Níveis séricos da IL-13 na esclerose sistêmica: uma revisão sistemática com meta-análise / Serum levels of IL-13 in systemic sclerosis: a systematic review with meta-analysis

A interleucina-13 (IL-13) sérica foi investigada na esclerose sistêmica (ES) por meio de uma meta-análise para avaliar a possível diferença nos níveis em pacientes com a doença e pessoas saudáveis. As buscas foram realizadas nas bases de dados Pubmed, ScienceDirect, Cochrane Library, LILACS e Scopus para estudos do tipo caso-controle pertinentes utilizando os descritores. Os níveis séricos dos pacientes com ES em relação aos controles saudáveis foram plotados usando o software Review Manager 5.3. A avaliação da qualidade de cada estudo elegível foi conduzida na Escala de Newcastle-Ottawa (NOS). Quatro estudos de caso-controle foram selecionados para esta meta-análise e continham um total de 120 pacientes com ES e 84 controles saudáveis. Nossos resultados demonstram níveis séricos elevados da IL-13 em pacientes com ES, com um agrupamento médio de 0,70 ng/ml (p=0,00001) (IC 95%: -0,42 a -0,99, p=0,6). A IL-13 está aumentada no soro de pacientes com ES em comparação com os controles saudáveis e pode ser útil como possível biomarcador da doença. 

Functional study of gene PAWR/Par-4 (Prostate apoptosis response-4) in normal and cancer breast cells

O câncer de mama é o tumor mais incidente entre as mulheres no mundo. Assim como em outros tumores, a tumorigênese nas mamas é um processo complexo resultante da combinação de fatores genéticos e ambientais que dirigem a transformação das células normais em células malignas. O gene PAWR, conhecido como PAR-4 (Prostatic apoptosis response-4) foi primeiramente identificado em células de câncer de próstata de rato induzidas a apoptose e codifica uma proteína de 342 aminoácidos que é efetiva na indução de apoptose nas células tumorais e causa regressão dos tumores ativando Fas/FasL e inibindo a atividade de NF-B. O aumento de Par-4 é suficiente para causar apoptose seletiva em células tumorais, mas não em células normais ou imortalizadas. Recentemente, um estudo de nosso grupo demonstrou que a expressão reduzida de Par-4 está associada a um pior prognóstico em câncer de mama e que esta proteína pode ter um papel importante na morfogênese da glândula mamária. O estudo funcional do gene Par-4 em diferentes linhagens de mama é importante para o melhor entendimento do papel deste gene no processo tumorigênico da glândula mamária. Portanto, a proposta do presente estudo foi investigar os efeitos do aumento de expressão ou supressão de Par-4 na proliferação celular e sobrevivência das células normais e tumorais de mama. As células MCF10A e MCF-7 foram transfectadas com os vetores de expressão para Par-4 (pCMV6-PAR-4) ou com oligos siRNA para supressão transiente de Par-4. A caracterização dos clones foi feita por Real Time PCR e Western Blot. Os ensaios de proliferação foram feitos por MTT e os ensaios de apoptose por dupla marcação com Laranja de Acridina/ Hoechst 33342 e por citometria de fluxo. O aumento da expressão de Par-4 diminuiu a proliferação de ambas às células comparadas às células-controle (p<0,01). Por outro lado, a diminuição de expressão de Par-4 por siRNA levou ao aumento da proliferação das células tumorais MCF-7 (p<0,01). A quantificação das células em apoptose mostrou um aumento significativo de apoptose nas células MCF-7 com aumento de Par-4 em relação às células controle MCF-7 pcNEO tratadas com ambas as concentrações de docetaxel (5 nM 13,24% versus 3,89%; p=0.001; 100 nM 24,81% versus 6,07%; p=0,0001) por 24 horas. Embora preliminares, os resultados de citometria também mostraram que as células MCF-7 com aumento de Par-4 apresentam maior porcentagem de células em apoptose na ausência de tratamento e após tratamento com 100 nM de docetaxel por 24 horas. Embora novos estudos sejam necessários, nossos dados sugerem que o aumento de expressão de Par-4 sensibilizou as células MCF-7 ao quimioterápico docetaxel. Pela primeira vez, mostramos o efeito inibitório de Par-4 no crescimento e sobrevivência das células epiteliais mamáriasBreast cancer is the most common tumor among women in the world. As for other malignancies the tumorigenic process of the breast involves genetic alterations that drive the progressive transformation of normal cells into malignant cells with and aggressive phenotype. Alterations in cells that upregulate proliferation or downregulate apoptosis are one of essential mechanisms that dictate tumor growth. The PAWR gene, also known as PAR-4 (Prostatic apoptosis response-4), was first identified in prostate cancer cells undergoing apoptosis and encodes a 332 aminoacid protein that is effective in inducing cancer cell apoptosis and cause regression of tumors by activating Fas/FasL and inhibiting NF-B activity. Interestingly, Par-4 overexpression is sufficient to cause apoptosis in cancer cells, but not in normal or immortalized cells. Recently, we demonstrated that reduced expression of PAR-4 is associated with breast cancer poor prognosis and this protein may have a role in the process of the mammary gland morphogenesis. The functional study of Par-4 gene in different cell lines of breast is important to better understand its role in the tumorigenic process of the breast. Therefore, the purpose of the present study was to investigate the effects of overexpression and suppression of PAR-4 in cell proliferation and survival in mammary epithelial cells. MCF10A and MCF-7 cells were transfected with expression vectors for PAR-4 overexpression (pCMV6-PAR-4) or with small interfering RNAs duplexed oligonucleotides. Clone characterization was performed using real time PCR and western blot. Proliferation assays were carried out using MTT and apoptotic assays were performed by doublefluorescence staining technique (Acridine Orange/Hoechst 33342) or using flow cytometry. PAR-4 overexpression decreased the proliferation rates in both MCF10A and MCF-7 cells compared to the parental or control cells (p<0,01). On the other hand, PAR-4 knockdown leads to increased proliferation in MCF7 cells (p<0,01). We observed a significant increase in apoptosis of MCF-7 cells with increased expression of Par-4 compared to control cells (MCF-7 pcNEO) in both concentrations of docetaxel (5 nM 13,24% versus 3,89%, p = 0,001; 100 nM 24,81% versus 6,07%, p < 0,0001). Cytometry analysis, although preliminary, showed that MCF-7 pcPar-4 have a higher percentage of apoptotic cells in the absence of treatment and after treatment of 100 nM of docetaxel. Although more studies are needed, our data suggest that increased expression of Par-4 sensitizes breast cancer cells to treatment with docetaxel. This is the first report showing that PAR-4 has inhibitory effects on mammary epithelial cells proliferation and surviva

Decline in Public Spending on Biopharmaceutics in Brazil

Biopharmaceuticals, mainly monoclonal antibodies, and fusion proteins are drugs that have gained notoriety in the treatment of various chronic and inflammatory diseases and have high prices. The study aimed to verify which monoclonal antibodies and fusion proteins were most incorporated into the Unified Health System (SUS), which therapeutic indication most benefited from them and to analyze public spending on these biopharmaceuticals from January 2012 to September 2019. This study performed a qualitative and quantitative analysis of biopharmaceuticals incorporated by SUS. The data were collected on the websites of CONITEC and the Health Price Bank. The results demonstrated that subcutaneous adalimumab was most frequently incorporated, and the most requested therapeutic indication was rheumatoid arthritis. Public spending on biopharmaceuticals exceeded R$28 billion (more than US$ 140 billion). However, a downward trend was confirmed (-266.7%) in the period evaluated. Despite the increase in demand and public spending on biologics in general, in Brazil and worldwide, the results of this research show that there was a drop in public spending on the biopharmaceuticals studied in the last seven years

Galectin-9 gene (LGALS9) polymorphisms are associated with rheumatoid arthritis in Brazilian patients.

IntroductionRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and hyperplasia, as well as cartilage and bone destruction. Several proteins are associated with the pathogenesis of the disease. Galectin-9 belongs to the family of lectins that are involved in various biological processes and have anti-inflammatory activity.ObjectiveTo investigate associations between the SNPs of the GAL-9 gene (LGALS9) and serum levels in rheumatoid arthritis patients. We extracted DNA from 356 subjects, 156 RA patients and 200 healthy controls from northeastern Brazil. Three polymorphisms (rs4795835, rs3763959, and rs4239242) in the LGALS9 gene were selected and genotyped using TaqMan SNP genotyping assay. Serum concentrations of galectin-9 were analyzed by ELISA.ResultsThe rs4239242 TT genotype showed a positive association with RA (p = 0.0032, odds ratio = 0.28), and heterozygous TC were prevalent in the control group compared to RA patients (p = 0.0001, odds ratio = 7.99). Galectin-9 serum levels were significantly increased in RA patients compared to the control group (p<0.0001). Patients in remission had high levels of galectin compared to the moderate activity group (p<0.0001). Regarding the Clinical Disease Activity Index (CDAI), patients in remission or low activity presented high levels of galectin when compared to patients in severity (p<0.0001). Patients performing moderate activity had a significant value compared to patients who were in high disease severity (p = 0.0064). Interestingly, the AG genotype (rs3763959) has been associated with a higher presence of bone erosion in RA patients (p = 0.0436). The SNP rs4239242 TT genotype showed a positive association with RA in comparison to the control group. The AG genotype (rs3763959) has been associated with a higher presence of bone erosion in RA patients

The Role of PPAR Gamma in Systemic Sclerosis

Fibrosis is recognized as an important feature of many chronic diseases, such as systemic sclerosis (SSc), an autoimmune disease of unknown etiology, characterized by immune dysregulation and vascular injury, followed by progressive fibrosis affecting the skin and multiple internal organs. SSc has a poor prognosis because no therapy has been shown to reverse or arrest the progression of fibrosis, representing a major unmet medical need. Recently, antifibrotic effects of PPARγ ligands have been studied in vitro and in vivo and some theories have emerged leading to new insights. Aberrant PPARγ function seems to be implicated in pathological fibrosis in the skin and lungs. This antifibrotic effect is mainly related to the inhibition of TGF-β/Smad signal transduction but other pathways can be involved. This review focused on recent studies that identified PPARγ as an important novel pathway with critical roles in regulating connective tissue homeostasis, with emphasis on skin and lung fibrosis and its role on systemic sclerosis

FUCA2 and TSTA3 expression in gastric cancer: candidate biomarkers of malignant transformation

Introduction. Aberrant fucosylation is closely related to malignant transformation, cancer detection, and evaluation of treatment efficacy. The fucosylation process requires GDP-L-fucose, fucosyltransferases, and fucosidases. In gastric cancer (GC), fucosylation alterations were associated with tumor formation, metastasis inhibition, and multi-drug resistance. It is not clear whether tissue-specific transplantation antigen P35B (TSTA3) and alpha-L-fucosidase 2 (FUCA2) have any effect on the development of GC. Materials and methods. We used immunohistochemistry to assess the expression of TSTA3 and FUCA2 in 71 gastric adenocarcinoma samples and their relationship with clinicopathological parameters. Results. TSTA3 expression was associated with lower histological grade I and II (P = 0.0120) and intestinal type Lauren classification (P = 0.0120). TSTA3 immunopositivity could predict Lauren’s classification. Analysis of mRNA expression in GC validation cohorts corroborates the significant TSTA3 association with histological grade observed in our study. However, no associations were found between TSTA3 staining and overall survival. FUCA2 expression was markedly increased in GC tissues compared with non-tumoral tissues (P &lt; 0.0001) and was associated with surgical staging III and IV (P = 0.0417) and advanced histological grade tumor states (P = 0.0125). Conclusions. Alterations of FUCA2 and TSAT3 immunoexpression could lay the basis for future studies using cell glycosylation as a biomarker for the planning of therapeutic strategy in primary gastric cancer

Diminuição dos Níveis Séricos do Receptor Solúvel da Oncostatina M (sOSMR) e Glicoproteína 130 (sgp130) em Pacientes com Doença Arterial Coronariana

Resumo Fundamento A oncostatina M (OSM) é uma citocina pleiotrópica que, após lesão arterial, demonstra ser expressa rapidamente. Objetivos Correlacionar os níveis séricos da OSM, do receptor solúvel de oncostatina M (sOSMR) e da fração solúvel de glicoproteína 130 (sgp130) em pacientes com doença arterial coronariana (DAC) a parâmetros clínicos. Métodos Os níveis de sOSMR e sgp130 foram avaliados por ELISA, enquanto os de OSM foram avaliados por Western Blot, em pacientes com SCC (n=100), pacientes com SCA (n=70) e 64 voluntários do grupo de controle sem manifestações clínicas da doença. Valores de p <0,05 foram considerados estatisticamente significativos. Resultados Pacientes com DAC exibiram níveis significativamente mais baixos de sOSMR e sgp130 e níveis mais altos de OSM em comparação ao grupo de controle (ambos p <0,0001). A análise clínica mostrou níveis mais baixos de sOSMR em homens ([OR] = 2,05, p = 0,026), jovens (OR = 1,68, p = 0,0272), hipertensos (OR = 2,19, p = 0,041), fumantes (OR = 2,19, p = 0,017), pacientes que não apresentavam dislipidemia (OR = 2,32, p = 0,013), pacientes com infarto agudo do miocárdio [IAM] (OR = 3,01, p = 0,001) e pacientes não tratados com estatina (OR = 1,95, p = 0,031), antiplaquetário (OR = 2,46, p = 0,005), inibidores dos canais de cálcio (OR = 3,15, p = 0,028) e antidiabéticos (OR = 2,97, p = 0,005). Os níveis de sOSMR também foram correlacionados a sexo, idade, hipertensão e uso de medicamentos na análise multivariada. Conclusões Nossos dados sugerem que o aumento dos níveis séricos de OSM e a diminuição dos níveis de sOSMR e sGP130 em pacientes com injúria cardíaca podem desempenhar um papel importante no mecanismo fisiopatológico da doença. Além disso, níveis mais baixos de sOSMR foram associados a sexo, idade, hipertensão e uso de medicamentos

IL-17A, IL-22, IL-6, and IL-21 Serum Levels in Plaque-Type Psoriasis in Brazilian Patients

Psoriasis is a chronic inflammatory skin disease characterized by alterations in cytokines produced by both Th1 and Th17 pathways. The aim of this study was to evaluate serum levels of pivotal cytokines and correlate them with clinical parameters. Serum samples from 53 psoriasis patients and 35 healthy volunteers, matched by the proportion of sex and age ratios, were collected for ELISA cytokine detection. Psoriasis Area and Severity Index (PASI) was assessed at the time of sampling in psoriasis patients. Our findings demonstrate that IL-17A, IL-22, and IL-6 serum concentrations were significantly higher in psoriasis patients than in the control group. No statistical correlation could be found between cytokines concentrations, PASI score, and age in this study. Although our results do not show any correlation between serum levels of IL-17A, IL-22, and IL-6 and disease activity, the present study confirms that they were increased in Brazilian psoriasis patients in comparison to healthy volunteers

Cytokine Profile in Gout: Inflammation Driven by IL-6 and IL-18?

<p><b>Introduction</b>: Gout is considered to be an autoinflammatory disease and the presence of monosodium urate (MSU) crystals stimulates activation of NPRL3 inflammasome and subsequently caspase-1, generating production of active IL-1β and IL-18. However, the association between serum cytokines levels and clinical manifestations of the disease is not yet well understood. We evaluated the serum profile of proinflammatory cytokines (IL-1β, IL-6, IL-8, IL-17A, IL-18, IL-22, and IL-23) and described their relationship with clinical and laboratory data.</p> <p><b>Methodology</b>: Thirty-nine male patients with gout (GG) were assessed for clinical and laboratory variables and cytokine levels were measured by ELISA. For the purposes of comparison, 34 males with no previous history of arthritis were also included in the study (CG).</p> <p><b>Results</b>: Seventeen participants (43%) exhibited active arthritis on evaluation. Levels of IL-18 were significantly higher in patients in relation to the CG (<i>p</i> = 0.0013). No statistically significant differences were found between the GG and CG for the other measured cytokines. There was a moderate correlation between IL-18 and ESR (<i>R</i> = 0.43, <i>p</i> = 0.0073), CRP (<i>R</i> = 0.47, <i>p</i> = 0.0025), and serum levels of IL-6 (<i>R</i> = 0.36, <i>p</i> = 0.023). An association was observed between serum levels of IL-6 and the presence of tophi (<i>p</i> = 0.005) and deformities (<i>p</i> = 0.0008), as well as a correlation between this cytokine and ESR (<i>R</i> = 0.41, <i>p</i> = 0.011) and CRP (<i>R</i> = 0.48, <i>p</i> = 0.02).</p> <p><b>Conclusions</b>: IL-18 is associated with inflammatory activity in gout, as well as with IL-6 levels, while IL-6 is associated with clinical and laboratory activity, the presence of tophi and articular deformities, and may be a prognostic marker of this pathology.</p