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20874243

RESUMO

Amino acid and proximate compositions were determined in six raw and cooked marine fish species that are commonly consumed in Turkey. The changes in amino acid and proximate content were found to be significant for all cooking methods in all fish species. Cooking did, in general, significantly increase the contents of essential, semiessential, and other amino acids compared with raw fish species. Grilled Atlantic bonito, anchovy, and bluefish and fried mullet and hake appeared to be more valuable fish dishes for obtaining the officially recommended appropriate daily intake of essential amino acids for humans. Moisture, fat, ash, and carbohydrate contents of raw fish ranged between 48.01% and 83.05%, 0.87% and 30.48%, 1.10% and 1.61%, and 0.09% and 8.70%, respectively. All fresh fish investigated were high in protein: 11.20-17.14 g/100 g. Wide variations in protein content (18.11-25.65 g/100 g) between species and methods of cooking were observed. Fried fish had intermediate fat values, whereas grilled and steamed fishes had a comparatively low value.


Assuntos
Aminoácidos/análise , Culinária/métodos , Peixes , Alimentos Marinhos/análise , Aminoácidos Essenciais/análise , Animais , Carboidratos da Dieta/análise , Gorduras na Dieta/análise , Proteínas na Dieta/análise , Gadiformes , Valor Nutritivo , Perciformes , Smegmamorpha , Turquia , Água/análise
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