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PubMed2003

Nods, Nalps and Naip: intracellular regulators of bacterial-induced inflammation.

The innate immune system is the most ancestral and ubiquitous system of defence against microbial infection. The microbial sensing proteins involved in innate immunity recognize conserved and often structural components of microorganisms. One class of these pattern-recognition molecules, the Toll-like receptors (TLRs), are involved in detection of microbes in the extracellular compartment whereas a newly discovered family of proteins, the NBS-LRR proteins (for nucleotide-binding site and leucine-rich repeat), are involved in intracellular recognition of microbes and their products. NBS-LRR proteins are characterized by three structural domains: a C-terminal leucine-rich repeat (LRR) domain able to sense a microbial motif, an intermediary nucleotide binding site (NBS) essential for the oligomerization of the molecule that is necessary for the signal transduction induced by different N-terminal effector motifs, such as a pyrin domain (PYD), a caspase-activating and recruitment domain (CARD) or a baculovirus inhibitor of apoptosis protein repeat (BIR) domain. Two of these family members, Nod1 and Nod2, play a role in the regulation of pro-inflammatory pathways through NF-kappaB induced by bacterial ligands. Recently, it was shown that Nod2 recognizes a specific peptidoglycan motif from bacteria, muramyl dipeptide (MDP). A surprising number of human genetic disorders have been linked to NBS-LRR proteins. For example, mutations in Nod2, which render the molecule insensitive to MDP and unable to induce NF-kappaB activation when stimulated, are associated with susceptibility to a chronic intestinal inflammatory disorder, Crohn's disease. Conversely, mutations in the NBS region of Nod2 induce a constitutive activation of NF-kappaB and are responsible for Blau syndrome, another auto-inflammatory disease. Nalp3, which is an NBS-LRR protein with an N-terminal Pyrin domain, is also implicated in rare auto-inflammatory disorders. In conclusion, NBS-LRR molecules appear as a new family of intracellular receptors of innate immunity able to detect specific bacterial compounds and induce inflammatory response; the dysregulation of these processes due to mutations in the genes encoding these proteins is involved in numerous auto-inflammatory disorders.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Insulin resistance and chronic cardiovascular inflammatory syndrome.

Insulin resistance is increasingly recognized as a chronic, low-level, inflammatory state. Hyperinsulinemia and insulin action were initially proposed as the common preceding factors of hypertension, low high-density lipoprotein cholesterol, hypertriglyceridemia, abdominal obesity, and altered glucose tolerance, linking all these abnormalities to the development of coronary heart disease. The similarities of insulin resistance with another inflammatory state, atherosclerosis, have been described only in the last few decades. Atherosclerosis and insulin resistance share similar pathophysiological mechanisms, mainly due to the actions of the two major proinflammatory cytokines, TNF-alpha and IL-6. Genetic predisposition to increased transcription rates of these cytokines is associated with metabolic derangement and simultaneously with coronary heart disease. Dysregulation of the inflammatory axis predicts the development of insulin resistance and type 2 diabetes mellitus. The knowledge of how interactions between metabolic and inflammatory pathways occur will be useful in future therapeutic strategies. The effective administration of antiinflammatory agents in the treatment of insulin resistance and atherosclerosis is only the beginning of a promising approach in the management of these syndromes.

Animals↗

PubMed2006

Ankylosing spondylitis and bowel disease.

Between 5 and 10% of cases of ankylosing spondylitis (AS) are associated with inflammatory bowel disease (IBD), either Crohn's disease or ulcerative colitis. A much larger percentage of AS patients have subclinical gut inflammation manifested either by endoscopic findings or by histology. The association with HLA-B27 is less strong in IBD-associated AS than in idiopathic AS, and there is evidence for an association between gut inflammation in AS with the Crohn's-disease-related CARD15 mutations. Despite the different genetics, the immunopathology suggests common inflammatory pathways in gut and joint inflammation in AS, and in gut inflammation in AS and IBD. Although this observation is of interest to unravel the pathophysiology of the disease, systematic screening of AS patients by ileocolonoscopy is not indicated in the absence of gut symptomatology as only a small proportion of AS patients with subclinical gut inflammation will develop overt IBD over time. Treatment of AS associated with IBD with non-steroidal anti-inflammatory drugs (NSAIDs) is problematic because of concerns of potential re-activation of IBD by NSAIDs. Major advances have been made in recent years with the establishment of anti-tumour necrosis factor (TNF) therapy in AS, the other spondyloarthritides and IBD. Anti-TNF agents are of particular relevance to AS patients with concomitant IBD who are at risk of exacerbation of the underlying bowel disease when treated with NSAIDs. In IBD, infliximab, unlike etanercept, is effective in treating clinical symptoms, inducing and maintaining remission, and mucosal healing. Adalimumab appears to be effective in treating both AS and IBD; however, official approval is pending. Currently, infliximab is the drug of choice for the treatment of patients with active AS associated with IBD.

Colitis, Ulcerative↗

PubMed2004

Medroxyprogesterone acetate, but not progesterone, protects against inflammation-induced parturition and intrauterine fetal demise.

OBJECTIVE: This study was undertaken to determine whether progestational agents can prevent inflammation-induced preterm parturition and fetal demise. STUDY DESIGN: The activation of contractile and inflammatory pathways in response to localized intrauterine inflammation was investigated by using quantitative polymerase chain reaction (PCR). Serum progesterone (P4) levels and alterations in progesterone receptor-B (PR-B) were determined with radioimmunoassay and quantitative PCR, respectively. With our in vivo model of intrauterine inflammation, animals were randomly assigned to pretreatment with P4 or medroxyprogesterone acetate (MPA) before intrauterine lipopolysaccharide (LPS). Animals were observed for preterm delivery. The number of live pups 48 hours after intrauterine LPS was recorded for each treatment group. The ability of MPA to alter signal transduction pathways leading to preterm parturition were investigated by quantitative PCR and histochemical studies. RESULTS: Intrauterine inflammation is associated with decreased serum progesterone levels and decreased transcription of PR-B. Preterm delivery rates were 100% for LPS alone, 63% for LPS+P4, and 0% for LPS+MPA. No live pups remained at 48 hours in the LPS or LPS+P4 groups. Pretreatment with MPA significantly preserved fetal viability. MPA suppressed activation of contraction-associated genes and inflammatory mediators and prevented cervical ripening in response to intrauterine inflammation. CONCLUSION: MPA, with its progestational and anti-inflammatory properties, prevented inflammation-induced preterm parturition and significantly preserved fetal viability.

Animals↗

PubMed2007

Nicotine exposure alters in vivo human responses to endotoxin.

The alpha 7 nicotinic receptor is reportedly a key element in the cholinergic anti-inflammatory pathway. Because a prototypical ligand for this receptor is nicotine, we studied the in vivo human response to bacterial endotoxin or lipopolysaccharide (LPS) in the context of nicotine or placebo pretreatment. Twelve adult male normal subjects were studied prospectively. Six received overnight transcutaneous nicotine administration by application of a standard patch (7 mg). Six hours later, all subjects were given an intravenous dose of endotoxin (2 ng/kg) and were evaluated for an additional 24 h for circulating levels of inflammatory biomarkers, vital signs and symptoms. The nicotine subjects had elevated blood levels of the nicotine metabolite, continine, prior to and throughout the 24-h post-endotoxin exposure phase. Subjects receiving nicotine exhibited a significantly lower temperature response as well as attenuated cardiovascular responses for 2.5-6 h after LPS exposure. In addition, increased circulating interkeukin (IL)-10 and cortisol levels were also noted in nicotine subjects. These data indicate an alteration in LPS-induced systemic inflammatory responses in normal subjects exposed to transcutaneous nicotine. In this model of abbreviated inflammation, nicotine exposure attenuates the febrile response to LPS and promotes a more prominent anti-inflammatory phenotype.

Administration, Cutaneous↗

PubMed2001

Rhinovirus-induced airway inflammation in asthma: effect of treatment with inhaled corticosteroids before and during experimental infection.

Asthma exacerbations are frequently linked to rhinovirus infections. However, the associated inflammatory pathways are poorly understood, and treatment of exacerbations is often unsatisfactory. In the present study we investigated whether antiinflammatory treatment with inhaled corticosteroids prevents any rhinovirus-induced worsening of lower airway inflammation. To that end, we selected 25 atopic patients with mild asthma who underwent experimental rhinovirus 16 (RV16) infection, while receiving double-blind, placebo-controlled treatment with the inhaled corticosteroid budesonide (800 microg twice a day) throughout the study period, starting 2 wk before infection. We assessed inflammatory cell numbers in the bronchial mucosa as obtained by bronchial biopsies 2 d before and 6 d after RV16 infection, and analyzed those in relation to cold symptoms, changes in blood leukocyte counts, airway obstruction, and airway hyperresponsiveness. RV16 colds induced an increase in CD3(+) cells in the lamina propria (p = 0.03) and tended to decrease the numbers of epithelial eosinophils (p = 0.06) in both groups analyzed as a whole. The T cell accumulation was positively associated with cold symptoms. Budesonide pretreatment improved airway hyperresponsiveness (p = 0.02) and eosinophilic airways inflammation (p = 0.04). Yet it did not significantly affect the RV16-associated changes in the numbers of any of the inflammatory cell types. We conclude that RV16 infection by itself induces only subtle worsening of airway inflammation in asthma, which is not improved (or worsened) by inhaled corticosteroids. The latter finding is in keeping with the limited protection of inhaled corticosteroids against acute asthma exacerbations.

Administration, Inhalation↗

PubMed2006

Carrageenan induces interleukin-8 production through distinct Bcl10 pathway in normal human colonic epithelial cells.

Carrageenan is a high molecular weight sulfated polygalactan used to improve the texture of commercial food products. Its use increased markedly during the last half century, although carrageenan is known to induce inflammation in rheumatological models and in intestinal models of colitis. We performed studies to determine its direct effects on human intestinal cells, including normal human intestinal epithelial cells from colonic surgeries, the normal intestinal epithelial cell line NCM460, and normal rat ileal epithelial cells. Cells were treated with high molecular weight lambda-carrageenan at a concentration of 1 mug/ml for 1-96 h. IL-8, IL-8 promoter activity, total and nuclear NF-kappaB, IkappaBalpha, phospho-IkappaBalpha, and Bcl10 were assessed by immunohistochemistry, Western blot, ELISA, and cDNA microarray. Increased Bcl10, nuclear and cytoplasmic NF-kappaB, IL-8 promoter activation, and IL-8 secretion were detected following carrageenan exposure. Knockdown of Bcl10 by siRNA markedly reduced the increase in IL-8 that followed carrageenan exposure in the NCM460 cells. These results show, for the first time, that exposure of human intestinal epithelial cells to carrageenan triggers a distinct inflammatory pathway via activation of Bcl10 with NF-kappaB activation and upregulation of IL-8 secretion. Since Bcl10 contains a caspase-recruitment domain, similar to that found in NOD2/CARD15 and associated with genetic predisposition to Crohn's disease, the study findings may represent a link between genetic and environmental etiologies of inflammatory bowel disease. Because of the high use of carrageenan as a food additive in the diet, the findings may have clinical significance.

Adaptor Proteins, Signal Transducing↗

PubMed2026

Sodium Overload-Related Molecular Subtypes and a Four-Gene Prognostic Signature Predict Survival, Immune Landscape, and Therapeutic Response in Acute Myeloid Leukemia.

Sodium overload has recently emerged as a critical metabolic stressor involved in cancer progression; however, its molecular characteristics and clinical relevance in acute myeloid leukemia (AML) remain unexplored. RNA-seq data sets, clinical annotations, and mutational profiles of AML patients were annotations from The Cancer Genome Atlas and integrated with Genotype-Tissue Expression normal samples. Sodium overload-related genes (SORGs) were obtained from GeneCards. Differentially expressed SORGs (DESORGs) screened by applying the limma statistical model, followed by univariate Cox proportional hazards regression, consensus clustering, functional enrichment, immune infiltration analysis, and pathway evaluation. A prognostic signature was developed through least absolute shrinkage and selection operator regression followed by multivariate Cox modeling. The model's performance was further verified in two external GEO data sets (GSE71014 and GSE37642). Nomogram construction, subgroup analysis, tumor mutational burden (TMB) assessment, drug sensitivity prediction, transcription factor (TF) analysis, and competing endogenous RNA (ceRNA) network analyses were also performed. A total of 57 DESORGs were identified, and 2 sodium overload-related molecular subtypes exhibited distinct survival, immune infiltration, and inflammatory pathway activation. A robust four-gene signature (DOCK1, GABRE, HTR7, ACSM1) stratified patients into high- and low-risk categories with significantly different survival across training and validation cohorts. High-risk patients displayed increased immune infiltration, higher TMB, reduced sensitivity to multiple chemotherapeutic drugs, and inferior predicted response to PD-L1 blockade. TF and ceRNA networks revealed multilayered transcriptional and post-transcriptional regulation of the signature genes. This study identifies sodium overload-related molecular heterogeneity in AML and establishes a validated four-gene prognostic signature that integrates genomic, immunologic, and therapeutic features, offering potential utility for personalized risk assessment and treatment optimization.

Humans↗

PubMed2006

Titanium dioxide nanoparticles induce emphysema-like lung injury in mice.

Titanium dioxide nanoparticles (nanoTiO2) have been widely used as a photocatalyst in air and water cleaning. However, these nanoparticles inhalation can induce pulmonary toxicity and its mechanism is not fully understood. In this study we investigated the pulmonary toxicity of nanoTiO2 and its molecular pathogenesis. The adult male ICR mice were exposed to intratracheal single dose of 0.1 or 0.5 mg nanoTiO2 (19-21 nm) and lung tissues were collected at 3rd day, 1st wk, and 2nd wk for morphometric, microarray gene expression, and pathway analyses. NanoTiO2 can induce pulmonary emphysema, macrophages accumulation, extensive disruption of alveolar septa, type II pneumocyte hyperplasia, and epithelial cell apoptosis. NanoTiO2 induced differential expression of hundreds of genes include activation of pathways involved in cell cycle, apoptosis, chemokines, and complement cascades. In particular, nanoTiO2 up-regulates placenta growth factor (PlGF) and other chemokines (CXCL1, CXCL5, and CCL3) expressions that may cause pulmonary emphysema and alveolar epithelial cell apoptosis. Cultured human THP-1 cell-derived macrophages treated with nanoTiO2 in vitro also resulted in up-regulations of PlGF, CXCL1, CXCL5, and CCL3. These results indicated that nanoTiO2 can induce severe pulmonary emphysema, which may be caused by activation of PlGF and related inflammatory pathways.

Animals↗

PubMed2006

Mechanical ventilation interacts with endotoxemia to induce extrapulmonary organ dysfunction.

INTRODUCTION: Multiple organ dysfunction syndrome (MODS) is a common complication of sepsis in mechanically ventilated patients with acute respiratory distress syndrome, but the links between mechanical ventilation and MODS are unclear. Our goal was to determine whether a minimally injurious mechanical ventilation strategy synergizes with low-dose endotoxemia to induce the activation of pro-inflammatory pathways in the lungs and in the systemic circulation, resulting in distal organ dysfunction and/or injury. METHODS: We administered intraperitoneal Escherichia coli lipopolysaccharide (LPS; 1 microg/g) to C57BL/6 mice, and 14 hours later subjected the mice to 6 hours of mechanical ventilation with tidal volumes of 10 ml/kg (LPS + MV). Comparison groups received ventilation but no LPS (MV), LPS but no ventilation (LPS), or neither LPS nor ventilation (phosphate-buffered saline; PBS). RESULTS: Myeloperoxidase activity and the concentrations of the chemokines macrophage inflammatory protein-2 (MIP-2) and KC were significantly increased in the lungs of mice in the LPS + MV group, in comparison with mice in the PBS group. Interestingly, permeability changes across the alveolar epithelium and histological changes suggestive of lung injury were minimal in mice in the LPS + MV group. However, despite the minimal lung injury, the combination of mechanical ventilation and LPS resulted in chemical and histological evidence of liver and kidney injury, and this was associated with increases in the plasma concentrations of KC, MIP-2, IL-6, and TNF-alpha. CONCLUSION: Non-injurious mechanical ventilation strategies interact with endotoxemia in mice to enhance pro-inflammatory mechanisms in the lungs and promote extra-pulmonary end-organ injury, even in the absence of demonstrable acute lung injury.

Animals↗

PubMed2006

Diabetes, obesity, and hypertension may enhance associations between air pollution and markers of systemic inflammation.

Airborne particulate matter (PM) may lead to increased cardiac risk through an inflammatory pathway. Therefore, we investigated associations between ambient PM and markers of systemic inflammation among repeated measures from 44 senior citizens (>/= 60 years of age) and examined susceptibility by conditions linked to chronic inflammation. Mixed models were used to identify associations between concentrations of fine PM [aerodynamic diameter </= 2.5 microm (PM2.5)] averaged over 1-7 days and measures of C-reactive protein (CRP) , interleukin-6 (IL-6) , and white blood cells (WBCs) . Effect modification was investigated for diabetes, obesity, hypertension, and elevated mean inflammatory markers. We found positive associations between longer moving averages of PM2.5 and WBCs across all participants, with a 5.5% [95% confidence interval (CI) , 0.10 to 11%] increase per interquartile increase (5.4 microg/m3) of PM2.5 averaged over the previous week. PM2.5 and CRP also exhibited positive associations among all individuals for averages longer than 1 day, with the largest associations for persons with diabetes, obesity, and hypertension. For example, an interquartile increase in the 5-day mean PM)2.5 (6.1 microg/m3) was associated with a 14% increase in CRP (95% CI, -5.4 to 37%) for all individuals and an 81% (95% CI, 21 to 172%) increase for persons with diabetes, obesity, and hypertension. Persons with diabetes, obesity, and hypertension also exhibited positive associations between PM2.5 and IL-6. Individuals with elevated mean inflammatory markers exhibited enhanced associations with CRP, IL-6, and WBCs. We found modest positive associations between PM2.5 and indicators of systemic inflammation, with larger associations suggested for individuals with diabetes, obesity, hypertension, and elevated mean inflammatory markers.

Aged↗

PubMed2000

Update on inflammatory bowel disease genetics.

The idiopathic inflammatory bowel diseases (IBD), comprised of Crohn's disease (CD) and ulcerative colitis (UC), are related, complex genetic disorders. With the completion of the human genomic sequence, identification of genetic variants contributing to IBD susceptibility can now more systematically be identified. Significant genetic linkages have been observed on chromosomes 16, 12, 14, 19, 6, and 1, of which the linkage to CD on chromosome 16 is the most well-established. For many of the other regions, evidence for linkage has been observed for both CD and UC. Candidate gene association studies have largely focused on genes involved in inflammatory pathways, such as cytokines and cytokine receptors. With greater understanding of genetic differences underlying both disease susceptibility and response to medical therapy, the individualization of medical approaches based on this knowledge may soon be possible in patients with IBD.

Base Sequence↗

PubMed2005

Joint effect of asthma/atopy and an IL-6 gene polymorphism on lung cancer risk among lifetime non-smoking Chinese women.

Recent evidence suggests that inflammatory pathways are important mediators of carcinogenesis. Asthma, allergic rhinitis and atopic dermatitis are clinical manifestations of a systemic atopic disorder, which is associated with airway hyper-responsiveness and inflammation. We examined the effect of a history of asthma/atopy among 132 lung cancer cases (of which 72% were adenocarcinomas) and 163 controls, all of whom were non-smoking Chinese women, in combination with a single nucleotide polymorphism (-634C/G) in the interleukin-6 (IL-6) gene which regulates secretion of a pro-inflammatory cytokine found to be predominant in lung tumour tissue. We observed a slight increase in risk of lung cancer [odds ratio, OR = 1.5, 95% confidence interval (95% CI) = 0.8-2.6] and of adenocarcinoma (OR = 1.6, 95% CI = 0.9-3.1) with asthma/atopy alone. There was no effect of the IL-6 CG/GG genotype on lung cancer risk on its own. Among individuals with both asthma/atopy and the IL-6 -634 G allele, however, risk was increased at least 3-fold (OR = 3.1, 95% CI = 1.2-8.3 for all cancers and OR = 4.2, 95% CI = 1.5-11.6 for adenocarcinomas) relative to individuals with no asthma/atopy and the CC genotype. On stratified analysis, a significant increase in risk with asthma/atopy was restricted to those with the at-risk genotype (Pint < 0.05). Our findings are consistent with the role of chronic inflammation as an aetiologic factor among non-smoking Asian women, and suggest that asthma/atopy is a risk marker for susceptibility to the development of lung cancer.

Aged↗

PubMed2004

Acid suppression and chemoprevention in Barrett's oesophagus.

Barrett's oesophagus is a pre-malignant condition affecting 1% of the population in the West. Even though most patients with Barrett's will not develop oesophageal cancer, the incidence of adenocarcinoma is 0.45-1%, conferring a 40-fold increased risk compared with the general population. The risk rises to 40-50% within 5 years for those with high grade dysplasia. Currently, the only strategies available to diminish adenocarcinoma rates are surveillance endoscopy, endoscopic thermal or photodynamic ablation or tissue resection. The latter options are reserved for those who already have dysplasia. 10-50% of patients undergoing oesophagectomy for high grade dysplasia have been shown to have adenocarcinoma. Therefore approaches are needed to be that either remove or prevent stimuli propelling patients down the dysplasia-adenocarcinoma pathway. Both gastric acid and bile acids have been reported as potential insults involved in the pathogenesis of Barrett's oesophagus. This is thought to be mediated by a range of molecules including cyclo-oxygenase-2, c-myc and mitogen-activated protein kinase signalling. Proton pump inhibitors not only suppress acid but also bile reflux, although symptom control is a poor guide as to adequacy of acid suppression. There is some evidence that proton pump inhibitors cause partial regression in Barrett's oesophagus length, although the data is contradictory. Proton pump inhibitors have also been shown to increase cell differentiation and apoptosis, reduce proliferation and COX-2 levels, with the supposition that this may diminish cancer risk. However this role in decreasing cancer risk has not yet been evaluated. The use of NSAIDS and aspirin, most likely via inhibition of COX-2 and other inflammatory pathways, is associated with a reduction of adenocarcinoma rates. Both PPIs and NSAIDs/Aspirin may therefore be potential chemopreventative agents but further studies are required to appraise their use.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2026

Urban heat island and risk of rheumatoid arthritis: Insights from genetic predisposition and proteomics.

BACKGROUND: Urban heat island (UHI) exposure is an increasingly common consequence of urbanization and climate warming, but its association with rheumatoid arthritis (RA) risk remains unclear. OBJECTIVE: To investigate the association between UHI exposure and incident RA, and to further assess the roles of genetic susceptibility and plasma proteomic profiles in this association. METHODS: This study included 400,628 urban residents with UHI exposure data and free of RA at baseline. Cox proportional hazards models were used to evaluate the association between UHI exposure and incident RA. Polygenic risk scores were used to assess effect modification by genetic susceptibility. Proteomic analyses identified candidate proteins and enriched pathways underlying the association. Mendelian randomization, colocalization, and mediation analyses assessed causal relevance and mediation. RESULTS: Over a median follow-up of 14.05 years, 5397 incident RA cases were documented. Each standard-deviation increase in UHI exposure was associated with a 17% higher risk of RA. This association was more pronounced among older adults and individuals with lower socioeconomic status. An additive interaction was observed between UHI exposure and genetic risk for RA. Proteomic analyses suggested that this association may involve not only canonical immune-inflammatory pathways, but also hypoxia response and protein transport, with CD40, VCAM1, and SUGP1 emerging as potential molecular mediators. CONCLUSIONS: UHI exposure may be a modifiable environmental risk factor for RA and provide new insights into the biological mechanisms underlying this association.

Humans↗

PubMed2026

Genome-wide methylation profiling identifies signatures of pain, fatigue and health scores in women with systemic lupus erythematosus.

OBJECTIVES: People with systemic lupus erythematosus (SLE) experience high levels of pain and fatigue with poor overall health, which persist in those with low disease activity. By performing epigenome-wide DNA methylation analysis, this study aims to identify epigenetic alterations associated with self-reported scores for pain, fatigue and health in women with SLE. METHODS: Forty-eight women with SLE from the SLEGOT cohort were included. Study participants exhibited low disease activity (median SLEDAI-2K = 0) and minimal damage (median SLICC damage index = 0). An epigenome-wide DNA methylation analysis in whole blood identified 704 237 CpG loci, with 511 673 annotated to known genes. RESULTS: We identified 485, 591 and 577 differentially methylated CpGs linked to pain, fatigue and poor health, respectively. The association of reported pain with CpGs in GPR107, SPHK2, HBA1 and RERE genes suggested a potential role for neuromodulation in pain perception in SLE. For fatigue, enrichment analysis highlighted pathways related to neuronal development, morphogenesis and synaptic signalling. Nine genes, including BDNF and TGIF1, showed strong correlations with all three scores, suggesting a shared epigenetic influence that may underlie pain, fatigue and poor health in SLE. Specific microRNA genes were differentially methylated in relation to pain and fatigue. CONCLUSION: By studying a cohort of women with well-controlled SLE, we identified several CpGs and genes associated with pain, fatigue and general health. Our findings suggest that epigenetic changes in genes involved in neuronal modulation, rather than inflammatory pathways, could be involved in the development of these symptoms in patients with SLE.

Humans↗

PubMed1997

Amyloid-beta peptide-receptor for advanced glycation endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: a proinflammatory pathway in Alzheimer disease.

In Alzheimer disease (AD), neurons are thought to be subjected to the deleterious cytotoxic effects of activated microglia. We demonstrate that binding of amyloid-beta peptide (Abeta) to neuronal Receptor for Advanced Glycation Endproduct (RAGE), a cell surface receptor for Abeta, induces macrophage-colony stimulating factor (M-CSF) by an oxidant sensitive, nuclear factor kappaB-dependent pathway. AD brain shows increased neuronal expression of M-CSF in proximity to Abeta deposits, and in cerebrospinal fluid from AD patients there was approximately 5-fold increased M-CSF antigen (P < 0.01), compared with age-matched controls. M-CSF released by Abeta-stimulated neurons interacts with its cognate receptor, c-fms, on microglia, thereby triggering chemotaxis, cell proliferation, increased expression of the macrophage scavenger receptor and apolipoprotein E, and enhanced survival of microglia exposed to Abeta, consistent with pathologic findings in AD. These data delineate an inflammatory pathway triggered by engagement of Abeta on neuronal RAGE. We suggest that M-CSF, thus generated, contributes to the pathogenesis of AD, and that M-CSF in cerebrospinal fluid might provide a means for monitoring neuronal perturbation at an early stage in AD.

Alzheimer Disease↗

PubMed2005

CRP is or is not a reliable marker of ischaemic heart disease?

In recent years a growing body of evidence has emphasized the role of C-reactive protein (CRP) as a marker of future cardiovascular events. CRP is a pentameric molecule widely utilized as a marker of infections and inflammation. The evidence that inflammation plays an important role in the pathogenesis of coronary artery disease and in plaque destabilization has lead to use of CRP as a marker of cardiovascular disease as well. First described as a component of the inflammatory pathway in acute coronary syndromes, CRP has been consistently found to be associated with the risk of future events in no-ST elevation acute coronary syndromes, independently of other risk factors, including troponine. Subsequently CRP has been described as a powerful marker of risk of future events in large populations of apparently healthy subjects. So far there is very little doubt that CRP represents a reliable marker of cardiovascular events, but some issues remain unanswered such as why CRP is a good marker of cardiovascular events and whether or not a better inflammatory marker exists. It must be stressed that CRP, because of its analytical and biological properties and the large amount of available data, is the only inflammatory marker accepted for clinical use.

Biomarkers↗