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1.
Biochemistry (Mosc) ; 84(9): 1040-1046, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31693463

RESUMO

Preterm birth is not only medical, but also a social problem. The global goal of medicine is prevention of preterm labor and identification of risk factors leading to preterm birth. The objective of our study was to find the association between polymorphic markers in the cytokine IL-1ß, TNF-α, IL-1Ra, and IL-4 genes and development of preterm labor. The prospective study was conducted in 108 pregnant women with the risk of preterm birth. The main group consisted of 66 women whose pregnancy ended with preterm delivery despite the ongoing therapy. The comparison group included 42 women with the full-term delivery. The dominant T allele of the cytokine IL-1ß gene polymorphism rs1143634 (3953C→T) was 7.6 times more common in women with preterm delivery vs. the comparison group (36.4 and 4.8%, respectively; RR, 1.802; 95% CI, 1.420-2.288; p < 0.05); its homozygous form was detected only in women with preterm delivery at the very early gestation age (less than 26 weeks). The dominant proinflammatory allele 2R of the IL-1 receptor antagonist gene (IL-1Ra) was 1.5 times more common in women with preterm delivery than in the comparison group (63.6 and 42.8%, respectively; RR, 1.400; 95% CI, 1.009-1.943; p < 0.05), which makes the 2R allele the risk factor for preterm birth. The 2R/2R and 2R/4R genotypes led to a very early and early preterm delivery, respectively. The combination of three or four proinflammatory genotypes was detected only in women with a very early preterm delivery, which confirms that the combination of several proinflammatory genotypes is an extremely unfavorable factor for the full-term pregnancy. Identification of genetic polymorphisms in the interleukin genes at the periconceptional stage will help to prevent the risk of preterm delivery, which will reduce the incidence of preterm births, as well as perinatal morbidity and mortality.


Assuntos
Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1beta/genética , Interleucina-4/genética , Polimorfismo Genético/genética , Nascimento Prematuro/genética , Fatores de Necrose Tumoral/genética , Alelos , Feminino , Humanos , Gravidez , Estudos Prospectivos , Fatores de Risco
2.
Pediatr Rheumatol Online J ; 17(1): 37, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31286990

RESUMO

BACKGROUND: Deficiency of interleukin-36 receptor antagonist (DITRA) is a life threatening monogenic autoinflammatory disease caused by loss of function mutations in the IL36RN gene. Affected patients develop recurrent episodes of generalized pustular psoriasis (GPP) with systemic inflammation and fever. We here review and analyze the literature on pediatric DITRA patients who have been treated by biologicals targeting inflammatory cytokines. METHOD: A database research was performed to identify all relevant articles on pediatric DITRA patients treated with biologicals. According to defined response criteria therapeutic efficacy was analyzed. RESULTS: Our literature research revealed 12 pediatric patients with DITRA who have received treatment with biologicals and we add a further not yet reported patient. Out of these 13 patients 10 were homozygous including 6 with the p.Leu27Pro, 3 with the p.Arg10 Argfs* and 1 with the p.Thr123Met mutation. 3 patients were compound heterozygous. In total 28 flares were treated with biological agents- targeting IL-1, IL-17, IL-12/23 and TNF-α. Complete response was achieved in 16 flares (57%), a partial reponse was seen in 2 flares (7%), and no response was observed in 10 flares (36%). Response rates were heterogeneous among the different agents. While complete/partial/no response with inhibition of TNF-alpha could be achieved in 7 (58%)/1 (8%)/4 (33%), the inhibition of IL-17 and of IL-12/23 led in each 4 flares to a 100% complete response. IL-1 inhibition led to complete/partial response in each 1 (13%) and was not effective in 6 (76%) flares. Of note, the novel patient was successfully treated with weekly dosed adalimumab. CONCLUSIONS: DITRA is a rare disease that has to be considered in GPP with systemic inflammation and fever. It can be effectively treated with specific biological inhibition of TNF-alpha, IL-12/23 and IL- 17, while anti-IL-1 treatment seems less effective. Weekly dosed adalimumab appears to be a treatment option for pediatric patients. Further reports and studies of biological treated pediatric DITRA patients are warranted for evaluation of optimal treatment.


Assuntos
Produtos Biológicos/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/genética , Receptores de Interleucina/deficiência , Adolescente , Idade de Início , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Mutação com Perda de Função/genética , Masculino , Receptores de Interleucina/antagonistas & inibidores , Resultado do Tratamento
3.
J Clin Lab Anal ; 33(6): e22903, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31102307

RESUMO

BACKGROUND: Interleukin-1 promotes tumor angiogenesis through VEGF production. The interleukin-1 receptor antagonist can suppress tumors by blocking this effect. METHODS: Immunohistochemistry, WB, and gene sequencing were used to analyze the expression of IL-1RA in esophageal cancer patients. WB was used to detect the expression of IL-1RA and interleukin-1α in esophageal cancer cells. Stable ESCC cell models overexpressing the IL-1RA were constructed. Their cell functions were tested, and their effects on VEGF were examined. RESULTS: IL-1RA is downregulated in primary EC tumors, and this downregulation of IL-1RA is closely related to TNM staging and survival prognosis. The overexpression of IL-1RA increased the proliferation of KYSE410 EC cells, which have a high level of IL-1α expression. Overexpression of IL-1RA in KYSE410 cells promotes a decrease in the expression of VEGF-A. However, IL-1RA expression did not cause any changes in EC9706 cells with low IL-1α expression. CONCLUSION: IL-1RA acts as a tumor suppressor, and its deletion promotes tumor progression by increasing VEGF-A expression in ESCC.


Assuntos
Neoplasias Esofágicas/patologia , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1alfa/metabolismo , Idoso , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidade , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1alfa/genética , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Prognóstico , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
Chemotherapy ; 64(1): 28-35, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30995661

RESUMO

BACKGROUND: Recent evidence suggested that IL1RN (interleukin-1 receptor antagonist) polymorphisms increased the susceptibility to cancers. The present study aimed to evaluate whether IL1RN was related to esophageal cancer susceptibility in a Northwest Han Chinese population. METHODS: The case-control study was conducted on 384 esophageal cancer patients and 499 healthy controls. We successfully genotyped four SNPs distributed in IL1RN. The Gene Expression Profiling Interactive Analysis (GEPIA) database was used to observe the expression of IL1RN in esophageal cancer tissues and normal tissues. RegulomeDB and HaploReg v4.1 were used to calculate possible functional effects of the polymorphisms. We also used genetic models to detect any potential association between IL1RN variants and esophageal cancer risk. RESULTS: In our study, rs3181052 was associated with a reduced risk of esophageal cancer in the codominant (odds ratio [OR] = 0.70, 95% confidence interval [CI] 0.52-0.93, p = 0.040), the dominant (OR = 0.75, 95% CI 0.57-0.99, p = 0.041), and the overdominant (OR = 0.71, 95% CI 0.54-0.93, p = 0.012) model. The rs452204 was associated with a 0.76-fold (OR = 0.76, 95% CI 0.58-0.99; p = 0.043) decreased esophageal cancer risk under the overdominant model without adjustment. We also found that rs3181052 had a negative effect on esophageal cancer under the overdominant model (OR = 0.72, 95% CI 0.53-0.97, p = 0.033) adjusted for age and gender. In stratified analyses by age >55 years, rs3181052 reduced the risk of esophageal cancer in the dominant and overdominant models. In addition, rs315919 had a remarkable influence on esophageal cancer risk in females, while the association was not significant between rs3181052 and esophageal cancer risk in males. CONCLUSIONS: Our study provided the first evidence that IL1RN rs3181052, rs452204, and rs315919 are correlated with a decreased risk of esophageal cancer in a Northwest Han Chinese population. These findings may be useful for the development of early prognostics for esophageal cancer. However, further larger studies on different ethnic populations are warranted to verify these findings.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Neoplasias Esofágicas/patologia , Proteína Antagonista do Receptor de Interleucina 1/genética , Adulto , Idoso , Estudos de Casos e Controles , China , Bases de Dados Factuais , Neoplasias Esofágicas/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Fatores de Risco
5.
Tissue Eng Part A ; 25(9-10): 809-820, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30968743

RESUMO

IMPACT STATEMENT: We engineered a synthetic transcription system based on nuclear factor kappa-light-chain-enhancer of activated B cells signaling that can attenuate the effects of the inflammatory cytokine interleukin (IL)-1α in a self-regulating manner. This system responds in a time- and dose-dependent manner to rapidly produce therapeutic levels of IL-1 receptor antagonist (IL-1Ra). The use of lentiviral gene therapy allows this system to be utilized through different transduction methods and in different cell types for a variety of applications. Broadly, this approach may be applicable in developing autoregulated biologic systems for tissue engineering and drug delivery in a range of disease applications.


Assuntos
Produtos Biológicos/metabolismo , Redes Reguladoras de Genes , Genes Sintéticos , Terapia Genética , Proteína Antagonista do Receptor de Interleucina 1 , Interleucina-1alfa , Engenharia Tecidual , Animais , Células HEK293 , Humanos , Proteína Antagonista do Receptor de Interleucina 1/biossíntese , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1alfa/biossíntese , Interleucina-1alfa/genética , Camundongos
6.
Int J Mol Sci ; 20(6)2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30875826

RESUMO

BACKGROUND: Interleukin-1 (IL-1)ß and IL-1 receptor antagonist (IL-1Ra) have been proposed as important mediators during chronic liver diseases. We aimed to determine whether the modulation of IL-1ß signaling with IL-1Ra impacts on liver fibrosis. METHODS: We assessed the effects of IL-1ß on human hepatic stellate cells (HSC) and in mouse models of liver fibrosis induced by bile duct ligation (BDL) or carbon tetrachloride treatment (CCl-4). RESULTS: Human HSCs treated with IL-1ß had increased IL-1ß, IL-1Ra, and MMP-9 expressions in vitro. HSCs treated with IL-1ß had reduced α-smooth muscle actin expression. These effects were all prevented by IL-1Ra treatment. In the BDL model, liver fibrosis and Kuppfer cell numbers were increased in IL-1Ra KO mice compared to wild type mice and wild type mice treated with IL-1Ra. In contrast, after CCl-4 treatment, fibrosis, HSC and Kupffer cell numbers were decreased in IL-1Ra KO mice compared to the other groups. IL-1Ra treatment provided a modest protective effect in the BDL model and was pro-fibrotic in the CCl-4 model. CONCLUSIONS: We demonstrated bivalent effects of IL-1Ra during liver fibrosis in mice. IL-1Ra was detrimental in the CCl-4 model, whereas it was protective in the BDL model. Altogether these data suggest that blocking IL-1-mediated inflammation may be beneficial only in selective liver fibrotic disease.


Assuntos
Actinas/genética , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1beta/genética , Cirrose Hepática/genética , Metaloproteinase 9 da Matriz/genética , Animais , Tetracloreto de Carbono/efeitos adversos , Contagem de Células , Células Cultivadas , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Humanos , Macrófagos do Fígado/citologia , Macrófagos do Fígado/efeitos dos fármacos , Macrófagos do Fígado/imunologia , Cirrose Hepática/etiologia , Cirrose Hepática/imunologia , Masculino , Camundongos , Regulação para Cima
7.
J Int Med Res ; 47(4): 1696-1704, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30803280

RESUMO

OBJECTIVE: To investigate the association between single nucleotide polymorphisms (SNPs) in six candidate genes (enamelin [ ENAM]; tuftelin 1 [ TUFT1]; matrix metallopeptidase 13 [ MMP13]; interleukin 1 beta [ IL1B]; interleukin 10 [ IL10]; interleukin 1 receptor antagonist [ IL1RN]) and dental caries in children from northwest China. METHODS: This case-control study enrolled children (12-15 years) who underwent routine dental examinations. The children were divided into two groups based on the presence of dental caries. A saliva sample was collected and seven SNPs (rs3806804A/G in ENAM, rs3811411T/G in TUFT1, rs2252070A/G and rs597315A/T in MMP13, rs1143627C/T in IL1B, rs1800872A/C in IL10 and rs956730G/A in IL1RN) were genotyped. RESULTS: A total of 357 children were enrolled in the study: 161 with dental caries and 196 without dental caries. No significant difference was found in the alleles and genotypes of five genes ( ENAM, TUFT1, MMP13, IL10 and IL1RN) between those with and without dental caries. A significant relationship was found between the IL1B rs1143627C/T polymorphism and dental caries susceptibility with those carrying the rs1143627CT genotype having a lower risk of dental caries compared with those carrying the CC genotype (odds ratio 0.557; 95% confidence interval 0.326, 0.952). CONCLUSION: The IL1B rs1143627C/T polymorphism may be associated with dental caries susceptibility in children from northwest China.


Assuntos
Cárie Dentária/genética , Proteínas do Esmalte Dentário/genética , Proteínas da Matriz Extracelular/genética , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-10/genética , Interleucina-1beta/genética , Metaloproteinase 13 da Matriz/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Criança , Cárie Dentária/patologia , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Prognóstico
8.
Mol Genet Genomic Med ; 7(1): e00512, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30523673

RESUMO

BACKGROUND: The present study carried out a meta-analysis to investigate whether the interleukin-1 receptor antagonist (IL-1RN) VNTR polymorphism and three IL-10 single-nucleotide polymorphisms (SNPs) rs1800896, rs3021097, and rs1800872 are associated with psoriasis risk. METHODS: Wanfang, China National Knowledge Infrastructure, Medline, and PubMed databases were searched for potential studies published until 2 November 2017. Forest plots were generated. RESULTS: Thirteen case-control studies were included in the review. The results of meta-analyses revealed no association of the IL-1RN*2 allele with psoriasis in the overall populations (odds ratio [OR] = 1.16, 95% confidence intervals [CI]: 0.89-1.50, p = 0.279), Asians (OR = 1.27, 95% CI: 0.73-2.23, p = 0.403), and Caucasians (OR = 1.04, 95% CI: 0.88-1.23, p = 0.669). Under the allelic model, there was no statistically significant association of psoriasis with the IL-10 SNPs rs1800896 (G allele vs. A allele: OR = 1.03, 95% CI: 0.90-1.18, p = 0.639), rs3021097 (C allele vs. T allele: OR = 1.17, 95% CI: 0.88-1.56, p = 0.288), and rs1800872 (C allele vs. A allele: OR = 1.01, 95% CI: 0.81-1.25, p = 0.951). No publication bias was found by Egger's test and Begg's funnel plots. CONCLUSION: Current published studies fail to support an association of the IL-1RN VNTR polymorphism and IL-10 SNPs rs1800896, rs3021097, and rs1800872 with psoriasis risk.


Assuntos
Interleucina-10/genética , Polimorfismo de Nucleotídeo Único , Psoríase/genética , Humanos , Proteína Antagonista do Receptor de Interleucina 1/genética
9.
Artigo em Inglês | MEDLINE | ID: mdl-30360750

RESUMO

BACKGROUND: Diabetic peripheral neuropathy (DPN) is one of the most common complications of Type 2 diabetes mellitus (T2DM). This study was conducted to investigate the possible association between interleukin-1ß (IL-1ß) rs16944 /IL-1 receptor antagonist (IL-1Ra) VNTR variants and genetic susceptibility to DPN in a Turkish cohort. METHODS: A total of 200 subjects were enrolled in this study, 98 patients with DPN and 102 cases of age and sex-matched healthy controls. Genotyping was performed for all individuals using PCR-RFLP analysis. RESULTS: IL-1ß rs16944 CC genotype had a 3.20-fold increased risk for DPN (p=0.0003, OR=3.20, 95% Cl:1.72-5.96). IL-1ß rs16944 CT genotype was higher in healthy control than patients (p=0.004). IL-1ß rs16944 C allele was higher in the patient group compared to controls while T allele was lower in patients than controls (p=0.003). IL-1Ra VNTR a1/a1 and a2/a2 genotypes were lower in DPN patients while a1/a2 genotype was higher in patients (p=0.045). The patients carrying a1/T haplotype had decreased risk of DPN than control groups (p=0.004). The patients carrying a2/a2 genotype had lower HDL level (p=0.039). The subjects carrying a2/a2 genotype had higher total cholesterol level while the subjects carrying a1/a2 genotype had lower total cholesterol (p=0.026 and p=0.037, respectively). IL-1Ra a1 allele was associated with higher HDL level (p=0.041). CONCLUSION: Findings of this study indicated that the IL-1ß rs16944 and IL-1Ra VNTR variants are probably to be associated with susceptibility DPN risk in a Turkish cohort.


Assuntos
Neuropatias Diabéticas/genética , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1beta/genética , Polimorfismo Genético , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Análise Mutacional de DNA , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Neuropatias Diabéticas/epidemiologia , Feminino , Ligação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Repetições Minissatélites/genética , Polimorfismo de Nucleotídeo Único , Turquia/epidemiologia
10.
Immunol Res ; 67(1): 151-156, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30382562

RESUMO

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Genetic variations in cytokine genes and their receptors lead to the severity of the disease. The interleukin-1 receptor antagonist (IL1RN) is a cytokine that inhibits interleukin-1 (IL-1) activity by binding to IL-1 receptors. Also, interleukin-4 (IL-4) is an anti-inflammatory cytokine that can play an important role in several cancers. The present case-control study was aimed to evaluate the association of IL-4 and IL1RN VNTR polymorphisms with the susceptibility to CRC in a sample of Iranian population provided by the Research Center for Gastroenterology and Liver Disease at Taleghani Hospital, Tehran. A total of 123 patients diagnosed with CRC and 152 healthy controls were recruited in the present study. Genomic DNA was extracted by salting out method from whole blood and genotyping of IL1RN and IL-4 VNTR polymorphisms were determined by PCR-based technology. Our study manifested the frequency of 1/2 and 2/4 genotypes of IL1RN 68bp VNTR polymorphism are significantly different between both groups (p = 0.0001 and p = 0.01 respectively). However, we could not find any correlation between IL-4 VNTR polymorphism and CRC cancer. It seems that 1/2 and 2/4 genotypes of IL1RN are correlated with CRC susceptibility in our population, although, more studies are needed to confirm our results.


Assuntos
Neoplasias do Colo/genética , Neoplasias Colorretais/genética , Genótipo , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-4/genética , Idoso , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polimorfismo Genético , Risco
11.
Gynecol Obstet Invest ; 84(1): 12-19, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30007972

RESUMO

OBJECTIVE: To evaluate the placental and decidual gene expression and maternal and umbilical serum concentrations of tumor necrosis factor alpha, interleukin 6 (IL-6), IL-8, IL-10, IL-1 receptor antagonist (IL-1RA), intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 (VCAM-1), along with the proinflammatory/anti-inflammatory cytokine ratios in women with preeclampsia (PE) vs. women with normal pregnancy (NP), and to analyze PE classified as early- (EO) and late-onset (LO). METHODS: This cross-sectional study was performed with 50 women with PE (EO n = 30, LO n = 20) and 50 women with NP. Tissue gene expression levels were measured by real-time RT-PCR. Cytokines and adhesion molecules serum concentrations were measured by immunoassays. RESULTS: In PE, placental expression of IL-10 and IL-1RA was lower, while placental IL-8/IL-1RA ratio and maternal concentrations of VCAM-1 were higher vs. NP. In EO, placental expression of IL-10 was lower, while placental IL-8/IL-10 and IL-8/IL-1RA ratios were higher than LO and NP. Maternal concentrations of IL-6 were higher in LO than EO and NP. Throughout PE, maternal VCAM-1 concentrations were higher vs. NP. No significant differences were observed in the decidual expression and umbilical concentrations of the markers between the groups. CONCLUSION: PE associates with a proinflammatory placental state; however, EO associates with a proinflammatory placental state, while LO associates with systemic maternal inflammation. Both subtypes associated with maternal endothelial dysfunction.


Assuntos
Citocinas/sangue , Citocinas/genética , Decídua/metabolismo , Endotélio/fisiopatologia , Pré-Eclâmpsia/fisiopatologia , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos Transversais , Feminino , Sangue Fetal/metabolismo , Expressão Gênica , Humanos , Inflamação/etiologia , Molécula 1 de Adesão Intercelular/sangue , Molécula 1 de Adesão Intercelular/genética , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-10/sangue , Interleucina-10/genética , Interleucina-6/sangue , Interleucina-6/genética , Interleucina-8/sangue , Interleucina-8/genética , Pré-Eclâmpsia/sangue , Gravidez , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Molécula 1 de Adesão de Célula Vascular/sangue , Molécula 1 de Adesão de Célula Vascular/genética , Adulto Jovem
12.
Iran J Immunol ; 15(4): 321-328, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30593746

RESUMO

BACKGROUND: Chronic inflammation is associated with neoplasms and several types of cancer. Therefore, polymorphisms in the inflammation-related genes could modify the cancer susceptibility. OBJECTIVE: To investigate the associations between IL-1RN VNTR and rs419598 polymorphisms in IL-1 receptor antagonist (IL-1ra) and colorectal cancer (CRC) and gastric cancer (GC) in an Iranian population. METHODS: In this study, 126 cancer cases (91 CRC and 35 GC) and 97 healthy controls were included. Genotyping of IL-1RN VNTR and rs419598 was performed by PCR amplification and PCR-RFLP, respectively. Logistic regression was applied to identify the independent risk factors for colorectal and gastric cancers by computing the odds ratio (OR) and 95% confidence intervals (95% CI). All statistical analyses were performed using the SPSS statistical software. RESULTS: There were significant differences between cancer groups and control group concerning the frequency of A1/A2 genotypes in IL-1RN VNTR polymorphism. The carrier status of IL-1RN* 2 allele was associated with increased risk of CRC (p = 0.0003; OR = 0.02; 95% CI: 0.491-0.85) and GC (p = 0.0006; OR = 0.106; 95% CI: 0.321-0.035). Also, the homozygous ILRN *2/*2 genotype was associated with increased risk of gastric cancer (p = 0.04; OR = 0.133; 95% CI: 0.020-0.908). There was no association between different alleles of rs419598 and CRC and GC. CONCLUSION: This study demonstrates an association between the carrier status of IL-1RN* 2 and CRC and GC in an Iranian population.


Assuntos
Neoplasias Colorretais/genética , Genótipo , Proteína Antagonista do Receptor de Interleucina 1/genética , Neoplasias Gástricas/genética , Idoso , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Risco
13.
J Immunol Res ; 2018: 9208274, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30417021

RESUMO

Genetic research has shaped the inflammatory bowel disease (IBD) landscape identifying nearly two hundred risk loci. Nonetheless, the identified variants rendered only a partial success in providing criteria for the differential diagnosis between ulcerative colitis (UC) and Crohn's disease (CD). Transcript levels from affected intestinal mucosa may serve as tentative biomarkers for improving classification and diagnosis of IBD. The aim of our study was to identify gene expression profiles specific for UC and CD, in endoscopically affected and normal intestinal colonic mucosa from IBD patients. We evaluated a panel of 84 genes related to the IBD-inflammatory pathway on 21 UC and 22 CD paired inflamed and not inflamed mucosa and on age-matched normal mucosa from 21 non-IBD controls. Two genes in UC (CCL11 and MMP10) and two in CD (C4BPB and IL1RN) showed an upregulation trend in both noninflamed and inflamed mucosa compared to controls. Our results suggest that the transcript levels of CCL11, MMP10, C4BPB, and IL1RN are candidate biomarkers that could help in clinical practice for the differential diagnosis between UC and CD and could guide new research on future therapeutic targets.


Assuntos
Colite Ulcerativa/genética , Doença de Crohn/genética , Mucosa Intestinal/fisiologia , Adulto , Biomarcadores/metabolismo , Quimiocina CCL11/genética , Colite Ulcerativa/diagnóstico , Doença de Crohn/diagnóstico , Diagnóstico Diferencial , Feminino , Antígenos de Histocompatibilidade/genética , Humanos , Proteína Antagonista do Receptor de Interleucina 1/genética , Masculino , Metaloproteinase 10 da Matriz/genética , Pessoa de Meia-Idade , Transcriptoma , Regulação para Cima
14.
J Mater Sci Mater Med ; 29(10): 155, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30276528

RESUMO

Synovial inflammation mainly resulting from interleukin-1 beta (IL-1ß) plays a crucial role in the early and late stage of osteoarthritis. Recent progress in therapeutic gene delivery systems has led to promising strategies for local sustained target gene expression. The aim of this study was to design a nanoparticle made of chitosan (CS)/hyaluronic acid (HA)/plasmid-DNA (pDNA) encoding IL-1 receptor antagonist gene (pIL-1Ra) and furtherly use it to transfect the primary synoviocytes, and then investigate whether CS/HA/pIL-1Ra nanoparticles could make the synoviocytes overexpress functional IL-1Ra to attenuate inflammation induced by IL-1ß. In this study, CS was modified with HA to generate CS/HA nanoparticles and then combined with pIL-1Ra to form CS/HA/pIL-1Ra nanoparticles. The physicochemical characteristics results showed that CS/HA nanoparticles exhibited an appropriate particle size (144.9 ± 2.8 nm) and positive zeta potential ( + 28 mV). The gel retardation assay revealed that pDNA was effectively protected and released in a sustained manner more than 15 days. Cytotoxicity results showed that CS/HA/pIL-1Ra nanoparticles had a safe range (0-80 µg/ml) for the application to synoviocytes. RT-qPCR and western blot analysis demonstrated that CS/HA/pIL-1Ra nanoparticles were able to increase IL-1Ra expression in primary synoviocytes, and reduce the mRNA and protein levels of matrix metalloproteinase-3 (MMP-3), matrix metalloproteinase-13 (MMP-13), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in IL-1ß-induced synoviocytes. Our findings indicated that CS/HA/pIL-1Ra nanoparticles efficiently transfected synoviocytes and attenuated synovitis induced by IL-1ß, which will provide a potential strategy for OA synovitis.


Assuntos
Quitosana/química , DNA/química , Ácido Hialurônico/química , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1beta/farmacologia , Nanopartículas/química , Sinoviócitos/metabolismo , Animais , Sobrevivência Celular , Ciclo-Oxigenase 2/metabolismo , Técnicas de Transferência de Genes , Inflamação/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/genética , Metaloproteinase 3 da Matriz/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Tamanho da Partícula , Plasmídeos , Ratos Sprague-Dawley
15.
Stem Cell Res Ther ; 9(1): 265, 2018 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-30305185

RESUMO

BACKGROUND: In the bone marrow, MSCs reside in a hypoxic milieu (1-5% O2) that is thought to preserve their multipotent state. Typically, in vitro expansion of MSCs is performed under normoxia (~ 21% O2), a process that has been shown to impair their function. Here, we evaluated the characteristics and function of MSCs cultured under hypoxia and hypothesized that, when compared to normoxia, dedicated hypoxia will augment the functional characteristics of MSCs. METHODS: Human and porcine bone marrow MSCs were obtained from fresh mononuclear cells. The first study evaluated MSC function following both long-term (10 days) and short-term (48 h) hypoxia (1% O2) culture. In our second study, we evaluated the functional characteristics of MSC cultured under short-term 2% and 5% hypoxia. MSCs were evaluated for their metabolic activity, proliferation, viability, clonogenicity, gene expression, and secretory capacity. RESULTS: In long-term culture, common MSC surface marker expression (CD44 and CD105) dropped under hypoxia. Additionally, in long-term culture, MSCs proliferated significantly slower and provided lower yields under hypoxia. Conversely, in short-term culture, MSCs proliferated significantly faster under hypoxia. In both long-term and short-term cultures, MSC metabolic activity was significantly higher under hypoxia. Furthermore, MSCs cultured under hypoxia had upregulated expression of VEGF with concomitant downregulation of HMGB1 and the apoptotic genes BCL-2 and CASP3. Finally, in both hypoxia cultures, the pro-inflammatory cytokine, IL-8, was suppressed, while levels of the anti-inflammatories, IL-1ra and GM-CSF, were elevated in short-term hypoxia only. CONCLUSIONS: In this study, we demonstrate that hypoxia augments the therapeutic characteristics of both porcine and human MSCs. Yet, short-term 2% hypoxia offers the greatest benefit overall, exemplified by the increase in proliferation, self-renewing capacity, and modulation of key genes and the inflammatory milieu as compared to normoxia. These data are important for generating robust MSCs with augmented function for clinical applications.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Oxigênio/farmacologia , Animais , Apoptose/genética , Caspase 3/genética , Caspase 3/metabolismo , Diferenciação Celular/efeitos dos fármacos , Hipóxia Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais , Suínos , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
16.
PLoS One ; 13(10): e0205292, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30296277

RESUMO

PURPOSE: To investigate the immunopathogenesis of endophthalmitis, and determine if cytokine profiles could serve as biomarkers of disease severity in infectious endophthalmitis. MATERIALS AND METHODS: Vitreous samples of 46 patients clinically diagnosed as endophthalmitis (of which 25 were culture positive) and 20 non-infectious controls from patients with Retinal Detachment (RD) or diabetic retinopathy were included in the study. The cytokine and chemokine expression patterns of 40 immune mediators including 6 antiinflammatory cytokines, 15 proinflammatory cytokines, 9 Growth factors and 10 proinflammatory chemokines in the vitreous were were analyzed by multiplex cytokine immunoassay. In addition, significant immune mediators were correlated with initial and final visual acuity (VA). RESULTS: Our results demonstrated elevated expression of 16 mediators such as GCSF, GRO, IFN-γ, IL-1α, IL-1ß, IL-1 RA, IL-6, IL-8, IP-10, MCP-1, MCP-3, MIP-1α, IL-1ß, TGF-α, TNF-α in patients with culture positive endophthalmitis. Cytokine profile expression significantly differed between patients with proven endophthalmitis and the non-infectious controls in heat map analysis. PCoA plot indicated five mediators (IL-1RA, IL-6, IL-8, GRO, G-CSF) as biomarkers that could be Independent Predictors of Disease especially in culture negative cases. Correlation of cytokines with VA revealed strong association between the initial VA and intraocular levels of TGF-α, IL-1ß and IL-8 but there was no correlation with the severity or visual outcome of infection. CONCLUSION: In comparison to non-infectious ocular conditions, the pathogenesis of infectious endophthalmitis correlates with increased expression levels of IL-1RA, IL-6, IL-8, GRO, G-CSF. Understanding cytokine profiles in culture negative endophthalmitis patients could aid in therapy in non-responders to empirical antibiotic therapy.


Assuntos
Infecções Bacterianas/imunologia , Retinopatia Diabética/imunologia , Endoftalmite/imunologia , Descolamento Retiniano/imunologia , Corpo Vítreo/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/metabolismo , Infecções Bacterianas/patologia , Biomarcadores/metabolismo , Quimiocina CXCL1/genética , Quimiocina CXCL1/imunologia , Criança , Pré-Escolar , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Endoftalmite/diagnóstico , Endoftalmite/metabolismo , Endoftalmite/patologia , Feminino , Expressão Gênica , Bactérias Gram-Negativas/isolamento & purificação , Bactérias Gram-Positivas/isolamento & purificação , Fator Estimulador de Colônias de Granulócitos/genética , Fator Estimulador de Colônias de Granulócitos/imunologia , Humanos , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/metabolismo , Descolamento Retiniano/patologia , Índice de Gravidade de Doença , Acuidade Visual , Corpo Vítreo/metabolismo , Corpo Vítreo/patologia
17.
IUBMB Life ; 70(11): 1156-1163, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30253037

RESUMO

Sofosbuvir (SOF) and daclatasvir combination with or without ribavirin proved to be effective and safe in the treatment of hepatitis C virus infection. The study aimed to assess the efficacy of (SOF plus daclatasvir) combination + ribavirin in the treatment of treatment-experienced HCV genotype 4 Egyptian patients and to investigate the impact of IL-1ß _31, IL-1ß _511, and IL-1RN and T29C of ESR1 genes polymorphisms on treatment outcome. The study also aimed to assess the effect of the treatment on liver fibrosis. The sustained virologic response was assessed at 0, 4, 12, and 24 weeks from the beginning of treatment by RT-PCR. IL-1ß _31, IL-1ß _511, IL-1RN, and T29C genes polymorphisms were examined by PCR-based techniques in two groups of patients (responders and non-responders) and a control group of healthy subjects. A significant association between IL-1ß_511 gene polymorphism and SOF/DAV-induced response was observed, where the "CC" genotype was the most frequent in responders while the "CT" genotype was the most frequent among non-responders (P = 0.0001, OR = 39; 95% CI = 4.7-316). IL-1RN gene polymorphism also showed significant associations with response to treatment, genotypes that include allele "1" were the most frequent in responders, particularly the homozygous genotype "1/1" (P = 0.0001, OR = 2.3; 95% CI = 1.57-3.2). However, the genotypes "4/4" and "2/4" were the most frequent in non-responders; (P = 0.0001). At least 71% of the responders carry allele "1" while 54% of non-responders were allele "4" carriers (P value = 0.0001. OR = 2.8; 95% CI = 6.4-134.2). Liver fibrosis is significantly improved regardless of the response. © 2018 IUBMB Life, 70(11):1156-1163, 2018.


Assuntos
Antivirais/efeitos adversos , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Polimorfismo Genético , Estudos de Casos e Controles , Quimioterapia Combinada , Egito/epidemiologia , Receptor alfa de Estrogênio/genética , Hepatite C Crônica/virologia , Humanos , Imidazóis/efeitos adversos , Incidência , /epidemiologia , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1beta/genética , Cirrose Hepática/virologia , Sofosbuvir/efeitos adversos
18.
Medicine (Baltimore) ; 97(31): e11750, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30075593

RESUMO

OBJECTIVE: The results of published studies which examined the association between variable number tandem repeat (VNTR) polymorphism of interleukin-1 receptor antagonist (IL-1RN) and ischemic stroke (IS) are conflicting. Thus, we performed a meta-analysis to examine the potential association between IL-1RN VNTR polymorphism and IS risk. METHODS: A systematic literature search of PubMed, Embase, Medline, Web of Science, Cochrane Library, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, CQVIP, and WANFANG Database identified 10 studies with 2331 cases and 3335 controls. The pooled odds ratio (OR) with 95% confidence interval (95% CI) was calculated to evaluate the strength of the association. Subgroup analysis and meta-regression analysis were used to investigate the potential sources of heterogeneity. Begg funnel plots were used to explore the publication bias. RESULTS: In this study, no enough proof was found to prove the association between IL-1RN 86-bp VNTR polymorphism and IS risk with random-effects model in the homozygous model (1/1 vs 2/2, OR = 0.97, 95% CI = 0.50-1.87, Pheterogeneity = .00), the heterozygous model (1/2 vs 2/2, OR = 0.64, 95% CI = 0.41-1.01, Pheterogeneity = .10), the dominant model (1/1 + 1/2 vs 2/2, OR = 0.85, 95% CI = 0.51-1.42, Pheterogeneity = .02), the recessive model (1/1 vs 1/2 + 2/2, OR = 0.69, 95% CI = 0.46-1.03, Pheterogeneity = .00), and allelic model (1 vs 2, OR = 1.24, 95% CI = 0.89-1.74, Pheterogeneity = .00). A marginally significant negative association was observed between IL-1RN 86-bp VNTR polymorphism and IS risk in the heterozygous model in the fixed-effects model (1/2 vs 2/2, OR = 0.71, 95% CI = 0.53-0.95, Pheterogeneity = .10). In subgroup analyses, similar association was found in the group whose control size was lower than 300. CONCLUSION: In conclusion, our results suggested that there was no sufficient evidence to support the association between IL-1RN 86-bp VNTR polymorphism and IS. Further large epidemiologic studies need to be done to confirm these findings.


Assuntos
Isquemia Encefálica/genética , Proteína Antagonista do Receptor de Interleucina 1/genética , Acidente Vascular Cerebral/genética , Grupo com Ancestrais do Continente Asiático , Predisposição Genética para Doença , Humanos , Repetições Minissatélites , Razão de Chances , Polimorfismo Genético
19.
Arch Oral Biol ; 95: 195-201, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30142580

RESUMO

External apical root resorption (EARR) induced by orthodontic treatment and chronic periodontitis (CP) are complex phenotypes dependent on the interaction of multiple genetic and non-genetic risk factors. Apart from different environmental triggers, these phenotypes are caused by antagonistic biological mechanisms involving local immunoinflammatory reaction and alveolar bone metabolism, for which IL1 have a prominent role. Whereas EARR benefits from bone remodelling, CP is characterized by osteolytic damaged. Our aim was to verify if these two phenotypes have opposite genetic profiles, considering the most frequently analysed polymorphisms for both diseases. A review of the literature was performed searching for the association of rs1800587 from Interleukin-1 alpha (IL1A) gene and rs1143634 from interleukin-1 beta (IL1B) gene with EARR and CP. The electronic search included MEDLINE/PubMed, EBSCOhost, Cochrane and Web of Science databases. Twenty four articles met the inclusion and exclusion criteria. For IL1B polymorphism, two out of seven studies found a significant statistical association between EARR and CC genotype, whether for CP, there were eighth out of fifteen references describing a statistically significant associations with T allele. For IL1A variant, no significant association with EARR was described. In conclusion, literature review suggests that for IL1B SNP rs1143634, EARR and CP have an opposite genetic profile. For IL1A SNP, our hypothesis could not be confirmed.


Assuntos
Interleucina-1alfa/genética , Periodontite/genética , Reabsorção da Raiz/genética , Predisposição Genética para Doença , Humanos , Proteína Antagonista do Receptor de Interleucina 1/genética , Polimorfismo de Nucleotídeo Único
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