RESUMO
BACKGROUND: In recent years, drug resistance has become a most important challenge in chemotherapy of malignancies. Here, we investigated a novel approach to enhance therapeutic potential of doxorubicin (Dox as a common chemotherapeutic drug) by co-administration of apatinib (Apa as a monoclonal antibody) in breast cancer treatment. METHODS AND RESULTS: Effects of Apa, Dox, and their combinations (Apa-Dox) were investigated on proliferation of MDA-MB-231 breast cancer cells by MTT assay. Moreover, migration and invasion of the treated and untreated control cancer cells were evaluated by scratch and transwell methods, respectively. Apoptosis percentage of the treated cancer cells was investigated by flow cytometry method. Finally, apoptosis-, metastasis-, and angiogenesis-related gene expression at mRNA and protein levels in the cancer cells were investigated by Real-Time PCR and western blotting methods, respectively. Our results indicated that treatments of cancer cells by Apa, Dox, and Apa-Dox significantly decrease proliferation, migration, and invasion of MDA-MB-231 breast cancer cells. Treatments of the breast cancer cells by Apa, Dox, and Apa-Dox significantly increase apoptosis percentage. We observed that anticancer effects of Apa, Dox, and Apa-Dox may due to modification of apoptosis-, metastasis-, and angiogenesis-related gene expression (at mRNA and protein level) in the breast cancer cells. However, anticancer potential of Apa-Dox combination was significantly more than Apa and Dox monotherapy. CONCLUSION: We demonstrated that Apa significantly increases anticancer potential of Dox in MDA-MB-231 breast cells. However, further in-vitro, in-vivo, and clinical studies are required to confirm this result.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Doxorrubicina/uso terapêutico , Apoptose , RNA Mensageiro/genéticaRESUMO
OBJECTIVES: Fibrosis is a chronic inflammation caused by the loss of innate compensational mechanisms. Naringin (NR) is a flavonoid with antineoplastic and anti-inflammatory effects. Here, we aimed to investigate the antifibrotic effects of NR and underlying mechanisms in a Hypochlorous acid (HOCl)-induced mouse model of skin fibrosis. MATERIALS AND METHODS: A total of 24 six-week-old female BALB/c mice were randomly allocated into five groups: HOCl, Sham, PBS, HOCl + NR and DMSO and selected skin regions were treated for 6 weeks, until sacrifice. The histopathologic and collagenesis of skin resections were analyzed using H&E and PR staining. The mRNA levels of COL1, COL3 and αSMA genes were quantified. Serum samples were also used to evaluate TGF-ß levels and LDH activity. RESULTS: HOCl could increase the relative collagen content, while NR administration on HOCl-treated biopsies decreased collagenesis. COL1, COL3 and αSMA mRNA levels were significantly increased among HOCl-treated skin samples, while NR treatment could decrease these mRNA levels of genes to the extent equal to the levels in the Sham group. Similarly, Naringin-treated samples could decrease TGF-ß levels. CONCLUSIONS: We demonstrated that Naringin could exert protective effects against fibrotic complications of HOCL in skin tissue in vivo, by reducing the collagenesis and decreasing the levels of fibrosis-associated genes.
Assuntos
Flavanonas , Dermatopatias , Animais , Feminino , Camundongos , Anti-Inflamatórios/farmacologia , Colágeno/farmacologia , Dimetil Sulfóxido , Modelos Animais de Doenças , Fibrose , Flavanonas/farmacologia , Ácido Hipocloroso/efeitos adversos , Camundongos Endogâmicos BALB C , RNA Mensageiro , Fator de Crescimento Transformador beta , Dermatopatias/induzido quimicamente , Dermatopatias/tratamento farmacológicoRESUMO
Today, the increasing rate of cancer-related mortality, has rendered cancer a major global challenge, and the second leading cause of death worldwide. Conventional approaches in the treatment of cancer mainly include chemotherapy, surgery, immunotherapy, and radiotherapy. However, these approaches still come with certain disadvantages, including drug resistance, and different side effects such as gastrointestinal (GI) irritation (e.g., diarrhea, mucositis). This has encouraged scientists to look for alternative therapeutic methods and adjuvant therapies for a more proper treatment of malignancies. Application of probiotics as an adjuvant therapy in the clinical management of cancer appears to be a promising strategy, with several notable advantages, e.g., increased safety, higher tolerance, and negligible GI side effects. Both in vivo and in vitro analyses have indicated the active role of yeast probiotics in mitigating the rate of cancer cell proliferation, and the induction of apoptosis through regulating the expression of cancer-related genes and cellular pathways. Strain-specific anti-cancer activities of yeast probiotics strongly suggest that their administration along with the current cancer therapies may be an efficient method to reduce the side effects of these approaches. The main purpose of this article is to evaluate the efficacy of yeast probiotics in alleviating the adverse effects associated with cancer therapies.
Assuntos
Neoplasias Colorretais/terapia , Terapia Combinada/métodos , Diarreia/terapia , Probióticos/uso terapêutico , Saccharomyces/fisiologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bifidobacterium/fisiologia , Quimiorradioterapia Adjuvante/métodos , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/patologia , Diarreia/imunologia , Diarreia/microbiologia , Diarreia/patologia , Gerenciamento Clínico , Humanos , Imunoterapia/métodos , Lactobacillaceae/fisiologiaRESUMO
The effect of DNA methylation on gene expression triggered it as a susceptibility factor in various diseases including preeclampsia (PE). The pathogenesis of PE is closely associated with the methylation status and genetic variants of relevant genes. Therefore, the aim of the study was to investigate the possible impacts of the placental DNA methylation and rs3741219, rs217727, and rs2107425 polymorphisms of the H19 gene on the PE susceptibility as well as the its mRNA expression. Moreover, eight haplotypes of three loci in the H19 gene were analyzed. In this case-control study, the placentas of 107 preeclamptic and 113 non-preeclamptic women were collected after delivery. The methylation status was assessed by methylation-specific polymerase chain reaction (PCR). The H19 polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism or amplification refractory mutation system-polymerase chain reaction methods. The quantitative real time PCR was used for mRNA expression assay. The placental H19 rs3741219 and rs2107425 polymorphisms were not associated with PE. However, H19 rs217727CT and TT genotypes might be associated with a 9.2- and 17.7-fold increased risk of PE, respectively. The Trs3741219 Crs217727 Crs2107425 and Trs3741219 Crs217727 Trs2107425 haplotypes were significantly lower, whereas the Trs3741219 Trs217727 Crs2107425 and Crs3741219 Trs217727 Crs2107425 haplotypes were significantly higher in PE women. Promoter but not upstream region hypermethylation of H19 gene could be led to decreased risk of PE (MM vs. UM + UU). No significant difference was observed in the placental mRNA expression between two groups. The H19 expression was significantly higher in women with unmethylated (UU), compared to methylated promoter (MM). The H19 expression was 17- and 15-fold higher in H19-rs2107425 CC and CT genotypes in PE women. In conclusion, the H19 rs2107425 polymorphism was associated with a higher risk of PE and increased H19 mRNA expression. The promoter hypermethylation of H19 gene was associated with a lower risk of PE and decreased H19 mRNA expression.
Assuntos
Polimorfismo de Nucleotídeo Único , Pré-Eclâmpsia/genética , Regiões Promotoras Genéticas , RNA Longo não Codificante/genética , Adulto , Estudos de Casos e Controles , Metilação de DNA , Feminino , Expressão Gênica , Predisposição Genética para Doença , Haplótipos , Humanos , Desequilíbrio de Ligação , Idade Materna , Placenta/fisiologia , Gravidez , RNA Mensageiro/genéticaRESUMO
BACKGROUND: Preeclampsia (PE), as a multisystem disorder, is associated with maternal hypertension and proteinuria. Apoptosis seems to be involved in the pathophysiology of PE, although its precise pathogenic mechanisms are not well established. In this study, we aimed to identify the association between maternal TP53-rs1042522, P21-rs1801270, and P21-rs1059234 polymorphisms and PE. In addition, we examined the effects of promoter methylation and TP53 and P21 polymorphisms on placental mRNA expression in PE women. METHODS: The blood of 226 PE women and 228 normotensive pregnant women was examined in this study. In addition, the placentas were genotyped in 109 PE and 112 control women. The methylation status was assessed by a methylation-specific PCR assay, while mRNA expression was examined via Quantitative Real Time PCR. RESULTS: The maternal and placental P21-rs1801270 CA genotype had a significant association with the reduced risk of PE. In the dominant, recessive, and allelic models, maternal/placental P21-rs1059234 polymorphism had no statistically significant association with the risk of PE. On the other hand, the reduced risk of PE was associated with maternal, but not placental TP53-rs1042522 polymorphism in the dominant and recessive models. The maternal and placental P21-rs1801270 polymorphism was associated with PE risk. The maternal P21 Trs1059234Crs1801270 haplotype was associated with 3.4-fold increase in PE risk, However the maternal P21 Trs1059234Ars 1801270 haplotype and placental Crs1059234CA rs1801270 haplotype led to 0.5 and 0.4-fold decrease in PE risk, respectively. PE women showed 5.6 times higher levels of placental mRNA expression of TP53 gene, although it was not associated with rs1042522 polymorphism. The relative placental mRNA expression of P21 gene was 0.2 in PE women. It was also 2.4 times higher in individuals with rs1801270CA genotype than those with AA genotype. The hyper-methylation of P21 and TP53 genes in the promoter region was associated with a 3.4-fold and 3-fold increase in PE risk, respectively. However, no association was found between P21 and TP53 mRNA expression and promoter methylation. CONCLUSION: In conclusion, P21-rs1801270 and TP53-rs1042522 polymorphisms were involved in reduced risk of PE. P21-rs1801270 was associated with decreased P21 mRNA expression. The hyper-methylation of P21 and TP53 genes in the promoter region was associated with a higher PE risk.
Assuntos
Inibidor de Quinase Dependente de Ciclina p21/genética , Metilação de DNA , Polimorfismo de Nucleotídeo Único , Pré-Eclâmpsia/genética , Transcriptoma , Proteína Supressora de Tumor p53/genética , Adulto , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Humanos , Placenta/metabolismo , Gravidez , Regiões Promotoras Genéticas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Adulto JovemRESUMO
OPINION STATEMENT: Acute myeloid leukemia (AML) patients with a complex karyotype (CK-AML) show at least 3 unrelated clonal cytogenetic abnormalities with notoriously poor outcome. Such cases fall into either AML with myelodysplasia-related changes or therapy-related AML in the current World Health Organization classification of AML. Allogeneic stem cell transplantation is one of the only treatment modalities that can provide a long-term survival benefit and is recommended as a consolidative treatment in patients who are able to achieve complete remission. Unfortunately, transplantation is also associated with a higher relapse rate and more than half of CK-AML patients relapse from disease within the first 2 years. The probability of achieving remission with traditional induction using cytarabine and daunorubicin or idarubicin ("7 + 3") is so small that investigational therapies should be considered up front in these patients. Less intensive therapeutic backbones, typically using one of the hypomethylating agents, azacitidine or decitabine, minimize toxicity and show a trend toward the improved overall survival. CPX 351 (Vyxeos) is a liposomal formulation of cytarabine and daunorubicin and this encapsulation leads to prolonged exposure to the two drugs. This drug is approved for AML patients with MDS-related changes and therapy-related AML, both of which are frequently associated with complex karyotype. Such patients show improved outcome in trials using this combination. Combination therapy that includes venetoclax (BCL2 inhibitor) with hypomethylating agents may also be appropriate for such patients.
Assuntos
Aberrações Cromossômicas , Leucemia Mieloide Aguda/diagnóstico por imagem , Leucemia Mieloide Aguda/terapia , Antineoplásicos/uso terapêutico , Quimioterapia de Consolidação , Transplante de Células-Tronco Hematopoéticas , Humanos , Cariótipo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Prognóstico , Indução de Remissão , Proteína Supressora de Tumor p53/genéticaRESUMO
H19 is an imprinted gene transcribing a long noncoding RNA which was previously reported to be involved in some diseases. However, the association between the H19 polymorphisms and Pre-eclampsia (PE) susceptibility has remained elusive. This study aimed to evaluate the association between three H19 haplotype SNPs (rs3741219, rs217727, and rs2107425) and the risk of PE. The present case control study consisted of 193 PE women and 201 controls. The H19 rs3741219 and rs217727 polymorphisms were genotyped with PCR-RFLP (Polymerase chain reaction-restriction fragment length polymorphism) and the H19 rs2107425 polymorphism with ARMS-PCR (Amplification refractory mutation system) methods. The frequency of alleles and genotypes of H19 rs3741219 and rs2107425 polymorphisms did not differ between PE women and controls. The frequency of the H19 rs217727T allele was significantly higher in PE women (P < 0.0001). The H19 rs217727 polymorphism was associated with higher PE susceptibility in the Co-dominant (OR = 12.1, 95% CI = 5.7-24.5, P < 0.0001 for CT genotype and OR = 29.7, 95% CI = 12.9-68.1, P < 0.0001 for TT genotype), Dominant (OR = 15.1, 95% CI = 7.5-30.3, P = P < 0.0001), Recessive (OR = 4.5, 95% CI = 2.6-7.9, P = < 0.0001), and Over-dominant (OR = 2.1, 95% CI = 1.4-3.1, P = 0.0006) models. Furthermore, the CCC, TCT, TCC, and CCT haplotypes of H19 rs3741219, rs217727, rs2107425 were associated with lower risk of PE; however, the CTC, TTC, and TTT haplotypes were associated with higher risk of PE. In conclusion, the present study found the relationship between H19 rs217727 but not rs3741219 and rs2107425 polymorphisms and PE susceptibility. In addition, the CTC, TTC, and TTT haplotypes were associated with the higher risk of PE.
Assuntos
Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/patologia , RNA Longo não Codificante/genética , Adulto , Estudos de Casos e Controles , Feminino , Genótipo , Haplótipos , Humanos , Gravidez , Fatores de RiscoRESUMO
microRNAs (miRNAs) are negative regulators in a variety of cellular processes that occur in endometriosis. Therefore, functional polymorphisms in miRNA and miRNA binding sites may affect gene expression and contribute to susceptibility of endometriosis. In this study, we evaluated the association of two miRNA related polymorphisms, mir-126 rs4636297 and TGFßRI rs334348, with endometriosis risk and its severity. This case-control study was done on 157 endometriosis patients and 252 healthy women as a control group. Tetra amplification refractory mutation system-polymerase chain reaction (tetra-ARMS PCR) was designed to determine the polymorphisms. Our finding showed significant differences in genotype frequency of mir-126 rs4636297 between the groups (χ2 = 6.26, p = 0.044). A significant protection against endometriosis was found for mir-126 rs4636297 in allele (G versus A allele: OR = 0.695, 95% CI = 0.519-0.931, p = 0.015) and genotype (GG versus AA genotype: OR = 0.451, 95%CI = 0.233-0.873, p = 0.018). Significant association was also observed between the A allele and severity of endometriosis (OR = 0.478, 95%CI = 0.297-0.768, p = 0.002). Moreover, we found a significant association between AA genotype with the risk of endometriosis (OR = 0.493, 95%CI = 0.250-0.970, p = 0.041) and its severity (OR = 0.240, 95%CI = 0.065-0.883, p = 0.032) regarding TGFßRI rs334348 polymorphism. These finding suggest that, for the first time, mir-126 rs4636297 and TGFßRI rs334348 polymorphisms may influence individual's susceptibility to endometriosis and its severity.
Assuntos
Endometriose/genética , MicroRNAs/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Adulto , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Receptor do Fator de Crescimento Transformador beta Tipo IRESUMO
New-onset diabetes after transplantation (NODAT) is an important complication after solid organ transplantation. NODAT is a polygenic disease and KCNJ11 E23K polymorphism is considered as a diabetes-susceptibility gene. The present study aimed to assess the association between KCNJ11 (rs5219) variants and the risk of developing NODAT after liver transplantation. This study was conducted on 120 liver transplant recipients who had received tacrolimus-based immunosuppressive drugs. The liver transplant recipients were divided into an new onset diabetes mellitus (NODM) and a non-NODM group. The NODAT group consisted of 60 patients who developed diabetes in the first 6 months after transplantation, while the non-NODAT group included 60 patients who remained euglycemic. The patients were genotyped using polymerase chain reaction-restriction fragment length polymorphism and the incidence of NODAT was compared between the two groups. Nongenetic risk factors including donor gender and cold ischemia time, and recipient (MELD score, presence of viral hepatitis, acute rejection and steroid pulse therapy) were also considered. The KCNJ11 KK variant was associated with an increased risk for NODAT with respective odds ratio of 6.03 (95 % confidence interval 2.37-15.4; P < 0.001]. Donor age and male sex, recipient age as well as fasting plasma glucose before transplantation were significantly different between NODAT and non-NODAT groups (P < 0.05). The prednisolone daily dosage was significantly higher in the NODAT group (P = 0.01). These patients received pulse of methyl prednisolone for treatment of acute rejection. This study showed that polymorphisms in KCNJ11 might predispose the patients treated by tacrolimus to development of NODAT after liver transplantation.
Assuntos
Diabetes Mellitus/genética , Transplante de Fígado , Polimorfismo de Nucleotídeo Único , Canais de Potássio Corretores do Fluxo de Internalização/genética , Adolescente , Adulto , Fatores Etários , Glicemia , Diabetes Mellitus/epidemiologia , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores Sexuais , Tacrolimo/uso terapêutico , Doadores de Tecidos , Transplantados , Adulto JovemRESUMO
There is growing evidence that the long noncoding RNAs (lncRNAs) contribute to the pathogenesis of various neurodegenerative diseases such as multiple sclerosis (MS). The role of lncRNAs nuclear repressor of NFAT (NRON) and Taurine up-regulated 1 (TUG1) in the inflammatory processes occurring in the experimental autoimmune encephalomyelitis (EAE) model of MS is yet to be investigated. Transcript levels of NRON and TUG1 in acute and chronic phases of EAE and cultured macrophages as well as the correlation between NRON and TUG1 expression with inflammatory cytokines, were evaluated in this study. EAE experimental model was induced in female C57BL/6 mice with subcutaneous injection of MOG35-55/CFA. Mice were scored for 28 days and then sacrificed. The expression of lncRNAs TUG1 and NRON in lumbar spinal cords, activated and controlled macrophages as well as the expression of IL-1, IL-6, and CDe-3 inflammatory cytokines, were assayed by real-time RT-PCR. The lncRNAs TUG1 and NRON were significantly down-regulated in lumbar spinal cords tissues in the acute phase of EAE compared to the control group. TUG1 and NRON were significantly down-regulated in macrophages treated with 10 ng lipopolysaccharide (LPS) compared to the control macrophages. A negative correlation was identified between NRON and TUG1 expression and IL-1, IL-6, and CDe-3 inflammatory cytokines. The present study demonstrates the dysregulation of lncRNAs TUG1 and NRON in spinal cord tissue lesions of EAE and activated macrophages, pointing to their potential role in the pathogenesis of EAE.
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , RNA Longo não Codificante , Animais , Feminino , Camundongos , Citocinas/genética , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Inflamação/genética , Inflamação/patologia , Interleucina-1 , Interleucina-6 , Camundongos Endogâmicos C57BL , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
We investigated the association of MMP-9 rs1056628 and rs17576 polymorphisms with breast cancer (BC) relapse in a cohort of prospectively observed BC patients. The polymorphisms were genotyped in 200 BC subjects with(case) and without(control) relapse by Tetra-primer Amplification Refractory Mutation System-Polymerase Chain Reaction (T-ARMS-PCR) method. A significant association was found between the rs1056628C allele and increased risk of BC relapse (OR = 1.8, P = 0.006). Also, rs17576 allele and genotypes were shown protective effects against BC relapse. Increased risk of relapse was observed in haplotype CG (OR = 2.1, P = 0.001). Our results suggest for the first time that rs1056628 and rs17576 polymorphisms may influence BC relapse.
Assuntos
Neoplasias da Mama , Neoplasias da Mama/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Irã (Geográfico)/epidemiologia , Metaloproteinase 9 da Matriz/genética , Recidiva Local de Neoplasia/genética , Polimorfismo de Nucleotídeo Único , Estudos ProspectivosRESUMO
Cellular homeostasis and adaptation to various environmental conditions are importantly regulated by the sophisticated mechanism of autophagy and its crosstalk with Wnt signaling and other developmental pathways. Both autophagy and Wnt signaling are involved in embryogenesis and differentiation. Autophagy is responsible for degradation and recycling of cytosolic materials by directing them to lysosomes through the phagophore compartment. A dual feedback mechanism regulates the interface between autophagy and Wnt signaling pathways. During nutrient deprivation, ß-catenin and Dishevelled (essential Wnt signaling proteins) are targeted for autophagic degradation by LC3. When Wnt signaling is activated, ß-catenin acts as a corepressor of one of the autophagy proteins, p62. In contrast, another key Wnt signaling protein, GSK3ß, negatively regulates the Wnt pathway and has been shown to induce autophagy by phosphorylation of the TSC complex. This article reviews the interplay between autophagy and Wnt signaling, describing how ß-catenin functions as a key cellular integration point coordinating proliferation with autophagy, and it discusses the clinical importance of the crosstalk between these mechanisms.
Assuntos
Autofagia , Via de Sinalização Wnt , Diferenciação Celular , Proliferação de Células , Citosol/metabolismo , Humanos , Lisossomos/metabolismo , ProteóliseRESUMO
OBJECTIVE: Male infertility is a multifactorial disease resulting from the interaction between the genetic and environmental factors. Spermatogenic failure accounts for more than half of male infertility cases. Heat shock proteins (HSPs) are the molecular chaperones that are involved in different developmental stages of spermatogenesis. The current study was planned to investigate the role of HSPA1L rs2227956 and HSPA1B rs1061581 gene polymorphisms in idiopathic male infertility. STUDY DESIGN: This case-control study was conducted on 516 subjects consisted of 308 patients with idiopathic male infertility and 208 age matched-(±5) control subjects. HSPA1L rs2227956 and HSPA1B rs1061581 polymorphisms were genotyped by PCR-RFLP method. RESULTS: A significant association with male infertility was found for HSPA1L rs2227956 in genotypes (TT vs CT: ORâ¯=â¯2.049, 95% CIâ¯=â¯1.337-3.139, Pâ¯=â¯0.001; TT vs CC: ORâ¯=â¯3.028, 95% CIâ¯=â¯1.100-8.332, Pâ¯=â¯0.032). In the dominant genetic model, rs2227956C allele increased the risk of male infertility (ORâ¯=â¯2.049, 95% CIâ¯=â¯1.337-3.139, Pâ¯=â¯0.001). Also, the results showed a significant association between the HSPA1B rs1061581GG genotype and male infertility (ORâ¯=â¯2.638, 95% CI: 1.001-4.486, Pâ¯=â¯0.001). The rs1061581â¯G allele was a risk factor for male infertility (ORâ¯=â¯1.657, 95% CIâ¯=â¯1.278-2.148, Pâ¯<â¯0.001). Haplotype analysis showed CG and TA (rs2227956/ rs1061581) haplotype affect the risk of male infertility (Pâ¯<â¯0.001). CONCLUSION: HSPA1L rs2227956 and HSPA1B rs1061581 gene polymorphisms are associated with susceptibility to idiopathic male infertility in Iranian population. Further studies in different ethnicity are necessary to confirm these results.
Assuntos
Predisposição Genética para Doença , Proteínas de Choque Térmico HSP70/genética , Haplótipos , Infertilidade Masculina/genética , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Estudos de Casos e Controles , Estudos de Associação Genética , Genótipo , Humanos , Irã (Geográfico) , MasculinoRESUMO
INTRODUCTION: Evidence has confirmed that placental/fetal hypoxia plays a key role in both endothelial cell dysfunction and PE pathogenesis. The aim of the present study was to investigate whether maternal/placental hypoxia-inducible factor1-α (HIF1-α) C1772T (rs11549465) and/or G1790A (rs11549467) polymorphisms and HIF1-α mRNA expression are associated with PE development. METHODS: The blood samples of 203â¯PE and 202 control women and the placenta of 86â¯PE and 84 control women were collected after delivery. The HIF1-α polymorphisms were genotyped using PCR- RFLP method. The mRNA expression levels were measured by Quantitative Real -Time PCR. RESULTS: The present study found no association between maternal HIF1-α rs11549465 and rs11549467 and placental rs11549467 polymorphisms and PE. However, the placental rs11549465 polymorphism was associated with PE in the dominant model. The CT/GG combined genotypes and TG haplotype of placental rs11549465 and rs11549467 polymorphisms were associated with higher risk of PE. The HIF1-α mRNA expression was 3-fold higher in the PE women. The rs11549465â¯TT genotype was associated with higher HIF1-α mRNA expression in PE women and in total population and rs11549467â¯GA genotype was associated with higher mRNA expression in total population. The relative mRNA expression of HIF1-α gene was higher in presence of CC/GA, TT/GG and TT/GA combined genotypes. CONCLUSION: This study found an association between placental but not maternal HIF1-α rs11549465 polymorphism and PE in the dominant model. The HIF1-α mRNA expression was higher in the placenta of PE women and was associated with rs11549465 and rs11549467 polymorphisms.
Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Placenta/metabolismo , Polimorfismo de Nucleotídeo Único , Pré-Eclâmpsia/genética , Adulto , Estudos de Casos e Controles , Feminino , Expressão Gênica , Predisposição Genética para Doença , Genótipo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/metabolismo , Gravidez , RNA Mensageiro/metabolismo , Fatores de Risco , Adulto JovemRESUMO
Type 2 diabetes mellitus is a worldwide epidemic disorder with considerable health and economic consequences. Metformin is one of the most commonly prescribed oral antidiabetic drugs. Pharmacogenetic studies showed that variants in genes related to the pharmacokinetics of metformin were associated with glucose-lowering effect of metformin. The aim of this study was to evaluate pharmacogenetic variation in SLC47A1 (rs2289669) and metformin response in type 2 diabetes patients. Seventy one patients with type 2 diabetes were included in the study. The genotypes were determined by Tetra-ARMS-PCR method. There was a significant association between the study polymorphism and the response to metformin treatment with the highest HbA1C reduction in AG genotype. In the dominant model for A allele (AA+AG vs GG), patients with A allele had highest HbA1C reduction in response to metformin.
RESUMO
OBJECTIVE: Today, many single nucleotide polymorphisms in microRNA genes are known to alter the microRNA expression levels or processing causing susceptibility of several human diseases. The present study aimed to investigate the association of microRNA-146a (rs2910164) and microRNA-222 (rs2858060) polymorphisms with susceptibility to polycystic ovary syndrome (PCOS) in an Iranian population. MATERIALS AND METHODS: This case-control study was performed on 205 patients with PCOS and 205 normal women as the control group. After DNA extraction, Tetra-amplification refractory mutation system polymerase chain reaction (T-ARMS-PCR) was used to detect the polymorphisms. The association between genotypes and the risk of PCOS was examined by odds ratios (OR) and 95% of confidence intervals (CIs). RESULTS: Our results showed that there are significant differences in CG genotype frequencies between case and control groups regarding miR-146a rs2910164 polymorphism (OR = 2.03, CI = 1.3-3, P = 0.001). In a dominant model for the C allele, CC + CG genotypes were associated with PCOS risk (OR = 2, 95% CI = 1.3-2.9, P = 0.001) and the C allele increased the risk of PCOS (OR = 1.6, 95% CI = 1.1-2.1, P = 0.004). Furthermore, a positive association was observed between miR-222 CG genotype and the risk of PCOS (OR = 2.2, 95% CI = 1.1-4.1, P = 0.02). These results were evident after adjustment for age and body mass index. CONCLUSION: The present results suggest that the miR-146a rs2910164 and miR-222 rs2858060 polymorphisms are associated with an increased risk of PCOS. Therefore, both polymorphisms could play an important role as a genetic risk factor for development of PCOS in the Iranian population.
Assuntos
Predisposição Genética para Doença/genética , MicroRNAs/genética , Síndrome do Ovário Policístico/genética , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Povo Asiático/genética , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Irã (Geográfico) , Fatores de RiscoRESUMO
Nonalcoholic fatty liver disease (NAFLD) is an obesity-associated disease and dysregulation of adipokines has an important role in its development. Omentin-1 (ITLN1 protein) and resistin are two adipokine secreted from adipose tissue. Single nucleotide polymorphisms in the adipokine genes may affect expression and activity of the adipokine, and thus play a contributory role in NAFLD pathogenesis. The aim of the present study was to investigate the association between omentin-1 rs2274907 (326A/T) and resistin rs1862513 (-420 C/G) polymorphisms and risk of NAFLD in Iranian patients. This case-control study was done on 282 subjects included 94 patients with NAFLD and 188 healthy peoples. The genotypes were determined using PCR-RFLP method. The frequency of omentin-1 AT genotype in patients with NAFLD was significantly different from that in the control (OR=2.3, 95% CI: 1.3-3.8, P=0.003). A significant association was observed between NAFLD and the GG genotype regarding resistin rs1862513 polymorphism (OR=2.3, 95% CI: 1.1-4.8, P=0.03). In conclusion, Omentin-1 rs2274907 and resistin rs1862513 polymorphisms might be a candidate genetic factor for susceptibility to NAFLD.
RESUMO
BACKGROUND: Recurrent pregnancy loss (RPL) is defined as two or more miscarriages before the 20(th) week of gestation and its etiology is unknown in 50% of the cases. Interleukin 6 is an immune mediator, plays a regulatory role in embryo implantation and placental development. OBJECTIVE: The purpose was to assess the association between IL-6 -634C/G polymorphism and, susceptibility to idiopathic RPL for the first time in Iran. MATERIALS AND METHODS: In total 121 women with RPL and 121 healthy women as control group were enrolled in this case-control study. This study was performed from August 2013 to October 2014 in the Molecular Genetics Laboratory of Arsanjan University. Candidate polymorphism was evaluated by PCR-RFLP method on extracted genomic DNA. Data was analyzed using the statistical SPSS package. RESULTS: Our results showed an increased risk of RPL in patients with GG + GC genotype (OR=5.1, 95%CI: 1.04-25.3, p=0.04) in comparison to CC genotype. The frequency of mutant allele G in patients and controls was 0.75 and 0.66 respectively. The mutant allele G predisposes women to miscarriage 1.5 times greater than controls (OR=1.5, 95%CI: 1.03-2.27, p=0.036). The mean number of live births in RPL women (1.3±2.3) was significantly lower compared to control women (4.8±2.3). CONCLUSION: This study indicated that the promoter polymorphism (-634C/G) of the IL-6 gene has likely inï¬uence on individual susceptibility to RPL.
RESUMO
BACKGROUND: Multiple sclerosis (MS) as a complex neurological disease can be due to vitamin D deficiency. CYP27B1 is referred to as a vitamin D metabolizing enzyme. MATERIALS AND METHODS: This study compared the expression level of CYP27B1 in Relapsing-Remitting MS (RRMS) patients with normal individuals in Iran. The RNA was extracted from 50 RRMS patients and 50 normal controls. Quantitative RT-PCR was adopted to measure the expression level of CYP27B1 gene. RESULTS: The expression level of CYP27B1gene was significantly lower in the RRMS patients than their normal counterparts (P value = 0.04). Also, the RRMS females participating had a significant reduction in CYP27B1 gene expression compared to normal females (P-Value = 0.01). In addition, the correlation between CYP27B1 expression level, and the risk of Expanded Disability Status Scale of Kurtzke (EDSS) was not linear. Additionally, there was no significant correlation between expression status of CYP27B1gene and duration of the disease. CONCLUSION: A significant decrease in the expression level of CYP27A1 in female patients could indicate their greater vulnerability to MS than the male patients.
Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Esclerose Múltipla Recidivante-Remitente/genética , Vitamina D/sangue , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/imunologia , Adulto , Estudos de Casos e Controles , Regulação para Baixo , Feminino , Expressão Gênica , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/imunologia , Humanos , Fatores Imunológicos/uso terapêutico , Interferon beta/uso terapêutico , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/patologia , Fatores SexuaisRESUMO
Leptin is an adipocytokine made by fat cells and plays a key role in proliferation, cell survival, migration and immune response. It has a powerful effect on the initiation of puberty and in determining age at menarche. The current study is the first investigation to examine the effect of G-2548A leptin gene polymorphism on the age at menarche and breast cancer susceptibility. This case-control study was performed on 203 patients with breast cancer and 171 healthy women. The leptin genotypes were determined using the PCR-RFLP method and age at menarche was obtained by questionnaires. There was a significant difference between the leptin G-2548A genotypes between case and control groups (P<0.05). AA genotype is significantly higher in patients compared to the controls. Furthermore, women carrying the AA genotype had a significantly younger age at menarche (12.47 years) than women with the AG (12.94 years) and GG (13.47 years) genotypes. Also, we found that the AA genotype frequency in women with age at menarche <13 years was higher than in women with age at menarche ≥13 years (OR: 3.4, 95% CI: 1.7-6.7, P: 0.001). In conclusion, the G-2548A leptin gene polymorphism has an important role in the onset of menarche and breast cancer susceptibility.