Biomarker Commons

Biomarkers for systemic lupus erythematosus.

Transl Res. 2012 Apr;159(4):326-42

Authors: Ahearn JM, Liu CC, Kao AH, Manzi S

Abstract
The urgent need for lupus biomarkers was demonstrated in September 2011 during a Workshop sponsored by the Food and Drug Administration: Potential Biomarkers Predictive of Disease Flare. After 2 days of discussion and more than 2 dozen presentations from thought leaders in both industry and academia, it became apparent that highly sought biomarkers to predict lupus flare have not yet been identified. Even short of the elusive biomarker of flare, few biomarkers for systemic lupus erythematosus (SLE) diagnosis, monitoring, and stratification have been validated and employed for making clinical decisions. This lack of reliable, specific biomarkers for SLE hampers proper clinical management of patients with SLE and impedes development of new lupus therapeutics. As such, the intensity of investigation to identify lupus biomarkers is climbing a steep trajectory, lending cautious optimism that a validated panel of biomarkers for lupus diagnosis, monitoring, stratification, and prediction of flare may soon be in hand.

PMID: 22424435 [PubMed - indexed for MEDLINE]

Subject review: pancreatic ductal adenocarcinoma in the setting of mutations in the cystic fibrosis transmembrane conductance regulator gene: case report and review of the literature.

J Gastrointest Surg. 2011 Dec;15(12):2284-90

Authors: Rittenhouse DW, Talbott VA, Anklesaria Z, Brody JR, Witkiewicz AK, Yeo CJ

Abstract
BACKGROUND: Cystic fibrosis (CF) is the most commonly inherited lethal autosomal recessive genetic disease amongst Caucasians. CF results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Patients with homozygous or compound heterozygous CFTR mutations have a risk of pancreatitis, but typically do not live long enough to develop pancreatic ductal adenocarcinoma (PDA), a disease that has an average age at diagnosis of 65 years. Little is known about the risk of the development of PDA in people who are heterozygous for mutations in the CFTR gene.
PATIENTS AND METHODS: We report a case of a patient with PDA who underwent resection, who is a carrier for the W1282X nonsense mutation in the CFTR gene. The patient is of Ashkenazi Jewish ethnicity and has a family history of CF, but no family history of PDA. We reviewed the English language literature for the prevalence of PDA in CF patients (and CFTR mutations in the setting of PDA) and their significance in terms of screening, and the use of this mutation as a biomarker for an increased risk of the development of PDA.
CONCLUSION: We conclude that patients with CFTR mutations, who also have other risks for the development of PDA such as a family history of the disease, should undergo screening and be educated about their risks.

PMID: 21809164 [PubMed - indexed for MEDLINE]

Elevated N-terminal pro-brain natriuretic peptide is associated with mortality in tobacco smokers independent of airflow obstruction.

PLoS One. 2011;6(11):e27416

Authors: Stamm JA, Belloli EA, Zhang Y, Bon J, Sciurba FC, Gladwin MT

Abstract
BACKGROUND: Tobacco use is associated with an increased prevalence of cardiovascular disease. N-terminal pro-brain natiuretic peptide (NT-proBNP), a widely available biomarker that is associated with cardiovascular outcomes in other conditions, has not been investigated as a predictor of mortality in tobacco smokers. We hypothesized that NT-proBNP would be an independent prognostic marker in a cohort of well-characterized tobacco smokers without known cardiovascular disease.
METHODS: Clinical data from 796 subjects enrolled in two prospective tobacco exposed cohorts was assessed to determine factors associated with elevated NT-proBNP and the relationship of these factors and NT-proBNP with mortality.
RESULTS: Subjects were followed for a median of 562 (IQR 252-826) days. Characteristics associated with a NT-proBNP above the median (≥49 pg/mL) were increased age, female gender, and decreased body mass index. By time-to-event analysis, an NT-proBNP above the median (≥49 pg/mL) was a significant predictor of mortality (log rank p = 0.02). By proportional hazard analysis controlling for age, gender, cohort, and severity of airflow obstruction, an elevated NT-proBNP level (≥49 pg/mL) remained an independent predictor of mortality (HR = 2.19, 95% CI 1.07-4.46, p = 0.031).
CONCLUSIONS: Elevated NT-proBNP is an independent predictor of mortality in tobacco smokers without known cardiovascular disease, conferring a 2.2 fold increased risk of death. Future studies should assess the ability of this biomarker to guide further diagnostic testing and to direct specific cardiovascular risk reduction inventions that may positively impact quality of life and survival.

PMID: 22087311 [PubMed - indexed for MEDLINE]

Lewis score correlates more closely with fecal calprotectin than Capsule Endoscopy Crohn's Disease Activity Index.

Dig Dis Sci. 2012 Apr;57(4):987-93

Authors: Koulaouzidis A, Douglas S, Plevris JN

Abstract
BACKGROUND: Small-bowel capsule endoscopy (SBCE) is an invaluable imaging method for the small bowel. The Lewis score (LS) and the Capsule Endoscopy Crohn's Disease Activity Index (CECDAI) have been developed to standardize the reporting of small-bowel inflammation. Fecal calprotectin (FC) represents a highly reliable biomarker of intestinal inflammation.
AIM: To assess the performance of the two SBCE inflammation scoring systems by correlating them with FC. Furthermore, to define threshold levels for CECDAI.
METHODS: Retrospective study; patients who underwent SBCE and had FC measurement shortly before or after SBCE. LS and CECDAI were calculated by a single reviewer and correlated [Spearman's (r ( s ))] with the FC results. Linear regression analysis was used to identify threshold levels for CECDAI.
RESULTS: Forty-nine patients; three subgroups A, B and C (based on FC levels <100, 100-200, and ≥200 μg/g, respectively). LS appears to correlate with FC (r ( s ) = 0.448, p = 0.0014), unlike CECDAI, which does not demonstrate significant correlation (r ( s ) = 0.245, p = 0.089). Strongly positive correlation between FC and LS was observed in subgroup A (r ( s ) = 0.68, p = 0.0047), while in subgroups B and C, neither LS nor CECDAI showed correlation with FC. Significant correlation between LS and CECDAI was demonstrated (r ( s ) = 0. 6324, p < 0.0001). Linear regression analysis demonstrates that LS thresholds of 135 and 790 correspond with CECDAI levels of 3.8 and 5.8, respectively.
CONCLUSIONS: LS performs better than CECDAI in describing small-bowel inflammation, especially at FC levels of <100 μg/g. Furthermore, CECDAI levels of 3.8 and 5.8 seem to correspond to LS thresholds of 135 and 790, respectively.

PMID: 22057284 [PubMed - indexed for MEDLINE]

Hyperoxidized peroxiredoxins in peripheral blood mononuclear cells of asthma patients is associated with asthma severity.

Life Sci. 2012 Apr 9;90(13-14):502-8

Authors: Kwon HS, Bae YJ, Moon KA, Lee YS, Lee T, Lee KY, Kim TB, Park CS, Moon HB, Cho YS

Abstract
AIMS: Oxidative stress is involved in the pathogenesis of asthma, and peroxiredoxins (PRDX) may be critical in controlling intracellular oxidative stress. The aim of this study was to evaluate expressions of PRDX and their hyperoxidized forms in asthmatic individuals.
MAIN METHODS: The levels of expression of PRDX1, PRDX2, PRDX3, and PRDX6 and their hyperoxidized forms (PRDX-SO(3)) were measured in PBMCs from asthma patients and control subjects. In addition, cells from these subjects were treated with hydrogen peroxide (H(2)O(2)) and their intracellular concentrations of reactive oxygen species (ROS) were measured.
KEY FINDINGS: The ratios of hyperoxidized to total PRDX (PRDX-SO(3/)PRDX) in PBMCs were significantly higher in asthma patients than in normal subjects and were correlated with disease severity, with the highest ratio seen in patients with severe asthma. Furthermore, H(2)O(2) treatment of PBMCs, particularly lymphocytes, increased intracellular ROS concentrations with greater and more persistent increases observed in cells from asthmatic than from control subjects.
SIGNIFICANCE: Hyperoxidation of PRDX may serve as a biomarker of asthma severity and may predict enhanced susceptibility to oxidative stress load in PBMCs of asthmatics.

PMID: 22285837 [PubMed - indexed for MEDLINE]

Metagenomic biomarker discovery and explanation.

Genome Biol. 2011;12(6):R60

Authors: Segata N, Izard J, Waldron L, Gevers D, Miropolsky L, Garrett WS, Huttenhower C

Abstract
This study describes and validates a new method for metagenomic biomarker discovery by way of class comparison, tests of biological consistency and effect size estimation. This addresses the challenge of finding organisms, genes, or pathways that consistently explain the differences between two or more microbial communities, which is a central problem to the study of metagenomics. We extensively validate our method on several microbiomes and a convenient online interface for the method is provided at http://huttenhower.sph.harvard.edu/lefse/.

PMID: 21702898 [PubMed - indexed for MEDLINE]

[Role of microRNA in rheumatoid arthritis].

Nihon Rinsho Meneki Gakkai Kaishi. 2012;35(1):69-74

Authors: Mizoguchi F, Kohsaka H

Abstract
MicroRNAs (miRNAs) are endogenous non-coding small RNAs of approximately 22 nucleotides in length. miRNAs repress expression of target genes at the posttranscription level. Biological relevance of miRNAs have been investigated in physiological and pathological conditions, revealing their involvement in fine tuning of the biological events, such as cell proliferation, differentiation and cell death. In 2008, miR-146a and miR-155 were reported to be involved in the pathology of rheumatoid arthritis. Subsequently, expression and function of other miRNAs in rheumatoid arthritis have been reported. These reports suggest that miRNAs could be novel candidates for the therapeutic target or biomarker of rheumatoid arthritis. Further investigations are required to identify, characterize and modulate the key miRNA in the pathology of rheumatoid arthritis.

PMID: 22374446 [PubMed - indexed for MEDLINE]

HLA polymorphism among Chinese patients with chronic plaque psoriasis: subgroup analysis.

Br J Dermatol. 2012 Feb;166(2):288-97

Authors: Chiu HY, Huang PY, Jee SH, Hu CY, Chou CT, Chang YT, Hwang CY, Tsai TF

Abstract
BACKGROUND: HLA-Cw*06 has a strong influence on the clinical features and the susceptibility to psoriasis in different ethnicities. It is also used as a biomarker to predict the therapeutic efficacy of biologics, with inconsistent results. Additionally, most Asian patients with psoriasis do not carry HLA-Cw*06.
OBJECTIVES: To determine additional HLA alleles which confer susceptibility or affect the severity of psoriasis in Chinese Han individuals. In addition, the potential of using HLA to predict treatment outcomes was also investigated.
METHODS: We conducted a case-control association study in 199 Chinese patients with psoriasis and 200 unrelated healthy controls. HLA-B and HLA-C genotyping was performed and correlated with the therapeutic efficacy of the biologics, including alefacept, efalizumab, etanercept and ustekinumab. Patients with psoriasis were divided into group A (high-need patients with moderate to severe psoriasis) and B (general patients with psoriasis).
RESULTS: The frequencies of HLA-B*60, HLA-B*75, HLA-Cw*06 and HLA-Cw*10 were significantly increased in patients with psoriasis compared with the healthy controls. However, the prevalence of HLA-Cw*06 was lower in group A compared with group B (6% vs. 17%, Pc=0·04). HLA-B*46 was found to be strongly associated with group A but not with group B patients with psoriasis. HLA-Cw*01/HLA-B*46 was also identified as a risk haplotype for Chinese patients with psoriasis, compatible with the results in Thais. Significant differences in response to biologics were observed between HLA-Cw*01+ and HLA-Cw*01- individuals in the alefacept treatment group, and between HLA-B*37+ and HLA-B*37-, and HLA-B*58+ and HLA-B*58- individuals in the efalizumab treatment group.
CONCLUSIONS: In addition to HLA-Cw*06, the HLA-Cw*01/HLA-B*46 haplotype was also increased in Chinese patients with psoriasis. High-need patients with psoriasis had a lower frequency of HLA-Cw*06 but a higher prevalence of HLA-B*46 compared with general patients with psoriasis in our population.

PMID: 21985130 [PubMed - indexed for MEDLINE]

Predicting OA progression to total hip replacement: can we do better than risk factors alone using active shape modelling as an imaging biomarker?

Rheumatology (Oxford). 2012 Mar;51(3):562-70

Authors: Barr RJ, Gregory JS, Reid DM, Aspden RM, Yoshida K, Hosie G, Silman AJ, Alesci S, Macfarlane GJ

Abstract
OBJECTIVE: Previously, active shape modelling (ASM) of the proximal femur was shown to identify those individuals at highest risk of developing radiographic OA. Here we determine whether ASM predicts the need for total hip replacement (THR) independent of Kellgren-Lawrence grade (KLG) and other known risk factors.
METHODS: A retrospective cohort study of 141 subjects consulting primary care with new hip pain was conducted. Pelvic radiographs taken on recruitment were assessed for KLG, centre-edge angle, acetabular depth and femoral head migration. Clinical factors (duration of pain, use of a stick and physical function) were collected by self-completed questionnaires. ASM differences between shape mode scores at baseline for individuals who underwent THR during the 5-year follow-up (n = 27) and those whose OA did not progress radiographically (n = 75) were compared.
RESULTS: A 1 s.d. reduction in baseline ASM mode 2 score was associated with an 81% reduction in odds of THR (OR = 0.19, 95% CI 0.52, 0.70) after adjustment for KLG, radiographic and clinical factors. A similar reduction in odds of THR was associated with a 1 s.d. reduction in mode 3 (OR = 0.45, 95% CI 0.28, 0.71) and a 1 s.d. increase in mode 4 score (OR = 2.8, 95% CI 1.7, 4.7), although these associations were no longer significant after adjustment for KLG and clinical factors.
CONCLUSION: ASM of the hip joint is a reliable early biomarker of radiographic OA severity, which can improve the ability to identify patients at higher risk of rapid progression and poor outcome even when KLG and clinical risk factors are taken into account.

PMID: 22139532 [PubMed - indexed for MEDLINE]

Synovial infiltration with CD79a-positive B cells, but not other B cell lineage markers, correlates with joint destruction in rheumatoid arthritis.

J Rheumatol. 2011 Nov;38(11):2301-8

Authors: Mo YQ, Dai L, Zheng DH, Zhu LJ, Wei XN, Pessler F, Shen J, Zhang BY

Abstract
OBJECTIVE: The efficacy of B cell depletion in the treatment of patients with rheumatoid arthritis (RA) has revitalized interest in the pathogenic role(s) of B cells in RA. We evaluated the distribution of synovial B lineage cells and their correlation with histologic disease activity and joint destruction in RA.
METHODS: Synovial tissue samples were obtained by closed-needle biopsy from 69 Chinese patients with active RA, from 14 patients with osteoarthritis (OA), and from 15 with orthopedic arthropathies (OrthA) as disease controls. Serial tissue sections were stained immunohistochemically for CD79a (pro-B cell to plasma cell), CD20 (B cells), CD38 (plasma cells), CD21 (follicular dendritic cells), CD68 (macrophages), CD3 (T cells), and CD34 (endothelial cells). Densities of positive-staining cells were determined and correlated with histologic disease activity (Krenn 3-component synovitis score) and radiographic joint destruction (Sharp score).
RESULTS: Mean sublining CD79a-positive cell density was significantly higher in RA than in OA (p <0.001) or OrthA (p = 0.003). Receiver operating characteristic curve analysis showed that CD79a-positive cell density differentiated RA well from OA [area under the curve (AUC) = 0.79] or OrthA (AUC = 0.75). Spearman's rank order correlation showed significant correlations between sublining CD79a-positive cell density and the synovitis score (r = 0.714, p < 0.001), total Sharp score (r = 0.490, p < 0.001), and the erosion subscore (r = 0.545, p < 0.001), as well as the joint space narrowing subscore (r = 0.468, p = 0.001) in RA.
CONCLUSION: Synovial CD79a-positive B cells may be a helpful biomarker for histologic disease activity in RA and may be involved in the pathogenesis of joint destruction in RA.

PMID: 22002013 [PubMed - indexed for MEDLINE]

Protein modification by deamidation indicates variations in joint extracellular matrix turnover.

J Biol Chem. 2012 Feb 10;287(7):4640-51

Authors: Catterall JB, Hsueh MF, Stabler TV, McCudden CR, Bolognesi M, Zura R, Jordan JM, Renner JB, Feng S, Kraus VB

Abstract
As extracellular proteins age, they undergo and accumulate nonenzymatic post-translational modifications that cannot be repaired. We hypothesized that these could be used to systemically monitor loss of extracellular matrix due to chronic arthritic diseases such as osteoarthritis (OA). To test this, we predicted sites of deamidation in cartilage oligomeric matrix protein (COMP) and confirmed, by mass spectroscopy, the presence of deamidated (Asp(64)) and native (Asn(64)) COMP epitopes (mean 0.95% deamidated COMP (D-COMP) relative to native COMP) in cartilage. An Asp(64), D-COMP-specific ELISA was developed using a newly created monoclonal antibody 6-1A12. In a joint replacement study, serum D-COMP (p = 0.017), but not total COMP (p = 0.5), declined significantly after replacement demonstrating a joint tissue source for D-COMP. In analyses of 450 participants from the Johnston County Osteoarthritis Project controlled for age, gender, and race, D-COMP was associated with radiographic hip (p < 0.0001) but not knee (p = 0.95) OA severity. In contrast, total COMP was associated with radiographic knee (p < 0.0001) but not hip (p = 0.47) OA severity. D-COMP was higher in soluble proteins extracted from hip cartilage proximal to OA lesions compared with remote from lesions (p = 0.007) or lesional and remote OA knee (p < 0.01) cartilage. Total COMP in cartilage did not vary by joint site or proximity to the lesion. This study demonstrates the presence of D-COMP in articular cartilage and the systemic circulation, and to our knowledge, it is the first biomarker to show specificity for a particular joint site. We believe that enrichment of deamidated epitope in hip OA cartilage indicates a lesser repair response of hip OA compared with knee OA cartilage.

PMID: 22179616 [PubMed - indexed for MEDLINE]

[Research progress of C terminal propeptide of collagen type II].

Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2011 Jan;25(1):66-9

Authors: Bai L, Wang Y, Ba G

Abstract
OBJECTIVE: To review the research progress of C terminal propeptide of collagen type II (CTX-II), a osteoarthritis (OA) biomarker.
METHODS: Domestic and international literature about CTX-II was reviewed extensively and summarized.
RESULTS: CTX-II is investigated broadly and has the best performance of all currently available biomarkers. CTX-II is a truly useful biomarker for early diagnosis, prognosis, and measurement of treatment response in OA.
CONCLUSION: Single CTX-II may be not sufficient for early diagnosis and prognosis of OA, so a combination of CTX-II and other biomarkers or diagnosis methods is needed.

PMID: 21351613 [PubMed - indexed for MEDLINE]

Biomarkers in chronic obstructive pulmonary disease.

Transl Res. 2012 Apr;159(4):228-37

Authors: Rosenberg SR, Kalhan R

Abstract
Chronic obstructive pulmonary disease (COPD) is a complex disease with multiple phenotypes that cannot be identified through measurement of lung function alone. The importance of COPD risk assessment, phenotype identification, and diagnosis of exacerbation magnify the need for validated biomarkers in COPD. A large number of potential biomarkers have already been assessed and some appear promising, in particular fibrinogen, which is likely to be the first COPD biomarker presented to the Food and Drug Administration for qualification in the drug approval process. Blood fibrinogen and c-reactive protein (CRP) have been associated with the presence of COPD and, in some instances, future risk of developing COPD in targeted populations. Sputum neutrophil counts have been used preliminarily as biomarkers of favorable response to therapy in COPD, but use in clinical settings may be limited. Other potential blood biomarkers include pulmonary and activation-regulated chemokine (PARC/CCL-18) and the clara cell secretory protein 16 (CC-16). Integrative indices, such as the BODE index, provide a framework to determine prognosis, predict outcome, and may be responsive to therapeutic interventions. Computed tomography provides a means to assess phenotypes and identify the relative extents of small airways disease and emphysema, which themselves may inform prognosis and therapeutic decision making. Fibrinogen and other markers of systemic inflammation are elevated in the context of acute COPD exacerbations and may also identify those at risk of accelerated lung function decline and hospitalization. So far, no single biomarker in COPD warrants wide acceptance emphasizing the need for future investigation of biomarkers in large-scale longitudinal studies.

PMID: 22424427 [PubMed - indexed for MEDLINE]

Daily exhaled nitric oxide measurements and asthma exacerbations in children.

Allergy. 2012 Feb;67(2):265-71

Authors: van der Valk RJ, Baraldi E, Stern G, Frey U, de Jongste JC

Abstract
BACKGROUND: Fractional exhaled Nitric Oxide (FeNO) is a biomarker for eosinophilic airway inflammation and can be measured at home on a daily basis. A short-term increase in FeNO may indicate a higher risk of future asthma exacerbations.
OBJECTIVE: To assess changes in FeNO before and after asthma exacerbations compared to a stable control period.
METHODS: A post hoc analysis was performed on daily FeNO measurements over 30 weeks in children with asthma (n = 77). Moderate exacerbations were defined by an increase in symptom scores and severe exacerbations by prescription of prednisone. Individual mean and maximum FeNO, the variability of FeNO assessed by the coefficient of variation (CV), and slopes of FeNO in time were all quantified in 3-week blocks. Cross-correlation of FeNO with symptoms and autocorrelation of FeNO were assessed in relation to exacerbations and examined as predictors for exacerbations compared to reference periods using logistic regression.
RESULTS: Fractional exhaled nitric oxide could be assessed in relation to 25 moderate and 12 severe exacerbations. The CV, slope, cross-correlation, and autocorrelation of daily FeNO increased before moderate exacerbations. Increases in slope were also randomly seen in 19% of 2-week blocks of children without exacerbations. At least 3-5 FeNO measurements in the 3 weeks before an exacerbation were needed to calculate a slope that could predict moderate exacerbations. No specific pattern of FeNO was seen before severe exacerbations.
CONCLUSION: Fractional exhaled nitric oxide monitoring revealed changes in FeNO prior to moderate exacerbations. Whether this can be used to prevent loss of asthma control should be further explored.

PMID: 21999328 [PubMed - indexed for MEDLINE]

Recipe for a new imaging biomarker: carefully combine target, reagent, and technology.

Kidney Int. 2012 Jan;81(2):129-31

Authors: Kobayashi H, Choyke PL

Abstract
A careful combination of biological targeting moieties (C3 fragments), imaging reagents (a small particle of iron oxide), and appropriate technology (T2-weighted magnetic resonance imaging) is the key to the successful development of an imaging agent for glomerulonephritis. This recipe applies to virtually any molecular imaging probe for the kidney and throughout the body. However, each organ and disease requires a unique combination of these three components in order to achieve success.

PMID: 22205431 [PubMed - indexed for MEDLINE]

Detection of glomerular complement C3 fragments by magnetic resonance imaging in murine lupus nephritis.

Kidney Int. 2012 Jan;81(2):152-9

Authors: Sargsyan SA, Serkova NJ, Renner B, Hasebroock KM, Larsen B, Stoldt C, McFann K, Pickering MC, Thurman JM

Abstract
One of the challenges of treating patients with glomerulonephritis is to accurately assess disease activity. As renal biopsies are routinely stained for deposits of C3 activation fragments and glomerular C3 deposits are found in most forms of glomerulonephritis, we sought to determine whether a relatively noninvasive measure of C3 fragment deposition in the kidney can serve as a good biomarker of disease onset and severity. We recently developed a magnetic resonance imaging (MRI)-based method of detecting glomerular C3 and used this to track the progression of renal disease in the MRL/lpr mouse model of lupus nephritis using superparamagnetic iron oxide nanoparticles conjugated to complement receptor type 2 as a targeting agent. Quantitative immunofluorescence showed that glomerular C3b/iC3b/C3d deposition progressively increased with disease activity, a finding replicated by the T2-weighted MRI. The T2 relaxation times decreased with disease activity in the cortex and medulla of the MRL/lpr but not in MRL/Mpj control mice. Thus, MRI contrast agents targeted to glomerular C3 fragments can be used to noninvasively monitor disease activity in glomerulonephritis. As therapeutic complement inhibitors are used in patients with renal disease, this method, should it become feasible in humans, may identify those likely to benefit from complement inhibition.

PMID: 21956190 [PubMed - indexed for MEDLINE]

Serum levels of soluble receptor for advanced glycation endproducts (sRAGE) are higher in ulcerative colitis and correlate with disease activity.

J Crohns Colitis. 2011 Oct;5(5):402-6

Authors: Yilmaz Y, Yonal O, Eren F, Atug O, Hamzaoglu HO

Abstract
UNLABELLED: Interaction of the receptor for advanced glycation endproducts (RAGE) with its ligands results in expression of inflammatory mediators, activation of NF-κB, and induction of oxidative stress, all of which have been implicated in the pathogenesis of inflammatory bowel diseases (IBD). Soluble receptor for advanced glycation endproducts (sRAGE) has recently emerged as a reliable biomarker of inflammation in numerous RAGE-mediated disorders.
OBJECTIVE: To assess sRAGE levels in adult patients with IBD.
METHOD: Serum was collected from adult patients with Crohn's disease (CD, 56 patients), ulcerative colitis (UC, 60 patients), and healthy controls (HC, 113 subjects). Levels of sRAGE were determined by enzyme-linked immunosorbent assay.
RESULTS: Serum sRAGE levels were elevated in IBD compared to HC and were higher in UC patients compared to CD and HC. Levels of sRAGE were significantly higher in the serum of UC patients with active disease compared to patients with inactive disease, but no association with the Montreal Classification was evident. Serum sRAGE was lower in CD patients with biological therapies.
CONCLUSIONS: These findings suggest that serum levels of sRAGE are altered in patients with intestinal inflammation and may reflect distinct immunoinflammatory pathogenesis of UC and CD.

PMID: 21939913 [PubMed - indexed for MEDLINE]

Self-assembled micellar formulation of chafuroside A with improved anti-inflammatory effects in experimental asthma/COPD-model rats.

Eur J Pharm Sci. 2012 Jan 23;45(1-2):184-9

Authors: Onoue S, Matsui T, Aoki Y, Ishida H, Nukaya H, Kou K, Yamada S

Abstract
Chafuroside A (CFA), a poorly water-soluble flavone C-glycoside, was firstly isolated from oolong tea, and it acts as a potent anti-inflammatory agent. The present study was undertaken to develop a water-soluble formulation of CFA using a self-assembled micellar (SAM) system, with the aim of improved dissolution behavior and potent anti-inflammatory effects. The SAM formulation of CFA (CFA/SAM) was characterized in terms of its morphology, particle size distribution, crystallinity, and dissolution behavior. In dissolution testing, the CFA/SAM exhibited marked improvement in dissolution behavior when compared with crystalline CFA, and then, nano-micellar particles were constituted with a mean diameter of 84 nm. The therapeutic potential of the crystalline CFA and CFA/SAM was assessed using an experimental asthma/chronic obstructive pulmonary disease (COPD)-like model. Orally-administered CFA at 0.5mg/kg or higher could attenuate inflammatory symptoms in a dose-dependent manner, as evidenced by decreases of infiltrated granulocytes, including macrophages and neutrophils, and myeloperoxidase, a specific biomarker for neutrophilia. Biomarker profiling demonstrated that the CFA/SAM at 0.1mg CFA/kg was equipotent to CFA at 1.0mg/kg in ameliorating antigen-induced airway inflammation, suggesting the better pharmacological effect of CFA/SAM due to improved dissolution behavior. From these observations, the SAM formulation might be an efficacious approach for enhancing the therapeutic potential of CFA for treatment of inflammatory diseases.

PMID: 22108345 [PubMed - indexed for MEDLINE]

Self-assembled micellar formulation of chafuroside A with improved anti-inflammatory effects in experimental asthma/COPD-model rats.

Eur J Pharm Sci. 2012 Jan 23;45(1-2):184-9

Authors: Onoue S, Matsui T, Aoki Y, Ishida H, Nukaya H, Kou K, Yamada S

Abstract
Chafuroside A (CFA), a poorly water-soluble flavone C-glycoside, was firstly isolated from oolong tea, and it acts as a potent anti-inflammatory agent. The present study was undertaken to develop a water-soluble formulation of CFA using a self-assembled micellar (SAM) system, with the aim of improved dissolution behavior and potent anti-inflammatory effects. The SAM formulation of CFA (CFA/SAM) was characterized in terms of its morphology, particle size distribution, crystallinity, and dissolution behavior. In dissolution testing, the CFA/SAM exhibited marked improvement in dissolution behavior when compared with crystalline CFA, and then, nano-micellar particles were constituted with a mean diameter of 84 nm. The therapeutic potential of the crystalline CFA and CFA/SAM was assessed using an experimental asthma/chronic obstructive pulmonary disease (COPD)-like model. Orally-administered CFA at 0.5mg/kg or higher could attenuate inflammatory symptoms in a dose-dependent manner, as evidenced by decreases of infiltrated granulocytes, including macrophages and neutrophils, and myeloperoxidase, a specific biomarker for neutrophilia. Biomarker profiling demonstrated that the CFA/SAM at 0.1mg CFA/kg was equipotent to CFA at 1.0mg/kg in ameliorating antigen-induced airway inflammation, suggesting the better pharmacological effect of CFA/SAM due to improved dissolution behavior. From these observations, the SAM formulation might be an efficacious approach for enhancing the therapeutic potential of CFA for treatment of inflammatory diseases.

PMID: 22108345 [PubMed - indexed for MEDLINE]

Increased microRNA-146a/b, TRAF6 gene and decreased IRAK1 gene expressions in the peripheral mononuclear cells of patients with Sjögren's syndrome.

Immunol Lett. 2012 Jan 30;141(2):165-8

Authors: Zilahi E, Tarr T, Papp G, Griger Z, Sipka S, Zeher M

Abstract
MicroRNA-146a (miR-146a) is a microRNA supposed to regulate innate immune, inflammatory response and antiviral pathway negatively. Recently, its potential use as a biomarker for disease diagnosis, prevention and treatment has become widely investigated. In the current study, we measured the expression of miR-146a/b, and their target genes, IRAK1, IRAK4, TRAF6 in the peripheral mononuclear cells of patients with Sjögren's syndrome (n=21) and healthy controls (n=10) by quantitative reverse transcription polymerase chain reaction. We found that both miR-146a and miR-146b, furthermore, the gene of TRAF6 were significantly overexpressed in the Sjögren's patients, whereas the expression of IRAK1 gene was significantly decreased. The expression of IRAK4 did not differ significantly. These results suggest that in the peripheral mononuclear cells of Sjögren's patients, the transcriptional repression of IRAK1 is taking place, whereas the other NF-κB pathway regulating gene, TRAF6 is overexpressed. As IRAK1 has been regarded a crucial gene in the pathogenesis of systemic lupus erythematosus, TRAF6 can be a Sjögren's syndrome specific biomarker, confirming and partly explaining the existance of different pathogenic pathways in the two diseases. These observations, however, need still wider confirmations.

PMID: 22033216 [PubMed - indexed for MEDLINE]