Reaction of genotypes of sorghum to the nematode Pratylenchus brachyurus

Trabalho de Conclusão de Curso (Graduação)O nematoide das lesões radiculares, Pratylenchus brachyurus causa danos à família Poaceae, como, o sorgo. O controle do nematoide das lesões radiculares pode ser feito através de plantas geneticamente resistentes, sendo esta a medida mais viável economicamente. Dessa forma, objetivou-se avaliar a reação de sete genótipos de sorgo granífero para P. brachyurus com 10 repetições em casa de vegetação no município de Uberlândia, estado de Minas Gerais, de abril a agosto de 2017. Aos 10 dias após a semeadura realizou-se a inoculação do nematoide com 500 espécimes de P. brachyurus mL-1 por vaso, próximo as raízes das plântulas. Após 80 dias após a inoculação ocorreram as avaliações. As características avaliadas da planta permitem inferir que quanto a massa fresca de raiz e seca de parte aérea não foram encontradas diferenças entre os sete genótipos se sorgo granífero testados. Quanto à massa fresca de parte aérea observa-se que os genótipos 1, 3 e 5 apresentaram tolerância ao nematoide. Os resultados relativos à reprodução de P. brachyurus, expressos em Fator de Reprodução (FR), variaram entre os genótipos analisados, valores entre 1,01 a 4,56. Conclui-se que os genótipos 6 e 7 apresentaram os menores valores relacionados ao fator de reprodução, sendo assim, possuem resistência moderada ao nematoide das lesões, isso implica em genótipos promissores aos programas de melhoramento

Reaction of genotypes of sorghum to the nematode Pratylenchus brachyurus

Trabalho de Conclusão de Curso (Graduação)O nematoide das lesões radiculares, Pratylenchus brachyurus causa danos à família Poaceae, como, o sorgo. O controle do nematoide das lesões radiculares pode ser feito através de plantas geneticamente resistentes, sendo esta a medida mais viável economicamente. Dessa forma, objetivou-se avaliar a reação de sete genótipos de sorgo granífero para P. brachyurus com 10 repetições em casa de vegetação no município de Uberlândia, estado de Minas Gerais, de abril a agosto de 2017. Aos 10 dias após a semeadura realizou-se a inoculação do nematoide com 500 espécimes de P. brachyurus mL-1 por vaso, próximo as raízes das plântulas. Após 80 dias após a inoculação ocorreram as avaliações. As características avaliadas da planta permitem inferir que quanto a massa fresca de raiz e seca de parte aérea não foram encontradas diferenças entre os sete genótipos se sorgo granífero testados. Quanto à massa fresca de parte aérea observa-se que os genótipos 1, 3 e 5 apresentaram tolerância ao nematoide. Os resultados relativos à reprodução de P. brachyurus, expressos em Fator de Reprodução (FR), variaram entre os genótipos analisados, valores entre 1,01 a 4,56. Conclui-se que os genótipos 6 e 7 apresentaram os menores valores relacionados ao fator de reprodução, sendo assim, possuem resistência moderada ao nematoide das lesões, isso implica em genótipos promissores aos programas de melhoramento

Association of a variant in the regulatory region of NADPH oxidase 4 gene and metabolic syndrome in patients with chronic hepatitis C

Abstract\ud \ud Background\ud Given the important contribution of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system to the generation of reactive oxygen species induced by hepatitis C virus (HCV), we investigated two single nucleotide polymorphisms (SNPs) in the putative regulatory region of the genes encoding NADPH oxidase 4 catalytic subunit (NOX4) and its regulatory subunit p22phox (CYBA) and their relation with metabolic and histological variables in patients with HCV.\ud \ud \ud Methods\ud One hundred seventy eight naïve HCV patients (49.3% male; 65% HCV genotype 1) with positive HCV RNA were genotyped using specific primers and fluorescent-labeled probes for SNPs rs3017887 in NOX4 and −675 T → A in CYBA.\ud \ud \ud Results\ud No association was found between the genotype frequencies of NOX4 and CYBA SNPs and inflammation scores or fibrosis stages in the overall population. The presence of the CA + AA genotypes of the NOX4 SNP was nominally associated with a lower alanine aminotransferase (ALT) concentration in the male population (CA + AA = 72.23 ± 6.34 U/L versus CC = 100.22 ± 9.85; mean ± SEM; P = 0.05). The TT genotype of the CYBA SNP was also nominally associated with a lower ALT concentration in the male population (TT = 84.01 ± 6.77 U/L versus TA + AA = 109.67 ± 18.37 U/L; mean ± SEM; P = 0.047). The minor A-allele of the NOX4 SNP was inversely associated with the frequency of metabolic syndrome (MS) in the male population (odds ratio (OR): 0.15; 95% confidence interval (CI): 0.03 to 0.79; P = 0.025).\ud \ud \ud Conclusions\ud The results suggest that the evaluated NOX4 and CYBA SNPs are not direct genetic determinants of fibrosis in HCV patients, but nevertheless NOX4 rs3017887 SNP could indirectly influence fibrosis susceptibility due to its inverse association with MS in male patients

Association of single nucleotide polymorphisms in the genes GPX4, CYBB, CYBA, CAT e SLC2A2 and the susceptibility to chronic kidney disease in Brazilian and French cohorts of type 1 diabetes mellitus patients

A nefropatia diabética (ND) é uma das principais causas de nefropatia crônica, o que torna o diabetes mellitus (DM) responsável por 44% da prevalência de doença renal crônica (DRC) no mundo. O papel do estresse oxidativo na patogênese da ND está bem estabelecido e genes pertencentes a vias pró- e antioxidantes são possíveis candidatos a conferirem susceptibilidade genética a essa e a outras complicações crônicas. Além do estresse oxidativo, o transporte intracelular de glicose, mediado por transportadores específicos, também parece exercer influência sobre a ND e outras complicações. O objetivo deste trabalho foi avaliar a associação entre ND e alguns polimorfismos de um único nucleotídeo (SNPs) em genes que codificam proteínas transportadoras de glicose (GLUT2 [SLC2A2]), proteínas pró-oxidantes (p22phox [CYBA] e NOX-2 [CYBB]) e proteínas antioxidantes (glutationa peroxidase-4 [GPX4] e catalase [CAT]) em uma coorte brasileira (n=453; 45,8% de pacientes com ND) e três coortes francesas (SURGENE [n=340; 17,7% de pacientes com ND na fase basal], GENEDIAB [n=313; 66,7% de pacientes com ND] e GENESIS [n=636; 49,7% de pacientes com ND]) de pacientes portadores de DM tipo 1. Os SNPs foram genotipados com o uso da técnica de reação em cadeia da polimerase (PCR) em tempo real e os resultados expressos em odds ratio (OR) ou hazard ratio (HR), com seus respectivos intervalos de confiança (IC), determinados em modelos ajustados de regressão logística politômica ou regressão de risco proporcional de Cox, respectivamente. A razão albumina/creatinina urinária (ACR) ou a taxa de excreção urinária de albumina (EUA) foram utilizadas para definir os estágios de ND e os pacientes foram classificados de acordo com a presença ou ausência de ND incipiente (ACR 30 - 300 mg/g de creatinina ou EUA 20 - 200 ?g/min ou 20 - 200 mg/L) e creatinina plasmática 300 mg/g de creatinina ou EUA > 200 ug/min ou > 200 mg/L e creatinina plasmática 300 mg/g de creatinina ou EUA > 200 ug/min ou > 200 mg/L e creatinina plasmática > 1,7 mg/dL ou qualquer terapia de reposição renal) e também foram avaliadas associações dos SNPs com a taxa de filtração glomerular estimada (TFGe). O alelo raro A do SNP rs6610650 no gene CYBB foi associado com valores baixos de TFGe em mulheres na coorte brasileira e com a prevalência de ND estabilizada/avançada em mulheres da coorte francesa (OR 1,75; IC 95% 1,11 - 2,78; p=0,016). O alelo raro T do SNP rs713041 no gene GPX4 foi inversamente associado com a prevalência de ND estabilizada/avançada em homens na coorte brasileira (OR 0,30, IC95% 0,13 - 0,68, p=0,004) e com valores elevados de TFGe em homens na coorte francesa. O alelo raro A do SNP rs7947841 no gene CAT foi associado com a prevalência de ND incipiente (OR 2,79; IC95% 1,21 - 6,24; p=0,01) e ND estabilizada/avançada (OR 5,72; IC95% 1,62 - 22,03; p=0,007), bem como com a incidência de eventos renais, definidos como novos casos de microalbuminúria ou progressão para um estágio mais grave de ND durante o seguimento de estudo, na coorte SURGENE (HR 1,82; IC95% 1,13 - 2,81; p=0,01). O mesmo alelo de risco associou-se com a prevalência de ND incipiente (OR 3,13; IC95% 1,42 - 7,24; p=0,004) e com a incidência de insuficiência renal crônica terminal (IRCT) na coorte GENEDIAB (HR 2,11; IC95% 1,23 - 3,60; p=0,008) e com a prevalência de ND incipiente (OR 2,16; IC95% 1,14 - 4,10, p=0,02) e ND estabilizada/avançada (OR 2,71; IC95% 1,38 - 5,42; p=0,004) na coorte brasileira. O alelo raro T do SNP rs9932581 no gene CYBA foi inversamente associado com a prevalência de ND estabilizada/avançada (OR 0,60; IC95% 0,46 - 0,78; p=0,0001) e com valores mais baixos de TFGe nos pacientes de descendência europeia da coorte GENESIS/GENEDIAB. Este mesmo alelo foi associado com a incidência de eventos renais e de IRCT nas coortes SURGENE (HR 0,63; IC95% 0,46 - 0,86; p=0,003) e GENESIS/GENEDIAB (HR 0,51; IC95% 0,31 - 0,78; p=0,002), respectivamente. Entretanto estes resultados não foram replicados na coorte brasileira. O alelo raro T do SNP rs11924032 no gene SLC2A2 foi inversamente associado com a perda da TFGe ao logo do tempo (0,02%/ano vs 2,18%/ano para os pacientes portadores do genótipo GG; p=0,005), na coorte SURGENE. Este mesmo alelo foi inversamente associado com a incidência de IRCT nas coortes GENESIS/GENEDIAB (HR 0,53; IC95% 0,29 - 0,89; p=0,01). Os resultados observados para o gene SLC2A2 não forneceram fortes indícios para afirmarmos que este gene exerça um papel relevante no desenvolvimento da ND nos pacientes com DM tipo 1 nas coortes francesas estudadas. Em contrapartida, os SNPs nos genes que codificam as proteínas pró-oxidantes CYBA e CYBB e as proteínas antioxidantes GPX-4 e CAT foram capazes de modular o risco para doença renal em pacientes portadores de DM tipo 1, sendo que os SNPs presentes nos genes CYBB, GPX4 e CAT tiveram seus resultados replicados em coortes independentes, o que corrobora a importância destes genes e, consequentemente, do estresse oxidativo, na patogênese da NDDiabetic nephropathy (DN) is a major cause of chronic nephropathy, with diabetes mellitus (DM) accounting for 44% of the prevalence of chronic kidney disease (CKD) in the world. The role of oxidative stress in the pathogenesis of DN is well established and genes belonging to pro- and antioxidant pathways are possible candidates to confer genetic susceptibility to this and other chronic complications. Besides oxidative stress, intracellular glucose transport mediated by specific transporters, also appears to influence DN and other complications. The aim of this study was to evaluate the association between DN and some single nucleotide polymorphisms (SNPs) present in genes encoding glucose transport proteins (GLUT2 [SLC2A2]), pro- (p22phox [CYBA] and NOX-2 [CYBB]) and antioxidants (glutathione peroxidase-4 [GPX4] and catalase [CAT]) proteins, in a Brazilian cohort [n= 453; 45.8% f patients with DN], and three French cohorts (SURGENE [n=340; 17.7% of patients with DN at baseline], GENEDIAB [n=313; 66.7% of patients with DN], and GENESIS [n=636; 49.7% of patients with DN]) of patients with type 1 DM. The SNPs were genotyped using the technique of real time polymerase chain reaction (PCR) and results expressed as odds ratio (OR) and hazard ratio (HR), with their respectively 95% confidence intervals (CI), determined by adjusted models of polytomic logistic regression and Cox proportional hazard regression, respectively. The albumin/creatinine ratio (ACR) or the urinary albumin excretion (UAE) rate were used to define the DN stages and the patients were classified according to the presence or absence of incipient DN (ACR 30 - 300 mg/g of creatinine or UAE 20 - 200 ug/min or 20 - 200 mg/L) and plasmatic creatinine 300 mg/g of creatinine or EUA > 200 ug/min or > 200 mg/L and plasmatic creatinine 300 mg/g of creatinine or UAE > 200 ug/min or > 200 mg/L and plasmatic creatinine > 1,7 mg/dL or any renal replacement therapy). Associations for the estimated glomerular filtration rate (eGFR) were also evaluated. The rare allele A of the SNP rs6610650 in CYBB gene was associated with low values of eGFR in women in the Brazilian cohort and with the prevalence of established/advanced DN in women in the French cohort (OR 1.75, 95%CI 1.11 - 2.78, p=0.016). The rare allele T of the SNP rs713041 in GPX4 gene was inversely associated with the prevalence of established/advanced DN in men in the Brazilian cohort (OR 0.30, 95%CI 0.13 - 0.68, p=0.004) and with higher values of eGFR in men in the French cohort. The rare allele A of the SNP rs7947841 in CAT gene was associated with the prevalence of incipient DN (OR 2.79, 95%CI 1.21 - 6.24, p=0.01) and established/advanced DN (OR 5.72; 95%CI 1.62 - 22.03, p=0.007) as well as the incidence of renal events, defined as new cases of microalbuminuria or progression to a more severe stage during the follow-up study, in SURGENE cohort (HR 1.82, 95%CI 1.13 - 2.81, p=0.01). The same risk allele was associated with the prevalence of incipient DN (OR 3.13, 95%CI 1.42 - 7.24, p=0.004), the incidence of end-stage renal disease (ESRD) in the cohort GENEDIAB (HR 2.11, 95%CI 1.23 - 3.60, p=0.008) and with the prevalence of incipient DN (OR 2.16, 95%CI 1.14 - 4.10, p=0.02) and established/advanced DN (OR 2.71, 95%CI 1.38 - 5.42, p=0.004) in the Brazilian cohort. The rare T allele of the SNP rs9932581 in CYBA gene was inversely associated with the prevalence of established/advanced DN (OR: 0.60, 95%CI: 0.46 - .78, p=0.0001) and associated with lower values of eGFR in patients of GENESIS/GENEDIAB cohort. The same allele was inversely associated with the incidence of renal events and ESRD in SURGENE (HR 0.63, 95%CI 0.46 - 0.86, p=0.003) and GENESIS/GENEDIAB (HR 0.51, 95%CI 0.31 - 0.78, p=0.002) cohorts. However, these results were not replicated in the Brazilian cohort. The rare T allele of the SNP rs11924032 in SLC2A2 gene was inversely associated with the loss of eGFR during the follow-up (0.02%/year vs. 2.18%/year for patients with the GG genotype, p=0.005) in the SURGENE cohort. The same allele was inversely associated with the incidence of ESRD in the GENESIS/GENEDIAB cohorts (HR 0.53, 95%CI 0.29 - 0.89, p=0.01). The results observed for the SLC2A2 gene, in this study, did not provide strong evidence to state that this gene exerts a relevant role in the development of DN in patients with type 1 DM in the studied cohorts. However, SNPs in genes encoding the pro-oxidant proteins CYBA and CYBB, and the antioxidants proteins GPX-4 and CAT were able to modulate the risk of renal disease in patients with type 1 DM. The studied SNPs in CYBB, GPX4 and CAT genes had their results replicated in independent cohorts, which confirms the importance of these genes and, hence, of the oxidative stress in the pathogenesis of D

Metabolic Regulatory Pathways in Tolerogenic Bias Dendritic Cells

O diabetes mellitus tipo 1 (DM1) é uma doença autoimune na qual células dendríticas (DC) desempenham um papel relevante. DC são células apresentadoras de antígenos, centrais para a diferenciação de células T CD4&#43, incluindo células T reguladoras (Tregs). Quando o ambiente fornece sinais tolerogênicos, DC falham em induzir a proliferação de linfócitos T tendendo a induzir tolerância. Diferentes estímulos, como ácido retinóico (RA), dexametasona (Dex) e vitamina D3 (VitD3), são capazes de gerar DC tolerogênicas (tolDC). DC imunogênicas e tolDC diferem em expressão de moléculas co-estimulatórias, secreção de citocinas pró-inflamatórias, capacidade de gerar linfócitos T supressivos e perfil metabólico. Enquanto DC imunogênicas dependem da glicólise e de metabolismo anabólico, as vias metabólicas envolvidas na indução de Treg pelas tolDC são menos detalhados. AMPK é um sensor metabólico conhecido por antagonizar sinais anabólicos, promovendo catabolismo e estudos sugerem que tolDC sejam caracterizadas por um perfil catabólico. Entretanto, o papel da sinalização de AMPK na regulação metabólica e funcional de tolDC ainda não foi abordado. Ainda, a presença de VitD3 durante a diferenciação mo-DC, induz uma reprogramação metabólica inicial, dependente de glicose. Assim, o presente trabalho teve dois objetivos principais: (1) como a hiperglicemia é a principal característica do DM1, avaliou-se como a concentração de glicose afetaria a diferenciação de mo-DC tratadas com VitD3 (VitD-DC); (2) investigar como AMPK poderia controlar a diferenciação de tolDC induzida por VitD3, RA e Dex. Observou-se que, metabolicamente, VitD3 modula de maneira diferente mo-DC de controle e pacientes, induzindo tolDC em pacientes de maneira glicose independente. Em controles, VitD3 induziu aumento da glicólise e OXPHOS, que foram, pelo menos parcialmente, reduzidas em hiperglicemia, assim como a expressão de CD86, a secreção de TNF-a e a capacidade linfoestimulatória. Já em pacientes diabéticos, embora VitD3 reduziu tanto a expressão de CD86 quanto a secreção de TNF-a em hiperglicemia, o metabolismo das células não foi afetado, sugerindo que a reprogramação metabólica induzida pela VitD3 pode não depender da glicólise em pacientes. Na segunda parte do projeto, confirmamos que VitD3, Dex e RA induziram tolDC funcionais, já que estas tolDC diferenciaram células T CD4&#43 supressoras. Entretanto, metabolicamente, cada tolDC exibiu fenótipo distinto: VitD-DC aumentaram glicólise e OXPHOS, RA-DC reduziram a capacidade respiratória sobressalente e Dex-DC reduziram glicólise. A fosforilação de ACC, um alvo direto de AMPK, aumentou em VitD-DC e RA-DC, sugerindo aumento da atividade de AMPK. Coerentemente, o silenciamento de AMPK reverteu as alterações metabólicas induzidas por VitD3 e RA, mas não por Dex. Quando AMPK foi silenciada em RA-DC humana, tanto a atividade de ALDH (induzida pelo RA) como sua capacidade tolerogênica foram perdidas. Camundongos com DC deficientes em AMPK, apresentaram redução na atividade de ALDH e na frequência de DC CD103&#43CD11b&#43 intestinal, consideradas o equivalente in vivo das RA-DC. Isso sugere uma importância da sinalização de AMPK para a homeostase de DC tolerogênicas intestinais, promovendo ambiente anti-inflamatório via atividade de ALDH em DC CD103&#43CD11b&#43. Sendo assim, estes dados sugerem um papel fundamental da AMPK na homeostase intestinal e na regulação das propriedades metabólicas e tolerogênicas de RA-DC.Type 1 diabetes mellitus (T1D) is an autoimmune disease in which dendritic cells (DC) play a relevant role. DC are antigen presenting cells, central to CD4&#43 T cell differentiation, including regulatory T cells (Tregs). When the environment provides tolerogenic signals, DC fail to induce T lymphocyte proliferation and are prone to induce tolerance. Different stimuli, such as retinoic acid (RA), dexamethasone (Dex) and vitamin D3 (VitD3), are capable of generating tolerogenic DC (tolDC). Immunogenic DC and tolDC differ in expression of costimulatory molecules, proinflammatory cytokine secretion, ability to generate suppressive T lymphocytes and metabolic profile. While immunogenic DC rely on glycolysis and anabolic metabolism to support their activity, the metabolic pathways involved in the induction of Treg by tolDC are less well defined. AMPK is a metabolic sensor known to antagonize anabolic signals, promoting catabolism and studies suggest that tolDC are characterized by a catabolic profile. However, the role of AMPK signaling in regulating tolDC metabolism and function has not been addressed. Moreover, the presence of VitD3 during mo-DC differentiation induces an initial glucose-dependent metabolic reprogramming. Thus, the present study had two main objectives: (1) as hyperglycemia is the main characteristic of T1D, we aimed to evaluate how glucose availability would impact the differentiation of mo-DC treated with VitD3 (VitD DC); (2) to investigate how and if AMPK could control the differentiation of tolDC induced by VitD3, RA and Dex. Metabolically, VitD3 differently modulates controls mo-DC and patients, inducing tolDC in patients in a glucose-independent manner. In controls, VitD3 induced increase in glycolysis and OXPHOS, which were, at least partially, reduced in hyperglycemia, as well as CD86 expression, TNF-a secretion and lymphostimulatory capacity. In diabetic patients, while VitD3 reduced both CD86 expression and TNF-a secretion in hyperglycemia, cell metabolism was not affected, suggesting that VitD3- induced metabolic reprogramming may not rely on glycolysis in patients. In the second part of the project, we confirmed that VitD3, Dex and RA induced functional tolDCs, since these tolDC induced suppressor CD4&#43 T cells. Metabolically, however, each tolDC exhibited a distinct phenotype: VitD-DC had increased glycolysis and OXPHOS, RA-DC had reduced spare respiratory capacity and Dex-DC had reduced glycolysis. ACC phosphorylation, a direct downstream target of AMPK, was increased in VitD-DC and RA-DC, suggesting increased AMPK activity. Consistently, AMPK silencing reverted the metabolic changes induced by VitD3 and RA, but not by Dex. When AMPK was silenced in human RA-DC, both ALDH activity (that was increased by RA treatment) and their tolerogenic capacity were lost. Mice with a deficiency in AMPK selectively in DC showed a reduction in ALDH activity and frequency of gut CD103&#43CD11b&#43 DC, considered to be the in vivo equivalent of RA-DC. This suggests that AMPK signaling is important for homeostasis of tolerogenic DC in the gut by promoting an anti-inflammatory status via regulation of ALDH activity specifically in CD103&#43CD11b&#43 DC. Taken together, these data point towards a key role for AMPK in regulating both the metabolic and tolerogenic properties of RA-DC and the homeostasis of the gut

Metabolic heterogeneity of tissue-resident macrophages in homeostasis and during helminth infection

Abstract Tissue-resident macrophage populations constitute a mosaic of phenotypes, yet how their metabolic states link to the range of phenotypes and functions in vivo is still poorly defined. Here, using high-dimensional spectral flow cytometry, we observe distinct metabolic profiles between different organs and functionally link acetyl CoA carboxylase activity to efferocytotic capacity. Additionally, differences in metabolism are evident within populations from a specific site, corresponding to relative stages of macrophage maturity. Immune perturbation with intestinal helminth infection increases alternative activation and metabolic rewiring of monocyte-derived macrophage populations, while resident TIM4+ intestinal macrophages remain immunologically and metabolically hyporesponsive. Similar metabolic signatures in alternatively-activated macrophages are seen from different tissues using additional helminth models, but to different magnitudes, indicating further tissue-specific contributions to metabolic states. Thus, our high-dimensional, flow-based metabolic analyses indicates complex metabolic heterogeneity and dynamics of tissue-resident macrophage populations at homeostasis and during helminth infection

Acetate Improves the Killing of Streptococcus pneumoniae by Alveolar Macrophages via NLRP3 Inflammasome and Glycolysis-HIF-1α Axis

International audienceShort-chain fatty acids (SCFAs) are metabolites produced mainly by the gut microbiota with a known role in immune regulation. Acetate, the major SCFA, is described to disseminate to distal organs such as lungs where it can arm sentinel cells, including alveolar macrophages, to fight against bacterial intruders. In the current study, we explored mechanisms through which acetate boosts macrophages to enhance their bactericidal activity. RNA sequencing analyses show that acetate triggers a transcriptomic program in macrophages evoking changes in metabolic process and immune effector outputs, including nitric oxide (NO) production. In addition, acetate enhances the killing activity of macrophages towards Streptococcus pneumoniae in an NO-dependent manner. Mechanistically, acetate improves IL-1β production by bacteria-conditioned macrophages and the latter acts in an autocrine manner to promote NO production. Strikingly, acetate-triggered IL-1β production was neither dependent of its cell surface receptor free-fatty acid receptor 2, nor of the enzymes responsible for its metabolism, namely acetyl-CoA synthetases 1 and 2. We found that IL-1β production by acetate relies on NLRP3 inflammasome and activation of HIF-1α, the latter being triggered by enhanced glycolysis. In conclusion, we unravel a new mechanism through which acetate reinforces the bactericidal activity of alveolar macrophages

Glutathione peroxidase-1 gene (GPX1) variants, oxidative stress and risk of kidney complications in people with type 1 diabetes

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Allelic variations in the CYBA gene of NADPH oxidase and risk of kidney complications in patients with type 1 diabetes

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Linkage Disequilibrium With Hla-drb1-dqb1 Haplotypes Explains The Association Of Tnf-308g > A Variant With Type 1 Diabetes In A Brazilian Cohort

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Background: A functional variant in the promoter region of the gene encoding tumor necrosis factor (TNF; rs1800629, -308G>A) showed to confer susceptibility to T1D. However, TNF rs1800629 was found, in several populations, to be in linkage disequilibrium with HLA susceptibility haplotypes to T1D. We evaluated the association of TNF rs1800629 with T1D in a cohort of Brazilian subjects, and assessed the impact of HLA susceptibility haplotypes in this association.. Methods: 659 subjects with T1D and 539 control subjects were genotyped for TNF-308G>A variant. HLA-DRB1 and HIA-DQB1 genes were genotyped in a subset of 313 subjects with T1D and 139 control subjects. Results: Associations with T1D were observed for the A-allele of rs1800629 (OR 1.69,95% Cl 133-2.15, p < 0.0001, in a codominant model) and for 3 HLA haplotypes: DRB1*03:01-DQB1*02:01 (OR 5.37, 95% Cl 3.23-8.59, p < 0.0001), DRB1*04:01-DQB1*03:02 (OR 2.95, 95% Cl 1.21-7.21, p = 0.01) and DRB1*04:02-DQB1*03:02 (OR 2.14,95% Cl 1.02-4.50, p = 0.04). Linkage disequilibrium was observed between TNF rs1800629 and HLA-DRB1 and HLA-DQB1 alleles. In a stepwise regression analysis HLA haplotypes, but not TNF rs1800629, remained independently associated with T1D. Conclusion: Our results do not support an independent effect of allelic variations of TNF in the genetic susceptibility to T1D. (C) 2015 Elsevier B.V. All rights reserved.56815054Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [2010/04305-2