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ID PMID Title PublicationDate abstract
25078315 Discovery of highly potent TNFα inhibitors using virtual screen. 2014 Oct 6 Tumor necrosis factor-α (TNFα) is a validated therapeutic target for various autoimmune disorders such as rheumatoid arthritis and asthma. All TNFα inhibitors currently on the market are biologics, making the development of small molecule alternatives in urgent need. However, only a few successful cases of direct TNFα antagonization in vitro have been reported. Here, we present the identification of several small molecule candidates able to effectively reduce TNFα activity in vitro and in cell assays. Virtual screen targeting TNFα dimer was performed on the SPECS database and 101 compounds were selected for experimental testing. Two compounds, 1 and 2, displayed considerable inhibitory activity. Follow-up structure-activity relationship analysis of compound 1 identified 3 molecules with low micromolar cell-level inhibitory activity. Compound 11 showed an IC50 value of 14 μM, making it among the most potent TNFα small molecule inhibitors reported. These compounds provide new scaffolds for future development of small molecule drugs against TNFα.
25037725 Long-term mortality rates (>8-year) improve as compared to the general and obese populatio 2015 Mar INTRODUCTION: Sparse data are available on long-term patient mortality following bariatric surgery as compared to the general population. The purpose of this study was to assess long-term mortality rates and identify risk factors for all-cause mortality following bariatric surgery. METHODS: New York State (NYS) Planning and Research Cooperative System (SPARCS) longitudinal administrative data were used to identify 7,862 adult patients who underwent a primary laparoscopic bariatric surgery from 1999 to 2005. The Social Security Death Index database identified >30-day mortalities. Risk factors for mortality were screened using a univariate Cox proportional hazard (PH) model and analyzed using a multiple PH model. Based on age, gender, and race/ethnicity, actuarial projections for NYS mortality rates obtained from Centers of Disease Control were compared to the actual post-bariatric surgery mortality rates observed. RESULTS: The mean bariatric mortality rate was 2.5 % with 8-14 years of follow-up. Mean time to death ranged from 4 to 6 year and did not differ by operation (p = 0.073). From 1999 to 2010, the actuarial mortality rate predicted for the general NYS population was 2.1 % versus the observed 1.5 % for the bariatric surgery population (p = 0.005). Extrapolating to 2013, demonstrated the actuarial mortality predictions at 3.1 % versus the bariatric surgery patients' observed morality rate of 2.5 % (p = 0.01). Risk factors associated with an earlier time to death included: age, male gender, Medicare/Medicaid insurance, congestive heart failure, rheumatoid arthritis, pulmonary circulation disorders, and diabetes. No procedure-specific or perioperative complication impact for time-to-death was found. CONCLUSION: Long-term mortality rate of patients undergoing bariatric surgery significantly improves as compared to the general population regardless of bariatric operation performed. Additionally, perioperative complications do not increase long-term mortality risk. This study did identify specific patient risk factors for long-term mortality. Special attention and consideration should be given to these "at risk" patient sub-populations.
24997524 Factors affecting postoperative activities of daily living in patients with osteoporotic v 2015 Jul Surgical treatment of osteoporotic vertebral collapse (OVC) with neurological deficits presents significant clinical challenges because some patients have fragile bones and often have medical comorbidities, which affect the severity of osteoporosis. We hypothesized that clinical results of surgery in these patients depend on the extent of medical comorbidities that induce secondary osteoporosis. The aim of this study is to examine the effects of medical history and comorbidities on surgical outcomes for these patients, along with the factors that predict postoperative function in activities of daily living (ADL). We retrospectively reviewed data for 88 patients with OVC and neurological deficits who underwent surgery. We assessed clinical results regarding neurological deficits and function in ADL. The presence or absence of comorbidities responsible for secondary osteoporosis and treatments or medical events that affect bone metabolism were examined. We performed statistical analysis to examine prognostic factors for postoperative function in ADL. Of 88 patients, the distributions of comorbidities, treatment, and events in medical history were as follows: hypertension, 57 patients (64.8%); chronic kidney disease (CKD) stage 3 or 4, 32 (36.4%); diabetes mellitus, 16 (18.2%); liver dysfunction, 11 (12.5%); cardiovascular disease, 10 (11.4%); rheumatoid arthritis, 9 (10.2%); and glucocorticoid intake, 8 (9.1%). Twenty-five patients (28.4%) represented poor postoperative ADL (chair-bound or bed-bound), and 11 of 25 patients with poor postoperative ADL represented full neurological recovery. Multivariate analysis revealed decreased estimated glomerular filtration rate (odds ratio 0.96; 95% confidence interval 0.93-0.99; p = 0.005) and a high serum alkaline phosphatase (ALP) level (odds ratio 1.01; 95% CI 1.00-1.02; p = 0.01) were strong predictive factors for poor postoperative function in ADL. The majority of patients with poor postoperative function in ADL had advanced CKD with a disorder of bone metabolism as well as bone fragility.
24913775 Novel action and mechanism of auranofin in inhibition of vascular endothelial growth facto 2014 Auranofin is a gold compound initially developed for the treatment of rheumatoid arthritis. Recent data suggest that auranofin has promise in the treatment of other inflammatory and proliferative diseases. However, the mechanisms of action of auranofin have not been well defined. In the present study, we identify vascular endothelial growth factor receptor-3 (VEGFR3), an endothelial cell (EC) surface receptor essential for angiogiogenesis and lymphangiogenesis, as a novel target of auranofin. In both primary EC and EC cell lines, auranofin induces downregulation of VEGFR3 in a dose-dependent manner. Auranofin at high doses (≥1 µM) decreases cellular survival protein thioredoxin reductase (TrxR2), TrxR2-dependent Trx2 and transcription factor NF-κB whereas increases stress signaling p38MAPK, leading to EC apoptosis. However, auranofin at low doses (≤0.5 µM) specifically induces downregulation of VEGFR3 and VEGFR3-mediated EC proliferation and migration, two critical steps required for in vivo lymphangiogenesis. Mechanistically, we show that auranofin-induced VEGFR3 downregulation is blocked by antioxidant N-acetyl-L-cysteine (NAC) and lysosome inhibitor chloroquine, but is promoted by proteasomal inhibitor MG132. These results suggest that auranofin induces VEGFR3 degradation through a lysosome-dependent pathway. Auranofin may be a potent therapeutic agent for the treatment of lymphangiogenesis-dependent diseases such as lymphedema and cancer metastasis.
24909289 [The decline in lung function is associated with a decrease in the number of BTLA⁺ lymph 2014 Jun OBJECTIVE: To investigate the relationships between B, T lymphocyte attenuator (BTLA), regulatory T (Treg) cells and reduced lung function of patients with rheumatism. METHODS: The lung function of 482 patients of rheumatism, including rheumatoid arthritis (RA, 198 cases), ankylosing spondylitis (AS, 114 cases), Sjogren's syndrome (SS, 102 cases) and osteoarthritis (OA, 68 cases), were detected by spirometer. BTLA and Treg cells of peripheral blood in 482 patients with rheumatic diseases were observed using flow cytometry. RESULTS: Lung function and the expressions of BTLA and Treg cells were lower in patients with rheumatism than those in normal controls. Lung function parameters, such as forced expiratory volume in 1 second (FEV1), peak expiratory flow (PEF), forced expiratory flow at 50% of forced vital capacity (FEF50), forced expiratory flow at 75% of forced vital capacity (FEF75), were higher in the rheumatism group with normal BTLA and Treg cells than those in the group with abnormal BTLA and Treg cells (P<0.05 or P<0.01). Correlation analysis showed that there were positive correlations between lung function parameters orced vital capacity(FVC), maximal voluntary ventilation (MVV), FEV1, forced expiratory flow at 25% of forced vital capacity (FEF25), FEF50 and BTLA, Tregs. There were negative correlations between lung function parameters FVC, FEV1, FEF50, FEF75 and IL-4, IgA, IgM (P<0.05 or P<0.01). CONCLUSION: The decline in lung function of patients with rheumatism is related to down-regulation of BTLA, Tregs and excessively abnormal activation of T and B cells.
24859583 Risk factors for dural tears in the cervical spine. 2014 Aug 1 STUDY DESIGN: Retrospective review of prospective database. OBJECTIVE: To investigate the incidence of cervical dural tears (DTs), risk factors for occurrence and failure of treatment, and the effect on clinical outcomes. SUMMARY OF BACKGROUND DATA: Only 1 study has specifically investigated the impact of cervical DTs. METHODS: Cervical spine surgical procedures performed by the senior author (K.D.R.) at Washington University from 1995-2012 were evaluated. Demographic data, surgical history, operative data, and complications were recorded prospectively, and retrospectively reviewed. Intraoperative treatment of DTs was noted. Treatment failure was defined by reoperation or delayed lumbar drain placement. Patients who sustained a dural tear (DT group) were compared with those who did not sustain a dural tear (No-DT group) to identify risk factors. Comparison between successful and failed treatments was used to identify risk factors for treatment failure. RESULTS: A total of 3848 cervical surgical procedures were performed, with 38 occurrences (1.0%) of DT. Risk factors for DT were: older age (P < 0.01), rheumatoid arthritis (relative risk [RR] = 3.1, 95% confidence interval [CI] = 1.0-9.8), ossification of the posterior longitudinal ligament (RR = 19.2, 95% CI = 10.4-35.6), cervical deformity (RR = 3.3, 95% CI = 1.6-6.6), longer operative time (P = 0.01), greater number of surgical levels (P < 0.01), worse preoperative neurological status (P < 0.01), and performance of a corpectomy (RR = 2.1, 95% CI = 1.1-4.0) or revision laminectomy (RR = 20.0, 95% CI = 8.4-47.4). Initial treatments failed in 12 cases (32%) and hospital readmission was required for 5 patients (13%). Older age and ossification of the posterior longitudinal ligament were found to be risk factors for failure of the DT treatment. With an average follow-up of 18 months, there were no clinical sequelae from the DTs. CONCLUSION: In the largest series of cervical DTs reported, the incidence of DTs was found to be 1% and several risk factors were identified. Initial treatment failures occurred more often than previously reported. No significant clinical impact was found after successful DT treatment. LEVEL OF EVIDENCE: 4.
24609069 Body mass index and risk of autoimmune diseases: a study within the Danish National Birth 2014 Jun BACKGROUND: A possible aetiological link between obesity and certain autoimmune diseases (ADs) has been suggested. We investigated the associations between body mass index (BMI, kg/m2) and 43 ADs. METHODS: 75,008 women participating in the Danish National Birth Cohort were followed during a median time of 11 years. Diagnoses on ADs were retrieved from the Danish National Patient Register. Cox proportional hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated adjusting for potential confounders (smoking, alcohol, parity and socio-occupational status). RESULTS: During follow-up, 2430 women (3.2%) developed a total of 2607 new-onset ADs. Risk of any autoimmune disease was increased in obese women (HR, 1.27; 95% CI, 1.11 to 1.46) compared with normal weight women (18.5-≤25 kg/m2). Obese women (BMI≥30 kg/m2) were at increased risk of sarcoidosis (HR 3.59; 95% CI, 2.31 to 5.57) and type 1 diabetes mellitus (HR 2.67; 95% CI, 1.71 to 4.17). Risk of dermatitis herpetiformis increased by 14% (95% CI, 1% to 30%) per BMI unit. Conversely, risk of celiac disease and Raynaud's phenomenon decreased by 7% (95% CI, 1% to 13%) and 12% (95% CI, 4% to 19%) per BMI unit, respectively. Further associations between BMI and risk of psoriasis, rheumatoid arthritis and Crohn's disease were suggested. CONCLUSIONS: BMI was found to be associated with several Ads. This was most pronounced between obesity and risk of sarcoidosis and and risk of type 1 diabetes mellitus. These novel findings need confirmation and the possible role of adipose tissue-derived immunological changes in the development of autoimmune reactions needs consideration.
24516607 Prevalence of anti-citrullinated protein antibodies (ACPA) in patients with diffuse large 2014 BACKGROUND: Antibodies against citrullinated proteins (ACPA) have been recognised as the most specific serum marker for rheumatoid arthritis. However, serum autoantibodies such as anti-nuclear antibodies have also been detected in the sera of different lymphatic malignancies without accompanying rheumatologic disease. Therefore, we conducted a study to evaluate the prevalence of ACPA in diffuse large B-cell non-Hodgkin lymphoma (DLBCL). METHODS: Sera of 395 DLBCL patients and 258 age-matched healthy controls were investigated to evaluate the prevalence of ACPA and RF. ACPA-positive data were stratified into subgroups of RF positivity and established prognostic parameters for DLBCL, including overall survival. In addition, the ACPA serum concentrations levels were compared to an ACPA-positive RA cohort (n = 175). The statistics were performed with χ2 test and Mann- Whitney-U test; Kaplan-Meyer curves (log rank test) were used to analyse the overall survival. P-value <0.05 was statistically significant. RESULTS: ACPA, but not RF, occurred significantly more frequently in the sera of DLBCL patients than in healthy controls (3.5% versus 0.8%, p = 0.030). However, the ACPA serum concentration levels were significantly lower than in RA patients (median 10.4 versus 124.1 U/ml, p = 0.0001). After subgroup stratification, ACPA positivity in DLBCL was significantly associated with male gender (4.4% versus 0%, p = 0.022; odds ratio 1.046, CI 1.014-1.079) and with RF-IgM seropositivity (1.77% versus 0%, p = 0.043), but not with prognostic parameters for DLBCL. CONCLUSIONS: DLBCL is associated with a significantly higher prevalence of ACPA, with an increased prevalence in male patients, and simultaneous RF-IgM positivity. However, ACPA is not prognostic for DLBCL. The prevalence of RF-IgM, -IgA, or -IgG did not differ from healthy controls.
24470498 Endothelial cell-derived chemerin promotes dendritic cell transmigration. 2014 Mar 1 ChemR23 is a chemotactic receptor expressed by APCs, such as dendritic cells, macrophages, and NK cells. Chemerin, the ChemR23 ligand, was detected by immunohistochemistry, to be associated with inflamed endothelial cells in autoimmune diseases, such as lupus erythematosus, psoriasis, and rheumatoid arthritis. This study reports that blood and lymphatic murine endothelial cells produce chemerin following retinoic acid stimulation. Conversely, proinflammatory cytokines, such as TNF-α, IFN-γ, and LPS, or calcitriol, are not effective. Retinoic acid-stimulated endothelial cells promoted dendritic cell adhesion under shear stress conditions and transmigration in a ChemR23-dependent manner. Activated endothelial cells upregulated the expression of the atypical chemotactic receptor CCRL2/ACKR5, a nonsignaling receptor able to bind and present chemerin to ChemR23(+) dendritic cells. Accordingly, activated endothelial cells expressed chemerin on the plasma membrane and promoted in a more efficient manner chemerin-dependent transmigration of dendritic cells. Finally, chemerin stimulation of myeloid dendritic cells induced the high-affinity binding of VCAM-1/CD106 Fc chimeric protein and promoted VCAM-1-dependent arrest to immobilized ligands under shear stress conditions. In conclusion, this study reports that retinoic acid-activated endothelial cells can promote myeloid and plasmacytoid dendritic cell transmigration across endothelial cell monolayers through the endogenous production of chemerin, the upregulation of CCRL2, and the activation of dendritic cell β1 integrin affinity.
24434811 The association of interleukin-21 polymorphisms with interleukin-21 serum levels and risk 2014 Mar 15 Systemic lupus erythematosus (SLE) is one of the common autoimmune diseases, with complex genetic components. Interleukin-21 (IL-21) is the most recently discovered member of the type-I cytokine family, which has a variety of effects on the immune system, including B cell activation, plasma cell differentiation, and immunoglobulin production. Previous studies have identified that IL-21 was associated with different autoimmune and inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis and SLE. Variations in the DNA sequence in the IL-21 gene may lead to altered IL-21 production and/or activity, and thus this can modulate an individual's susceptibility to SLE. To test this hypothesis, we investigated the association of the IL-21 polymorphisms and its serum levels with the risk of SLE in a Chinese population. We analyzed three single nucleotide polymorphisms of IL-21 gene rs907715 C/T, rs2221903 T/C and rs2055979 C/A in 175 patients with SLE and 190 age- and sex-matched controls, using Snapshot SNP genotyping assays and DNA sequencing method. Soluble IL-21 (sIL-21) levels were measured by ELISA. There were significant differences in the genotype and allele frequencies of IL-21 gene rs2055979 C/A polymorphism between the group of patients with SLE and the control group (P<0.05). sIL-21 levels were increased in patients with SLE compared with controls (P<0.01). Moreover, genotypes carrying the IL-21 rs2055979 A variant allele were associated with increased IL-21 levels compared to the homozygous wild-type genotype in patients with SLE. The rs2055979 C/A polymorphism of IL-21 and its sIL-21 levels were associated with SLE in the Chinese population. Our data suggests that IL-21 gene may play a role in the development of SLE.
24400976 Rationale and design of the INNOVATE Trial: an international cooperative study on surgical 2014 Jan 8 BACKGROUND: Fractures of the odontoid process of the axis are the most common fractures of the geriatric cervical spine. As the population ages, their incidence is expected to increase progressively, as is the number of very old patients (>80 years) with an odontoid fracture. No consensus exists on the optimal treatment (surgical or conservative) and the most relevant outcome parameter (osseous union, fracture stability or clinical outcome). The aim of the INNOVATE (INterNational study on Odontoid frActure Treatment in the Elderly) Trial is to prospectively assess fracture healing and clinical outcome after surgical and conservative treatment for odontoid fractures in the elderly patient, with a specific focus on the very old patient. METHODS/DESIGN: The trial is an observational study in which eleven centres in five European countries are involved. All patients admitted to one of these centres who meet the selection criteria (≥55 years, acute (
24272316 Oral health among residents of publicly supported housing in Boston. 2014 Aug Tooth loss in adults diminishes quality of daily life, affecting eating, speaking, appearance, and social interactions. Tooth loss is linked to severe periodontitis and caries; and to risk of stroke, cardiovascular disease, rheumatoid arthritis, and dementia. At the national (USA) level, poverty and African-American race have been linked to lower utilization of dental services, suggesting that the 7.5 million residents of publicly supported housing may be at risk of tooth loss and poor overall oral health. We assessed whether residence in publicly supported housing in Boston was associated with four oral health-related indicators. Compared to residents of nonpublicly supported housing, after adjusting for covariates residents of both public housing developments (PHDs) and rental assistance units (RAUs) had significantly lower odds of having had a dental cleaning in the past year (PHD, OR = 0.64 (95 % CI, 0.44-0.93); RAU, OR = 0.67 (95 % CI, 0.45-0.99))-despite parity in having had a past year dental visit. Further, residents of RAUs had double the odds of having had six or more teeth removed (OR = 2.20 (95 % CI, 1.39-3.50)). Associations of race/ethnicity and housing type with dental insurance were interrelated. Unadjusted results document a deficit in oral health-related indicators among public housing residents, taken as a group, giving a clear picture of an oral health care gap and identifying a defined real-world population that could benefit from services. Existing public housing infrastructure could provide both a venue and a foundation for interventions to reduce oral health disparities on a broad scale.
23820041 The association between silica exposure and development of ANCA-associated vasculitis: sys 2013 Oct BACKGROUND: Crystalline silica is among the environmental exposures associated with increased risk of autoimmune diseases, including rheumatoid arthritis, systemic sclerosis and systemic lupus erythematosus. Silica exposure has also been related to the development of ANCA-associated vasculitides (AAV), but past studies appear to conflict as to the presence and magnitude of the associated risks of disease. We aimed to conduct a systematic review of the existing studies and meta-analysis of their results. METHODS: We searched EMBASE, MEDLINE and international scientific conference abstract databases for studies examining the association of silica exposure with AAV. Studies in English, French, or Spanish were included and those examining the association of silica with ANCA-positivity alone were excluded. We assessed study quality using the Newcastle-Ottawa Scale. We meta-analyzed the results using random effects models and tested for heterogeneity. We performed sensitivity and subgroup analyses, examining studies that adjusted for smoking and occupational risk factors as well as studies that analyzed by subtypes of AAV. RESULTS: We identified 158 potential manuscripts and 3 abstracts related to silica exposure and risk of AAV. 147 were excluded after abstract review and 14 underwent detailed evaluation of full manuscript/abstract. After further application of exclusion criteria, 6 studies (all cases-controls) remained. The studies had moderate heterogeneity in selection of cases and controls, exposure assessment, disease definition and controlling for potential confounders. We found an overall significant summary effect estimate of silica "ever exposure" with development of AAV (summary OR 2.56, 95% CI 1.51-4.36), with moderate heterogeneity (I(2)=48.40%). ORs were similar for studies examining only MPA (OR 3.95, CI 95% 1.89-8.24), compared to those only studying GPA (OR 3.56, CI 95% 1.85-6.82). CONCLUSION: Despite moderate heterogeneity among studies, the totality of the evidence after meta-analysis points to an association between silica exposure and risk for developing AAV.
23785729 (111)In-1,4,7-Triazacyclononane,1-glutaric acid-4,7-acetic acid-Glu-[cyclo(Arg-Gly-Asp-d-P 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. Antagonists of α(v)β(3) are being studied as antitumor and antiangiogenic agents, and the agonists of α(v)β(3) are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). Extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) contain a tripeptide sequence consisting of Arg-Gly-Asp (RGD), which binds to a variety of integrins, including α(v)β(3). Various radiolabeled antagonists have been introduced for use with the imaging of tumors and tumor angiogenesis (10). Most cyclic RGD peptides are composed of five amino acids. Haubner et al. (11) reported that various cyclic RGD (c(RGD)) peptides exhibit selective inhibition of binding to α(v)β(3) (inhibition concentration (IC(50)), 7–40 nM) but not to integrins α(v)β(5) (IC(50), 600–4,000 nM) or α(IIb)β(3) (IC(50), 700–5,000 nM). Various radiolabeled c(RGD) peptides have been found to have high accumulation in tumors in nude mice (12). Dijkgraaf et al. (13) reported the evaluation of (111)In-1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid-Glu-[cyclo(Arg-Gly-Asp-d-Phe-Lys)](2) ((111)In-NODAGA-E-[c(RGDfK)](2)) for use with single-photon emission computed tomography (SPECT) imaging of α(v)β(3) in tumors.
23620772 Predictors for half-year outcome of impairment in daily life for back pain patients referr 2013 BACKGROUND AND OBJECTIVE: From observational studies, there is only sparse information available on the predictors of development of impairment in daily life for patients receiving physiotherapy. Therefore, our aim was to identify factors which predict impairment in daily life for patients with back pain 6 months after receiving physiotherapy. METHODS: We conducted a prospective cohort study with 6-month follow-up. Patients were enrolled for treatment in private physiotherapy practices. Patients with a first physiotherapy referral because of thoracic or low back pain, aged 18 to 65 years were included. Primary outcome impairment was measured utilising the 16-item version of the Musculoskeletal Function Assessment Questionnaire. Therapy was documented on a standardized form. Baseline scores for impairment in daily life, symptom characteristics, sociodemographic and psychosocial factors, physical activity, nicotine consumption, intake of analgesics, comorbidity and delivered primary therapy approach were investigated as possible predictors. Univariate and multiple linear regression analyses were performed. RESULTS: A total of 792 patients participated in the study (59% female, mean age 44.4 (SD 11.4), with 6-month follow-up results available from 391 patients. In univariate analysis 17 variables reached significance. In multiple linear regression identified predictors were: impairment in daily life before therapy, mental disorders, duration of the complaints, self-prognosis on work ability, rheumatoid arthritis, age, form of stress at work and physical activity. The variables explain 34% of variance (adjusted R(2), p<0.001). CONCLUSIONS: With minimal information available from observational studies on the predictors of development of back problems for physiotherapy patients, this study adds new knowledge for forming appropriate referral guidelines. Impairment in daily life before therapy, mental disorder as comorbidity and the duration of the complaints can be named as outstanding factors. The results of this study can be used to facilitate comparison of patient therapy goals with the prognosis in everyday practice.
23372751 Blockade but not overexpression of the junctional adhesion molecule C influences virus-ind 2013 Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing beta-cells in the pancreas. Recruitment of inflammatory cells is prerequisite to beta-cell-injury. The junctional adhesion molecule (JAM) family proteins JAM-B and JAM-C are involved in polarized leukocyte transendothelial migration and are expressed by vascular endothelial cells of peripheral tissue and high endothelial venules in lympoid organs. Blocking of JAM-C efficiently attenuated cerulean-induced pancreatitis, rheumatoid arthritis or inflammation induced by ischemia and reperfusion in mice. In order to investigate the influence of JAM-C on trafficking and transmigration of antigen-specific, autoaggressive T-cells, we used transgenic mice that express a protein of the lymphocytic choriomeningitis virus (LCMV) as a target autoantigen in the β-cells of the islets of Langerhans under the rat insulin promoter (RIP). Such RIP-LCMV mice turn diabetic after infection with LCMV. We found that upon LCMV-infection JAM-C protein was upregulated around the islets in RIP-LCMV mice. JAM-C expression correlated with islet infiltration and functional beta-cell impairment. Blockade with a neutralizing anti-JAM-C antibody reduced the T1D incidence. However, JAM-C overexpression on endothelial cells did not accelerate diabetes in the RIP-LCMV model. In summary, our data suggest that JAM-C might be involved in the final steps of trafficking and transmigration of antigen-specific autoaggressive T-cells to the islets of Langerhans.
23301082 Inhibition of sphingosine kinase-2 in a murine model of lupus nephritis. 2013 Sphingosine-1-phosphate (S1P), a potent bioactive lipid, is emerging as a central mediator in inflammation and immune responses. We have previously implicated S1P and its synthetic enzyme sphingosine kinase (SK) in inflammatory and autoimmune disorders, including inflammatory bowel disease and rheumatoid arthritis. Generation of S1P requires phosphorylation of sphingosine by SK, of which there are two isoforms. Numerous studies have implicated SK1 in immune cell trafficking, inflammation and autoimmune disorders. In this study, we set out to determine the role of SK and S1P in lupus nephritis (LN). To this end, we examined S1P and dihydro-S1P (dh-S1P) levels in serum and kidney tissues from a mouse model of LN. Interestingly dh-S1P was significantly elevated in serum and kidney tissue from LN mice, which is more readily phosphorylated by SK2. Therefore, we employed the use of the specific SK2 inhibitor, ABC294640 in our murine model of LN. Treatment with ABC294640 did not improve vascular or interstitial pathology associated with LN. However, mice treated with the SK2 inhibitor did demonstrate decreases in glomerular pathology and accumulation of B and T cells in the spleen these were not statistically different from lpr mice treated with vehicle. LN mice treated with ABC294640 did not have improved urine thromboxane levels or urine proteinuria measurements. Both S1P and dh-S1P levels in circulation were significantly reduced with ABC294640 treatment; however, dh-S1P was actually elevated in kidneys from LN mice treated with ABC294640. Together these data demonstrate a role for SKs in LN; however, they suggest that inhibition of SK1 or perhaps both SK isoforms would better prevent elevations in S1P and dh-S1P and potentially better protect against LN.
23220116 Stimulation of human TRPA1 channels by clinical concentrations of the antirheumatic drug a 2013 Feb 15 Gold compounds, which were widely used to treat rheumatoid arthritis, have been recently used as experimental agents for tumor treatment. Transient receptor potential (TRP) ankyrin repeat 1 (TRPA1) is a Ca(2+)-permeable ion channel that senses acute and inflammatory pain signals. Electrophilic compounds such as mustard oil and cinnamaldehyde activate TRPA1 by interacting with TRPA1 cysteine residues. Here we investigate the effects of the gold compound auranofin (AUR) on TRPA1 channels. Intracellular Ca(2+) and whole cell patch-clamp recordings were performed on human embryonic kidney cells transiently expressed with TRPA1, TRP melastatin 8 (TRPM8), and vanilloid type TRP (TRPV1-4) channels. AUR stimulated TRPA1 in a concentration-dependent manner with a half-maximum potency of around 1.0 μM. The AUR-induced response was effectively blocked by HC030031, a TRPA1 antagonist. On the other hand, AUR failed to activate TRPM8 and TRPV1-4 channels, which are highly expressed in sensory neurons as nociceptors. The stimulatory effect on TRPA1 channels depended on the C414, C421, C621, and C633 cysteine residues and not on the inhibition of thioredoxin reductase by AUR. Moreover, AUR effectively activated TRPA1 channels expressed in human differentiated neuroblastoma cell lines. The study shows that AUR is a potent stimulator of TRPA1 channels.
23202984 Structural analysis of the inhibition of APRIL by TACI and BCMA through molecular dynamics 2013 Feb APRIL (a proliferation-inducing ligand) is a member of the tumour necrosis factor (TNF) superfamily that binds the receptors (TNFRs) TACI and BCMA. Since it was discovered, a great amount of evidence has been reported about the involvement of APRIL in autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren's syndrome (SS) and multiple sclerosis (MS). In addition, an important role of APRIL has been described in different types of tumour cell lines and in a variety of primary tumour tissues where, in contrast with the normal ones, high mRNA levels have been detected. Accordingly, the design of compounds mimicking the inhibition of APRIL by its receptors appears to be a promising way to treat autoimmune and cancer diseases. As a first step to achieve these goals and in order to better understand the key interactions involved in these systems, we report a structural analysis of the inhibition of human and murine APRIL by its human receptors TACI and BCMA obtained by molecular dynamics simulations. Although most of the key interactions can be obtained from the existing experimental information, new described interactions between human APRIL and its receptors can contribute to a better design of APRIL inhibitors.
23026290 Gleditsioside B, a triterpene saponin isolated from the anomalous fruits of Gleditsia sine 2013 Jan Angiogenesis has become an attractive target for the treatment of certain diseases such as cancer and rheumatoid arthritis. Our previous studies demonstrated that the saponin fraction from Gleditsia sinensis fruits had anti-angiogenic potential, and Gleditsiosides B (GB) was probably the main active constituent. In the present study, we assessed the effect of GB on endothelial cell migration, a crucial event in angiogenesis, and explored the underlying mechanisms. The migration of endothelial cells was assessed by transwell. The expressions of MMP-2/-9 and TIMP-1/-2 were analyzed by Western blotting, and the activities of MMP-2/-9 were detected by gelatin zymography assay. Moreover, migration-related proteins and signaling pathways, including FAK, MAPKs and PI3K/AKT, were analyzed by Western blotting. It was shown that GB, at a concentration of 10 μM without significant cytotoxicity, could effectively abrogate the migration of human umbilical vein endothelial cells (HUVECs) induced by bFGF. GB also inhibited the expression and activity of MMP-2, elevated the expression of TIMP-1, and restrained the phosphorylations of FAK, ERK, PI3K and AKT in a concentration-dependent manner. The findings suggest that GB was able to abrogate the migration of endothelial cells through down-regulating the activation of MMP-2 and FAK via preventing ERK and PI3K/AKT signaling pathways.