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1.
Arch Physiol Biochem ; 128(6): 1421-1425, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32574121

RESUMEN

This meta-analysis aimed to investigate the association of the rs9939609 FTO gene polymorphism and body fat percentage (BF%). To the best of our knowledge, this study is the first meta-analysis to evaluate the relationship between FTO rs9939609 polymorphism and BF%. We searched PubMed, Web of science, Scopus and Embase to identify studies investigating the relations between the rs9939609 FTO gene polymorphism and BF%. Studies that meet inclusion criteria were collected for the final analysis. There was significant differences in the level of BF% between different genotypes of FTO rs9939609 polymorphism, and the carriers of the A allele of FTO rs9939609 polymorphism had higher BF%. The association was significant between carriers of TT genotype compared to carriers of AA (p = .007) and AT genotypes (p = .04), but not between AT and AA genotypes. This study identified that the carriers of the A allele of FTO rs9939609 polymorphism have higher BF%.


Asunto(s)
Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Predisposición Genética a la Enfermedad , Humanos , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Índice de Masa Corporal , Obesidad/genética , Polimorfismo Genético , Genotipo , Polimorfismo de Nucleótido Simple
2.
Iran J Med Sci ; 46(6): 493-497, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34840390

RESUMEN

Pelizaeus-Merzbacher-Like Disease 1 is a genetic disorder affecting the central nervous system with an autosomal recessive inheritance pattern. It is a rare genetic disorder that affects the central nervous system. In this report, we demonstrated the clinical and paraclinical features of an Iranian consanguine pedigree with suspected hypomyelinating leukodystrophy, without any defined diagnosis. The proband, a 15-month-old girl, visited the Razi pathobiology and medical genetic laboratory of Karaj, where the study was conducted in 2020. Following whole-exome sequencing analysis of the proband and segregation analysis, a novel pathogenic mutation was discovered. GJC2 (NM_020435.4):c.1096dupG was found to be homozygous in the proband and heterozygous in both parents. This mutation was in the coding region of the protein, which results in D366Gfs*126 (p.Asp366GlyfsTer126). The site of mutation was at the 3' region of the connexin superfamily domain. The frameshift results in a different peptide sequence of the C-terminal and extended protein. Our findings led to the diagnosis of the proband's disease as Pelizaeus-Merzbacher-Like Disease 1 and led to the end of the diagnostic odyssey. We provided effective genetic counseling through the identification of a novel pathogenic mutation in gap junction protein C2 in this family and suggested preimplantation genetic diagnosis for the next pregnancy. Furthermore, our findings confirmed the association of GJC2 mutations with PMLD1. This discovery added to the repertoire of genetic mutations of Pelizaeus-Merzbacher-Like Disease 1. This knowledge could be applied for expanded carrier screening of other families, especially for Iranian consanguine marriages.


Asunto(s)
Conexinas/genética , Proteínas del Tejido Nervioso/genética , Enfermedad de Pelizaeus-Merzbacher/diagnóstico , Femenino , Humanos , Lactante , Irán , Mutación/genética , Enfermedad de Pelizaeus-Merzbacher/genética , Secuenciación del Exoma
3.
Diabetol Metab Syndr ; 13(1): 138, 2021 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-34801066

RESUMEN

BACKGROUND: FTO gene is considered to play an important role in many metabolic diseases. Evidence from studies indicated the possible association between the FTO rs9939609 polymorphisms with serum lipid profile. Therefore, this study aimed to investigate the association of FTO rs9939609 polymorphism with lipid profile in Iranian women. METHODS: This cross-sectional study was carried out on 380 adult women. Information about age, height, weight, BMI, physical activity, and dietary intake were collected. The serum levels of Low Density Lipoprotein (LDL), High Density Lipoprotein (HDL), Triglyceride (TG), and total cholesterol were measured. The FTO gene was genotyped for rs9939609 polymorphism. The participants were divided into two groups of TT and AT/AA considering dominant model of FTO rs9939609 polymorphism. RESULTS: General characteristics of the participants with different FTO genotypes were not significantly different. The lower levels of HDL were observed in AT/AA genotypes compared to the TT wild type genotype of FTO rs9939609 polymorphism (P = 0.004). Adjustments of age, BMI, and physical activity did not change the results. CONCLUSIONS: However, the significant association between FTO genotype and the HDL level was disappeared after further adjustments for dietary intake. Further studies are warranted to identify the underlying mechanisms of the possible association between FTO gene and serum lipid profile.

4.
J Cell Mol Med ; 25(7): 3252-3257, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33634577

RESUMEN

Contradictory results were reported on the effect of fat mass- and obesity-associated (FTO) gene and anthropometric measurements on breast cancer (BC). This study aimed to assess the interactions between rs9939609 polymorphism of FTO gene, anthropometric indices and BC risk in Iranian women. This case-control study was performed on 540 women including 180 women with BC and 360 healthy women in Tehran, Iran. Physical activity and dietary intakes were assessed by validated questionnaires. Data on sociodemographic and pathologic factors of the participants as well as their blood samples were collected. The rs9939609 FTO gene polymorphism was genotyped using the tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR). No significant association was found between BC and risk allele of FTO rs9939609 polymorphism after adjustments for the confounders. However, there was a significant association between rs9939609 polymorphism risk allele and BC risk in females with overweight, even after adjusting for age, family history of BC, abortion, BMI and the number of pregnancies (P < .05). The association was disappeared after further adjustments for lifestyle factors including smoking, alcohol consumption, calorie and macronutrients intake, and physical activity. The FTO gene polymorphism was associated with the risk of BC in overweight individuals. This association was influenced by environmental factors including diet, alcohol consumption and smoking. Future studies are required to confirm the association between the FTO gene and BC in overweight females and to identify the underlying mechanisms.


Asunto(s)
Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Peso Corporal , Neoplasias de la Mama/genética , Polimorfismo de Nucleótido Simple , Factores de Edad , Neoplasias de la Mama/epidemiología , Femenino , Humanos , Estilo de Vida
5.
Cell Oncol (Dordr) ; 42(4): 491-504, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31025257

RESUMEN

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, is the fourth most common cause of cancer-related death in the USA. Local progression, early tumor dissemination and low efficacy of current treatments are the major reasons for its high mortality rate. The ERBB family is over-expressed in PDAC and plays essential roles in its tumorigenesis; however, single-targeted ERBB inhibitors have shown limited activity in this disease. Here, we examined the anti-tumor activity of dacomitinib, a pan-ERBB receptor inhibitor, on PDAC cells. METHODS: Anti-proliferative effects of dacomitinib were determined using a cell proliferation assay and crystal violet staining. Annexin V/PI staining, radiation therapy and cell migration and invasion assays were carried out to examine the effects of dacomitinib on apoptosis, radio-sensitivity and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses were applied to elucidate the molecular mechanisms underlying the anti-tumor activity of dacomitinib. RESULTS: We found that dacomitinib diminished PDAC cell proliferation via inhibition of FOXM1 and its targets Aurora kinase B and cyclin B1. Moreover, we found that dacomitinib induced apoptosis and potentiated radio-sensitivity via inhibition of the anti-apoptotic proteins survivin and MCL1. Treatment with dacomitinib attenuated cell migration and invasion through inhibition of the epithelial-to-mesenchymal transition (EMT) markers ZEB1, Snail and N-cadherin. In contrast, we found that the anti-tumor activity of single-targeted ERBB agents including cetuximab (anti-EGFR mAb), trastuzumab (anti-HER2 mAb), H3.105.5 (anti-HER3 mAb) and erlotinib (EGFR small molecule inhibitor) were marginal. CONCLUSIONS: Our findings indicate that dacomitinib-mediated blockade of the ERBB receptors yields advantages over single-targeted ERBB inhibition and provide a rationale for further investigation of the therapeutic potential of dacomitinib in the treatment of ERBB-driven PDAC.


Asunto(s)
Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/patología , Receptores ErbB/antagonistas & inhibidores , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Quinazolinonas/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Receptores ErbB/metabolismo , Humanos , Modelos Biológicos , Invasividad Neoplásica , Quinazolinonas/farmacología , Tolerancia a Radiación , Neoplasias Pancreáticas
6.
Tumori ; 105(1): 84-91, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30021477

RESUMEN

INTRODUCTION:: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy worldwide and despite an initial response to therapeutic agents, the majority of patients have chemoresistant disease. There is no treatment strategy with proven efficacy against chemoresistant EOC and in this setting, overcoming therapy resistance is the key to successful treatment. METHODS:: This study aimed to investigate expression of interleukin-6 (IL-6) (IL-6) and IL-6 receptor (IL-6R) in a panel of the EOC cell lines. To achieve this, the expression of IL-6 and its receptor were compared in the EOC cells using quantitative reverse transcription polymerase chain reaction. MTT assay was performed to obtain chemosensitivity of the EOC cells. RESULTS:: In this report, we show that expressions of IL6 and IL6R are higher in therapy-resistant EOC cells compared to sensitive ones. Higher expression of IL6 and its receptor correlated with resistance to certain chemotherapeutic agents. Moreover, our findings showed that combination of tocilizumab (Actemra; Roche), an anti-IL-6R monoclonal antibody, with carboplatin synergistically inhibited growth and proliferation of the EOC cells and the most direct axis for IL-6 gene expression was NF-κB pathway. CONCLUSION:: Collectively, our findings suggest that blockade of the IL-6 signaling pathway with anti-IL-6 receptor antibody tocilizumab might resensitize the chemoresistant cells to the current chemotherapeutics.


Asunto(s)
Interleucina-6/metabolismo , Neoplasias Ováricas/metabolismo , Receptores de Interleucina-6/metabolismo , Anticuerpos Monoclonales Humanizados/farmacología , Carboplatino/farmacología , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , FN-kappa B/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos
7.
Anticancer Drugs ; 29(10): 1011-1020, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30096128

RESUMEN

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy worldwide. Development of chemoresistance and peritoneal dissemination are the major reasons for low survival rate in the patients. The bromodomain and extraterminal domain (BET) proteins are known as epigenetic 'readers,' and their inhibitors are novel epigenetic strategies for cancer treatment. Accumulating body of evidence indicates that epigenetic modifications have critical roles in development of EOC, and overexpression of the BET family is a key step in the induction of important oncogenes. Here, we examined the mechanistic activity of I-BET151, a pan-inhibitor of the BET family, in therapy-resistant EOC cells. Our findings showed that I-BET151 diminished cell growth, clonogenic potential, and induced apoptosis. I-BET151 inhibited cell proliferation through down-modulation of FOXM1 and its targets aurora kinase B and cyclin B1. I-BET151 attenuated migration and invasion of the EOC cells by down-regulation of epithelial-mesenchymal transition markers fibronectin, ZEB2, and N-cadherin. I-BET151 synergistically enhanced cisplatin chemosensitivity by down-regulation of survivin and Bcl-2. Our data provide insights into the mechanistic activity of I-BET151 and suggest that BET inhibition has potential as a therapeutic strategy in therapy-resistant EOC. Further in vivo investigations on the therapeutic potential of I-BET151 in EOC are warranted.


Asunto(s)
Carcinoma Epitelial de Ovario/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Neoplasias Ováricas/tratamiento farmacológico , Proteínas/antagonistas & inhibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Carcinoma Epitelial de Ovario/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Epigénesis Genética/genética , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Humanos , Neoplasias Ováricas/patología
8.
Tumour Biol ; 37(3): 3913-23, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26482609

RESUMEN

Epithelial ovarian cancer (EOC) is the most fatal gynecological malignancy due to its high proliferative and invasive capacities. A heregulin (HRG)/HER3 autocrine loop increases proliferative and metastatic properties of EOC cells, suggesting that modulators of this signaling pathway may prove effective to trammel growth and motility of these cells. This study aimed to evaluate the effects of multi-tyrosine kinase inhibitor silibinin on proliferative and invasive characteristics of EOC cell lines OVCAR8 and SKOV3 through suppression of the HRG/HER3 pathway. To achieve this, the effects of silibinin on proliferation, DNA synthesis, clonogenicity, cell cycle progression, cathepsin B enzymatic activity, and migration and invasion were explored in vitro. Silibinin suppressed proliferation, DNA synthesis, and clonogenic abilities of OVCAR8 and SKOV3 cells through inhibition of the autocrine HRG/HER3 circuit. Silibinin-mediated attenuation of the HER3 signaling disabled the HER3/AKT/survivin axis and thereby, induced G1/S cell cycle arrest. Furthermore, silibinin reduced invasive potentials of the EOC cells through quelling the HRG/HER3 pathway and suppression of cathepsin B activity. Altogether, these results suggest that silibinin is a potential anti-cancer drug to inhibit proliferative and invasive characteristics of the EOC cells that exhibit an autocrine HRG/HER3 pathway.


Asunto(s)
Proliferación Celular/efectos de los fármacos , Neurregulina-1/metabolismo , Receptor ErbB-3/metabolismo , Transducción de Señal/efectos de los fármacos , Silimarina/farmacología , Antioxidantes/farmacología , Western Blotting , Carcinoma Epitelial de Ovario , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Proliferación Celular/genética , ADN de Neoplasias/biosíntesis , ADN de Neoplasias/genética , Femenino , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Puntos de Control de la Fase G1 del Ciclo Celular/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Proteínas Inhibidoras de la Apoptosis/metabolismo , Invasividad Neoplásica , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Glandulares y Epiteliales/metabolismo , Neoplasias Glandulares y Epiteliales/patología , Neurregulina-1/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor ErbB-3/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Silibina , Survivin
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