Home About us Contact
|
Home About us Contact | ||
|
|
||
Inflammatory Pathways (inflammatory + pathway)
Selected AbstractsInflammatory pathways between placenta and foetusACTA PAEDIATRICA, Issue 1 2001Mikko Hallman Recent evidence indicates that intra-amniotic endotoxin (LPS) and interleukin-1 alpha (IL-1,) accelerate foetal lung maturity and protect from respiratory distress syndrome (RDS) more effectively than does antenatal glucocorticoid. Inflammatory cytokines promote development of chronic lung disease in the premature, acute RDS (ARDS) in children and adults. Systemic exposure to LPS or cytokines can result in generalized multiorgan damage. The abnormal host defence in the foetus and the premature newborn need to be considered in therapeutic interventions. [source] Platelet-activating factor-induced NF-,B activation and IL-8 production in intestinal epithelial cells are Bcl10-dependentINFLAMMATORY BOWEL DISEASES, Issue 4 2010Alip Borthakur PhD Abstract Background: Platelet-activating factor (PAF), a potent proinflammatory phospholipid mediator, has been implicated in inducing intestinal inflammation in diseases such as inflammatory bowel disease (IBD) and necrotizing enterocolitis (NEC). However, its mechanisms of inducing inflammatory responses are not fully understood. Therefore, studies were designed to explore the mechanisms of PAF-induced inflammatory cascade in intestinal epithelial cells. Methods: Nuclear factor kappa B (NF-,B) activation was measured by luciferase assay and enzyme-linked immunosorbent assay (ELISA), and interleukin 8 (IL-8) production was determined by ELISA. B-cell lymphoma 10 (Bcl10), caspase recruitment domain-containing membrane-associated guanylate kinase protein 3 (CARMA3), and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) mRNA and protein levels were assessed by real-time reverse-transcription polymerase chain reaction (RT-PCR) and Western blot, respectively. siRNA silencing of Bcl10 was used to examine its role in PAF-induced NF-,B activation and IL-8 production. The promoter region of the Bcl10 gene was cloned with the PCR method and promoter activity measured by luciferase assay. Results: The adaptor protein Bcl10 appeared to play an important role in the PAF-induced inflammatory pathway in human intestinal epithelial cells. Bcl10 was required for PAF-induced I,B, phosphorylation, NF-,B activation, and IL-8 production in NCM460, a cell line derived from normal human colon, and Caco-2, a transformed human intestinal cell line. PAF also stimulated Bcl10 interactions with CARMA3 and MALT1, and upregulated Bcl10 expression in these cells via transcriptional regulation. Conclusions: These findings highlight a novel PAF-induced inflammatory pathway in intestinal epithelial cells, requiring Bcl10 as a critical mediator and involving CARMA3/Bcl10/MALT1 interactions. The proinflammatory effects of PAF play prominent roles in the pathogenesis of IBD and this pathway may present important targets for intervention in chronic inflammatory diseases of the intestine. (Inflamm Bowel Dis 2009;) [source] Expression of inflammatory molecules and associations with BMI in childrenEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 5 2010George V. Z. Dedoussis Eur J Clin Invest 2010; 40 (5): 388,392 Abstract Background, Adipose tissue secrets several adipokines that have been proposed to be enrolled in many inflammatory pathways. Our aim was to investigate the adipokine expression in adipose tissue and peripheral blood mononuclear cells (PBMCs) in children. Materials and methods, Thirty-one (17 males and 14 females) healthy children aged 10·9 ± 1·8 years with a body mass index (BMI) of 19·3 ± 3·5 kg m,2 were enrolled. Adipokines (TNF-alpha, IL-6 and leptin) gene expression was quantified by real-time quantitative PCR in adipose tissue and PBMCs from the same children. Their serum levels were also measured. Results, BMI was positively correlated with leptin gene expression in adipose tissue and with leptin serum levels (, = 0·476, P = 0·006 and , = 0·576, P = 0·003 respectively). Leptin's serum levels were positively correlated with leptin gene expression in adipose tissue (, = 0·462, P = 0·02). Adipose tissue gene expression of leptin and TNF-alpha and serum leptin and TNF-alpha serum levels were positively correlated (, = 0·752, P < 0·001, , = 0·311 and P = 0·015 respectively). In PBMCs, a positive correlation between TNF-alpha and IL-6 expression was found (, = 0·526, P = 0·042). Conclusion, We demonstrated powerful correlations of adipokines gene expression in adipose tissue and PBMCs in children, underlying that these molecules share common pathways related to childhood obesity. [source] Maternal high-fat feeding primes steatohepatitis in adult mice offspring, involving mitochondrial dysfunction and altered lipogenesis gene expression,HEPATOLOGY, Issue 6 2009Kimberley D. Bruce Nonalcoholic fatty liver disease (NAFLD) describes an increasingly prevalent spectrum of liver disorders associated with obesity and metabolic syndrome. It is uncertain why steatosis occurs in some individuals, whereas nonalcoholic steatohepatitis (NASH) occurs in others. We have generated a novel mouse model to test our hypothesis: that maternal fat intake contributes to the development of NAFLD in adult offspring. Female mice were fed either a high-fat (HF) or control chow (C) diet before and during gestation and lactation. Resulting offspring were fed either a C or a HF diet after weaning, to generate four offspring groups; HF/HF, HF/C, C/HF, C/C. At 15 weeks of age, liver histology was normal in both the C/C and HF/C offspring. Kleiner scoring showed that although the C/HF offspring developed nonalcoholic fatty liver, the HF/HF offspring developed NASH. At 30 weeks, histological analysis and Kleiner scoring showed that both the HF/C and C/HF groups had NAFLD, whereas the HF/HF had a more severe form of NASH. Therefore, exposure to a HF diet in utero and during lactation contributes toward NAFLD progression. We investigated the mechanisms by which this developmental priming is mediated. At 15 weeks of age, hepatic mitochondrial electron transport chain (ETC) enzyme complex activity (I, II/III, and IV) was reduced in both groups of offspring from HF-fed mothers (HF/C and HF/HF). In addition, measurement of hepatic gene expression indicated that lipogenesis, oxidative stress, and inflammatory pathways were up-regulated in the 15-week-old HF/C and HF/HF offspring. Conclusion: Maternal fat intake contributes toward the NAFLD progression in adult offspring, which is mediated through impaired hepatic mitochondrial metabolism and up-regulated hepatic lipogenesis. (HEPATOLOGY 2009.) [source] Defining the transcriptome of accelerated and replicatively senescent keratinocytes reveals links to differentiation, interferon signaling, and Notch related pathways,JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2006Ranjan J. Perera Abstract Epidermal keratinocytes (KCs) undergo highly orchestrated morphological and molecular changes during transition from proliferative compartment into growth arrested early and late differentiation layers, prior to dying in outermost cornified layers of normal skin. Creation of stratum corneum is vital to barrier function protecting against infection. Transcriptional events in KCs regulating complex processes of differentiation and host defense required to maintain constant epidermal thickness and resistance to infection in either young or aged skin are largely unknown. Furthermore, as terminal differentiation is characterized by irreversible loss of replicative potential culminating in dead layers at the skin surface, this process may be viewed as a form of senescence. However, a complete transcriptional profile of senescent (SN) human KCs has not been previously defined to permit delineation of molecular boundaries involving differentiation and senescence. To fill this void, we utilized global transcriptional analysis of KCs maintained in vitro as either cultures of proliferating (PR) cells, early and late confluent (LC) (accelerated senescence) cultures, or KCs undergoing replicative senescence. Global gene expression profiling revealed early confluent (EC) KCs were somewhat similar to PR KCs, while prominent differences were evident when compared to LC KCs; which were also distinct from replicatively SN KCs. While confluent KCs have in common several genes regulating differentiation with replicatively SN KCs, the latter cells expressed elevated levels of genes involved in interferon signaling and inflammatory pathways. These results provide new insights into cell autonomous transcriptional-based programs operative within KCs contributing to replicative senescence, with partial sharing of genes involved in differentiation. In addition, regulation of KC senescence may involve participation of interferon signaling pathways derived from the important role of KCs in protecting skin from infection. Integrating all of the transcriptional data revealed a key role for Notch receptor mediated signaling in the confluency induced differentiation phenotype using this model system. J. Cell. Biochem. 98: 394,408, 2006. © 2006 Wiley-Liss, Inc. [source] New molecular markers of early and progressive CJD brain infectionJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2004Zhi Yun Lu Abstract Transmissible spongiform encephalopathies (TSEs), including human Creutzfeldt,Jakob disease (CJD), are caused by a related group of infectious agents that can be transmitted to many mammalian species. Because the infectious component of TSE agents has not been identified, we examined myeloid cell linked inflammatory pathways to find if they were activated early in CJD infection. We here identify a specific set of transcripts in CJD infected mouse brains that define early and later stages of progressive disease. Serum amyloid A3 and L-selectin mRNAs were elevated as early as 20 days after intracerebral inoculation. Transcripts of myeloid cell recruitment factors such as MIP-1,, MIP-1,, and MCP1, as well as IL1, and TNF, were upregulated >10 fold between 30 and 40 days, well before prion protein (PrP) abnormalities that begin only after 80 days. At later stages of symptomatic neurodegenerative disease (100,110 days), a selected set of transcripts rose by as much as 100 fold. In contrast, normal brain inoculated controls showed no similar sequential changes. In sum, rapid and simple PCR tests defined progressive stages of CJD brain infection. These markers may also facilitate early diagnosis of CJD in accessible peripheral tissues such as spleen and blood. Because some TSE strains can differentially target particular cell types such as microglia, several of these molecular changes may also distinguish specific agent strains. The many host responses to the CJD agent challenge the assumption that the immune system does not recognize TSE infections because these agents are composed only of the host's own PrP. © 2004 Wiley-Liss, Inc. [source] HIV-Tat protein induces oxidative and inflammatory pathways in brain endotheliumJOURNAL OF NEUROCHEMISTRY, Issue 1 2003Michal Toborek Abstract Impaired function of the brain vasculature might contribute to the development of HIV-associated dementia. For example, injury or dysfunction of brain microvascular endothelial cells (BMEC) can lead to the breakdown of the blood,brain barrier (BBB) and thus allow accelerated entry of the HIV-1 virus into the CNS. Mechanisms of injury to BMEC during HIV-1 infection are not fully understood, but the viral gene product Tat may be, at least in part, responsible for this effect. Tat can be released from infected perivascular macrophages in the CNS of patients with AIDS, and thus BMEC can be directly exposed to high concentrations of this protein. To study oxidative and inflammatory mechanisms associated with Tat-induced toxicity, BMEC were exposed to increasing doses of Tat1,72, and markers of oxidative stress, as well as redox-responsive transcription factors such as nuclear factor-,B (NF-,B) and activator protein-1 (AP-1), were measured. Tat1,72 treatment markedly increased cellular oxidative stress, decreased levels of intracellular glutathione and activated DNA binding activity and transactivation of NF-,B and AP-1. To determine if Tat1,72 can stimulate inflammatory responses in brain endothelium in vivo, expression of monocyte chemoattractant protein-1 (MCP-1), an NF-,B and AP-1-dependent chemokine, was studied in brain tissue in mice injected with Tat1,72 into the right hippocampus. Tat1,72 markedly elevated the MCP-1 mRNA levels in brain tissue. In addition, a double immunohistochemistry study revealed that MCP-1 protein was markedly overexpressed on brain vascular endothelium. These data indicate that Tat1,72 can induce redox-related inflammatory responses both in in vitro and in vivo environments. These changes can directly lead to disruption of the BBB. Thus, Tat can play an important role in the development of detrimental vascular changes in the brains of HIV-infected patients. [source] Protein hydrolysates from ,-conglycinin enriched soybean genotypes inhibit lipid accumulation and inflammation in vitroMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 8 2009Cristina Martinez-Villaluenga Abstract Obesity is a worldwide health concern and a well recognized predictor of premature mortality associated with a state of chronic inflammation. The objective was to evaluate the effect of soy protein hydrolysates (SPH) produced from different soybean genotypes by alcalase (SAH) or simulated gastrointestinal digestion (SGIH) on lipid accumulation in 3T3-L1 adipocytes. The anti-inflammatory effect of SPH produced by alcalase on LPS-induced macrophage RAW 264.7 cell line was also investigated. SAH (100 ,M) derived from soybean enriched in ,-conglycinin (BC) (up to 47% total protein) decreased lipid accumulation (33,37% inhibition) through downregulation of gene expression of lipoprotein lipase (LPL) and fatty acid synthase (FAS). SGIH (100 ,M) inhibited lipid accumulation to a lesser extent (8,14% inhibition) through inhibition of LPL gene expression. SAH (5 ,M) decreased the production of nitric oxide (NO) (18,35%) and prostaglandin E2 (PGE2) (47,71%) and the expression of inducible nitric oxide synthase (iNOS) (31,53%) and cycloxygenase-2 (COX-2) (30,52%). This is the first investigation showing that soy hydrolysates inhibit LPS-induced iNOS/NO and COX-2/PGE2 pathways in macrophages. Soybeans enriched in BCs can provide hydrolysates that limit fat accumulation in fat cells and inflammatory pathways in vitro and therefore warrant further studies as a healthful food. [source] Blocking leukocyte influx and function to prevent chronic lung disease of prematurityPEDIATRIC PULMONOLOGY, Issue 5 2003Richard L. Auten MD Abstract Inflammation is strongly linked to the pathogenesis of chronic lung disease of prematurity (CLD). Premature gas-breathing of ambient or supplemental oxygen in a host with relatively deficient and poorly inducible antioxidant defenses may itself be injurious, and further amplified by mechanical stretch injury in the surfactant-insufficient lung.1 Cellular injury provokes an inflammatory response. Since inflammation is often detected at birth in the lungs of newborns who later develop CLD,2 it has been an attractive strategy to abrogate inflammation, but the arsenal is limited. Glucocorticoids have been widely used but are acknowledged to be potentially harmful to neurologic and somatic development, and are not recommended outside controlled trials.3 The number that benefit is comparable to the number harmed, according to meta-analysis.4 More specific blockade of harmful inflammation could overcome this obstacle. Examination of the inflammatory pathways that initiate and propagate lung injury and subsequent abnormal development points to promising new strategies that may one day be tailored to individual patients. Pediatr Pulmonol. 2003; 35:335,341. © 2003 Wiley-Liss, Inc. [source] Regulation of insulin action by an extract of Artemisia dracunculus L. in primary human skeletal muscle culture: A proteomics approach,PHYTOTHERAPY RESEARCH, Issue 9 2010Indu Kheterpal Abstract An ethanolic extract of Artemisia dracunculus L. (PMI 5011) has been observed to decrease glucose and insulin levels in animal models and enhance cellular signaling in cultured cells. To determine the mechanism of action of PMI-5011, we have measured changes in protein expression in human primary skeletal muscle culture (HSMC) from subjects with Type 2 diabetes. After obtaining skeletal muscle biopsies, HSMCs were initiated, grown to confluence, and exposed to 10,µg/mL PMI 5011 overnight. Two-dimensional difference in-gel electrophoresis was used to separate proteins, and liquid chromatography mass spectrometry was used to identify differentially regulated proteins. Additionally, real-time polymerase chain reaction (PCR) was used to confirm candidate proteins identified. These data demonstrate that a well characterized botanical extract of Artemisia dracunculus L. significantly modulates proteins involved in regulating inflammatory pathways, particularly the NF,B complex system. Copyright © 2010 John Wiley & Sons, Ltd. [source] Age and energy intake interact to modify cell stress pathways and stroke outcomeANNALS OF NEUROLOGY, Issue 1 2010Thiruma V. Arumugam PhD Objective Age and excessive energy intake/obesity are risk factors for cerebrovascular disease, but it is not known if and how these factors affect the extent of brain damage and outcome in ischemic stroke. We therefore determined the interactions of age and energy intake on the outcome of ischemic brain injury, and elucidated the underlying mechanisms. Methods We utilized a novel microchip-based immunoaffinity capillary electrophoresis technology to measure a panel of neurotrophic factors, cytokines, and cellular stress resistance proteins in brain tissue samples from young, middle-aged, and old mice that had been maintained on control or energy-restricted diets prior to middle cerebral artery occlusion and reperfusion. Results Mortality from focal ischemic stroke was increased with advancing age and reduced by an intermittent fasting (IF) diet. Brain damage and functional impairment were reduced by IF in young and middle-aged mice, but not in old mice. The basal and poststroke levels of neurotrophic factors (brain-derived neurotrophic factor and basic fibroblast growth factor), protein chaperones (heat shock protein 70 and glucose regulated protein 78), and the antioxidant enzyme heme oxygenase-1 were decreased, whereas levels of inflammatory cytokines were increased in the cerebral cortex and striatum of old mice compared with younger mice. IF coordinately increased levels of protective proteins and decreased inflammatory cytokines in young, but not in old mice. Interpretation Reduction in dietary energy intake differentially modulates neurotrophic and inflammatory pathways to protect neurons against ischemic injury, and these beneficial effects of IF are compromised during aging, resulting in increased brain damage and poorer functional outcome. ANN NEUROL 2010;67:41,52 [source] Cryopyrin-associated periodic syndromes and autoinflammationCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 1 2008K. Shinkai Summary Autoinflammatory syndromes are a distinct class of inherited diseases of cytokine dysregulation with important cutaneous features. Several disorders, including familial cold autoinflammatory syndrome (FCAS), Muckle,Wells syndrome and neonatal onset multisystem inflammatory disorder (NOMID), are associated with mutations in a common gene, CIAS-1. These disorders are now believed to represent related conditions along a spectrum of disease severity, in which FCAS is the mildest and NOMID is the most severe phenotype. Patients typically present with lifelong atypical urticaria with systemic symptoms, with potential for developing end-organ damage due to chronic inflammation. Advances in the understanding of the genetic basis of these syndromes have also revealed cytokine signalling molecules that are critical to normal regulation of inflammatory pathways. The dramatic response of these syndromes to anakinra, an interleukin (IL)-1 antagonist, highlights the important role of IL-1 cytokine signalling in the pathogenesis of this rare but fascinating class of diseases. [source] | |||||||||||||