Possible role of pomegranate fruit in reversing renal damage in rats exposed to Phenylhydrazine.

Background: Pomegranate granatum (molasses and peels) and its constituents showed protective effects against natural toxins such as phenylhydrazine (PHZ) as well as chemical toxicants such as arsenic, diazinon, and carbon tetrachloride. Aim: The current study aimed to assess the effect of pomegranate molasses (PM), white peel extract, and red peel extract on nephrotoxicity induced by PHZ. Methods: 80 male rats were divided into eight equal groups; a control group, PM pure group, white peel pomegranate pure group, red peel pomegranate pure group, PHZ group, PM + PHZ group, white peel pomegranate + PHZ group and red peel pomegranate + PHZ group. Kidney function, inflammation markers, antioxidant activities, and renal tissue histopathology were investigated. Results: The results revealed that PHZ group showed a significant increase in lactate Dehydrogenase (LDH), malondialdehyde (MDA), creatinine, uric acid, BUNBUN, C - reactive protein (CRP), tumor necrosis factor, thiobarbituric acid reactive substances (TBARSs), and total antioxidant capacity (TAC) with a significant decrease of catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) as compared with a control group. Other pomegranate-treated and PHZ co-treated groups with pomegranate showed a significant decrease of LDH, MDA, creatinine, uric acid, BUN, tumor necrosis factor, TBARSs, and TAC with a significant increase of CAT, GPx, and SOD as compared with PHZ group. Conclusion: Collectively, our data suggest that red, white peels, and molasses have anti-toxic and anti-inflammatory effects on renal function and tissues.

TWEAK and Fn14 are overexpressed in immune-mediated necrotizing myopathy: implications for muscle damage and repair.

OBJECTIVES: TNF-like weak inducer of apoptosis (TWEAK) and its sole receptor fibroblast growth factor-inducible 14 (Fn14) are involved in various inflammatory conditions. This study was performed to investigate the potential role of TWEAK/Fn14 in immune-mediated necrotizing myopathy (IMNM). METHODS: Muscle biopsies from patients with IMNM (n = 37) and controls (n = 11) were collected. Human muscle cells were treated with TWEAK in vitro. Muscle biopsies and cultured muscle cells were analysed by immunostaining and quantitative PCR. Serum levels of TWEAK and Fn14 were detected by ELISA. RESULTS: TWEAK and Fn14 were overexpressed in IMNM muscle biopsies. The percentage of Fn14-positive myofibers correlated with disease severity, myonecrosis, regeneration and inflammation infiltrates. Fn14-positive myofibers tended to be surrounded or invaded by CD68+ macrophages. TWEAK treatment had a harmful effect on cultured muscle cells by inducing the production of multiple chemokines and pro-inflammatory cytokines. Serum Fn14 levels were increased in patients with IMNM and correlated with muscle weakness. CONCLUSIONS: TWEAK/Fn14 signalling was activated in IMNM, most likely aggravating muscle damage via amplifying inflammatory response and macrophages chemotaxis. Fn14 seems to be a biomarker for assessing disease severity in IMNM. In addition, Fn14 may also contribute to muscle injury repair.

Evaluation of Silver Nanoparticles Caffeic Acid Complex Compound as New Potential Therapeutic Agent against Cancer Incidence in Mice.

OBJECTIVE: The present work was designed to study the effect of new conjugated caffeic and folic acid with silver nanoparticles with definite molecular size applied with and without gamma radiation exposure, as an antitumor agent against experimentally induced Ehrlich tumor and attempted to identify their potential molecular mechanisms of action throughout determination of anti-tumor activities using MTT cytotoxic assay against two human carcinoma cell lines in vitro, such as apoptosis analysis by flow cytometry through caspase-8, caspase-3 and TNF determination in vivo. MATERIALS AND METHODS: Adult female albino mice were used and divided into five groups. Animals were sacrificed and the following parameters were estimated, glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD) in blood in addition to caspase8, caspase 3 and tumor necrosis factor (TNF) of tumor tissue, liver and kidney function also measured in plasma. The tumor specimens were processed for histopathological examination. RESULTS: Nano-silver folate caffeic (NSFC) complex compound treatment resulted in growth inhibition in Ehrlich solid tumor, Hep-G2, and MCF-7 cells (IC50 0.062 mg, 7.70 µM, and 14.50 µM, respectively). Flow cytometric analysis revealed that (NSFC) with radiation IR had apoptotic effects at caspases 8 (Mean±SD) (49.4±14), caspase3 (39.97±9.75), and TNF (40.1±3.4) more than any other groups. Those disturbances were found to be associated with a kinetic induction of apoptosis and showed modulation of the antioxidant system {glutathione (GSH), glutathione peroxidase (GPx) and superoxide dismutase (SOD) which were 60.70±0.80, 26.73±0.80, 39.52±0.58 respectively}at the group which took (NSFC+IR), besides its high percentage of necrotic cells by histopathological studies. In conclusion, the present study showed that the treatment of (NSFC) exhibits very efficient oncolytic activity in delaying tumor growth in mice bearing Ehrlich Solid Carcinoma (ESC) and the mechanisms underlying the inhibitory effect of the present compound involve both an apoptotic effect against Hep-G2 and MCF-7 cells and modulation of antioxidant system.

Adipocytokine expression, platelet-to-lymphocyte ratio and TGF-ß1/Smad signaling activity in diabetic patients complicated with pulmonary infection.

OBJECTIVE: To investigate adipocytokine expression levels, platelet-to-lymphocyte ratio (PLR) and transforming growth factor (TGF)-ß1/Smad signaling activity in diabetic patients with pulmonary infection. METHODS: Eighty-two type 2 diabetic patients with pulmonary infection were included in the observation group and 75 patients with simple type 2 diabetes were recruited into the control group. The fasting blood glucose (FBG), glycated hemoglobin (HbA1c), and PLR in the two groups were compared. Complement-C1q/tumor necrosis factor related protein 3 (CTRP-3), complement-C1q/tumor necrosis factor related protein 9 (CTRP-9), leptin, adiponectin, and TGF-ß1/Smad signaling pathway activity in peripheral blood mononuclear cells (PBMCs) was detected. RESULTS: Compared with patients in the control group, patients in the observation group presented with increased levels of FGB, HbA1c, and leptin, an increase in the PLR, and decreased serum CTRP-3, CTRP-9, and adiponectin levels. TGF-ß1, p-Smad2, and p-Smad3 protein expression levels were up-regulated in PBMCs from patients in the observation group compared with the control group. CONCLUSIONS: These results show that in type 2 diabetic patients with pulmonary infection, adipocytokine expression is altered, PLR is disturbed, and the TGF-ß1/Smad signaling pathways in PBMCs are significantly activated.

Dysregulation of macrophage development and phenotype in diabetic human macrophages can be rescued by Hoxa3 protein transduction.

Controlled inflammatory responses of myeloid cells recruited to wounds are essential for effective repair. In diabetes, the inflammatory response is prolonged and augmented over time, with increased myeloid cells present in the wound that fail to switch from a pro-inflammatory phenotype to a pro-healing phenotype. These defects lead to delayed angiogenesis and tissue repair and regeneration, and contribute to chronic wound formation. In mouse models of diabetes, this aberrant phenotype is partially mediated by stable intrinsic changes to the developing myeloid cells in the bone marrow, affecting their maturation and polarization potential. Previous studies have shown that freshly isolated peripheral blood mononuclear cells from diabetic patients are more inflammatory than non-diabetic counterparts. However, the phenotype of macrophages from human diabetic patients has not been well characterized. Here we show that diabetic-derived human macrophages cultured for 6 days in vitro maintain a pro-inflammatory priming and hyperpolarize to a pro-inflammatory phenotype when stimulated with LPS and INF-É£ or TNF. In addition, diabetic-derived macrophages show maturation defects associated with reduced expression of the RUNX1 transcription factor that promotes myeloid cell development. Targeting intrinsic defects in myeloid cells by protein transduction of the Hoxa3 transcription factor can rescue some inflammation and maturation defects in human macrophages from diabetic patients via upregulation of Runx1. In addition, Hoxa3 can modulate the levels of p65/NF-κB and histone acetyltransferase and deacetylase activity, as well as inhibit acetylation of the TNF promoter. Altogether, these results show a link between myeloid cell maturation and inflammatory responses, and that diabetes induces intrinsic changes to human myeloid cells that are maintained over time, as well as potentially therapeutic Hoxa3-mediated mechanisms of controlling the inflammatory response in diabetes.

Dialysate cell-free mitochondrial DNA fragments as a marker of intraperitoneal inflammation and peritoneal solute transport rate in peritoneal dialysis.

BACKGROUND: Mitochondrial DNA (mtDNA) released into extracellular subsequent to cell injury and death can promote inflammation in patients and animal models. However, the effects of peritoneal dialysate cell-free mtDNA on intraperitoneal inflammation and peritoneal solute transport rate (PSTR) in peritoneal dialysis (PD) patients remain unclear. METHODS: We select the incident patients who began PD therapy between January 1, 2009, and December 30, 2010. Peritoneal dialysate was collected at the time of peritoneal equilibration test. The cell-free mtDNA, IL-6, IL-17A, TNF-α and IFN-γ were measured. All patients were followed till December 2017. The results were compared with PSTR and patient survival. RESULTS: One hundred and eighty-nine patients were included in the study. The average age was 47.1 ± 13.5 years, 55.6% of the patients were males. The average PSTR was 0.66 ± 0.12, the median dialysate mtDNA levels were 4325 copies/ul. The median concentrations of IL-6, IL-17A, TNF-α and IFN-γ were 25.9, 10.8, 25.8 and 17.9 pg/ml, respectively. We found that dialysate mtDNA was significantly correlated with PSTR (r = 0.461, P < 0.001), IL-6 (r = 0.568, P < 0.001), TNF-α (r = 0.454, P < 0.001) and IFN-γ (r = 0.203, P = 0.005). After adjustment for multiple covariates, dialysate mtDNA levels were independently correlated with IL-6 and PSTR. Dialysate mtDNA levels were not associated with patient survival. CONCLUSIONS: We found that dialysate mtDNA levels correlated with the degree of intraperitoneal inflammatory status in PD patients. Peritoneal effluent mtDNA was an independent determinant of PSTR but did not affect patient survival.

Identification of a Novel OX40L+ Dendritic Cell Subset That Selectively Expands Regulatory T cells.

We have previously shown GM-CSF derived bone-marrow dendritic cells (G-BMDCs) can induce the selective expansion of Tregs through the surface-bound molecule OX40L; however, the physiological role of this ex vivo derived DC subset remained to be elucidated. We determined GM-CSF administration to mice induced the generation of in vivo derived OX40L+ DCs, phenotypically similar to ex vivo OX40L+G-BMDCs, in the spleen, brachial lymph nodes and liver. The generation of OX40L+ DCs correlated with increased percentages of functionally suppressive Tregs in the spleen, brachial lymph nodes, and liver of GM-CSF treated mice. DCs from GM-CSF treated mice expanded Tregs in CD4+ T-cell co-cultures in an OX40L dependent manner, suggesting OX40L+ DCs may play a role in peripheral Treg homeostasis. Furthermore, comparing the transcriptome data of OX40L+ DCs to that of all immune cell types revealed OX40L+ DCs to be distinct from steady-state immune cells and, microarray analysis of OX40L+G-BMDCs and OX40L-G-BMDCs revealed higher expression of molecules that are associated with tolerogenic phenotype and could play important roles in the function of OX40L+ DCs. These findings suggest that OX40L+ DCs may represent a unique DC subset induced under inflammatory conditions that may play an essential role in maintaining Treg homeostasis.

Dichotomous Expression of TNF Superfamily Ligands on Antigen-Presenting Cells Controls Post-priming Anti-viral CD4+ T Cell Immunity.

T cell antigen-presenting cell (APC) interactions early during chronic viral infection are crucial for determining viral set point and disease outcome, but how and when different APC subtypes contribute to these outcomes is unclear. The TNF receptor superfamily (TNFRSF) member GITR is important for CD4+ T cell accumulation and control of chronic lymphocytic choriomeningitis virus (LCMV). We found that type I interferon (IFN-I) induced TNFSF ligands GITRL, 4-1BBL, OX40L, and CD70 predominantly on monocyte-derived APCs and CD80 and CD86 predominantly on classical dendritic cells (cDCs). Mice with hypofunctional GITRL in Lyz2+ cells had decreased LCMV-specific CD4+ T cell accumulation and increased viral load. GITR signals in CD4+ T cells occurred after priming to upregulate OX40, CD25, and chemokine receptor CX3CR1. Thus IFN-I (signal 3) induced a post-priming checkpoint (signal 4) for CD4+ T cell accumulation, revealing a division of labor between cDCs and monocyte-derived APCs in regulating T cell expansion.

Radionecrosis versus progresión de la enfermedad en metástasis cerebrales: valor del 18F-DOPA PET/TC/RM / Radionecrosis versus disease progression in brain metastasis. Value of 18F-DOPA PET/CT/MRI

La utilización del 18F-DOPA PET/TC junto a la superposición con imágenes de resonancia magnética y el empleo de métodos de análisis visual y semicuantitativo permitió diferenciar entre las alteraciones posradiocirugía vs. sospecha de progresión de la enfermedad en un paciente con metástasis cerebrales de melanoma, permitiendo tomar una conducta quirúrgica correcta precozmente (AU)

The use of 18F-DOPA PET/CT with magnetic resonance imaging fusion and the use of visual methods and quantitative analysis helps to differentiate between changes post-radiosurgery vs. suspicion of disease progression in a patient with brain metastases from melanoma, thus facilitating taking early surgical action (AU)

Effect of montelukast on clinical score and cytokine levels of infants for clinically diagnosed acute bronchiolitis

BACKGROUND: Acute bronchiolitis comprises a major cause for morbidity in infants with viral infection which induces an immune inflammatory response that may produce long lasting harmful effects. Currently, there is no effective therapy for bronchiolitis. OBJECTIVE: Our aim was to investigate the efficacy of five-day montelukast therapy in acute bronchiolitis management. METHODS: The study included 50 infants with acute bronchiolitis. The infants with first episode of acute bronchiolitis were randomly assigned to receive daily montelukast dose of 4 mg over five days after admission or no treatment. Plasma eotaxin, IL-4, IL-8 and IFN-gamma levels were evaluated before and after treatment by ELISA method. In the present study, the primary outcome measure was change in clinical severity score, whilst secondary outcome measures were changes in plasma eotaxin, IL-4, IL-8, IFN-gamma levels. RESULTS: No significant differences was found in clinical severity score with five-day montelukast treatment (p > 0.05, Mann-Whitney U test). There were no significant differences in plasma eotaxin, IL-4, IL-8, IFN-gamma levels between the groups (p > 0.05 Mann-Whitney U test). There was significant decrease in plasma IFN-gamma levels following five-day montelukast treatment (p = 0.027, Wilcoxon). There were no significant differences in plasma IL-4, IL-8, IFN-gamma levels between the groups after five-day montelukast treatment (p > 0.05, Wilcoxon). There was significant increase in eotaxin levels after five-day montelukast treatment (p = 0.009, Wilcoxon). CONCLUSION: Our study showed that montelukast affected plasma IFN-gamma and eotaxin levels after five days of treatment. Further studies are needed to demonstrate effects of montelukast on chemokine levels in bronchiolitis

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Cytokine levels in plasma and gingival crevicular fluid in chronic periodontitis.

PURPOSE: To evaluate the Th1/Th2/Th17 cytokine levels in plasma and gingival crevicular fluid (GCF) from chronic periodontitis patients and healthy controls. METHODS: The concentration of interleukin-2 (IL-2), IL-4, IL-6, IL-10, IL-17, TNF, and IFN-γ were determined using a flow cytometric multiplex immunoassay (CBA), and was compared between the periodontitis group and the healthy group. Spearman rho coefficient was used to correlate cytokines in GCF in the periodontitis group and the healthy group, respectively. RESULTS: Comparisons of two groups of Th1/Th2/Th17 cytokine levels in plasma and GCF showed no statistically significant differences (P > 0.05), except Th17 (IL-17) level in plasma that was higher in the periodontitis group than the healthy group (P < 0.05). A stronger correlation between IL-17/IL-4 and IL-17/IL-10 was observed in periodontitis patients than in healthy controls.

Reacciones psoriasiformes paradójicas durante el tratamiento con terapia anti-factor de necrosis tumoral. Manejo clínico / Clinical Management of Paradoxical Psoriasiform Reactions During TNF-alfa; Therapy

Paradójicamente se han descrito casos de inducción o empeoramiento de una psoriasis durante el tratamiento con todos los agentes anti-factor de necrosis tumoral α (anti-TNFα) (infliximab, etanercept, adalimumab y certolizumab). Se ha postulado que la alteración del equilibrio entre el TNFα y el interferón α estaría implicada en su etiopatogenia. Clínicamente se distinguen varios patrones de reacciones psoriasiformes paradójicas: la psoriasis de novo en pacientes que no han presentado anteriormente esta enfermedad y que reciben este tratamiento por otra enfermedad inflamatoria, que es la más frecuente y la mejor descrita, y la exacerbación de una psoriasis preexistente durante la terapia anti-TNFα, que puede presentarse con o sin un cambio de morfología. En este trabajo realizamos una revisión de la literatura en relación con las características clínicas e histológicas de este tipo de reacciones, así como de su evolución y tratamiento, y planteamos un esquema de manejo en la práctica clínica

There have been reports of paradoxical induction or worsening of psoriasis during treatment with tumor necrosis factor (TNF) α agents (infliximab, etanercept, adalimumab, and certolizumab). It has been hypothesized that an imbalance between TNF-α and interferon α might have a role in the etiology and pathogenesis of these reactions. Paradoxical psoriasiform reactions can be divided clinically into de novo psoriasis and exacerbation of preexisting psoriasis. The first, which is more common and more extensively described in the literature, occurs in patients without a history of psoriasis who are receiving TNF-α therapy for another inflammatory disorder. The second can occur with or without changes in the morphology of the lesions. In this article, we review the literature on the clinical and histologic features of paradoxical psoriasiform reactions, analyze their clinical course and treatment, and propose a clinical management model for use in routine practice

The influence of nutritional status and disease on adiponectin and TNF-ALFA levels in colorectal cancer patients / Influencia del estado nutritivo y la enfermedad sobre las concentraciones de adiponectina y TNF-ALPHA en pacientes con cáncer colorrectal

Background: The aim of this study was to evaluate the association between adiponectin and tumor necrosis factor-α (TNF-α) serum levels in colorectal cancer (CRC) patients and compare these levels to clinical stage and nutritional status. Methods: A total of 79 patients were enrolled in the study (39 with CRC and 40 in the control). Nutritional status was assessed by Patient-Generated Subjective Global Assessment (PG-SGA), body mass index (BMI), and phase angle (PhA). Adiponectin and TNF-α serum concentrations were determined using an enzyme-linked immunosorbent assay. Results: Serum adiponectin levels were higher among CRC patients (p = 0.001). TNF-α serum levels were not significantly different between the groups, but patients with stage III or IV CRC had higher levels of TNF-α than those with lower stage disease (p = 0.037). The three tools used for the assessment of nutritional status (BMI, PhA, and PG-SGA) demonstrated that patients with a more severe nutritional deficit had higher adipocytokine levels, although these differences were significant only to TNF- α, when distributed PhA in tertiles. Conclusions: Adiponectin levels were higher among CRC patients. Although TNF-α serum levels from CRC patients did not differ significantly to the control group, CRC patients with stage III or IV had higher levels compared to those with stage I and II tumors. Nutritional status, as determined by BMI, PhA, and PG-SGA, demonstrated that patients with a greatest nutritional deficit, had higher levels of adipocytokines; however, these differences were significant only for TNF-α, when distributed PhA in tertiles (AU)

Antecedentes: El propósito de este estudio fue evaluar la asociación entre las concentraciones séricas de adiponectina y de factor de necrosis tumoral-α (TNF-α) en paciente con cáncer colorrectal (CCR) y comparar estas concentraciones con el estadio clínico y el estado nutritivo. Métodos: Se reclutó a un total de 79 pacientes en el estudio (39 con CCR y 40 en el grupo control). Se evaluó el estado nutritivo mediante la Evaluación Global Subjetiva Generada por el Paciente (PG-SGA), el índice de masa corporal (IMC) y el ángulo de fase (AF). Se determinaron las concentraciones séricas de adiponectina y de TNF-α mediante un inmunoensayo de absorción ligado a enzima. Resultados: Las concentraciones séricas de adiponectina fueron superiores en los pacientes con CCR (p = 0,001). Las concentraciones séricas de TNF-α no fueron significativamente distintas entre los grupos pero los pacientes con CC en estadios III o IV tuvieron mayores concentraciones de TNF-α que aquellos con un menor estadio de la enfermedad (p = 0,037). Las tres herramientas empleadas para evaluar el estado nutritivo (IMC, AF y PG-SGA) demostraron que los pacientes con un déficit nutricional más pronunciado presentaban mayores concentraciones de adipocitocina, aunque algunas diferencias sólo fueron significativas para el TNF-α cuanto se distribuyó el AF en terciles. Conclusiones: Las concentraciones de adiponectina fueron superiores en pacientes con CCR. Aunque las concentraciones séricas de TNF-α de los pacientes con CCR no diferían significativamente de las del grupo control, los pacientes con CCR en estadios III o IV tuvieron concentraciones superiores en comparación con aquellos con tumores en estadios I y II. El estado nutritivo, determinado por IMC, AF y PG-SGA, demostró que los pacientes con un mayor déficit nutricional tenían concentraciones superiores de adipocitocinas; sin embargo, estas diferencias sólo fueron significativas para el TNF-α cuando el AF se distribuyó en terciles (AU)

Expression of tumor necrosis factor-like weak inducer of apoptosis and fibroblast growth factor-inducible 14 in patients with polymyositis and dermatomyositis.

INTRODUCTION: The aim of this study was to investigate the expression of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) in patients with polymyositis (PM) and dermatomyositis (DM), and their relation to clinical manifestations. METHODS: Serum levels of TWEAK were detected in 98 PM/DM patients and 37 healthy controls by using the ELISA method. Total RNA isolated from fresh-frozen muscle tissue samples of 36 PM/DM patients and 10 healthy controls were used for analyzing the mRNA levels of TWEAK and Fn14 by quantitative reverse transcription polymerase chain reaction (RT-PCR). Immunofluorescence staining of TWEAK and Fn14 was conducted on muscle biopsy specimens from 23 PM/DM patients and seven healthy controls. RESULTS: Serum levels of TWEAK were significantly decreased in the PM/DM patients compared to those in the healthy controls (P < 0.001), and serum TWEAK levels negatively correlated with serum CD163 levels in PM/DM patients (r = -0.49, P < 0.001). The expression of Fn14 mRNA was significantly increased in the muscle tissue of PM/DM patients than in the muscle tissue of healthy controls (P < 0.01), whereas the expression of TWEAK mRNA in PM/DM patients was not statistically different from that of the healthy controls (P > 0.05). Fn14 mRNA levels in muscle tissue positively correlated with muscle disease activity (r = 0.512, P < 0.01). Patients with oropharyngeal dysphagia had significantly higher Fn14 mRNA levels than patients without oropharyngeal dysphagia (P < 0.05). The results of immunofluorescence staining showed that 19 out of 23 PM/DM patients were TWEAK-positive, and 20 out of 23 PM/DM patients were Fn14-positive. No detectable expressions of TWEAK or Fn14 were observed in the healthy controls. CONCLUSIONS: TWEAK-Fn14 axis may be involved in the pathogenesis of PM/DM. Further understanding of TWEAK-Fn14 function in PM/DM may help to define therapeutic targets for PM/DM.

Distinct human T-lymphocyte responses triggered by Porphyromonas gingivalis capsular serotypes.

AIM: Porphyromonas gingivalis can synthesize an extracellular capsule and different serotypes have been described based on capsular antigenicity. On dendritic cells (DCs), the type of capsule present plays a role on the strength of the developed immune response. This study aimed to investigate the T-lymphocyte responses when stimulated with autologous mature DCs exposed to different P. gingivalis K-serotypes. MATERIALS AND METHODS: Naïve CD4(+) T-lymphocytes were obtained from healthy subjects and stimulated with autologous DCs primed with increasing multiplicity of infections of the different P. gingivalis K-serotypes. The Th1, Th2, Th17 and T-regulatory cytokines and transcription factor levels were quantified. RESULTS: Distinct types of response were detected when T-lymphocytes were stimulated by DCs primed with the different P. gingivalis K-serotypes. T-lymphocytes stimulated by K1 or K2-primed DCs elicited higher levels of Th1 and Th17-associated cytokines, T-bet and RORC2 than T-lymphocytes stimulated with DCs primed with the other serotypes. Conversely, the serotypes K3-K5 induced higher levels of Th2-associated cytokines and GATA-3 than the others. CONCLUSIONS: These results demonstrate that DCs primed with the different P. gingivalis K-serotypes elicited distinct T-cell responses. Strains K1 (W83) and K2 (HG184) induced a Th1/Th17 pattern of immune response and K3 (A7A1-28), K4 (ATCC(®49417™) ), and K5 (HG1690) a Th2 response.

Osteoprotegerin in exosome-like vesicles from human cultured tubular cells and urine.

Urinary exosomes have been proposed as potential diagnostic tools. TNF superfamily cytokines and receptors may be present in exosomes and are expressed by proximal tubular cells. We have now studied the expression of selected TNF superfamily proteins in exosome-like vesicles from cultured human proximal tubular cells and human urine and have identified additional proteins in these vesicles by LC-MS/MS proteomics. Human proximal tubular cells constitutively released exosome-like vesicles that did not contain the TNF superfamily cytokines TRAIL or TWEAK. However, exosome-like vesicles contained osteoprotegerin (OPG), a TNF receptor superfamily protein, as assessed by Western blot, ELISA or selected reaction monitoring by nLC-(QQQ)MS/MS. Twenty-one additional proteins were identified in tubular cell exosome-like vesicles, including one (vitamin D binding protein) that had not been previously reported in exosome-like vesicles. Twelve were extracellular matrix proteins, including the basement membrane proteins type IV collagen, nidogen-1, agrin and fibulin-1. Urine from chronic kidney disease patients contained a higher amount of exosomal protein and exosomal OPG than urine from healthy volunteers. Specifically OPG was increased in autosomal dominant polycystic kidney disease urinary exosome-like vesicles and expressed by cystic epithelium in vivo. In conclusion, OPG is present in exosome-like vesicles secreted by proximal tubular epithelial cells and isolated from Chronic Kidney Disease urine.

Adipoquinas en el niño sano y con obesidad / Adipokines in healthy and obese children

El incremento universal de la prevalencia de obesidad en niños y adolescentes durante las últimas décadas, junto con la evidencia creciente de que el establecimiento de obesidad en etapas precoces de la vida, está asociado con un incremento de la prevalencia de comorbilidades y del riesgo de muerte prematura, con gran repercusión económica en los sistemas sanitarios de los países occidentales, y ha impulsado la investigación en esta área. Estos estudios han remarcado la importante actividad endocrina del tejido adiposo, ejercida por medio de la síntesis y secreción de un gran número de péptidos y citoquinas, denominados adipoquinas. En esta revisión se resume el estado actual de los conocimientos, así como los estudios más relevantes, en relación con la dinámica de secreción de las principales adipoquinas en niños, centrándose en el control de la homeostasia energética, la regulación metabólica (fundamentalmente el metabolismo de los hidratos de carbono) y la inflamación. Así mismo, se analizan las particularidades de la síntesis, secreción y acciones de las adipoquinas desde el nacimiento hasta la adolescencia, reseñando el efecto que, sobre ellas, ejerce la instauración de la obesidad(AU)

The worldwide increase in the prevalence of obesity in children and adolescents during the last decades, as well as the mounting evidence indicating that obesity is associated with an increased incidence of comorbidities and the risk of premature death, resulting in a high economic impact, has stimulated obesity focused research. These studies have highlighted the prominent endocrine activity of adipose tissue, which is exerted through the synthesis and secretion of a wide variety of peptides and cytokines, called adipokines. This review presents a summary of the current knowledge and most relevant studies of adipokine dynamics and actions in children, focusing on the control of energy homeostasis, metabolic regulation (particularly carbohydrate metabolism), and inflammation. The particularities of adipose secretion and actions in healthy children, from birth to adolescence, and the modifications induced by early onset obesity are highlighted(AU)

[Effect of dexamethasone on expressions of TWEAK and Fn14 in the lung of asthmatic mice].

AIM: To investigate the effect of dexamethasone (Dex) on the expressions of TNF-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible immediate-early response protein 14 (Fn14) in the lung of asthmatic mice. METHODS: Ovalbumin (OVA) was used to induce asthma in BALB/c mice. Thirty-six female mice were randomly divided into control group (n=12), asthmatic group (n=12) and Dex treated group (n=12). The airway inflammation was evaluated by HE staining. The expressions of TWEAK and Fn14 at mRNA and protein levels were detected by RT-PCR and immunohistochemistry, respectively. RESULTS: Both mRNA and protein levels of TWEAK and Fn14 in the asthmatic model group were significantly higher than those of control group (P<0.01), and both mRNA and protein levels of TWEAK and Fn14 in the Dex treated group were significantly lower than those of asthmatic group (P<0.01). CONCLUSION: Dex can reduce the airway inflammation through inhibiting the expressions of TWEAK and Fn14.

GITR-expressing regulatory T-cell subsets are increased in tumor-positive lymph nodes from advanced breast cancer patients as compared to tumor-negative lymph nodes.

Lymph node (LN) infiltration by neoplastic process involves important changes in lymph node immune microenvironment. In particular, regulatory T cells (Treg) seem to have a key role in altering the immunoediting function of the immune system which leads to the elusion of the tumor from immune surveillance. In this study, we evaluated the expression of T-cell markers in CD4+ and CD8+ subsets from tumor-positive and tumor-negative lymph nodes from the same, advanced stage breast cancer patient. The study was carried out on 3 patients and similar results were obtained. Flow cytometric analysis of CD8+ cells demonstrated a significant difference in the expression of CD25, CD45RA, CD45RO, and GITRL (Glucocorticoid-Induced TNF receptor-Related ligand). Flowcytometric analysis of CD4+ cells demonstrated a significant difference in the expression of GITR (Glucocorticoid-Induced TNF receptor-Related), CD25, FoxP3 (Forkhead box P3), CD28, and CD45RA. Multiple staining allowed the identification of two Treg subpopulations, CD4+ CD25 highGITR+ CD127-/low and CD4+ CD25 low GITR+ CD127+ cells, proving that both are increased in the positive nodes in comparison with the negative nodes from the same patient. We identified for the first time the CD4+ CD25 low GITR+ CD127+ Treg subpopulation in cancer, and the 2.6 fold increase in positive LN suggests that this Treg subpopulation could be a key player in metastasis. We also found GITRL expression in the CD8 lymphocytes, which may also contribute to the changes of metastatic lymph node microenvironment. These findings make both GITR and GITRL good possible co-candidates for future therapeutical intervention against metastasis and perhaps also as disease evolution biomarkers.

Therapeutic approaches for tumor necrosis factor inhibition

Tumor necrosis factor (TNF) consists of an inflammatory cytokine essential for homeostasis and organism defense. Despite its physiological relevance, both increased biosynthesis and release of TNF lead to the exacerbation of inflammatory and oxidative responses, which are related to the pathogenesis of a host of diseases of an inflammatory, autoimmune and/or infectious nature. In this context, effective therapeutic approaches for the modulation of TNF have been the focus of research efforts. Approximately one million individuals worldwide have been treated with biotechnological inhibitors of this cytokine, the so-called anti-TNF biopharmaceuticals. However, given the high risk of infection and the limitations related to cost and administration routes, new therapeutic approaches aimed at biological targets that directly or indirectly modulate the production and/or activation of TNF appear promising alternatives for the discovery of new anti-inflammatory and immunomodulatory orally active drugs and are therefore discussed in this paper.

O fator de necrose tumoral (do inglês, tumor necrosis factor - TNF) consiste em uma citocina inflamatória essencial para a homeostase e defesa do organismo. A despeito de sua relevância fisiológica, o aumento da biossíntese e liberação do TNF conduzem à exacerbação das respostas inflamatória e oxidativa, as quais estão relacionadas à patogênese de várias doenças de natureza inflamatória, auto-imune e/ou infecciosa. A busca por abordagens terapêuticas eficientes na modulação do TNF tem sido alvo de diversos esforços de pesquisa. Aproximadamente um milhão de pessoas ao redor do mundo já foi tratado com inibidores biotecnológicos desta citocina, os chamados biofármacos anti-TNF. Entretanto, em face ao elevado risco de infecções e as limitações relacionadas ao custo e a via de administração, novas abordagens terapêuticas com foco em alvos que modulem, de forma direta ou indireta, a produção e/ou ativação do TNF surgem como alternativas promissoras para a descoberta de novos fármacos antiinflamatórios e imunomoduladores ativos por via oral e serão discutidas neste trabalho.