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ID PMID Title PublicationDate abstract
26615094 The Special Relationship in the Development and Function of T Helper 17 and Regulatory T C 2015 T helper 17 (Th17) cells play an essential role in the clearance of extracellular pathogenic bacteria and fungi. However, this subset is critically involved in the pathology of many autoimmune diseases, e.g., psoriasis, multiple sclerosis, allergy, rheumatoid arthritis, and inflammatory bowel diseases in humans. Therefore, Th17 responses need to be tightly regulated in vivo to mediate effective host defenses against pathogens without causing excessive host tissue damage. Foxp3(+) regulatory T (Treg) cells play an important role in maintaining peripheral tolerance to self-antigens and in counteracting the inflammatory activity of effector T helper cell subsets. Although Th17 and Treg cells represent two CD4(+) T cell subsets with opposing principal functions, these cell types are functionally connected. In this review, we will first give an overview on the biology of Th17 cells and describe their development and in vivo function, followed by an account on the special developmental relationship between Th17 and Treg cells. We will describe the identification of Treg/Th17 intermediates and consider their lineage stability and function in vivo. Finally, we will discuss how Treg cells may regulate the Th17 cell response in the context of infection and inflammation, and elude on findings demonstrating that Treg cells can also have a prominent function in promoting the differentiation of Th17 cells.
26569115 Diagnostic Magnetic Resonance Imaging of Atherosclerosis in Apolipoprotein E Knockout Mous 2015 Cardiovascular disease is the leading cause of death in Western cultures. The vast majority of cardiovascular events, including stroke and myocardial infarction, result from the rupture of vulnerable atherosclerotic plaques, which are characterized by high and active macrophage content. Current imaging modalities including magnetic resonance imaging (MRI) aim to characterize anatomic and structural features of plaques rather than their content. Previously, we reported that macrophage-targeted delivery of gadolinium (Gd)-based contrast agent (GBCA-HDL) using high density lipoproteins (HDL)-like particles significantly enhances the detection of plaques in an apolipoprotein (apo) E knockout (KO) mouse model, with an atherosclerotic wall/muscle normalized enhancement ratio (NER) of 120% achieved. These particles are comprised of lipids and synthetic peptide fragments of the major protein of HDL, apo A-I, that contain a naturally occurring modification which targets the particles to macrophages. Targeted delivery minimizes the Gd dose and thus reduces the adverse effects of Gd. The aims of the current study were to test whether varying the GBCA-HDL particle shape and composition can further enhance atherosclerotic plaque MRI and control organ clearance of these agents. We show that the optimized GBCA-HDL particles are efficiently delivered intracellularly to and uptaken by both J774 macrophages in vitro and more importantly, by intraplaque macrophages in vivo, as evidenced by NER up to 160% and higher. This suggests high diagnostic power of our GBCA-HDL particles in the detection of vulnerable atherosclerotic plaques. Further, in contrast to discoidal, spherical GBCA-HDL exhibit hepatic clearance, which could further diminish adverse renal effects of Gd. Finally, activated macrophages are reliable indicators of any inflamed tissues and are implicated in other areas of unmet clinical need such as rheumatoid arthritis, sepsis and cancer, suggesting the expanded diagnostic and prognostic use of this method.
26212856 Immunogenetics of systemic sclerosis: Defining heritability, functional variants and share 2015 Nov Systemic sclerosis (SSc) is a clinically heterogeneous connective tissue disorder of complex etiology. The development of large-scale genetic studies, such as genome-wide association studies (GWASs) or the Immunochip platform, has achieved remarkable progress in the knowledge of the genetic background of SSc. Herein, we provide an updated picture SSc genetic factors, offering an insight into their role in pathogenic mechanisms that characterize the disease. We review the most recent findings in the HLA region and the well-established non-HLA loci. Up to 18 non-HLA risk factors fulfilled the selected criteria and they were classified according to their role in the innate or adaptive immune response, in apoptosis, autophagy or fibrosis. Additionally, SSc heritability has remained as a controversial question since twin studies provided low SSc heritability estimates. However, we have recalculated the lower bond of narrow sense SSc heritability using GWAS data. Remarkably, our results suggest a greater influence of genetics on SSc than previously reported. Furthermore, we also offer a functional classification of SSc-associated SNPs and their proxies, based on annotated data, to provide clues for the identification of causal variants in these loci. Finally, we explore the genetic overlap between SSc and other autoimmune diseases (ADs). The vast majority of SSc risk loci are shared with at least one additional AD, being the overlap between SSc and systemic lupus erythematous the largest. Nevertheless, we found that an important portion of SSc risk factors are also common to rheumatoid arthritis or primary biliary cirrhosis. Considering all these evidences, we are confident that future research will be successful in understanding the relevant altered pathways in SSc and in identifying new biomarkers and therapeutic targets for the disease.
25888527 Phylogeny and evolution of plant macrophage migration inhibitory factor/D-dopachrome tauto 2015 Apr 14 BACKGROUND: The human (Homo sapiens) chemokine-like protein macrophage migration inhibitory factor (HsMIF) is a pivotal mediator of inflammatory, infectious and immune diseases including septic shock, colitis, malaria, rheumatoid arthritis, and atherosclerosis, as well as tumorigenesis. HsMIF has been found to exhibit several sequential and three-dimensional sequence motifs that in addition to its receptor binding sites include catalytic sites for oxidoreductase and tautomerase activity, which provide this 12.5 kDa protein with a remarkable functional complexity. A human MIF paralog, D-dopachrome tautomerase (HsDDT), has been identified, but its physiological relevance is incompletely understood. MIF/DDT-like proteins have been described in animals, protists and bacteria. Although based on sequence data banks the presence of MIF/DDT-like proteins has also been recognized in the model plant species Arabidopsis thaliana, details on these plant proteins have not been reported. RESULTS: To broaden the understanding of the biological role of these proteins across kingdoms we performed a comprehensive in silico analysis of plant MIF/DDT-like (MDL) genes/proteins. We found that the A. thaliana genome harbors three MDL genes, of which two are chiefly constitutively expressed in aerial plant organs, while the third gene shows stress-inducible transcript accumulation. The product of the latter gene likely localizes to peroxisomes. Structure prediction suggests that all three Arabidopsis proteins resemble the secondary and tertiary structure of human MIF. MIF-like proteins are found in all species across the plant kingdom, with an increasing family complexity towards evolutionarily advanced plant taxa. Plant MDL proteins are predicted to lack oxidoreductase activity, but possibly share tautomerase activity with human MIF/DDT. CONCLUSIONS: Peroxisome localization seems to be a specific feature of a subset of MIF/DDT orthologs found in dicotyledonous plant species, which together with its stress-inducible gene expression might point to convergent evolution in higher plants and vertebrates towards neofunctionalization of MIF/MDL proteins in stress response pathways including innate immunity.
25785145 Genetic polymorphisms of interleukin-16 are associated with susceptibility to primary knee 2015 Interleukin-16 (IL-16) polymorphisms have been associated with various disease states, and its activity is dysregulated in synovial fibroblasts of individuals with rheumatoid arthritis. Here, the association between genetic polymorphisms in the gene encoding IL-16 and susceptibility to primary knee osteoarthritis was investigated in the Chinese Han population. The study included 228 unrelated patients, half of whom presented with primary knee osteoarthritis (OA); the remainder was healthy individuals. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to examine single nucleotide polymorphisms (SNPs) in IL16 in these patients. Statistical analysis was performed using the chi-square goodness-of-fit test, Hardy-Weinberg (H-W) equilibrium, linkage disequilibrium analysis, and logistic regression analysis. The genotype distributions of three IL16 SNPs, rs11556218, rs4778889, and rs4072111, were found to be in line with Hardy-Weinberg equilibrium criteria (P > 0.05). The single-factor logistic regression analysis showed that, compared with the T/T genotype, the T/G genotype decreased the risk of primary knee OA in rs11556218 (OR = 0.37, 95% CI = 0.18~0.82) and, compared with the C/C genotype, the C/T genotype increased the risk of primary knee OA in rs4072111 (OR = 1.83, 95% CI = 1.07~3.59). There was linkage disequilibrium between rs4778889 and rs11556218 (D= 0.592, r(2) = 0.213). Finally, logistic regression analysis showed that compared to haplotype TTC, the TTT haplotype was associated with an increased risk of primary knee OA (OR = 2.10, 95% CI = 1.09-4.98); however, the GCC haplotype was associated with a reduced risk of primary knee OA (OR = 0.36, 95% CI = 0.12-0.93). Thus, the genetic polymorphisms rs11556218, rs4778889, and rs4072111 in the gene encoding IL-16 are associated with primary knee OA in Chinese Han population.
25582999 [High resolution peripheral quantitative computed tomography for the assessment of morphol 2015 Jul High resolution peripheral quantitative computed tomography (HR-pQCT) is a new technology commercially available for less than 10 years that allows performing in vivo assessment of bone parameters. HR-pQCT assesses the trabecular thickness, trabecular separation, trabecular number and connectivity density and, in addition, cortical bone density and thickness and total bone volume and density in high-definition mode, which additionally allows obtaining digital constructs of bone microarchitecture. The application of mathematics to captured data, a method called finite element analysis (FEA), allows the estimation of the physical properties of the tissue, simulating supported loads in a non-invasive way. Thus, HR-pQCT simultaneously acquires data previously provided separately by dual energy x-ray absorptiometry (DXA), magnetic resonance imaging and histomorphometry, aggregating biomechanical estimates previously only possible in extracted tissues. This method has a satisfactory reproducibility, with coefficients of variation rarely exceeding 3%. Regarding accuracy, the method shows a fair to good agreement (r(2) = 0.37-0.97). The main clinical application of this method is in the quantification and monitoring of metabolic bone disorders, more fully evaluating bone strength and fracture risk. In rheumatoid arthritis patients, this allows gauging the number and size of erosions and cysts, in addition to joint space. In osteoarthritis, it is possible to characterize the bone marrow edema-like areas that show a correlation with cartilage breakdown. Given its high cost, HR-pQCT is still a research tool, but the high resolution and efficiency of this method reveal advantages over the methods currently used for bone assessment, with a potential to become an important tool in clinical practice.
25550360 Antioxidant vitamin intake and mortality: the Leisure World Cohort Study. 2015 Jan 15 To assess the relationship between antioxidant vitamin intake and all-cause mortality in older adults, we examined these associations using data from the Leisure World Cohort Study, a prospective study of residents of the Leisure World retirement community in Laguna Hills, California. In the early 1980s, participants (who were aged 44-101 years) completed a postal survey, which included details on use of vitamin supplements and dietary intake of foods containing vitamins A and C. Age-adjusted and multivariate-adjusted (for factors related to mortality in this cohort—smoking, alcohol intake, caffeine consumption, exercise, body mass index, and histories of hypertension, angina, heart attack, stroke, diabetes, rheumatoid arthritis, and cancer) hazard ratios for death were calculated using Cox regression for 8,640 women and 4,983 men (median age at entry, 74 years). During follow-up (1981-2013), 13,104 participants died (median age at death, 88 years). Neither dietary nor supplemental intake of vitamin A or vitamin C nor supplemental intake of vitamin E was significantly associated with mortality after multivariate adjustment. A compendium that summarizes previous findings of cohort studies evaluating vitamin intake and mortality is provided. Attenuation in the observed associations between mortality and antioxidant vitamin use after adjustment for confounders in our study and in previous studies suggests that such consumption identifies persons with other mortality-associated lifestyle and health risk factors.
26202855 Methotrexate inhibits osteoclastogenesis by decreasing RANKL-induced calcium influx into o 2016 Sep The increasing number of osteoporosis patients is a pressing issue worldwide. Osteoporosis frequently causes fragility fractures, limiting activities of daily life and increasing mortality. Many osteoporosis patients take numerous medicines due to other health issues; thus, it would be preferable if a single medicine could ameliorate osteoporosis and other conditions. Here, we screened 96 randomly selected drugs targeting various diseases for their ability to inhibit differentiation of osteoclasts, which play a pivotal role in development of osteoporosis, and identified methotrexate (MTX), as a potential inhibitor. MTX is currently used to treat sarcomas or leukemic malignancies or auto-inflammatory diseases such as rheumatoid arthritis (RA) through its anti-proliferative and immunosuppressive activities; however, a direct effect on osteoclast differentiation has not been shown. Here, we report that osteoclast formation and expression of osteoclastic genes such as NFATc1 and DC-STAMP, which are induced by the cytokine RANKL, are significantly inhibited by MTX. We found that RANKL-dependent calcium (Ca) influx into osteoclast progenitors was significantly inhibited by MTX. RA patients often develop osteoporosis, and osteoclasts are reportedly required for joint destruction; thus, MTX treatment could have a beneficial effect on RA patients exhibiting high osteoclast activity by preventing both osteoporosis and joint destruction.
25612566 Infliximab drug and antibody levels in patients with dermatological conditions. 2015 Apr BACKGROUND: In recent years, studies monitoring infliximab in rheumatoid arthritis and inflammatory bowel disease have confirmed the relationship between the clinical response and the infliximab and anti-infliximab antibodies serum levels. However, there is only limited evidence in the field of dermatology. OBJECTIVE: The aim of this study was to establish the correlation between plasma infliximab levels, the presence of anti-infliximab antibodies and the clinical response in dermatological conditions. SETTING: Retrospective observational study in a tertiary hospital (University Hospital of La Coruña, Spain). METHOD: Patients with dermatological conditions being treated with infliximab (5 mg/kg/8 weeks after the induction dose) were included in the study. The concentrations of infliximab and anti-infliximab antibodies were quantified by two sandwich-type ELISA immunoassays. The patients were classified into three groups based on the efficacy: good, partial or non-efficacy at the time of each blood assessment. The development of adverse reactions was also evaluated. MAIN OUTCOME MEASURES: Plasma levels of infliximab and anti-infliximab antibodies, clinical response and infusion reactions. RESULTS: 17 patients (45 assessments) were included. The good/partial efficacy rate was significantly higher in the case of >0.05 than <0.05 μg/mL infliximab concentration (93.3 vs. 40.0 %, p < 0.001). Anti-infliximab antibodies were only detected in five samples. Their presence was associated with a higher frequency of infusion reactions and a lower efficacy rate in comparison with the group without antiinfliximab antibodies (100.0 vs. 0.0 %, p < 0.001 and 0.0 vs. 85.0 %, p < 0.001 respectively). CONCLUSIONS: The results obtained show that the presence of infliximab concentrations higher than 0.05 μg/mL are correlated with a good clinical response and the absence of toxicity. The incidence of anti-infliximab antibodies is low, although a correlation was observed between the presence of antibodies, absence of infliximab concentration, loss of clinical response and the development of infusion reactions.
25576661 Epigenetic control of autoimmune diseases: from bench to bedside. 2015 Mar Genome-wide association studies have revealed several genes predisposing to autoimmunity, however, concordance rates in monozygotic twins are significantly below 50% for several autoimmune diseases. The limited presence of a strong genetic association only in some patients supports that other non-genetic mechanisms are active in these pathologies. Epigenetic modifications such as DNA methylation, histone modification, and microRNA signaling regulate gene expression and are sensitive to external stimuli and they might be as bridging between genetic and environmental factors. Some evidence has highlighted the involvement of epigenetic alterations in the pathogenesis of various autoimmune diseases giving rise to great expectations among clinicians and researchers. The direct role of these alterations in the initiation/progression of autoimmune diseases is still unclear. The knowledge in depth of these pathogenic and epigenetic mechanisms will increase the possibility of the control and/or prevention of autoimmune diseases through the use of drugs that target epigenetic pathways. Moreover, we could use epigenetic-related biomarkers to follow this complicated framework (for example H3K4me3 and miRNA-155 are among those proposed biomarkers). This article reviews current understanding of the epigenetic involvement in the field of autoimmune diseases especially in systemic lupus erythematosus, rheumatoid arthritis, sclerosis multiple and type 1 diabetes.
25482338 Buccal mucosal delivery of a potent peptide leads to therapeutically-relevant plasma conce 2015 Feb 10 Stichodactyla helianthus neurotoxin (ShK) is an immunomodulatory peptide currently under development for the treatment of autoimmune diseases, including multiple sclerosis and rheumatoid arthritis by parenteral administration. To overcome the low patient compliance of conventional self-injections, we have investigated the potential of the buccal mucosa as an alternative delivery route for ShK both in vitro and in vivo. After application of fluorescent 5-Fam-ShK to untreated porcine buccal mucosa, there was no detectable peptide in the receptor chamber using an in vitro Ussing chamber model. However, the addition of the surfactants sodium taurodeoxycholate hydrate or cetrimide, and formulation of ShK in a chitosan mucoadhesive gel, led to 0.05-0.13% and 1.1% of the applied dose, respectively, appearing in the receptor chamber over 5h. Moreover, confocal microscopic studies demonstrated significantly enhanced buccal mucosal retention of the peptide (measured by mucosal fluorescence associated with 5-Fam-ShK) when enhancement strategies were employed. Administration of 5-Fam-ShK to mice (10mg/kg in a mucoadhesive chitosan-based gel (3%, w/v) with or without cetrimide (5%, w/w)) resulted in average plasma concentrations of 2.6-16.2nM between 2 and 6h, which were substantially higher than the pM concentrations required for therapeutic activity. This study demonstrated that the buccal mucosa is a promising administration route for the systemic delivery of ShK for the treatment of autoimmune diseases.
25402257 The use of natural language processing of infusion notes to identify outpatient infusions. 2015 Jan PURPOSE: Outpatient infusions are commonly missing in Veterans Health Affairs (VHA) pharmacy dispensing data sets. Currently, Healthcare Common Procedure Coding System (HCPCS) codes are used to identify outpatient infusions, but concerns exist if they correctly capture all infusions and infusion-related data such as dose and date of administration. We developed natural language processing (NLP) software to extract infusion information from medical text infusion notes. The objective was to compare the sensitivity of three approaches to identify infliximab administration dates and infusion doses against a reference standard established from the Veterans Affairs rheumatoid arthritis (VARA) registry. METHODS: We compared the sensitivity and positive predictive value (PPV) of NLP to that of HCPCS codes in identifying the correct date and dose of infliximab infusions against a human extracted reference standard. RESULTS: The sensitivity was 0.606 (0.585-0.627) for HCPCS alone, 0.858 (0.842-0.873) for NLP alone, and 0.923 (0.911-0.934) for the two methods combined, with a PPV of 0.735 (0.716-0.754), 0.976 (0.969-0.983), and 0.957 (0.948-0.965) for each method, respectively. The mean dose of infliximab was 433 mg in the reference standard, 337 mg from HCPCS, 434 mg from NLP, and 426 mg from the combined method. CONCLUSIONS: HCPCS codes alone are not sufficient to accurately identify infliximab infusion dates and doses in the VHA system. The use of NLP significantly improved the sensitivity and PPV for estimating infusion dates and doses, especially when combined with HCPCS codes.
25002114 Predictors of in-hospital mortality in coronary artery dissection: Findings from the Natio 2015 BACKGROUND: The pathophysiology of coronary artery dissection (CD) remains poorly under-stood and little is known about the factors predicting mortality in these patients. We aimed to study the epidemiology of CD and predictors of mortality in these patients. METHODS: All patients diagnosed with CD in the Nationwide Inpatient Sample 2009-2010 database using International Classification of Diseases ninth revision 414.12 were included in the study. Chronic conditions included in the analysis were diabetes mellitus, hypertension, hyperlipidemia, coronary artery disease (CAD), obesity, alcohol use, smoking, heart failure and ventricular arrhythmias. Non-cardiovascular conditions were connective tissue disorders, fibromuscular dysplasia, Ehlers-Danlos syndrome, Marfan's syndrome, sarcoidosis, Crohn's disease, polycystic kidney disease, rheumatoid arthritis, vasculitis including giant cell arteritis, polyarteritis nodosa and Takayasu's disease, cocaine use, early or premature labor. RESULTS: The prevalence of CD in the United States was 0.02% (n = 11,255), based on the hospital admissions reviewed in the database. The mean age was 63.25 years with women (64.62 years) being older than men (62.25 years) (p < 0.001). In-hospital mortality rate was 4.2%, with women (5.5%) having higher mortality than men (3.2%) (p = 0.009). Ventricular arrhythmias (OR 5.86, p < 0.001) predicted higher mortality, while hyperlipidemia (OR 0.26, p < 0.001) and CAD (OR 0.31, p = 0.001) predicted lower mortality in multivariate analysis. CONCLUSIONS: Our study demonstrated that CD was more prevalent in men but women had higher mortality than men. Age, heart failure and ventricular arrhythmias were independent predictors of increased mortality but hyperlipidemia CAD predicted lower mortality in patients with CD.
27917700 Posterior reversible encephalopathy syndrome following elevated mean arterial pressures fo 2018 Jan BACKGROUND: Increasing the mean arterial pressure (MAP) is an accepted treatment modality to minimize the risk for irreversible neurologic damage secondary to spinal cord ischemia. Posterior reversible encephalopathy syndrome (PRES) is a rare complication occurring after transplantation surgery, in persons having an autoimmune disorder or after abrupt increases in blood pressure of various etiologies. STUDY DESIGN: Case report. METHODS: Retrospective evaluation of medical records. RESULTS: A 68-year-old female with long-standing diabetes, and rheumatoid arthritis (treated with methotrexate) presented with bilateral upper extremity weakness and numbness developing several days after a motor vehicle accident. Physical examination confirmed decreased upper extremity motor strength and decreased sensation to light touch and pinprick in the C5-C6 dermatomal distribution. Magnetic resonance imaging (MRI) demonstrated C5-C6 subluxation with spinal cord compression. The patient had traction applied and mean arterial pressures were elevated greater than 85 mmg. The following day the patient underwent anterior and posterior cervical spine fusion and decompression. Immediately post-operatively, the patient developed status epilepticus. Head MRI revealed areas of high T2 signal intensity in the bilateral occipital lobes, consistent with a diagnosis of PRES. Two weeks later, the patient had resolution of her symptoms and resolution of PRES on imaging. CONCLUSION: This is the first report of posterior reversible encephalopathy syndrome secondary to therapeutic blood pressure increase in the setting of cervical spine fracture with neurological deficits. The patients had resolution of symptoms following discontinuation of the MAP goals. Posterior reversible encephalopathy syndrome (PRES) is a life-threatening condition characterized by seizures, confusion, visual disturbance, and headaches alongside neuroradiological findings indicative of posterior cerebral hemispheric white matter edema.(1,2) PRES has been described in association with abrupt blood pressure elevation, autoimmune disorders, or transplantation.(1-4) In this case report PRES presented with typical status epilepticus(5) but in an unexpected clinical setting, immediately after anterior cervical decompression and fusion (ACDF) and posterior cervical fusion (PCF) with laminectomy of C5-C6.
27843534 Phytochemical Content and Pharma-Nutrition Study on Eleutherococcus senticosus Fruits Intr 2016 In the past two decades public interest in herbal products has increased significantly in Europe, especially in the plant-based products from non-European traditions. Eleutherococcus senticosus has been used for the treatment of inflammatory diseases, anemia, and rheumatoid arthritis. The Eleutherococcus senticosus fruits intractum was examined for the content of phenolic acids (LC-ESI-MS/MS), minerals (AAS), TPC, and TFC (spectrophotometric assay). The antioxidant activity was determined using free radical scavenging assay and TLC-DB-DPPH(∗) dot-blot test. An anti-Hyal activity was evaluated by the spectrophotometric assay method. Cytotoxicity towards HL-60, HL-60/MX1, HL-60/MX2, CEM/C1, and CCRF/CEM leukemic cell lines was done using trypan blue test. Among eight phenolic acids, trans-caffeic acid was found in the largest amount (41.2 mg/g DE). The intractum presented a high amount of macroelements (Ca, Mg, K; 1750, 1300, and 21000 mg/kg) and microelements (Fe, Mn; 32.7, 54.3 mg/kg), respectively. The content of TPC and TFC was 130 and 92 mg/g DE, respectively. The intractum showed anti-Hyal activity (2.16-60%) and an antioxidant capacity (EC(50); 52 μg/mL). The intractum most strongly inhibited the growth of HL-60, HL-60/MX1, and CCRF/CEM. A better understanding of the intractum health benefits is important in order to increase its utility and enrich dietary sources of health promoting compounds.
27813112 Developmental toxicity of auranofin in zebrafish embryos. 2017 May Auranofin (AF) is used in clinic for the treatment of rheumatoid arthritis, repurposing of AF as an anticancer drug has just finished a phase I/II clinical trial, but the developmental toxicity of AF remains obscure. This study focused on its developmental toxicity by using zebrafish embryos. Zebrafish embryos were exposed to different concentrations (1, 2.5, 5, 10 μm) of AF from 2 h post-fertilization (hpf) to 72 hpf. At 72 hpf, two major developmental defects caused by AF were found, namely severe pericardial edema and hypopigmentation, when embryos were exposed to concentrations higher than 2.5 μm. Biochemical detection of oxidative stress enzyme combined with expressions of a series of genes related to oxidative stress, cardiac, metal stress and pigment formation were subsequently tested. The superoxide dismutase activity was decreased while malondialdehyde content was accumulated by AF treatment. The expression of oxidative stress-related genes (sod1, gpx1a, gst), pigment-related genes (mitfb, trp-1a) and one metal stress-related gene ctr1 were all decreased by AF exposure. The expressions of cardiac-related genes (amhc, vmhc) and one metal-related gene hsp70 were found to be significantly upregulated by AF exposure. These findings indicated the potential developmental toxicity of AF on zebrafish early development. Copyright © 2016 John Wiley & Sons, Ltd.
27781421 Pharmacokinetics and food-effect of fosdagrocorat (PF-04171327), a dissociated agonist of 2016 Dec OBJECTIVE: Fosdagrocorat (PF-04171327) is a pro-drug form of PF-00251802, a dissociated agonist of the glucocorticoid receptor, under investigation for the treatment of rheumatoid arthritis. This study investigates the pharmacokinetics (PK) of single and multiple doses of fosdagrocorat in healthy Japanese and Western volunteers, the effect of food on fosdagrocorat PK, and the effect of fosdagrocorat on bone biomarkers. METHODS: This was a phase 1, randomized, placebo-controlled, dose-escalation study. For single-escalating-dose evaluation, Japanese (n = 9) and Western (n = 9) subjects were randomized (1 : 1 : 1) to treatment sequences including 3 doses of fosdagrocorat (5, 10, or 30 mg) or placebo. For multiple-dose evaluation, Japanese subjects were randomized (3 : 1) to receive fosdagrocorat 20 mg or placebo once daily (QD) for 12 days. Subjects were aged 18 - 55 years; body mass index 17.5 - 30.5 kg/m2; total body weight > 45 kg. RESULTS: Following single doses of fosdagrocorat, the PK of PF-00251802 and its metabolite PF-04015475 were similar between Japanese (PF-00251802: mean area under the curve (AUC)inf (range across doses), 791 - 3,460 ng×h/mL; individual half-life (t1/2) 14.1 - 28.9 hours; PF-04015475: mean AUCinf, 395 - 1,740 ng×h/mL; individual t1/2 21.6 - 40.3 hours) and Western (PF-00251802: mean AUCinf, 750 - 4,150 ng×h/mL; individual t1/2 17.7 - 40.4 hours; PF-04015475: mean AUCinf, 394 - 2,160 ng×h/mL; individual t1/2 24.5 - 63.7 hours) subjects. Steady-state concentrations were reached within 9 days following multiple doses of fosdagrocorat. Food did not affect total exposure of PF-00251802 and PF-04015475. Multiple-dose administration of fosdagrocorat 20 mg QD resulted in suppression of bone formation markers and cortisol and increased bone resorption markers vs. placebo. Adverse events (AEs) were mild in severity and no serious AEs, deaths, or severe AEs were reported. CONCLUSIONS: The PK profile of fosdagrocorat was similar between Japanese and Western subjects, with little effect of food on PK parameters. Fosdagrocorat was well tolerated in both Japanese and Western subjects.
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27631190 A Comprehensive Proteomics Analysis of the Human Iris Tissue: Ready to Embrace Postgenomic 2016 Sep The annual economic burden of visual disorders in the United States was estimated at $139 billion. Ophthalmology is therefore one of the salient application fields of postgenomics biotechnologies such as proteomics in the pursuit of global precision medicine. Interestingly, the protein composition of the human iris tissue still remains largely unexplored. In this context, the uveal tract constitutes the vascular middle coat of the eye and is formed by the choroid, ciliary body, and iris. The iris forms the anterior most part of the uvea. It is a thin muscular diaphragm with a central perforation called pupil. Inflammation of the uvea is termed uveitis and causes reduced vision or blindness. However, the pathogenesis of the spectrum of diseases causing uveitis is still not very well understood. We investigated the proteome of the iris tissue harvested from healthy donor eyes that were enucleated within 6 h of death using high-resolution Fourier transform mass spectrometry. A total of 4959 nonredundant proteins were identified in the human iris, which included proteins involved in signaling, cell communication, metabolism, immune response, and transport. This study is the first attempt to comprehensively profile the global proteome of the human iris tissue and, thus, offers the potential to facilitate biomedical research into pathological diseases of the uvea such as Behcet's disease, Vogt Koyonagi Harada's disease, and juvenile rheumatoid arthritis. Finally, we make a call to the broader visual health and ophthalmology community that proteomics offers a veritable prospect to obtain a systems scale, functional, and dynamic picture of the eye tissue in health and disease. This knowledge is ultimately pertinent for precision medicine diagnostics and therapeutics innovation to address the pressing needs of the 21st century visual health.
27621816 The blocking of uPAR suppresses lipopolysaccharide-induced inflammatory osteoclastogenesis 2016 Sep INTRODUCTION: Chronic inflammatory diseases, such as rheumatoid arthritis and periodontitis, cause the bone destruction by promotion of the differentiation of monocyte/macrophage lineage cells into mature osteoclasts (OCs) with active bone-resorbing character. However, the detailed mechanisms underlying this disorder remain unclear. We herein investigated the role of urokinase plasminogen activator receptor (uPAR) in the bone destruction caused by chronic inflammation. METHODS: We investigated that the effect of uPAR on inflammatory OC formation induced by lipopolysaccharide (LPS) in inflammatory diseases. RESULTS: We found that the LPS more weakly induced OC formation and the resultant bone loss in uPAR-deficient mice than in wild-type mice. Additionally, we demonstrated that uPAR significantly potentiated LPS-induced OC formation of RAW264.7 mouse monocyte/macrophage linage cells in integrin β3/Akt-dependent manner. Moreover, we showed that the blocking of uPAR function by the administration of anti-uPAR neutralizing antibody significantly attenuated the LPS-induced OC formation and the resultant bone loss in mice. CONCLUSIONS: These results strongly suggest that uPAR negatively regulates the LPS-induced inflammatory OC formation and the resultant bone loss mediated through the integrin β3/Akt pathway. Our findings partly clarify the molecular mechanisms underlying bone destruction caused by chronic inflammatory diseases, and would benefit research on identifying antibody therapy for the treatment of these diseases.
27512062 NF-κB and IRF1 Induce Endogenous Retrovirus K Expression via Interferon-Stimulated Respon 2016 Oct 15 Thousands of endogenous retroviruses (ERV), viral fossils of ancient germ line infections, reside within the human genome. Evidence of ERV activity has been observed widely in both health and disease. While this is most often cited as a bystander effect of cell culture or disease states, it is unclear which signals control ERV transcription. Bioinformatic analysis suggests that the viral promoter of endogenous retrovirus K (ERVK) is responsive to inflammatory transcription factors. Here we show that one reason for ERVK upregulation in amyotrophic lateral sclerosis (ALS) is the presence of functional interferon-stimulated response elements (ISREs) in the viral promoter. Transcription factor overexpression assays revealed independent and synergistic upregulation of ERVK by interferon regulatory factor 1 (IRF1) and NF-κB isoforms. Tumor necrosis factor alpha (TNF-α) and LIGHT cytokine treatments of human astrocytes and neurons enhanced ERVK transcription and protein levels through IRF1 and NF-κB binding to the ISREs. We further show that in ALS brain tissue, neuronal ERVK reactivation is associated with the nuclear translocation of IRF1 and NF-κB isoforms p50 and p65. ERVK overexpression can cause motor neuron pathology in murine models. Our results implicate neuroinflammation as a key trigger of ERVK provirus reactivation in ALS. These molecular mechanisms may also extend to the pathobiology of other ERVK-associated inflammatory diseases, such as cancers, HIV infection, rheumatoid arthritis, and schizophrenia. IMPORTANCE: It has been well established that inflammatory signaling pathways in ALS converge at NF-κB to promote neuronal damage. Our findings suggest that inflammation-driven IRF1 and NF-κB activity promotes ERVK reactivation in neurons of the motor cortex in ALS. Thus, quenching ERVK activity through antiretroviral or immunomodulatory regimens may hinder virus-mediated neuropathology and improve the symptoms of ALS or other ERVK-associated diseases.