Inflammation of the Hypothalamus Leads to Defective Pancreatic Islet Function

Type 2 diabetes mellitus results from the complex association of insulin resistance and pancreatic beta-cell failure. Obesity is the main risk factor for type 2 diabetes mellitus, and recent studies have shown that, in diet-induced obesity, the hypothalamus becomes inflamed and dysfunctional, resulting in the loss of the perfect coupling between caloric intake and energy expenditure. Because pancreatic beta-cell function is, in part, under the control of the autonomic nervous system, we evaluated the role of hypothalamic inflammation in pancreatic islet function. In diet-induced obesity, the earliest markers of hypothalamic inflammation are present at 8 weeks after the beginning of the high fat diet; similarly, the loss of the first phase of insulin secretion is detected at the same time point and is restored following sympathectomy. Intracerebroventricular injection of a low dose of tumor necrosis factor a leads to a dysfunctional increase in insulin secretion and activates the expression of a number of markers of apoptosis in pancreatic islets. In addition, the injection of stearic acid intracerebroventricularly, which leads to hypothalamic inflammation through the activation of tau-like receptor-4 and endoplasmic reticulum stress, produces an impairment of insulin secretion, accompanied by increased expression of markers of apoptosis. The defective insulin secretion, in this case, is partially dependent on sympathetic signal-induced peroxisome proliferator receptor-gamma coactivator Delta a and uncoupling protein-2 expression and is restored after sympathectomy or following PGC1 alpha expression inhibition by an antisense oligonucleotide. Thus, the autonomic signals generated in concert with hypothalamic inflammation can impair pancreatic islet function, a phenomenon that may explain the early link between obesity and defective insulin secretion.

Excessiva atividade de remodelamento ventricular sinaliza limitada resposta terapêutica ao manejo agressivo da insuficiência cardíaca avanaçada

Introdução: Níveis de fator de necrose tumoral–alfa (TNF-α), N-peptídeo do pró-colágeno III (PIIINP) e metaloproteinase de matriz –1 (MMP-1), marcadores biológicos de remodelamento ventricular, estão elevados em pacientes com insuficiência cardíaca (IC), talvez refletindo elevadas pressões de enchimento. A correlação destes marcadores com variáveis clínicas e hemodinâmicas permanece pouco compreendida, particularmente no contexto ambulatorial da IC. Objetivo: Avaliar níveis séricos de marcadores biológicos de remodelamento ventricular em pacientes com IC, comparando tratamento guiado por ecocardiografia (ECO), buscando redução de pressões de enchimento, versus tratamento convencional (CLÍNICO), baseado em sinais e sintomas. Métodos: Ensaio clínico randomizado. Pacientes estáveis com IC e fração de ejeção menor do que 40% foram alocados entre os grupos de tratamento e submetidos a ecocardiograma e coletas de sangue no início do estudo e em 180 dias. TNF-α e MMP- 1 foram medidos por ELISA, e PIIINP, por radioimunoensaio. Resultados: Incluiu-se 80 pacientes, com 59 ± 15 anos e fração de ejeção de 26 ± 7%; 25% isquêmicos e 52% masculinos. Houve redução dos marcadores biológicos intragrupos, não havendo diferença entre os tratamentos. No grupo CLÍNICO, os níveis de TNF-α, MMP-1 e PIIINP apresentaram diferenças estatisticamente significativas entre os momentos basal e final (respectivamente, 3,11 ± 2,90 versus 1,24 ± 0,60 pg/mL p < 0,0003; 2,66 ± 1,00 versus 1,16 ± 0,40 ng/mL p < 0,0001; 6,12 ± 2,60 versus 3,89 ± 1,60 μg/L p < 0,0001). De maneira semelhante, tal diferença também foi observada no grupo ECO para os três marcadores (respectivamente, 3,90 ± 4,90 versus 1,40 ± 1,30 pg/mL p < 0,0001; 2,50 ± 0,90 versus 1,09 ± 0,40 ng/mL p < 0,0001; 6,09 ± 2,60 versus 3,50 ± 1,30 μg/L p<0,0001). Ao final da intervenção, no entanto, não foi observada diferença significativa dos valores de TNF-α , MMP-1 e PIIINP entre os dois grupos de tratamento (p = 0,7; p = 0,8; e p = 0,2; respectivamente). A combinação dos valores basais das variáveis biológicas gerou um escore que se associou significativamente com o comportamento final das pressões atrial direita e sistólica da artéria pulmonar. Pacientes com marcadores biológicos basais no quartil 75% mantiveram níveis superiores de pressões atrial direita (13 mmHg; p = 0,034) e sistólica de artéria pulmonar (60 mmHg; p = 0,007) ao final do seguimento. Conclusão: Independente do tratamento alocado, houve redução dos níveis de marcadores biológicos ao final do seguimento; no entanto, níveis basais mais elevados destes marcadores foram preditores de menor redução das pressões em átrio direito e sistólica da artéria pulmonar. Os dados sugerem que indicativos de intenso processo de remodelamento ventricular se associam à progressão da IC e a pressões de enchimento elevadas.

Avaliação do efeito citotóxico da lectina da esponja marinha Cliona varians contra células de leucemia mielóide crônica

In this study, a BCR-ABL expressing human chronic myelogenous leukaemia cell line (K562) was used to investigate the antitumoral potential of a novel lectin (CvL) purified from the marine sponge Cliona varians. CvL inhibited the growth of K562 cells with an IC50 value of 70 g/ml, but was ineffective to normal human peripheral blood lymphocytes in the same range of concentrations tested (180 g/ml). Cell death occurred after 72 h of exposure to the lectin and with sign of apoptosis as analysed by DAPI staining. Investigation of the possible effectors of this process showed that cell death occurred in the presence of Bcl-2 and Bax expression, and involved a caspase-independent pathway. Confocal fluorescence microscopy indicated a major role for the lysosomal protease cathepsin B in mediating cell death. Accordingly, pre-incubation of K562 cells with the cathepsin inhibitor L-trans-epoxysuccinyl-L-leucylamido-(4-guanidino)butane (E-64) abolished the cytotoxic effect of CvL. Furthermore, we found upregulation of tumor necrosis factor receptor 1 (TNFR1) and down-modulation of p65 subunit of nuclear factor kappa B (NFB) expression in CvL-treated cells. These effects were accompanied by increased levels of p21 and downmodulation of pRb, suggesting that CvL is capable of cell cycle arrest. Collectively, these findings suggest that cathepsin B acts as death mediator in CvL-induced cytotoxicity possibly in a still uncharacterized connection with the membrane death receptor pathway

The role of obesity as a modifying factor in patients undergoing non-surgical periodontal therapy

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Sporothrix schenckii lipid inhibits macrophage phagocytosis: Involvement of nitric oxide and tumour necrosis factor-alpha

The role of cell-wall compounds in the immune response to sporotrichosis is unknown. The effect of cell-wall compounds and exoantigen obtained from Sporothrix schenckii in macrophage/fungus interaction was analysed with respect to nitric oxide (NO) and tumour necrosis factor-alpha (TNF-alpha). The lipid compound of the cell wall plays an important role in the pathogenesis of this mycosis and was found to inhibit the phagocytic process and to induce high liberation of NO and TNF-alpha in macrophage cultures in the present study. This is a very interesting result because it is the first report about one compound of the fungus S. schenckii that presents this activity.

High concentrations of the melatonin metabolite, N-1-acetyl-N (2)-formyl-5-methoxykynuramine, in cerebrospinal fluid of patients with meningitis: a possible immunomodulatory mechanism

We evaluated the presence of the melatonin metabolite N-1-acetyl-N-2-formyl-5-methoxykynuramine (AFMK), in cerebrospinal fluid (CSF) of patients with viral meningitis (n = 20) and control samples (n = 8) and correlate AFMK levels with inflammatory markers such as cellularity, protein, tumor necrosis factor (TNF)-alpha, interleukin (IL)-8 and IL-1 beta levels. A portion of the CSF was extracted with dichloromethane (1:5) and analyzed by high-performance liquid chromatography (HPLC) under standardized conditions for AFMK. AFMK was detected in 16 of 20 CSF samples of patients with viral meningitis; the concentration of AFMK was found to be above the quantification limit (50 nmol/L) in six of these samples. AFMK was not detected in any of the eight control samples. The samples were classified into groups according to AFMK levels: undetectable (< 10 nmol/L, group I), detectable but below the quantification limit (< 50 nmol/L, group II), and quantified (> 50 nmol/L, group III). Group II presented the highest levels of proteins and IL-8, whereas group III showed the lowest levels of the inflammatory parameters. This study supports our hypothesis that inflammation favors the formation of AFMK and that this compound has immunomodulatory activity in vivo.

4-Fluoro-2-methoxyphenol, an apocynin analog with enhanced inhibitory effect on leukocyte oxidant production and phagocytosis

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

TLR4 and CD14 receptors expressed in rat pineal gland trigger NFKB pathway

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Inflammation and Overweight in Peritoneal Dialysis: Is There an Association?

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

TNF-308G > A Single Nucleotide Polymorphism Is Associated With Leprosy Among Brazilians: A Genetic Epidemiology Assessment, Meta-Analysis, and Functional Study

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Silibinin modulates the NF-kappa b pathway and pro-inflammatory cytokine production by mononuclear cells from preeclamptic women

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Fatty acid composition of mid-trimester amniotic fluid in women of different ethnicities

Objective: To determine whether the fatty acid composition of mid-trimester amniotic fluid differs by ethnicity and pregnancy outcome. Methods: Fatty acid composition was analyzed by gas chromatography in 198 women undergoing amniocentesis at 15-19 weeks gestation. Cytokine levels were determined by ELISA in a subgroup of 52 subjects. Results: The major fatty acids detected were palmitic acid (31.8%) and stearic acid (31.5%). The n-6 polyunsaturated fatty acids (PUFA), linoleic acid (LA, 18: 2) and arachidonic acid (AA, 20: 4), were 11.3%, while the n-3 PUFA fatty acids, alpha linolenic acid (ALA, 18: 3) and docosahexaenoic acid (DHA, 22: 6), were 3.8% of the total. Palmitic acid was a higher percentage in Asians (40.5%) and Whites (34.5%) than in Blacks (22.2%) and Hispanics (23.7%) (p <= 0.0012). Oleic acid (18:1 n-9) was a higher percentage in Blacks (12.2%) and Hispanics (12.1%) than in Whites (9.2%) or Asians (7.5%) (<= 0.0002). LA and AA were higher in Blacks (9.0%, 5.4%) and Hispanics (8.6%, 4.1%) than in Whites (6.1%, 3.7%) and Asians (5.5%, 2.9%) (p <= 0.0002). DHA did not differ among the ethnic groups or according to pregnancy outcome. A reduced palmitic acid percentage was identified in the six women with preeclampsia (p = 0.0233). Tumor necrosis factor-alpha levels were inversely proportional to the palmitic acid percentage (p = 0.0275) and positively associated with the percentages of stearic (18:0) (p = 0.0132) and oleic (p = 0.0290) acids. Conclusions: Amniotic fluid fatty acid composition differed among the ethnic groups and may influence inflammatory mediator production and susceptibility to preeclampsia.

Inhibitory effect of silibinin on tumour necrosis factor-alpha and hydrogen peroxide production by human monocytes

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Analysis of the expression of toll-like receptors 2 and 4 and cytokine production during experimental Leishmania chagasi infection

Toll-like receptors (TLRs) recognise pathogen-derived molecules and influence immunity to control parasite infections. This study aimed to evaluate the mRNA expression of TLRs 2 and 4, the expression and production of the cytokines interleukin (IL)-12, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL-17, IL-10 and transforming growth factor (TGF)-β and the production of nitric oxide (NO) in the spleen of mice infected with Leishmania chagasi. It also aimed to evaluate any correlations between mRNA expression TLR2 and 4 and cytokines and NO production. Infection resulted in increased TLR2-4, IL-17, TNF-α and TGF-β mRNA expression during early infection, with decreased expression during late infection correlating with parasite load. IFN-γ and IL-12 mRNA expression decreased at the peak of parasitism. IL-10 mRNA expression increased throughout the entire time period analysed. Although TGF-β, TNF-α and IL-17 were highly produced during the initial phase of infection, IFN-γ and IL-12 exhibited high production during the final phase of infection. IL-10 and NO showed increased production throughout the evaluated time period. In the acute phase of infection, there was a positive correlation between TLR2-4, TNF-α, IL-17, NO, IL-10 and TGF-β expression and parasite load. During the chronic phase of infection, there was a positive correlation between TLR2-4, TNF-α, IL-17 and TGF-β expression and parasite load. Our data suggest that infection by L. chagasi resulted in modulation of TLRs 2 and 4 and cytokines.