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1.
Clin Rheumatol ; 39(8): 2399-2408, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32103372

RESUMO

BACKGROUND: Osteoarthritis (OA) is a degenerative chronic illness that most frequently occurs in the knee joint. Daidzein (DZ) an isoflavone has anti-inflammatory and antioxidant activity. The aim of this study was to evaluate the effectiveness of DZ as a treatment for experimental knee OA (KOA) in rats. METHOD: An experimental KOA model was induced by monosodium iodoacetate (MIA) in rats. Thereafter, 49 Wistar albino male rats (250-300 g, 12-16 weeks old) were randomly divided into 7 groups: C (healthy control); DC (KOA + saline); hyaluronic acid (HA); HA+ intraarticular (ia) DZ; oral (po) DZ; ia DZ; HA + po DZ groups. DZ and/or HA were administered intraarticularly to the rats as 50 µL on days 1, 7, 14, and 21. Alternatively, the DZ was administered orally as 0.5 mL twice daily for 21 days. After the treatment, rats were sacrificed by decapitation under general anesthesia. Serum samples were analyzed to determine the total oxidant status (TOS) and total antioxidant status (TAS) and the levels of TNF-α, IL-1ß, MMP-13, and DZ. Knee joint samples underwent histopathological examination, and TNF-α, IL-1ß, NOS2, and MMP-13 were analyzed with immunohistochemical methods. RESULTS: HA, DZ, and DZ + HA effectively reduced the levels of TNF-α, IL-1ß, and MMP-13 in the serum of the DC group (p < 0.001). In groups that received HA, DZ, or DZ + HA, the serum TAS increased compared with the DC group (p < 0.05). When the DZ + HA combination was used, a more pronounced reduction in the levels of TNFα, NOS2, IL-1ß, and MMP-13 was observed in knee joints. In addition, the cracks on the cartilage surface and fibrillation were completely improved in the groups that received HA, DZ, or DZ + HA compared with the DC group. CONCLUSION: DZ had anti-inflammatory and antioxidant effects in a rat OA model. Therefore, DZ, as monotherapy or especially in combination with HA, may be a promising and beneficial therapy for OA. Key Points •DZ has been shown to reduce TNF-α, IL-1ß, and MMP-13 both in serum and in tissue samples taken from the knee-joints. •The cracks on the cartilage surface and fibrillation in KOA were completely improved by using DZ and DZ + HA combination. •DZ may be useful to eliminate/reduce/ameliorate inflammation and oxidative damage in the pathogenesis of KOA. •DZ, alone or in combination with HA, may be a promising natural compound with beneficial effects in the treatment of KOA.

2.
Biomed Chromatogr ; 34(2): e4738, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31677392

RESUMO

ST segment elevation myocardial infarction (STEMI) is one of the most common global causes of cardiovascular disease-related death. Several metabolites may change during STEMI. Hence, analysis of metabolites in body fluid may be considered as a rapid and accurate test for initial diagnosis. This study has therefore attempted to determine the variation in metabolites identified in the serum of STEMI patients (n = 20) and 15 controls. Samples collected from the Cardiology Department, Medical Faculty, Ataturk University, were extracted by liquid-liquid extraction and analysed using liquid chromatography quadrupole time-of-flight mass spectrometry. The METLIN database was used for the identification and characterization of metabolites. According to Q-TOF/MS measurements, 231 m/z values, which were significantly different between groups (P < 0.01 and fold analysis >1.5) were detected. Metabolite identification was achieved via the Human Metabolome database. According to the multivariate data analysis, leucine, isoleucine, l-proline, l-alanine, glycine, fumaric acid, citrate, succinate and carnitine levels were decreased, whereas levels of propionic acid, maleic acid, butyric acid, urea, oleic acid, palmitic acid, lysoPC [18:2(9Z)], glycerol, phoshpatidylethanolamine, caffeine and l-lactic acid were increased in STEMI patients compared with controls. In conclusion, malonic acid, maleic acid, fumaric acid and palmitic acid can be used as biomarkers for early risk stratification of patients with STEMI.


Assuntos
Cromatografia Líquida/métodos , Espectrometria de Massas/métodos , Metabolômica/métodos , Infarto do Miocárdio com Supradesnível do Segmento ST , Aminoácidos/sangue , Feminino , Fumaratos/sangue , Humanos , Masculino , Maleatos/sangue , Malonatos/sangue , Metaboloma/fisiologia , Pessoa de Meia-Idade , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/metabolismo
3.
Curr Rheumatol Rev ; 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31878858

RESUMO

OBJECTIVE: Knee osteoarthritis (KOA) is defined as a chronic degenerative joint disease. Obesity is a significant risk factor for KOA. Omentin is an adipose tissue-induced adipokine. The aim of the present study was to investigate the correlation between obesity and serum omentin levels in patients with KOA. METHODS: This study included 60 patients with KOA, 34 obese individuals (O-KOA) and 26 nonobese individuals (NO-KOA) and 40 controls, 17 obese individuals (OC) and 23 nonobese individuals (NOC) matched in terms of age, sex, and body mass index (BMI) who were recruited from the same polyclinic. Blood samples and knee radiographs were obtained from all the subjects, and clinical features, BMI, and laboratory parameters were recorded. The Kellgren-Lawrence (KL) grade and Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index were used to classify the radiographic and clinical findings, respectively. Serum omentin levels were determined using an ELISA. RESULTS: Serum omentin levels in patients were significantly lower than those in the controls (p < 0.05). When the BMI values and KL scores were considered, serum omentin levels significantly decreased in severe O-KOA versus in mild-to-moderate O-KOA. There was no statistically significant decrease in severe NO-KOA versus mild-to-moderate NO-KOA. There was a significant negative correlation between the serum omentin level and BMI and WOMAC index. All findings were supported by a receiver operating characteristic curve analysis. CONCLUSION: Serum omentin levels were inversely related to obesity and the severity of KOA. The data indicate that omentin may be a new biomarker of KOA to our knowledge and may aid the diagnosis of early-stage O-KOA.

4.
Mol Biol Rep ; 46(4): 4017-4025, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31079315

RESUMO

Homocysteine (hcy) is an amino acid that contains sulfur species. In healthy individuals, plasma hcy levels are low. The aim of this study was to investigate the potential neurotoxic effects of hcy and sulfite (sft) molecules alone and in their combination, and also to identify the relationship of these substances on oxidative stress. SH-SY5Y cells were used as an invitro neurodegenerative disease model. The SH-SY5Y cells were treated with various concentrations of hcy alone, sft alone (final concentrations in the well were 10-250 µM and 0.1-5 mM, respectively) and a combination of both (hcy + sft). Their cytotoxicity and genotoxic effects were investigated using the XTT test and Comet assay and, their impact on oxidative stress was examined using total antioxidant-oxidant status (TAS-TOS) kits. The highest toxic doses of hcy and sft were found to be 250 µM and 5 mM, respectively, but the maximum toxic effect was observed for hcy + sft (p < 0.001). In addition, an increase in DNA damage was evident in all groups, but maximal damage was inflicted using in hcy + sft (p < 0.001). The oxidative stress index was significantly increased in hcy + sft (p < 0.05). Determining the increase in sft and hcy levels may contribute to delaying the occurrence of diseases before symptoms of neurodegenerative disease appear.


Assuntos
Homocisteína/toxicidade , Doenças Neurodegenerativas/metabolismo , Sulfitos/toxicidade , Aminoácidos Sulfúricos/metabolismo , Antioxidantes/metabolismo , Linhagem Celular Tumoral , Ensaio Cometa , Dano ao DNA/efeitos dos fármacos , Homocisteína/metabolismo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Sulfito Oxidase/metabolismo , Sulfitos/metabolismo
5.
Clin Rheumatol ; 38(5): 1351-1360, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30637603

RESUMO

OBJECTIVE: Osteoarthritis (OA), the most encountered arthritis form, result from degeneration of articular cartilage. Obesity is accepted as a significant risk factor for knee OA (KOA). In this study, it is aimed to determine the variation of metabolites between control and patients with KOA and observe the effect of obesity on KOA via untargeted metabolomics method. METHODS: Serum samples of following groups were collected: patient group including 14 obesity (OKOA) and 14 non-obesity (NOKOA) (n = 28) and control group (n = 15) from orthopedics and traumatology policlinic. Serum proteins were denatured by acetonitrile and chromatographic separation of metabolites was achieved by LC/Q-TOF/MS/MS method. Data acquisition, classification, and identification were achieved by METLIN database. Cluster analysis was performed with MATLAB2017a-PLS Toolbox 7.2. RESULTS: Obtained results showed that 244 (patient vs control) and 274 (OKOA vs NOKOA) m/z ratios were determined in accordance with LC/Q-TOF/MS/MS analysis. Multivariate data analysis was applied 41 and 36 m/z signal (p ≤ 0.01; fold analysis > 1.5) were filtered for patient vs control group and OKOA vs NOKOA, respectively. Twenty-one different metabolites were identified for patient vs control group and 15 metabolites were determined for OKOA vs NOKOA group. CONCLUSION: Acid concentration and oxidative stress agents were high in inflammation group and their levels were much higher in obesity. It is claimed that obesity cause oxidative stress and acidosis in arthritis patients. Valine was found to be the only BCAA molecule whose concentration has significantly different in KOA patients. The relation between KOA and obesity was firstly investigated with metabolomics method.


Assuntos
Metaboloma , Obesidade/complicações , Osteoartrite do Joelho/diagnóstico , Idoso , Cromatografia Líquida , Análise por Conglomerados , Bases de Dados Factuais , Feminino , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Análise Multivariada , Obesidade/metabolismo , Osteoartrite do Joelho/metabolismo , Espectrometria de Massas em Tandem
6.
Int J Low Extrem Wounds ; 18(1): 56-64, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30612496

RESUMO

Parietin is one of the well-known anthraquinone compounds that can be extracted from Rheum ribes L. In this study, we aimed to investigate the effects of parietin isolated from Rheum ribes L on an in vitro wound model using human dermal fibroblast cells and compare its effectiveness against zinc. The antioxidant effect of parietin was determined by using the 1,1-diphenyl-2-picrylhydrazine (DPPH) method. Human dermal fibroblast cells were cultured in proculture medium and were kept until 100% confluence was achieved. The wound model was created by using a pipette tip. After that, different concentrations of parietin and zinc (final concentrations in the well to be 5-250 µM and 25-200 µM, respectively) were added into the medium. The proliferation-inducing effect on cell viability was determined by using MTT assay. Images of cells were taken at 0, 12, and 24 hours. According to the DPPH method, parietin exhibited have antioxidant activity. According to the MTT results, parietin exhibited significant proliferation-inducing effect on cell viability in a dose range of 5 to 10 M, and zinc showed significant proliferation-inducing effect on cell viability at dose 50 µM ( P < .05). In addition, the image of cell proliferation was also shown at the same doses at 24 hours. In this study, we claim that parietin induces cell proliferation at low doses in cases of dermal fibroblast loss. In conclusion, parietin as an alternative to zinc in wound healing could be used by clinicians in the future with more extensive studies.


Assuntos
Emodina/análogos & derivados , Fibroblastos/efeitos dos fármacos , Cicatrização/fisiologia , Ferimentos e Lesões/terapia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Emodina/farmacologia , Humanos , Técnicas In Vitro , Rheum , Ribes , Sensibilidade e Especificidade , Cicatrização/efeitos dos fármacos
7.
Eurasian J Med ; 50(3): 168-172, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30515037

RESUMO

Objective: Isoorientin (ISO) is a flavonoid compound extracted from plant species. The goal of this study was to determine the potential antiproliferative effects of ISO in HT-29 human colorectal adenocarcinoma cell line in vitro, specifically on cell viability, apoptosis, and cell cycle pathways. Materials and Methods: The cytotoxic effect of ISO isolated from E. spectabilis was measured using 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assay in HT-29 cell lines. Total RNA was isolated using Tri-Reagent protocol. The effects of ISO on apoptosis-related gene were detected using real-time polymerase chain reaction (RT-PCR). The findings were analyzed using "Delta-Delta CT" ΔΔCT method and evaluated using a computer program. Volcano plot analysis was used for comparing groups and the data obtained were statistically analyzed using Student t test. Results: According to XTT result analysis, the 50% inhibitory concentration (IC50) value of ISO was 125 µM at the 48th h in HT-29 cells. The RT-PCR analysis in HT-29 cells showed that Cyclin D1 (CCND1 ), Cyclin-dependent kinase 6 (CDK6), BAX, BCL-2, Checkpoint kinase 1-2 (CHEK1, CHEK2) and Excision repair cross-complementing 1 (ERCC1) expressions were reduced in ISO-treated cells compared with those in the control group of cells. P53, P21, Caspase-3 (CASP-3), Caspase-8 (CASP-8), and Caspase-9 (CASP-9) gene expressions were increased Ataxia Telengiectasia and Rad-3 related (ATR) was activated in the ISO-treated group of cells compared with those in the control group of cells (p<0.05). Conclusion: ISO affected the proliferation of colorectal cancer (CRC) cells via cell cycle pathways. It also altered apoptosis gene expression. These results demonstrated that ISO can be a therapeutic agent for CRC treatment; however, more studies are needed to investigate its mechanism of actions.

8.
Drug Chem Toxicol ; : 1-7, 2018 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-30394111

RESUMO

Daidzein (DZ) has anti-inflammatory and antioxidant effects, as well as the dose-dependent inhibition effect on cancer cells. In this study, the cytotoxic and genotoxic effects of DZ on HT-29 (human colorectal adenocarcinoma cells) and MIA PaCa-2 (human pancreatic cancer cells) cell lines were determined using the XTT method and Comet assay, respectively. IC50 concentrations of DZ were found to be 200 µM in both MIA PaCa-2 and HT-29 cells treated with DZ for 48 hours (h). When the cells were treated with 200 µM of DZ for 48 h, DNA damage was observed in both cell lines. DNA tail length (TL), tail moment (TM), and tail intensity (TI) increased more in MIA PaCa-2 cells treated with 200 µM of DZ than those in the control cell (untreated MIA PaCa-2 cell) group (p < 0.01). However, only DNA-TI and DNA-TM exhibited higher increases in HT-29 cells treated with 200 µM of DZ than those in the control cell (untreated HT-29 cell) group (p < 0.01). This shows that DZ has cytotoxic and genotoxic effects on both cell lines. The observed genotoxic effects of DZ still need to be confirmed in additional future studies.

9.
Clin Rheumatol ; 37(8): 2179-2186, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29549492

RESUMO

Adropin is newly discovered peptide hormone. Osteoarthritis (OA) is a kind of joint disease characterized by progressive joint cartilage loss and joint pain. The present study was carried out to investigate adropin and tumor necrosis factor alpha (TNF-α) levels and the relationship between adropin in patients with knee OA classified by Kellgren-Lawrence (KL). A total of 60 knee OA patients and 30 healthy controls were included in this study. KL grading was carried out using the radiographic findings. Demographic characteristics and laboratory parameters were recorded. Adropin and TNF-α levels were determined by using enzyme-linked immunosorbent assay (ELISA). Adropin level was lower in the knee OA patients compared with the healthy controls (p < 0.001), whereas TNF-α level was higher (p < 0.001). Adropin level was negatively correlated with TNF-α level, blood white blood cell (WBC) count, and neutrophil-lymphocyte ratio (NLR). However, there was a significant decrease in adropin level and an increase in TNF-α level parallel to the increase in the KL grade. In addition, serum adropin level was found to be significantly lower in KL grade 1 groups compared with healthy controls (p < 0.01). There was a decrease in adropin level parallel to the increase in the body mass index (BMI), and there was a statistically significant decrease in adropin level in knee OA patients higher than BMI > 30 (p < 0.01). Mean NLR of KL grade 4 was significantly increased compared with other grades (p < 0.05). The consequence of the present study suggested that serum adropin level could be used as a new biomarker indicating the early grade of knee OA.


Assuntos
Osteoartrite do Joelho/sangue , Peptídeos/sangue , Fator de Necrose Tumoral alfa/sangue , Idoso , Biomarcadores/sangue , Proteínas Sanguíneas , Estudos de Casos e Controles , Feminino , Humanos , Articulação do Joelho , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico por imagem , Radiografia , Índice de Gravidade de Doença , Turquia
10.
Life Sci ; 143: 27-34, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26506573

RESUMO

AIM: The aim of this study is to determine the anticancer effect of sulfite on SH-SY5Y neuroblastoma cells in vitro conditions and elucidate underlying molecular mechanism of sulfite and explore its therapeutic activity. MAIN METHODS: In this study, cytotoxic effects of sulfite in SH-SY5Y cels were detected over time in a dose dependent manner with the IC50 doses ranging from 0.5 to 10 mM. Genotoxic effect of sulfite was shown by comet assay. IC50 doses in the SH-SY5Y cells were detected as 5 mM. Expression profiles of the target genes related to apoptosis and cell cycle control were determined by quantitative RT-PCR. Protein changes were determined by western blot analysis. KEY FINDINGS: URG4/URGCP, CCND1, CCND2, CDK4, CDK6, E2F4 and BCL-2 gene expression levels were significantly reduced and RB1, TP53, BAX, BID, CASP2, CASP3, CASP9 and DIABLO gene expressions were significantly increased in dose group cells. The mechanism of this result may be related to sulfite dependent inhibition of cell cycle at the G1 phase by down-regulating URG4/URGCP or CCND1, CDK4, CDK6 gene expression and stimulating apoptosis via the intrinsic pathway. Sulfite suppressed invasion and colony formation in SH-SY5Y cell line using matrigel invasion chamber and colony formation assay, respectively. SIGNIFICANCE: It is thought that sulfite demonstrates anticarcinogenesis activity by affecting cell cycle arrest, apoptosis s, invasion, and colony formation on SH-SY5Y cells. Sulfite may be an effective agent for treatment of neuroblastoma as a single agent or in combination with other agents.


Assuntos
Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/biossíntese , Neuroblastoma/metabolismo , Oncogenes/efeitos dos fármacos , Sulfitos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Humanos , Neuroblastoma/tratamento farmacológico , Oncogenes/fisiologia , Sulfitos/uso terapêutico , Resultado do Tratamento
11.
Ren Fail ; 37(2): 192-7, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25565258

RESUMO

BACKGROUND: Diabetic nephropathy is the most common cause of end-stage renal disease. Emerging evidences indicate that many mechanistic pathways including apoptosis play an important role in the pathogenesis and progression of macrovascular and microvascular complications of diabetes mellitus. The aim of the present study is to show the effects of grape seed extract (GSE) on oxidative stress and apoptosis in the kidney of streptozotocin-induced diabetic rats. MATERIALS AND METHODS: The study included control group, diabetic group without treatment and diabetic group treated with GSE (n=7) group. GSE was given orally (100 mg/kg/day) for six weeks. Following parameters were evaluated; oxidative stress index, caspase 1, IL1-alpha, caspase 2, IL1-beta, BCL2-associated agonist of cell death (BAD), X-linked inhibitor of apoptosis (XIAP), DNA fragmentation factor, alpha subunit and beta bubunit (DFFA, DFFB), BH3 interacting domain death agonist (BID), caspase 6, Bcl2-like 1 (BCL-XL), caspase 8, tumor necrosis factor receptor superfamily, member 1 b (TNFRSF1B) and IAP-binding mitochondrial protein (DIABLO). RESULTS: Oxidative stress index levels were significantly increased in the kidney of diabetic group without treatment compared to control group, and decreased in diabetic+GSE group compared to diabetic group without treatment. In the kidney of diabetic group without treatment, caspase 1, IL-1 alpha, BAD, DFFA, DFFB and caspase-6 gene expressions were significantly higher compared to control group. In diabetic+GSE group caspase 1, caspase 2, XIAP, DFFA, BID, BCL-XL and TNFRSF1B genes were significantly decreased compared to control group. CONCLUSIONS: Grape seed reduces oxidative stress and apoptosis gene expression suggesting the protective effect on diabetic nephropathy.


Assuntos
Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas , Extrato de Sementes de Uva/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Proteínas Reguladoras de Apoptose , Proteínas de Transporte/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Proteínas Inibidoras de Apoptose/metabolismo , Interleucina-1alfa/metabolismo , Masculino , Proteínas Mitocondriais/metabolismo , Ratos , Ratos Wistar , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Resultado do Tratamento , Proteína de Morte Celular Associada a bcl/metabolismo
12.
Gene ; 555(2): 119-26, 2015 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-25445279

RESUMO

We aimed to investigate the effects of grape seed extract (GSE) and vitamin E (Vit E) on oxidative stress and apoptosis in the hippocampus of streptozotocin-induced diabetic rats. In Control, Diabetic, and Diabetic treated with GSE (Diabetic+GSE) and vitamin E (Diabetic+Vit E) groups, oxidative stress index (OSI), TUNEL staining and Bcl-2, Bcl-XL, Bax, caspase-3, -9, and -8, Cyt-c, TNF-α, and NF-κB gene expressions were evaluated. OSI was significantly increased in the plasma and hippocampus of the Diabetic compared to Control group and decreased in Diabetic+GSE and Diabetic+Vit E groups compared to Diabetic. TUNEL positive neurons significantly increased in the hippocampus of the Diabetic group compared to Control and decreased in Diabetic+GSE (more prominently) and Diabetic+Vit E groups compared to Diabetic. In the hippocampus of the Diabetic group, Bcl-2 and Bcl-XL gene expressions were significantly decreased; Bax, caspase-3, -9, and -8, Cyt-c, TNF-α, and NF-κB gene expressions were significantly increased compared to Control. In Diabetic+GSE and Diabetic+Vit E groups, Bcl-2 gene expressions were significantly increased; Bcl-XL gene expressions did not differ compared to the Diabetic group. The expression of Bax, caspase-3, -9, and -8, Cyt-c, TNF-α, and NF-κB genes in the Diabetic+GSE group and the expression of caspase-3 and -9, TNF-α, and NF-κB genes in the Diabetic+Vit E group were significantly decreased compared to Diabetic. In conclusion, GSE (more prominently) and vitamin E decreased oxidative stress and neuronal apoptosis occurring in the hippocampus of diabetic rats.


Assuntos
Apoptose , Diabetes Mellitus Experimental/tratamento farmacológico , Extrato de Sementes de Uva/farmacologia , Hipocampo/efeitos dos fármacos , Estresse Oxidativo , Vitamina E/farmacologia , Animais , Antioxidantes/farmacologia , Glicemia/metabolismo , Peso Corporal , Catequina/farmacologia , Ácido Gálico/farmacologia , Hipocampo/patologia , Masculino , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Estreptozocina
13.
Mol Biol Rep ; 41(7): 4595-9, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24652203

RESUMO

Valproic acid (VPA), used for the treatment of epilepsy and bipolar disorder, regulates several signaling pathways in brain cells. The up-regulated gene 4 (URG4/URGCP) is a novel gene located on 7p13. URG4/URGCP stimulates cyclin D1 (CCND1) mRNA expression, and URG4/URGCP silencing diminishes CCND1 mRNA expression in HepG2 cells. This study was performed to investigate the anti-cancer mechanism of action of VPA by analyzing the expression of novel gene URG4/URGCP, CCND1, p21, p53, p65 (RelA), Bax, and Bcl-2 in SHSY5Y neuroblastoma (NB) cancer cells. Cytotoxic effects of VPA in SHSY5Y were noticed in time and dose dependent manner with the IC50 doses within the range of 0.5-10 mM. IC50 doses in the SHSY5Y were detected as 7.5 mM. Expression profiles were determined by semi quantitative RT-PCR and URG4/URGCP protein change by western blot analysis. Our results suggest that VPA induces cell cycle arrest in SHSY5Y due to the decrease in URG4/URGCP, CCND1 gene expression and the increase in p65. To conclude, VPA may be a prospective agent for the treatment of NB as a single agent or in combination with other drugs. Thus, more studies should be designed to find a safe dose with the best effects of VPA.


Assuntos
Antineoplásicos/farmacologia , Ciclina D1/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/antagonistas & inibidores , Neurônios/efeitos dos fármacos , Ácido Valproico/farmacologia , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclina D1/genética , Ciclina D1/metabolismo , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Transdução de Sinais , Fator de Transcrição RelA/agonistas , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo
14.
Tumour Biol ; 34(6): 3853-7, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23821302

RESUMO

Neuroblastoma (NB), originating from neural crest cells, is the most common extracranial tumor of childhood. Retinoic acid (RA) which is the biological active form of vitamin A regulates differentiation of NB cells, and RA derivatives have been used for NB treatment. PPARα (peroxisome proliferator-activated receptor) plays an important role in the oxidation of fatty acids, carcinogenesis, and differentiation. URG4/URGCP gene is a proto-oncogene and that overexpression of URG4/URGCP is associated with metastasis and tumor recurrence in osteosarcoma. It has been known that URG4/URGCP gene is an overexpressed gene in hepatocellular carcinoma and gastric cancers. This study aims to detect gene expression patterns of PPARα and URG4/URGCP genes in SH-SY5Y NB cell line after RA treatment. Expressions levels of PPARα and URG4/URGCP genes were analyzed after RA treatment for reducing differentiation in SH-SY5Y NB cell line. To induce differentiation, the cells were treated with 10 µM RA in the dark for 3-10 days. Gene expression of URG4/URGCP and PPARα genes were presented as the yield of polymerase chain reaction (PCR) products from target genes compared with the yield of PCR products from the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene. SH-SY5Y cells possess small processes in an undifferentiated state, and after treatment with RA, the cells developed long neurites, resembling a neuronal phenotype. PPARα gene expression increased in RA-treated groups; URG4/URGCP gene expression decreased in SH-SY5Y cells after RA treatment compared with that in the control cells. NB cell differentiation might associate with PPARα and URG4/URGCP gene expression profile after RA treatment.


Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Neoplasias/genética , PPAR alfa/genética , Tretinoína/farmacologia , Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Linhagem Celular Tumoral , Humanos , Neuroblastoma/genética , Neuroblastoma/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo
15.
Contemp Oncol (Pozn) ; 17(4): 346-9, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24592121

RESUMO

Retinoic acid (RA) plays important roles in development, growth, and differentiation by regulating the expression of its target genes. The pro-apoptotic Bax gene may form channels through oligomerization in the mitochondrial membrane and facilitate the cytosolic release of cytochrome c. The anti-apoptotic Bcl-2 gene can inhibit this process. Up-regulated gene 4/Upregulator of cell proliferation (URG4/URGCP) is a novel gene located on 7p13. URG4/URGCP also stimulates cyclin D1 (CCND1) mRNA expression, and RNAi-mediated URG4/URGCP silencing diminishes CCND1 mRNA expression in HepG2 cells. In this study, the effects of RA treatment on URG4/URGCP, CCND1, Bcl-2 and Bax gene expression changes in undifferentiated and differentiated SHSY5Y neuroblastoma cells was analyzed. SHSY5Y cells were cultured in the appropriate conditions. To induce differentiation, the cells were treated with 10 micromolar RA in the dark for 3-10 days. SHSY5Y cells possess small processes in an undifferentiated state, and after treatment with RA, the cells developed long neurites, resembling a neuronal phenotype. Total RNA was isolated with Tri-Reagent. Expression profiles of the target genes were determined by semi-quantitative RT-PCR. According to the results, Bcl-2 and CCND1 gene expression levels were increased, while URG4/URGCP and Bax gene expression was decreased in RA treated cells compared to the control cells. Our preliminary results suggest that RA may induce cell proliferation and escape apoptosis using a novel pathway by the URG4/URGCP gene. Further investigations are needed to clarify more direct transcriptional targets of RA signaling and the interaction of RA pathways with other pro-regenerative signals.

16.
Neurochem Int ; 61(3): 341-6, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22709673

RESUMO

Sulfites are compounds commonly used as preservatives in foods, beverages and pharmaceuticals. Sulfite is also endogenously generated during the metabolism of sulfur-containing amino acids and drugs. It has been shown that sulfite is a highly toxic molecule. Many studies have examined the effects of sulfite toxicity, but the effect of ingested sulfite on the number of neurons in the hippocampus has not yet been reported. The present study was undertaken to investigate the effect of ingested sulfite on pyramidal neurons by counting cells in CA1 and CA3-2 subdivisions of the rat hippocampus. For this purpose, rats were assigned to one of four groups (6 rats per group): control (C), sulfite (S), deficient (D) and deficient+sulfite (DS). Sulfite oxidase deficiency was established by feeding rats a low molybdenum diet and adding 200ppm tungsten (W) to their drinking water. Sulfite (70mg/kg) was also administered to the animals via their drinking water. At the end of the experimental period, the rats were sacrificed by exsanguination under anesthesia, and their brains and livers quickly removed. The livers were used for a SOX activity assay, and the brains were used for neuronal counts in a known fraction of the CA1 and CA3-2 subdivisions of the left hippocampus using the optical fractionator method, which is a stereological method. The results showed that sulfite treatment caused a significant decrease in the total number of pyramidal neurons in three subdivisions of the hippocampus (CA1 and CA3-2) in the S, D and DS groups compared with the control group. It is concluded that exogenous administration of sulfite causes loss of pyramidal neurons in CA1 and CA3-2 subdivisions in both normal and SOX deficient rat hippocampus. This finding provides supporting evidence that sulfite is a neurotoxic molecule.


Assuntos
Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Sulfito Oxidase/metabolismo , Sulfitos/farmacologia , Animais , Hipocampo/citologia , Masculino , Ratos , Ratos Wistar
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