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1.
Int J Mol Sci ; 25(11)2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38891810

RESUMO

Aminobisphosphonates (NBPs) are the first-choice medication for osteoporosis (OP); NBP treatment aims at increasing bone mineral density (BMD) by inhibiting the activity of farnesyl diphosphate synthase (FDPS) enzyme in osteoclasts. Despite its efficacy, inadequate response to the drug and side effects have been reported. The A allele of the rs2297480 (A > C) SNP, found in the regulatory region of the FDPS gene, is associated with reduced gene transcription. This study evaluates the FDPS variant rs2297480 (A > C) association with OP patients' response to alendronate sodium treatment. A total of 304 OP patients and 112 controls were enrolled; patients treated with alendronate sodium for two years were classified, according to BMD variations at specific regions (lumbar spine (L1-L4), femoral neck (FN) and total hip (TH), as responders (OP-R) (n = 20) and non-responders (OP-NR) (n = 40). We observed an association of CC genotype with treatment failure (p = 0.045), followed by a BMD decrease in the regions L1-L4 (CC = -2.21% ± 2.56; p = 0.026) and TH (CC = -2.06% ± 1.84; p = 0.015) after two years of alendronate sodium treatment. Relative expression of the FDPS gene was also evaluated in OP-R and OP-NR patients. Higher expression of the FDPS gene was also observed in OP-NR group (FC = 1.84 ± 0.77; p = 0.006) when compared to OP-R. In conclusion, the influence observed of FDPS expression and the rs2897480 variant on alendronate treatment highlights the importance of a genetic approach to improve the efficacy of treatment for primary osteoporosis.


Assuntos
Alendronato , Conservadores da Densidade Óssea , Densidade Óssea , Geraniltranstransferase , Osteoporose , Polimorfismo de Nucleotídeo Único , Falha de Tratamento , Humanos , Alendronato/uso terapêutico , Alendronato/farmacologia , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/genética , Feminino , Geraniltranstransferase/genética , Geraniltranstransferase/metabolismo , Masculino , Osteoporose/tratamento farmacológico , Osteoporose/genética , Idoso , Pessoa de Meia-Idade , Conservadores da Densidade Óssea/uso terapêutico , Genótipo , Alelos , Estudos de Casos e Controles
2.
Int J Immunogenet ; 50(2): 75-81, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36725689

RESUMO

Bone remodeling is marked by bone synthesis and absorption balance, and any altered dynamic in this process leads to osteoporosis (OP). The interaction of hormonal, environmental and genetic factors regulate bone metabolism. Since vitamin D displays a classic role in bone metabolism regulation, acting through vitamin D receptor (VDR), the genetic variants within VDR were the first ones associated with bone density and remodelling. Therefore, we investigated whether three single nucleotide polymorphisms (SNPs) within VDR were associated with OP differential susceptibility and clinical profile from postmenopausal versus healthy women from Northeast Brazil. Genetic association study enrolling 146 postmenopausal osteoporotic women as the patient group and 95 healthy age-matched women as the control group. We assessed three SNPs within VDR (rs11168268, rs1540339 and rs3890733), considering the clinical profile of all patients. Our results showed an association of rs11168268 G/G genotype with higher bone mineral density (BMD) mean for the total hip (A/A = 0.828 ± 0.09; A/G = 0.081 ± 0.13; G/G = 0.876 ± 0.12, p = .039), and the rs3890733 T/T genotype was associated with increased OP risk in patients below 60 years old (odds ratio [OR] = 5.12, 95% confidence interval [CI ]= 1.13-23.27, p = .012). The rs1540339 T/T genotype was associated with protection for individuals with low melanin deposition when compared to the high melanin deposition group (OR = 0.24, 95%CI = 0.06-0.94, p = .029). Additionally, 61% of patients presented deficient vitamin D serum levels. The SNP rs11168268 G/G was associated with a significantly increased mean total hip BMD in patients OP, highlighting this SNP and its relationship with BMD.


Assuntos
Osteoporose Pós-Menopausa , Osteoporose , Feminino , Humanos , Pessoa de Meia-Idade , Densidade Óssea/genética , Genótipo , Melaninas/genética , Osteoporose/genética , Osteoporose Pós-Menopausa/genética , Polimorfismo de Nucleotídeo Único , Pós-Menopausa/genética , Receptores de Calcitriol/genética , Vitamina D
3.
Int J Immunogenet ; 49(3): 181-192, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35560516

RESUMO

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disorder that displays an important genetic background. Vitamin D3 (VD3 ) through its receptor (VDR) plays an important immunomodulatory role in autoimmune misbalance, being capable of modulating immune responses. Genetic alterations in VDR gene may contribute to an altered risk in SLE development and clinical manifestations. We investigated VDR SNPs (single nucleotide polymorphisms) frequencies in 128 SLE patients and 138 healthy controls (HC) and mRNA differential expression in 29 patients and 17 HC regarding SLE susceptibility as well as clinical features. We observed that rs11168268 G allele (OR = 1.55, p = .01) and G/G genotype (OR = 2.69, p = .008) were associated with increased SLE susceptibility. The rs2248098 G allele and A/G and G/G genotypes were associated to lower SLE susceptibility (OR = 0.66, p = .01; OR = 0.46, p = .01; OR = 0.44, p = .02, respectively). Regarding clinical features, we observed lower risk for: rs11168268 A/G genotype and nephritis (OR = 0.31, p = .01); rs4760648 T/T genotype and photosensitivity (OR = 0.24, p = .02); rs1540339 T/T genotype and antibody anti-dsDNA (OR = 0.19, p = .015); rs3890733 T/T genotype and serositis (OR = 0.10, p = .01). We identified a significant downregulation in VDR expression levels when compared patients and controls overall (p = 1.04e-7 ), in Cdx-2 A/G and G/G (p = .008 and p = .014, respectively) and in patients with nephritis (p = .016) Our results suggested that VDR SNPs influence upon SLE susceptibility and in particular clinical features, acting on mRNA expression in SLE patients overall and the ones with nephritis.


Assuntos
Lúpus Eritematoso Sistêmico , Nefrite , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/genética , Nefrite/complicações , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , Receptores de Calcitriol/genética
4.
Int J Immunogenet ; 48(5): 429-434, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34180145

RESUMO

Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are influenced by genetic variants in immune system HLA genes. The Class II Major Histocompatibility Complex Transactivator (CIITA) is an important co-activator of the HLA transcriptional complex; the single nucleotide variant (SNV) rs3087456 localized in the gene promoter region (-168 A/G) has been reported as able to modify its transcription level. In our study, we assessed CIITA rs3087456 SNV in 1,044 Brazilians from two Brazilian regions (Northeast and South) to verify the association with susceptibility and clinical manifestations of (SLE) and (RA) using TaqMan SNP Genotyping Assays System. We observed a protection for a recessive model (GG x AA+AG) for RA susceptibility and increased risk for erosion development in AG genotype patients. No significant association was observed for SLE susceptibility; however, we observed significant increased risk for Class IV and V nephritis development in G allele and GG genotype patients. In conclusion, we showed the contribution of CIITA rs3087456 to SLE or RA clinical features and RA susceptibility in the studied populations.


Assuntos
Artrite Reumatoide , Lúpus Eritematoso Sistêmico , Proteínas Nucleares/genética , Transativadores/genética , Artrite Reumatoide/genética , Estudos de Casos e Controles , Estudos de Coortes , Predisposição Genética para Doença , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único
5.
Int J Mol Sci ; 22(22)2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34830358

RESUMO

Lupus nephritis (LN) is the most frequent and severe of systemic lupus erythematosus (SLE) clinical manifestations and contributes to the increase of morbidity and mortality of patients due to chronic kidney disease. The NLRP3 (NLR pyrin domain containing 3) is a member of the NLR (NOD-like receptors), and its activation results in the production of pro-inflammatory cytokines, which can contribute to the pathogenesis of LN. In this review manuscript, we approach the relation between the NLRP3 inflammasome, SLE, and LN, highlighting the influence of genetic susceptibility of NLRP3 polymorphisms in the disease; the main functional studies using cellular and animal models of NLRP3 activation; and finally, some mechanisms of NLRP3 inhibition for the development of possible therapeutic drugs for LN.


Assuntos
Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Nefrite Lúpica/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Humanos , Inflamassomos/genética , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/patologia , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia
6.
Immunogenetics ; 72(4): 217-224, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32020248

RESUMO

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder involving heterogeneous clinical manifestations and numerous susceptibility genes. Several findings evidence the critical role of inflammasomes in the predisposition to autoimmune diseases and in SLE. We investigated whether inflammasome polymorphins could affect susceptibility to develop and/or severity SLE. Moreover, differences in inflammasome activation in peripheral blood were also evaluated in SLE patients and controls. The distribution of 13 SNPs in eight inflammasome genes was evaluated. To assess inflammasome priming in peripheral blood monocytes of SLE and controls, differential expression of selected inflammasome genes and IL-1ß production was analyzed in resting condition as well as after LPS and ATP stimulation. Results showed that the gain-of-function variant rs10754558 (NLRP3) was significantly more frequent in SLE patients with nephritis, reinforcing the concept of a key role of NLRP3 inflammasome not only in SLE but also especially in kidney disease. SLE monocytes in resting condition showed a higher level of IL-1ß expression and produced higher levels of IL-1ß when stimulated with LPS+ATP comparing to controls. The stimulation induced a significant expression of NLRP1, AIM2, CASP1, and IL1B genes, suggesting that the NLRP1 inflammasome is responsible for the IL-1ß production observed in monocytes. These data emphasized once more the important contribution of inflammasome in SLE-associated inflammation.


Assuntos
Inflamassomos/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Proteínas Reguladoras de Apoptose/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas de Ligação ao Cálcio/genética , Estudos de Casos e Controles , Caspase 1/genética , Proteínas de Ligação a DNA/genética , Feminino , Expressão Gênica , Humanos , Interleucina-1beta/genética , Lúpus Eritematoso Sistêmico/complicações , Masculino , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas NLR , Proteínas de Neoplasias/genética , Nefrite/genética
7.
Inflamm Res ; 67(3): 255-264, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29230505

RESUMO

OBJECTIVE: In the present study, we analyzed the possible association of inflammasome gene variants and expression to rheumatoid arthritis (RA)'s development and severity in the Brazilian population. MATERIALS AND METHODS: Thirteen single nucleotide polymorphisms within six inflammasome genes (NLRP1, NLRP3, NLRC4, AIM2, CARD8, CASP1) as well as IL1B and IL18 genes in two different Brazilian populations (from Northeast and Southeast Brazil) were analyzed. We also evaluated inflammasome gene expression profile in resting and LPS + ATP-treated monocytes from RA patients and healthy individuals. For genetic association study, 218 patients and 307 healthy controls were genotyped. For gene expression study, inflammasome genes mRNA levels of 12 patients and ten healthy individuals were assessed by qPCR. RESULTS: Our results showed that rs10754558 NLRP3 and rs2043211 CARD8 polymorphisms are associated with RA development (p value = 0.044, OR = 1.77, statistical power = 0.999) and severity measured by Health Assessment Questionnaire (HAQ) (p value = 0.03), respectively. Gene expression analyses showed that RA patients display activation of CASP1, IL1B and IL1R genes independently of LPS + ATP activation. In LPS + ATP-treated monocytes, NLRP3 and NLRC4 expressions were also significantly higher in patients compared with controls. CONCLUSIONS: The first reported results in Brazilian populations support the role of inflammasome in the development of RA.


Assuntos
Artrite Reumatoide/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Inflamassomos/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas de Neoplasias/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Proteínas Reguladoras de Apoptose/genética , Brasil , Proteínas de Ligação ao Cálcio/genética , Caspase 1/genética , Proteínas de Ligação a DNA/genética , Feminino , Expressão Gênica , Humanos , Interleucina-18/genética , Interleucina-1beta/genética , Masculino , Pessoa de Meia-Idade , Proteínas NLR , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença
8.
Genet Mol Biol ; 41(4): 727-734, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30508004

RESUMO

Turner syndrome (TS) is characterized by a set of clinical conditions, including autoimmune/inflammatory diseases and infectious conditions, that can compromise a patient's quality of life. Here we assessed polymorphisms in CTLA-4 +49A/G (rs231775), PTPN22 +1858G/A (rs2476601), and MBL2 -550 (H/L) (rs11003125), -221(X/Y) (rs7096206) and exon 1 (A/O) in women from northeastern Brazil to determine whether polymorphisms within these key immune response genes confer differential susceptibility to clinical conditions in TS. A case-control genetic association study was performed, including 86 female TS patients and 179 healthy women. An association was observed for the A/G genotype of CTLA-4 +49A/G in TS patients (p=0.043, odds ratio [OR]=0.54). In addition, an association between the CTLA-4 G/G genotype and obesity was detected in TS patients (p=0.02, OR=6.04). Regarding, the -550(H/L) polymorphism in the MBL2 promoter, the frequency of the H/L genotype was significantly higher in the TS group than healthy controls (p=0.01, OR=1.96). The H/H genotype indicated a protective effect in TS patients (p=0.01, OR=0.23). No differences were observed in the distribution of -221(X/Y), MBL2 exon 1 variants, and PTPN22 +1858G/A in any assessed groups. CTLA-4 variants are potentially involved in obesity in this cohort of TS patients from northeastern Brazil.

10.
Ann Hum Genet ; 80(1): 1-6, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26464189

RESUMO

Systemic lupus erythemathosus (SLE) and rheumatoid arthritis (RA) are complex autoimmune diseases characterized by an immune balance breakdown and by chronic inflammation. Several findings link SLE and RA development with the complement system and ficolin components have emerged as candidates for disease development. Since genetic association studies with ficolin genes in SLE and RA have not yet been conducted in a Brazilian population, the aim of this study was to determine whether polymorphisms of ficolin-1(FCN1) and ficolin-2 (FCN2) genes are associated with SLE and RA susceptibility as well as disease manifestation. Two SNPs within FCN1 (rs2989727 and 1071583) and three in FCN2 (rs17514136, rs3124954, and rs7851696) were studied in 208 SLE and184 RA patients as well as 264 healthy individuals in a Southeast Brazilian population. For SLE patients, the FCN2 rs17514136 SNP was associated with a more severe disease (SLICC) (p = 0.0067). Furthermore, an association between the occurrence of nephritis and the T/T genotype for FCN2 rs3124954 SNP (p = 0.047, OR = 3.17, 95%CI = 1.34-7.5) was observed. No association was observed between the studied polymorphisms and RA development. Thus, our data support involvement of the FCN2 gene in the SLE phenotype.


Assuntos
Artrite Reumatoide/genética , Lectinas/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Brasil , Estudos de Casos e Controles , Estudos de Associação Genética , Genótipo , Humanos , Fenótipo , Ficolinas
12.
Mol Biol Rep ; 43(1): 41-51, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26686848

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and important joint commitment, being the most common systemic autoimmune disease worldwide. RA displays important genetic background with a variety of genes contributing to the immune balance breakdown. Recent studies have demonstrated that vitamin D, through its receptor (VDR), is able to regulate the immune balance and suppress the autoimmunity process, being a potential target in autoimmune diseases. In the present genetic association study, we assessed 5 Tag single nucleotide polymorphisms (SNPs) (rs11168268, rs2248098, rs1540339, rs4760648 and rs3890733), which cover most of the VDR gene, in three different Brazilian populations (from Northeast, Southeast and South Brazil). We also evaluated the VDR expression profile in whole blood and monocytes from RA patients. For genotyping study, 428 RA patients and 616 healthy controls were genotyped with fluorogenic allele specific probes on an ABI7500 platform. For gene expression study, VDR mRNA levels of 15 RA patients and 26 healthy individuals were assessed by RT-PCR. Our results showed that SNPs rs4760648 and rs3890733 are associated to RA susceptibility (p value = 0.0026, OR 1.31 and p value = 0.0091, OR 1.28 with statistical power = 0.999 and 0.993, respectively). Regarding RA clinical features, the studied SNPs did not show significant associations. The gene expression assays showed that VDR mRNA levels were down regulated in both whole blood (-3.3 fold) and monocytes (-3.2 fold) of RA patients when compared to healthy controls. Our results, the first reported for distinct Brazilian populations, support a role of the VDR gene in the susceptibility to RA.


Assuntos
Artrite Reumatoide/genética , Receptores de Calcitriol/genética , Alelos , Artrite Reumatoide/sangue , Brasil , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores de Calcitriol/sangue
13.
Mol Biol Rep ; 41(4): 2249-56, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24415301

RESUMO

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder with a strong genetic background. Nevertheless, SLE might also be triggered due to environmental factors, such as UV light exposure. DNA double strand breaks (DSBs) may be induced secondarily by UV radiation, increasing DNA immunogenicity and in SLE patients DNA repair is diminished, allowing the accumulation of DSBs and genomic instability. LIG4 and RAD52 genes play important roles in DNA repair mechanisms and a recent microarray analysis showed their differential expression in active SLE patients. In this study we investigated a potential association between LIG4 and RAD52 single nucleotide polymorphisms (SNPs) and SLE predisposition in a Southeast Brazilian population. We assessed four Tag SNPs in LIG4 and three in RAD52 gene region, encompassing most of the gene sequence, in 158 SLE patients and 212 healthy controls. We also performed SNPs analysis considering clinical manifestation, gender and ethnicity in SLE patients. Our data did not show association between LIG4 and RAD52 SNPs and SLE, its clinical manifestations or ethnicity in the tested population. The analysis regarding ethnicity and SLE clinical manifestations indicated Caucasian-derived patients as more susceptible to cutaneous and hematological alterations than the African-derived. To our knowledge, this is the first association study involving LIG4 and RAD52 genes and SLE predisposition.


Assuntos
DNA Ligases/genética , Reparo do DNA , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Proteína Rad52 de Recombinação e Reparo de DNA/genética , Adulto , Alelos , Brasil , Estudos de Casos e Controles , DNA Ligase Dependente de ATP , Etnicidade/genética , Feminino , Ligação Genética , Genótipo , Haplótipos , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Masculino , Pessoa de Meia-Idade , Razão de Chances
15.
Genes (Basel) ; 13(12)2022 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-36553538

RESUMO

The immune system plays a critical role in bone homeostasis and, consequently, in the pathophysiology of postmenopausal osteoporosis (OP) since estrogen deficiency induces the inflammasome and increases production of pro-inflammatory cytokines, such as IL-1ß and IL-18. NLRP3 inflammasome complex genes have been related with bone homeostasis in cellular and animal models. Here, we performed an association study evaluating SNVs (single-nucleotide variants) in inflammasome NLRP3 pathway genes (NLRP3, CARD8, CASP1, IL-18, and IL-1ß) to assess whether variants in these genes could be related to susceptibility to primary OP in postmenopausal women. METHODS: We genotyped 196 postmenopausal OP patients and 103 healthy controls using SNV-specific Taqman® probes. Data and statistical analyses were performed using the SNPstats and GraphPad Prism 8 software. RESULTS: We showed an association between NLRP3 rs35829419 CA genotype and lower bone mineral density (BMD) mean at the lumbar spine (p = 0.001); we also observed an association between IL-1ß rs16944 AA genotype and higher BMD mean at the total hip (p = 0.009). The IL-1ß rs16944 GG was associated with lower alkaline phosphatase levels (ALP) (p = 0.009), and the IL-18 rs1946519 AA was associated with lower vitamin D levels (p = 0.018). Additionally, OP patients presented deficient vitamin D and parathyroid hormone (PTH). CONCLUSIONS: The NLRP3 inflammasome complex SNVs were associated with OP severity, possibly indicating these genes' participation in bone metabolism and its dysregulation.


Assuntos
Inflamassomos , Osteoporose Pós-Menopausa , Humanos , Feminino , Inflamassomos/genética , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Interleucina-18/genética , Interleucina-18/metabolismo , Polimorfismo de Nucleotídeo Único , Osteoporose Pós-Menopausa/genética , Vitamina D , Proteínas de Neoplasias/genética , Proteínas Adaptadoras de Sinalização CARD/genética
16.
Autoimmunity ; 55(8): 515-519, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36177494

RESUMO

Childhood- onset systemic lupus erythematosus (cSLE) is a multisystem inflammatory disease that can lead to severe clinical conditions resulting in early comorbidities. Several genetic, environmental, and immunological factors are known to influence the onset of the disease. MiRNAs have been already considered as potential actors involved in the development and activity of the SLE. Thus, understanding the behavior of these regulators can contribute to clarify the inflammatory process affecting SLE patients. Among miRNAs, miR-125b-5p and miR-9-5p targeting NFKB1 and TRAF6 genes can be involved in the etio-pathogenesis of the disease by modulating inflammation. In this study we evaluated miR-9-5p and miR-125b-5p expression and its target genes NFKB1 and TRAF6 in peripheral blood samples (PBMC) from the 35 cSLE patients and 35 healthy controls. MiRNAs and gene target expression have been evaluated by using RT-PCR with specific TaqMan® probes. Both miR-9-5p [Fold Change (FC) = -2.21; p = 0.002] and miR-125b-5p (FC= -3.30; p < 0.0001) and NFKB1 (FC = -1.84; p < 0.001) were downregulated in cSLE patients, while TRAF6 was upregulated (FC = 1.80; p = 0.006) in cSLE patients when compared to controls. A significant correlation was found between miR-125b-5p and its target gene NFKB1 [Spearman (r) = 0.47; p = 0.023]. Our results showed miR-125b-5p and miR-9-5p differential expression in cSLE patients, possibly contributing to better understanding the role of these regulators in cSLE development and disease pathogenesis.


Assuntos
Lúpus Eritematoso Sistêmico , MicroRNAs , Subunidade p50 de NF-kappa B , Fator 6 Associado a Receptor de TNF , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Leucócitos Mononucleares/metabolismo , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Subunidade p50 de NF-kappa B/genética , Subunidade p50 de NF-kappa B/metabolismo , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo
17.
J Clin Pathol ; 74(12): 796-803, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33023941

RESUMO

AIMS: Hospitalised patients with COVID-19 have a variable incidence of acute kidney injury (AKI) according to studies from different nationalities. The present systematic review and meta-analysis describes the incidence of AKI, need for renal replacement therapy (RRT) and mortality among patients with COVID-19-associated AKI. METHODS: We systematically searched electronic database PubMed, SCOPUS and Web of Science to identify English articles published until 25 May 2020. In case of significant heterogeneity, the meta-analyses were conducted assuming a random-effects model. RESULTS: From 746 screened publications, we selected 21 observational studies with 15 536 patients with COVID-19 for random-effects model meta-analyses. The overall incidence of AKI was 12.3% (95% CI 7.3% to 20.0%) and 77% of patients with AKI were critically ill (95% CI 58.9% to 89.0%). The mortality among patients with AKI was 67% (95% CI 39.8% to 86.2%) and the risk of death was 13 times higher compared with patients without AKI (OR=13.3; 95% CI 6.1 to 29.2). Patients with COVID-19-associated AKI needed for RRT in 23.4% of cases (95% CI 12.6% to 39.4%) and those cases had high mortality (89%-100%). CONCLUSION: The present study evidenced an incidence of COVID-19-associated AKI higher than previous meta-analysis. The majority of patients affected by AKI were critically ill and mortality rate among AKI cases was high. Thus, it is extremely important for health systems to be aware about the impact of AKI on patients' outcomes in order to establish proper screening, prevention of additional damage to the kidneys and adequate renal support when needed.


Assuntos
Injúria Renal Aguda/epidemiologia , COVID-19/epidemiologia , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/mortalidade , Injúria Renal Aguda/terapia , Adulto , Idoso , COVID-19/diagnóstico , COVID-19/mortalidade , COVID-19/terapia , Estado Terminal , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Terapia de Substituição Renal , Medição de Risco , Fatores de Risco
18.
Immunobiology ; 226(6): 152152, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34735922

RESUMO

Rheumatoid arthritis (RA) is a well-known chronic inflammatory disorder. Two molecular players act in the inflammation balance of the disease: MyD88 (Myeloid differentiation primary response 88) is related to TLR (Toll-like receptors) response and promotes the formation of myddosome complex resulting in increased inflammation; IRAK3 (Interleukin-1 receptor associated kinase 3) acts suppressing the myddosome complex thus decreasing inflammation. In this scenario, MYD88 and IRAK3 gene expression profile in RA patients and its correlation with clinical features is still partially known. So, we evaluated the MYD88 and IRAK3 gene expressions in CD14 + monocytes from RA patients and healthy controls and its relation with patients' clinical features and cytokine plasma levels. CD14 + monocytes were isolated using positive selection by magnetic cell separation. The MYD88 and IRAK3 gene expressions were measured through real time relative quantitative PCR with specific primers; relative quantification was normalized to ACTB, GAPDH, 18S and RPLP0 reference genes. Cytokine levels were analyzed by CBA (cytokine beads assays). CD14 + monocytes from RA patients showed lower IRAK3 expression level compared to controls although with a borderline statistical significance (Fold change (FC) = -1.63; p = 0.054). Furthermore, RA patients with high disease activity had lower levels of IRAK3 when compared to patients with low/moderate activity measured by the CDAI index (FC = -1.78; p = 0.030). No significant differences were observed for MYD88 gene expression (FC = 1.20; p = 0.294) between patients and controls analyzed. Additionally, we did not we did not observe correlation between IRAK3 and MYD88 gene expression and TNF-α, IL-6, IL-2 and IL-10 levels. We suggested that IRAK3 gene expression in CD14 + monocytes appears to be relevant to the RA etiology and clinical activity, whereas, in this study, MYD88 does not play a role in RA onset and development.


Assuntos
Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Citocinas/metabolismo , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Adulto , Idoso , Artrite Reumatoide/diagnóstico , Biomarcadores , Citocinas/genética , Suscetibilidade a Doenças , Feminino , Perfilação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Pessoa de Meia-Idade
19.
Inflammation ; 44(3): 1014-1022, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33405020

RESUMO

Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease with strong genetic influence, especially upon immune response components. Several cytokines from the toll-like receptors activation pathway display recognized role for RA establishment. However, few studies have verified the role of key mediators such as MYD88 gene and its genetic variants. In the present study, we aim to evaluate the rs6853 functional single-nucleotide variation (SNV) role in RA etiopathogenesis, clinical severity status, and its impact in MYD88 mRNA levels and IL-lß protein levels. For the association study, a total of 423 RA patients and 346 health individuals, enrolled as control, from Northeast and Southeast Brazil were genotyped using specific Taqman probe. For the gene expression assays, we performed a MYD88 rs6853 genotype-guided monocyte cell culture divided into non-stimulated and lypopolysaccharides (LPS)-stimulated cells from healthy individuals. MYD88 gene expression was measured using primer specifics while IL-1ß levels were evaluated by ELISA. We observed that A allele and AA genotype were associated to an increased risk to RA development (OR = 1.60; 95% CI 1.24-2.08; p = 0.0004/OR = 2.83; 95% CI 1.25-6.41; p = 0.0152). The AA genotype exhibited lower MYD88 mRNA levels than GG genotype in non-stimulated monocyte cell culture (FC - 3.83; p = 0.003). Additionally, we verified an increase of IL-1ß levels when AA genotype non-stimulated monocytes were compared to AA genotype LPS-stimulates (p = 0.021). In summary, MYD88 rs6853 polymorphism associated to RA development in our Brazilian cohort and showed influence upon MYD88 mRNA levels' expression and IL-lß production.


Assuntos
Artrite Reumatoide/genética , Leucócitos Mononucleares/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Polimorfismo de Nucleotídeo Único , Adulto , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Brasil , Estudos de Casos e Controles , Células Cultivadas , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Interleucina-1beta/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Lipopolissacarídeos/toxicidade , Masculino , Pessoa de Meia-Idade , Fator 88 de Diferenciação Mieloide/metabolismo , Fenótipo
20.
Arthritis Res Ther ; 22(1): 91, 2020 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-32334613

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is a complex multi-system disease, characterized by both autoimmune and autoinflammatory clinical and laboratory features. The role of type I interferon (IFN) in SLE has been demonstrated from the 2000s, by gene expression analyses showing significant over-expression of genes related to type I IFN signalling pathway (IFN signature). However, several studies questioned the role of measuring the intensity of IFN signature (IFN score) to chase SLE activity. We would assess if the IFN signature can help the clinical and therapeutic stratification of patients with pediatric SLE. METHODS: We measured the IFN score in peripheral whole blood from a series of subjects with childhood-onset SLE and correlated the results with clinical and laboratory parameters. RESULTS: Thirty-one subjects were included in the study, among which the 87% displayed a positive IFN score. The only significant relation was found for high IFN score in subjects with normocomplementemia. No correlation was observed between IFN score and SLEDAI-2K, BILAG-2004 and SLICC. Patients with high IFN score and normal complement levels also presented lower anti-dsDNA antibodies. CONCLUSIONS: The integration between IFN signature analysis and complement levels may easily distinguish two groups of subjects, in which the autoimmune or autoinflammatory component of the disease seems to be prevalent.


Assuntos
Autoimunidade/imunologia , Proteínas do Sistema Complemento/metabolismo , Inflamação/imunologia , Interferon Tipo I/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Adolescente , Autoanticorpos/sangue , Criança , Proteínas do Sistema Complemento/análise , Estudos Transversais , Feminino , Humanos , Interferon Tipo I/genética , Lúpus Eritematoso Sistêmico/sangue , Masculino , Transcriptoma/imunologia
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