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ID PMID Title PublicationDate abstract
27579026 Early IL-1 Signaling Promotes iBALT Induction after Influenza Virus Infection. 2016 Inducible bronchus-associated lymphoid tissue (iBALT) is a long lasting tertiary lymphoid tissue that can be induced following influenza A virus (IAV) infection. Previous studies have shown that iBALT structures containing germinal center (GC) B cells protect against repeated infection by contributing locally to the cellular and humoral immune response. If we are to exploit this in vaccination strategies, we need a better understanding on how iBALT structures are induced. One hypothesis is that the strength of the initial innate response dictates induction of iBALT. In the present study, we investigated the role of interleukin (IL)-1 and IL-1R signaling on iBALT formation. Mice lacking the IL-1R had a delayed viral clearance and, thus, a prolonged exposure to viral replication, leading to increased disease severity, compared to wild-type mice. Contradictorily, iBALT formation following clearance of the virus was heavily compromised in Il1r1 (-/-) mice. Quantification of gene induction after IAV infection demonstrated induction of IL-1α and to a much lesser extent of IL-1β. Administration of recombinant IL-1α to the lungs of wild-type mice, early but not late, after IAV infection led to more pronounced iBALT formation and an increased amount of GC B cells in the lungs. Bone marrow chimeric mice identified the stromal compartment as the crucial IL-1 responsive cell for iBALT induction. Mechanistically, Q-PCR analysis of lung homogenates revealed a strongly diminished production of CXCL13, a B cell-attracting chemokine, in Il1r (-/-) mice during the early innate phase of IAV infection. These experiments demonstrate that appropriate innate IL-1α-IL-1R signaling is necessary for IAV clearance and at the same time instructs the formation of organized tertiary lymphoid tissues through induction of CXCL13 early after infection. These findings are discussed in the light of recent insights on the pathogenesis of tertiary lymphoid organ formation in the lung in various diseases where the IL-1 axis is hyperactive, such as rheumatoid arthritis and COPD.
27462504 Once-weekly teriparatide improves glucocorticoid-induced osteoporosis in patients with ina 2016 BACKGROUND: Patients with glucocorticoid-induced osteoporosis (GIOP) are at very high risk of fracture, and patients with severe GIOP often experience fractures during treatment with bisphosphonates. Teriparatide (TPTD) is the only currently available anabolic agent expected to be effective for GIOP. Once-weekly TPTD decreased bone resorption marker with primary osteoporosis different from daily TPTD, but it has not yet been tested with GIOP. OBJECTIVES: To evaluate the efficacy of once-weekly TPTD for patients with GIOP and inadequate response to bisphosphonates. METHODS: Patients with GIOP and collagen diseases treated with prednisolone for at least 6 months with inadequate responses to bisphosphonates were administered once-weekly TPTD. Bone density of the lumbar spine and femoral neck, measured as percent young adult mean (YAM); serum concentrations of cross-linked N-terminal telopeptides of type I collagen (NTx), bone alkaline phosphatase (BAP), and calcium; and FRAX were measured at baseline and 6, 12 and 18 months after starting TPTD. RESULTS: Of the 12 GIOP patients with collagen diseases enrolled, nine (seven females, two males; mean age 57.4 ± 11.1 years) completed treatment, including six with systemic lupus erythematosus, two with rheumatoid arthritis, and one with adult onset still disease. Only one new fracture event, a lumbar compression fracture, occurred during the study period, although seven patients experienced eight fracture events within 18 months before starting TPTD (p = 0.04). Lumbar spine YAM significantly improved at 18 months (p = 0.04), whereas femoral neck YAM did not (p = 0.477). Serum NTx, BAP, Ca, and FRAX were not significantly affected by TPTD treatment. CONCLUSIONS: Once-weekly TPTD reduces fracture events and increases bone density of the lumbar spine of GIOP patients with inadequate response to bisphosphonates.
27437101 Delivering a one-stop, integrated, and patient-centered service for patients with rheumati 2016 OBJECTIVE: To describe a one-stop, integrated rheumatology service and assess patient satisfaction. METHODS: A descriptive report and patient satisfaction survey of a rheumatology clinic model first developed in 1996 to enhance the patient "journey" through rheumatology services. A patient-satisfaction survey over a 3-week period assessed several aspects of care including quality of services, consultations, and patient education. RESULTS: All referrals are screened by a rheumatologist to pre-schedule laboratory/radiology/other tests for the visit. Upon arrival to the clinic, patients check-in at an electronic desk, and then complete the electronic GoTreatIT monitoring system which assesses patient-reported outcomes. The patient is reviewed by a doctor in a 30- to 60-min consultation, and then by a nurse (for diagnosis/treatment education, vaccinations). An ultrasound machine and capillaroscopy are available for use in the clinic. Patients can be scheduled on the same day to see a nutritionist, physiotherapist, or other heath professionals as necessary. An "early-rheumatoid arthritis treatment path" is available to ensure early, intensive treatment. A patient satisfaction survey revealed high rating of the overall service (90.6/100). None of the patients felt that they lacked education on their disease or medication. Only 6% of the respondents gave negative feedback, reasons including feeling overwhelmed with information or not being given a cause for their symptoms. The multi-disciplinary approach was highly valued and only 3% would rather see a doctor and nurse on separate days. CONCLUSION: The specific clinic model provides an ideal setting for a one-stop service, avoiding unnecessary visits, collecting patient data, and enhancing the patient experience and journey through the system. Where possible, the specific clinic model could be used or adapted to build similar models in other rheumatology departments. The clinic model could also form the basis for services in other specialties dealing with chronic conditions.
27354586 Inhibitory Effect of Anti-rheumatic Drug Iguratimod for Hepatocellular Carcinogenesis by I 2016 Jul BACKGROUND/AIM: Angiogenesis is a known factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to assess the property of iguratimod, that is an anti-inflammatory drug for rheumatoid arthritis, on anti-angiogenesis and anti-carcinogensis for HCC. MATERIALS AND METHODS: In vitro, human umbilical vein endothelial cells were cultured under interleukin-8 (IL-8) with or without iguratimod. In vivo, a rat model with HCC received iguratimod or distilled water for 6 weeks. Diameter of the largest tumor, number of tumors and serum interleukin-8 concentration were compared between iguratimod and control groups. RESULTS: By an in vitro angiogenesis assay, it was found angiogenesis in iguratimod group was significantly lower than that in control group (p=0.013). In vivo, largest tumor diameter (p=0.036), number of the tumor (p=0.011) and serum interleukin-8 concentration (p=0.036) in the iguratimod group were significantly smaller and lower than those in the control group. CONCLUSION: Iguratimod may inhibit hepatocellular carcinogensis by inhibition of interleukin-8 production in a rat model.
27348134 Trends and Associations in Hospitalizations Due to Corneal Ulcers in the United States, 20 2016 Aug PURPOSE: To estimate incidence, temporal trends, and factors associated with inpatient hospitalization due to corneal ulcers in the United States. METHODS: Data on inpatient hospitalizations due to corneal ulcers between 2002 and 2012 were reviewed using the National Inpatient Sample. A literature review was conducted to identify the most common causes of corneal ulcers, and use of contact lenses. RESULTS: An estimated 19,878 patients were seen in US emergency departments for evaluation of corneal ulcers in 2012. Rates of inpatient hospitalization due to corneal ulcers remained comparable over the decade (2003: 4.9, 95% confidence interval, CI, 3.0-6.7; 2012: 2.7, 95% CI 2.2-3.3 patients per million US population). Among those hospitalized for ophthalmic disease, patients holding public or no insurance (odds ratio, OR, 1.8 and 2.5, respectively, p<0.001), from low-income neighborhoods (OR 1.6, p < 0.001), and of older age (OR 3.4, p < 0.001) were more likely to be hospitalized for corneal ulceration. Medical conditions associated with hospitalization for corneal ulcer included history of keratitis (7.7%, p < 0.001), HIV infection (2.6%, p = 0.003), history of contact lens-related complications (2.5%, p < 0.001), and history of eye injury (2.5%, p = 0.001). Patients with a history of keratitis (p = 0.006) or rheumatoid arthritis (p = 0.001) were each twice as likely to receive a corneal transplant. CONCLUSIONS: Factors associated with hospitalization for corneal ulcer include insurance status in addition to history of contact lens-related disease and keratitis. Efforts should be made to address these factors prior to development of severe ulcers.
27252254 From autoantibody research to standardized diagnostic assays in the management of human di 2016 Jul Testing for autoantibodies (AABs) is becoming more and more relevant, not only for diagnosing autoimmune diseases (AIDs) but also for the differentiation of defined AID subtypes with different clinical manifestations, course and prognosis as well as the very early diagnosis for adequate management in the context of personalized medicine. A major challenge to improve diagnostic accuracy is to harmonize or even standardize AAB analyses. This review presents the results of the 12th Dresden Symposium on Autoantibodies that focused on several aspects of improving autoimmune diagnostics. Topics that are addressed include the International Consensus on ANA Patterns (ICAP) and the International Autoantibody Standardization (IAS) initiatives, the optimization of diagnostic algorithms, the description and evaluation of novel disease-specific AABs as well as the development and introduction of novel assays into routine diagnostics. This review also highlights important developments of recent years, most notably the improvement in diagnosing and predicting the course of rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, and of autoimmune neurological, gastrointestinal and liver diseases; the potential diagnostic role of anti-DFS70 antibodies and tumor-associated AABs. Furthermore, some hot topics in autoimmunity regarding disease pathogenesis and management are described.
27241254 Leptin inhibitors from fungal endophytes (LIFEs): Will be novel therapeutic drugs for obes 2016 Jul Treatment of obesity and its associated immune mediated diseases is challenging due to impaired function of leptin system. Thus leptin is providing an interesting target for therapeutic intervention. Leptin, an adipose tissue-derived adipokine, displays a variety of immune functions, and regulate both innate and adaptive immune responses. The increased secretion of leptin (hyperleptinemia) and production of proinflammatory cytokines has been implicated in the pathogenesis of obesity-related immune diseases such as diabetes mellitus, hypertension, atherosclerosis, cancer, systemic lupus erythematosus, rheumatoid arthritis, crohn's disease and multiple sclerosis. These disorders are managed through antibiotics and by cytokines replacement. However, the effectiveness of cytokines coupled to the complexity of the cytokine network leads to severe side-effects, which can still occur after careful preclinical evaluation. In addition, synthetic immunotherapeutics carries a degree of risk, is time-consuming and expensive. Hence, the complexity of existing therapy and adverse effects emphasizes the need of an alternative approach for the management of immune dysfunction associated with obesity and its related diseases. For the aforementioned diseases that are related to leptin overabundance, new drugs blocking leptin signaling need to be generated. The research on the discovery of clinically important novel compounds from natural source is expanding due to their safety and no side effect. The fungal endophytes are the microbes that colonize internal tissue of plants without causing negative effects to the host. They produce plethora of substances of potential use to modern medicinal and pharmaceutical industry. The increasing body of evidence associated with application of bioactive metabolites derived from fungal endophytes in diverse disease states merits its use as therapeutic drugs. In particular, the saponins have been extensively proved to modulate the immune system, which has raised a significant interest in their potential as immunomodulators. Thus, our hypothesis is that the saponins derived from fungal endophytes can be explored as clinical applicable leptin inhibitors for treating immune mediated diseases.
27116027 A new implementation of digital X-ray radiogrammetry and reference curves of four indices 2016 Digital X-ray radiogrammetry performs measurements on a hand radiograph in digital form. We present an improved implementation of the method and provide reference curves for four indices for the amount of bone. We collected 1662 hand radiographs of healthy subjects of age 9-100 years. PURPOSE: The digital X-ray radiogrammetry (DXR) method has been shown to be efficient for diagnosis of osteoporosis and for assessment of progression of rheumatoid arthritis. The aim of this work is to present a new DXR implementation and reference curves of four indices of cortical bone and to compare their relative SDs in healthy subjects at fixed age and gender. MATERIALS AND METHODS: A total of 1662 hand radiographs of healthy subjects of age 9-100 years were collected in Jena in 2001-2005. We also used a longitudinal study of 116 Danish children born in 1952 with on average 11 images taken over the age range 7 to 40 years. The new DXR method reconstructs the whole metacarpal contour so that the metacarpal lengths can be measured and used in two of the indices. The new DXR method automatically validates 97 % of the images and is implemented as a local server for PACS users. RESULTS: The Danish bone health index (BHI) data are consistent with the Jena data and also with the published BHI reference for healthy children. BHI is found to have smaller relative SD than the other three indices in the Jena cohort over the age range 20-80 years. CONCLUSION: The new DXR method is an extension of the existing BoneXpert method for children, which allows patients to be followed from childhood into adulthood with the same method. By making all four indices of cortical bone available within the same medical device, it becomes possible to decide which index has the best relation to fracture risk in future studies.
27114638 Anti-inflammatory and anti-granuloma activity of Berberis aristata DC. in experimental mod 2016 Mar OBJECTIVE: Berberis aristata (Berberidaceae) is an important medicinal plant used in traditional system of medicine for the treatment of rheumatoid arthritis and other inflammatory disorders. The aim of the present study is to scientifically validate the traditional use of BA in the treatment of inflammatory disorders. MATERIALS AND METHODS: Anti-inflammatory and anti-granuloma activity of BA hydroalcoholic extract (BAHE) were evaluated in experimental models, viz., carrageenan-induced paw edema, cotton pellet-induced granuloma formation, and complete Freund's adjuvant-induced stimulation of peritoneal macrophages in rats. Expression of inflammatory mediators, viz., tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-10, TNF-R1, and cyclooxygenase-2 (COX-2) was carried out in serum and peritoneal macrophages to derive the plausible mechanism of BAHE in activated peritoneal macrophages. RESULTS: Pretreatment with BAHE produced a dose-dependent reduction (P < 0.01) in carrageenan-induced paw edema and cotton pellet-induced granuloma model. BAHE treatment produced significant (P < 0.01) reduction in serum inflammatory cytokine levels as compared to control. Protein expression of pro-inflammatory markers, IL-1β, IL-6, TNF-R1, and COX-2, was found to be reduced in stimulated macrophages whereas anti-inflammatory cytokine, IL-10, was upregulated in peritoneal macrophages. CONCLUSION: The result of the present study thus demonstrates the anti-inflammatory and anti-granuloma activity of BAHE which may be attributed to its inhibitory activity on macrophage-derived cytokine and mediators.
27056250 Feasibility and efficacy of a robotic device for hand rehabilitation in hemiplegic stroke 2017 Mar OBJECTIVE: The purpose of the study was to evaluate the feasibility and efficacy of robot-assisted hand rehabilitation in improving arm function abilities in sub-acute hemiplegic patients. DESIGN: Randomized controlled pilot study. SETTING: Inpatient rehabilitation centers. PARTICIPANTS: Thirty hemiplegic stroke patients (Ashworth spasticity index <3) were recruited and randomly divided into a Treatment group (TG) and Control group (CG). INTERVENTIONS: Patients in the TG received intensive hand training with Gloreha, a hand rehabilitation glove that provides computer-controlled, repetitive, passive mobilization of the fingers, with multisensory feedback. Patients in the CG received the same amount of time in terms of conventional hand rehabilitation. MAIN OUTCOME MEASURES: Hand motor function (Motricity Index, MI), fine manual dexterity (Nine Hole Peg Test, NHPT) and strength (Grip and Pinch test) were measured at baseline and after rehabilitation, and the differences, (Δ) mean(standard deviation), compared between groups. Results Twenty-seven patients concluded the program: 14 in the TG and 13 in the CG. None of the patients refused the device and only one adverse event of rheumatoid arthritis reactivation was reported. Baseline data did not differ significantly between the two groups. In TG, ΔMI 23(16.4), ΔNHPT 0.16(0.16), ΔGRIP 0.27(0.23) and ΔPINCH 0.07(0.07) were significantly greater than in CG, ΔMI 5.2(9.2), ΔNHPT 0.02(0.07), ΔGRIP 0.03(0.06) and ΔPINCH 0.02(0.03)] ( p=0.002, p=0.009, p=0.003 and p=0.038, respectively). CONCLUSIONS: Gloreha Professional is feasible and effective in recovering fine manual dexterity and strength and reducing arm disability in sub-acute hemiplegic patients.
27025255 Soluble alpha-enolase activates monocytes by CD14-dependent TLR4 signalling pathway and ex 2016 Mar 30 Rheumatoid arthritis (RA) is the most common form of chronic inflammatory rheumatism. Identifying auto-antigens targeted by RA auto-antibodies is of major interest. Alpha-enolase (ENO1) is considered to be a pivotal auto-antigen in early RA but its pathophysiologic role remains unknown. The main objective of this study was to investigate the in vitro effects of soluble ENO1 on peripheral blood mononuclear cells (PBMC) from healthy donors and RA patients in order to determine the potential pathogenic role of ENO1. ELISA, transcriptomic analysis, experiments of receptor inhibition and flow cytometry analysis were performed to determine the effect, the target cell population and the receptor of ENO1. We showed that ENO1 has the ability to induce early production of pro-inflammatory cytokines and chemokines with delayed production of IL-10 and to activate the innate immune system. We demonstrated that ENO1 binds mainly to monocytes and activates the CD14-dependent TLR4 pathway both in healthy subjects and in RA patients. Our results establish for the first time that ENO1 is able to activate in vitro the CD14-dependent TLR4 pathway on monocytes involving a dual mechanism firstly pro-inflammatory and secondly anti-inflammatory. These results contribute to elucidating the role of this auto-antigen in the pathophysiologic mechanisms of RA.
26853723 Trans-presentation of interleukin-15 by interleukin-15 receptor alpha is dispensable for t 2017 Jul Interleukin-15 (IL-15) is a pro-inflammatory cytokine that is required for the survival and activation of memory CD8(+)T cells, natural killer (NK) cells, innate lymphoid cells, macrophages and dendritic cells. IL-15 is implicated in the pathogenesis of various autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, psoriasis and autoimmune type 1 diabetes (T1D). IL-15 receptor (IL-15R) consists of a specific α chain, the β chain that is shared with IL-2R and the common γ chain. IL-15 is unique in the manner in which it binds and signals through its receptor subunits. IL-15 that is complexed with IL-15Rα binds to the βγ receptor complex present on the responding cell to mediate its biological effects through a process referred to as trans-presentation. The trans-presented IL-15 is essential to mediate the biological effects on T lymphocytes and NK cells. Here we show that IL-15, but not IL-15Rα, is required for the development of spontaneous and virus-induced T1D, viral clearance and for antigen cross-presentation to CD8(+) T lymphocytes. Our findings provide insight into the complexities of IL-15 signalling in the initiation and maintenance of CD8(+) T cell-mediated immune responses.
26614192 Increased risk of pulmonary and extra-pulmonary tuberculosis in patients with rheumatic di 2015 Dec SETTING: Impaired immunity in patients with rheumatic diseases can increase the risk of pulmonary tuberculosis (PTB). However, it is less clear whether rheumatic diseases affect the risk of extra-pulmonary tuberculosis (EPTB). OBJECTIVE: To investigate the risk of PTB and EPTB in patients with rheumatic diseases using a population-based database. DESIGN: From Taiwan's National Health Insurance Research Database, 8536 patients with tuberculosis (TB) were frequency-matched with 42,680 controls for sex, 10-year age group and index year. Subjects were retrospectively traced back for their first diagnosis of rheumatic diseases. The association between TB and rheumatic diseases was assessed using multivariate logistic regression analyses. RESULTS: The risk of developing PTB was significantly higher in patients with systemic lupus erythematosus (adjusted odds ratio [aOR] 4.90, P < 0.001), rheumatoid arthritis (RA) (aOR 2.00, P < 0.001) and Sjögren's syndrome (aOR 6.11, P < 0.001). In addition, the risks of developing EPTB were significantly higher in RA patients (aOR 4.67, P < 0.001), those with Sjögren's syndrome (aOR 5.94, P < 0.001), and the group comprising progressive systemic sclerosis, polymyositis or dermatomyositis (aOR 8.31, P = 0.021). CONCLUSION: Elevated risks of PTB and EPTB were associated with various rheumatic diseases. Rheumatologists should be vigilant to the possibility of TB, and particularly EPTB, in their patients.
26538822 Marine Diterpenoids as Potential Anti-Inflammatory Agents. 2015 The inflammatory response is a highly regulated process, and its dysregulation can lead to the establishment of chronic inflammation and, in some cases, to death. Inflammation is the cause of several diseases, including rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis, and asthma. The search for agents inhibiting inflammation is a great challenge as the inflammatory response plays an important role in the defense of the host to infections. Marine invertebrates are exceptional sources of new natural products, and among those diterpenoids secondary metabolites exhibit notable anti-inflammatory properties. Novel anti-inflammatory diterpenoids, exclusively produced by marine organisms, have been identified and synthetic molecules based on those structures have been obtained. The anti-inflammatory activity of marine diterpenoids has been attributed to the inhibition of Nuclear Factor-κB activation and to the modulation of arachidonic acid metabolism. However, more research is necessary to describe the mechanisms of action of these secondary metabolites. This review is a compilation of marine diterpenoids, mainly isolated from corals, which have been described as potential anti-inflammatory molecules.
26524851 A Hospital-Based Analysis in the Department of Clinical Chemistry for the Patients with HB 2015 Mar OBJECTIVES: Anti-cancer and immunosuppressive drugs often induce hepatitis B virus (HBV) reactivation, resulting in lethal hepatitis in the worst cases. It is to elucidate the clinical characteristics of the patients in our hospital, who underwent HBV-related examinations to help prevent HBV-associated hepatitis by reactivation during the two-year period after the announcement of new guidelines by the Ministry of Health, Labour and Welfare of Japan in January 2009. STUDY DESIGN: We enrolled 811 patients who were examined for HBs antigen, anti-HBc antibody, anti-HBs antibody and HBV DNA regarding HBV reactivation. RESULTS: The underlying diseases were hematological malignancies, followed by various other cancers, rheumatoid arthritis, Crohn's disease, and so on. The patients in their 60s showed the peak in the age distribution. The positive ratio of anti-HBc antibody was higher over the age of 40. The rate of reactivation was 7.7% in HBV carriers and 2.0% in the HBV-resolved patients. HBV reactivation occurred in two HBV carriers and four HBV-resolved patients. The three patients, showing hepatitis were two HBV carriers and one HBV-resolved patient without monitoring of HBV DNA, because their therapies started before announcement of the guidelines. In other three patients with reactivation from HBV-resolved infections, HBV DNA returned under detection by immediate administration of entecavir without following hepatitis. CONCLUSION: The patients at high risk of HBV reactivation were prevented from HBV-related hepatitis only by following the guideline. The screening for such patients and monitoring HBV DNA in the guideline are requisite to prevent HBV-related hepatitis.
26493164 Intravenous infusion of H2-saline suppresses oxidative stress and elevates antioxidant pot 2015 Oct 23 Upon intensive, exhaustive exercise, exercise-induced reactive oxygen species may exceed the antioxidant defence threshold, consequently resulting in muscular damage or late-onset chronic inflammation. Recently, the therapeutic antioxidant and anti-inflammatory effects of molecular hydrogen (H2) for human rheumatoid arthritis have been demonstrated. However, it is also important to clarify the effects of administrating H2 in large animals other than humans, as H2 is thought to reach the target organ by passive diffusion upon delivery from the blood flow, indicating that the distance from the administration point to the target is critical. However, data on the effects of H2 on oxidative stress in real-life exhaustive exercise in large animals are currently lacking. We here investigated 13 Thoroughbred horses administered intravenous 2-L saline with or without 0.6-ppm H2 (placebo, N = 6; H2, N = 7) before participating in a high-intensity simulation race. Intravenous H2-saline significantly suppressed oxidative stress immediately, 3 h, and 24 h after the race, although the antioxidant capability was not affected throughout the study. The serum creatine kinase, lactate, and uric acid levels were increased in both groups. Taken together, these results indicate that intravenous H2-saline can significantly and specifically suppress oxidative stress induced after exhaustive racing in Thoroughbred horses.
26450448 Eriodicyol inhibits osteoclast differentiation and ovariectomy-induced bone loss in vivo. 2015 Dec 10 Osteoclasts are responsible for bone erosion in diseases such as osteoporosis and rheumatoid arthritis. In the present study, we investigate the effects of eriodictyol, a flavonoid found naturally in citrus fruits, on the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation using mouse bone marrow macrophages (BMMs). Eriodictyol inhibited RANKL-induced osteoclast formation in a dose-dependent manner without cytotoxicity. In addition, eriodictyol suppressed bone resorption activity of differentiated osteoclasts. The inhibitory effect of eriodictyol was associated with impaired activation of multiple signaling events downstream of RANK, including extracellular signal-regulated kinase, p38, and c-Jun terminal kinase phosphorylation, followed by decreased nuclear factor of activated T cells (NFAT)c1 expression. Ectopic overexpression of a constitutively active form of NFATc1 completely rescued the anti-osteoclastogenic effect of eriodictyol, suggesting that the anti-osteoclastogenic effect was mainly attributed to the reduction in NFATc1 expression. Consistent with the in vitro anti-osteoclastogenic effect, eriodictyol suppressed lipopolysaccharide-induced osteoclast formation in the calvarial model and ovariectomy-induced bone loss in vivo. Taken together, our data demonstrate that eriodictyol is a new therapeutic agent with the potential to prevent bone destructive diseases by reducing both osteoclast differentiation and function.
26219390 Small Molecules as Anti-TNF Drugs. 2015 Tumor necrosis factor (TNF, TNF-α, cachectin) is a pleiotropic, proinflammatory cytokine with multiple biological effects, many of which are not yet fully understood. Although TNF was initially described as an anti-tumor agent more than three decades ago, current knowledge places it central to immune system homeostasis. TNF plays a critical role in host defense against infection, as well as an inhibitory role in autoimmune disease. However, TNF overproduction generates deleterious effects by inducing the transcription of genes involved in acute and chronic inflammatory responses including asthma, rheumatoid arthritis, Crohn's disease, and psoriasis. Direct inhibition of TNF by biologics, such as monoclonal antibodies and circulating TNF receptor constructs, has produced effective treatments for these disorders and validated the inhibition of this proinflammatory cytokine as an effective therapy. Unfortunately, these biological therapies suffer from several drawbacks, including high cost and the induction of autoantibody production. Thus, the development of small molecules able to modulate TNF production or signaling pathways remains a central challenge in Medicinal Chemistry. Considerable efforts have been made over the past two decades to develop such inhibitors, which could potentially be administered orally and would presumably be cheaper. This review is focused on the recent development of compounds that modulate the activity of this cytokine by acting at different levels, such as TNF expression, processing, binding to its receptors and direct inhibition. These approaches will be compared and discussed.
26202894 Factors associated with atypical femoral fracture. 2016 Jan We aimed to investigate the proportion of atypical femoral fractures (AFF) among Korean femoral fracture patients and examined the factors associated with the development of AFF. Between 2003 and 2013, 607 female patients with low-energy femoral fractures who were hospitalized at a single university hospital were retrospectively enrolled in this study. Patients were classified into two groups according to the fracture site: Patients with subtrochanteric or diaphyseal femoral fractures were included in the AFF group, while patients with intertrochanteric or neck fractures were included in the typical femoral fracture (TFF) group. After comparing clinical and radiographic characteristics between groups, we used multivariable logistic regression analysis to explore risk factors for AFF. Thirty patients (4.9 %) with AFF and 577 patients (95.1 %) with TFF were identified. The AFF group was younger than the TFF group (p < 0.01), and more patients with AFF were treated with bisphosphonate (BP) (p < 0.01) or proton-pump inhibitor (p = 0.02). When comparing the radiographic parameters, the AFF group tended to have a higher cortical thickness index (p = 0.02) and lateral-to-medial cortex ratio (p < 0.01). After adjusting for clinical variables, BP use (OR 8.09, CI 3.09-21.19) and younger age (OR 1.06, CI 1.01-1.11) were associated with AFF. The proportion of AFF was 4.9 % among patients with femoral fractures. Younger age and use of BP before fracture increased the risk of development of AFF in Korean patients.
26164648 Genetics and novel aspects of therapies in systemic lupus erythematosus. 2015 Nov Autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, autoimmune hepatitis and inflammatory bowel disease, have complex pathogeneses and the factors which cause these disorders are not well understood. But all have in common that they arise from a dysfunction of the immune system, interpreting self components as foreign antigens. Systemic lupus erythematosus (SLE) is one of these complex inflammatory disorders that mainly affects women and can lead to inflammation and severe damage of virtually any tissue and organ. Recently, the application of advanced techniques of genome-wide scanning revealed more genetic information about SLE than previously possible. These case-control or family-based studies have provided evidence that SLE susceptibility is based (with a few exceptions) on an individual accumulation of various risk alleles triggered by environmental factors and also help to explain the discrepancies in SLE susceptibility between different populations or ethnicities. Moreover, during the past years new therapies (autologous stem cell transplantation, B cell depletion) and improved conventional treatment options (corticosteroids, traditional and new immune-suppressants like mycophenolate mofetile) changed the perspective in SLE therapeutic approaches. Thus, this article reviews genetic aspects of this autoimmune disease, summarizes clinical aspects of SLE and provides a general overview of conventional and new therapeutic approaches in SLE.