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ID PMID Title PublicationDate abstract
20004733 Metabolic engineering of omega-3 long-chain polyunsaturated fatty acids in plants using an 2010 May Long-chain (> or = C20) polyunsaturated fatty acids (LC-PUFA) EPA and DHA (20:5(Delta5,8,11,14,17) and 22:6(Delta4,7,10,13,16,19)) have well-documented health benefits against coronary heart disease, rheumatoid arthritis and other disorders. Currently, the predominant sources of these fatty acids are marine fish and algal oils, but research is being conducted to ensure that a sustainable, land-based production system can be developed. We here describe the metabolic engineering of an artificial pathway that produces 26% EPA in leaf triacylglycerol using a newly-identified Delta6-desaturase from the marine microalga Micromonas pusilla. We also demonstrate that this enzyme appears to function as an acyl-CoA desaturase that has preference for omega3 substrates both in planta and in yeast. Phylogenetic analysis indicates that this desaturase shares highly conserved motifs with previously described acyl-CoA Delta6-desaturases.
19997529 Do Genetic Alterations in Sex Steroid Receptors Contribute to Lacrimal Gland Disease in Sj 2009 BACKGROUND: Defects in sex steroid receptors have been linked to the onset, progression and severity, as well as the sex-related prevalence, of a variety of autoimmune disorders, including lupus, rheumatoid arthritis, multiple sclerosis and diabetes. We hypothesize that defects in estrogen receptor alpha (ESR1), estrogen receptor beta (ESR2) and/or the androgen receptor (AR) may also contribute to the development of lacrimal gland autoimmune sequelae in Sjögren's syndrome. To begin to test this hypothesis, we examined whether mutations exist in the coding regions of ESR1, ESR2 and AR transcripts in lacrimal tissues of mouse models of Sjögren's syndrome. METHODS: Lacrimal and submandibular glands were collected from adult MRL/MpJ-Tnfrsf6(lpr), nonobese diabetic and/or BALB/c mice. Tissues were pooled according to sex and experiment and processed for cDNA generation. PCR primers were designed to amplify 566-875 base pair segments of the entire open reading frame of each receptor. Segments were amplified, purified and then sequenced. Receptor sequences were assembled and compared to each other and to known NCBI sequences. RESULTS: Our results show that almost all ESR1, ESR2 and AR sequences in exocrine tissues of male and female autoimmune and non-autoimmune mice were identical to those of NCBI standards. There was a G-->A shift at position 998 of the ESR2 complete coding sequence in all tissue samples when compared to NCBI reference sequence U81451.1, but this polymorphism was not found in other ESR2 reference sequences. CONCLUSIONS: Our findings indicate that defects in the coding region of sex steroid receptors do not contribute to the pathogenesis of lacrimal gland disease in mouse models of Sjögren's syndrome.
19796558 An evaluation of the efficacy of the toe brachial index measuring vascular involvement in 2009 May OBJECTIVE: The ankle and toe brachial indices (ABI and TBI) are calculated as the ankle and toe systolic blood pressures divided by the highest brachial systolic pressure, respectively. We sought to evaluate the efficacy of ABI and TBI as an objective, non-invasive assessment of vascular involvement in patients with systemic sclerosis (SSc) and to investigate the clinical significance of TBI in SSc. METHODS: ABI and TBI were measured using an oscillometric method in 136 outpatients, including 77 with SSc, 29 with systemic lupus erythematosus (SLE), 16 with primary Sjögren's syndrome (SjS), and 14 with dermatomyositis (DM). We also analyzed 21 healthy controls. RESULTS: The mean ABI and frequency of reduced ABI values (%1.0) did not differ significantly between disease groups. TBI values in patients with SSc and lSSc were significantly lower than in those with SjS and DM, respectively (p%0.01). Patients with SSc and lSSc had significantly lower TBI values than healthy controls (p%0.05). Reduced TBI values (%0.6) were significantly more common in patients with SSc, including both dSSc and lSSc, than in those with SLE (p%0.05). Similarly, the frequency of decreased TBI was higher in patients with SSc and dSSc than in those with SjS or healthy controls (p%0.05). Skin ulcers (p=0.041) or overlap with rheumatoid arthritis (p=0.018) were associated with reduced TBI values by logistic regression analysis. CONCLUSION: The TBI value is a useful, non-invasive tool to evaluate vascular involvement in SSc.
19947998 Clinical characteristics of acute respiratory deterioration in pulmonary fibrosis associat 2010 Jan BACKGROUND AND OBJECTIVE: To clarify the clinical characteristics and risk factors for acute respiratory deterioration following anti-cancer therapy in patients with pulmonary fibrosis (PF) and lung cancer. METHODS: Patients with primary lung cancer and PF were identified by review of medical records. Of the 865 consecutive patients with primary lung cancer who had been treated between June 1999 and September 2007, 53 were diagnosed as having PF. This retrospective study analysed the prevalence of and risk factors for acute respiratory deterioration after treatment of lung cancer in these patients. RESULTS: Acute respiratory deterioration was found in 10 (24%) of the 41 patients who received anti-cancer therapy, and six (60%) of these patients died of respiratory failure. The incidence of acute respiratory deterioration was 28% (8/29) after chemotherapy and 16% (2/12) after surgery. Mortality after acute respiratory deterioration was 50% (4/8) among patients with idiopathic PF and 100% (2/2) among the patients with PF associated with rheumatoid arthritis. Logistic regression analysis revealed that a higher smoking index (cigarettes smoked per day x years of smoking) was a significant risk factor for acute respiratory deterioration (odds ratio: 1.002, P = 0.025). CONCLUSIONS: Patients with lung cancer who have pre-existing PF should be carefully managed because of their high risk for developing acute respiratory deterioration after anti-cancer therapy.
19861045 Nontuberculous mycobacteria infections and anti-tumor necrosis factor-alpha therapy. 2009 Oct Patients receiving anti-tumor necrosis factor-alpha (anti-TNF-alpha) therapy are at increased risk for tuberculosis and other granulomatous diseases, but little is known about illness caused by nontuberculous mycobacteria (NTM) in this setting. We reviewed the US Food and Drug Administration MedWatch database for reports of NTM disease in patients receiving anti-TNF-alpha therapy. Of 239 reports collected, 105 (44%) met NTM disease criteria. Median age was 62 years; the majority of patients (66, 65%) were female, and most (73, 70%) had rheumatoid arthritis. NTM infections were associated with infliximab (n = 73), etanercept (n = 25), and adalimumab (n = 7); most patients were taking prednisone (n = 68, 65%) or methotrexate (n = 58, 55%) concurrently. Mycobacteria avium (n = 52, 50%) was most commonly implicated, and 9 patients (9%) had died at the time their infections were reported. A high rate of extrapulmonary manifestations (n = 46, 44%) was also reported.
19731623 RANKL/RANK as key factors for osteoclast development and bone loss in arthropathies. 2009 Osteoporosis or rheumatoid arthritis are bone diseases affecting hundreds of millions of people worldwide and thus pose a tremendous burden to health care. Ground-breaking discoveries made in basic science over the last decade shed light on the molecular mechanisms of bone metabolism and bone turnover. Thereby, it became possible over the past years to devise new and promising strategies for treating such diseases. In particular, three molecules, the receptor activator of NF-kappaB (RANK), its ligand RANKL and the decoy receptor of RANKL, osteoprotegerin (OPG), have been a major focus of scientists and pharmaceutical companies alike, since experiments using mice in which these genes have been inactivated unanimously established their pivotal role as central regulators ofosteoclast function. RANK(L) signaling not only activates a variety of downstream signaling pathways required for osteoclast development, but crosstalk with other signaling pathways also fine-tunes bone homeostasis both in normal physiology and disease. Consequently, novel drugs specifically targeting RANK-RANKL and their signaling pathways in osteoclasts are expected to revolutionize the treatment ofvarious bone diseases, such as cancer metastases, osteoporosis, or arthropathies.
19527714 Methotrexate and aminopterin lack in vivo antimalarial activity against murine malaria spe 2009 Oct The antifolate anticancer drug methotrexate (MTX) has potent activity against Plasmodium falciparum in vitro. Experience of its use in the treatment of rheumatoid arthritis indicates that it could be safe and efficacious for treating malaria. We sought to establish a murine malaria model to study the mechanism of action and resistance of MTX and its analogue aminopterin (AMP). We used Plasmodium berghei, Plasmodium yoelii yoelii, Plasmodium chabaudi and Plasmodium vinckei. None of these species were susceptible to either drug. We have also tested the efficacy of pyrimethamine in combination with folic acid in P. berghei, and data indicate that folic acid does not influence pyrimethamine efficacy, which suggests that P. berghei may not transport folate. Since MTX and AMP utilise folate receptor/transport to gain access to cells, their lack of efficacy against the four tested murine malaria species may be the result of inefficiency of drug transport.
19326065 [Quadsparing approach in total knee arthroplasty]. 2009 Mar OBJECTIVE: Approach to the knee joint for total knee arthroplasty (TKA) with gentle soft-tissue handling. INDICATIONS: Primary TKA with range of motion>or=100 degrees, leg axis up to 10 degrees varus or valgus, body weight<100 kg. CONTRAINDICATIONS: Contracted knees, leg axis>10 degrees varus or valgus, obesity, previous knee surgery except arthroscopic procedures, rheumatoid arthritis. SURGICAL TECHNIQUE: Anterior midline incision. Soft-tissue preparation and capsule incision start at the upper tip of the patella and are continued distally along the medial patellar border ending at the tibial tuberosity. After opening of the joint, the patella is dislocated laterally without everting it. Exposure of the articular surface using a "mobile window". Preparation and insertion of the TKA components using special instruments. Wound closure in layers. POSTOPERATIVE MANAGEMENT: Mobilization on crutches with full weight bearing starting on the day of surgery. Daily medical training therapy. Passive motion therapy continued twice a day. Low-dose heparin s.c. for 35 days after surgery. RESULTS: In a prospective randomized clinical study, 50 patients with a quadsparing (QS) approach were observed up to 3 months after surgery. In three patients, the use of large femoral components required an extended approach. During the hospital stay knee flexion was significantly greater in patients with the QS approach than in patients with the standard procedure (midvastus approach). There were no differences in implant positioning, Knee Society Score and complication rate between both groups. Use of the QS approach prolonged the duration of surgery by 25 min.
19005742 Nanometer- and submicrometer-sized hollow spheres of chondroitin sulfate as a potential fo 2009 Feb PURPOSE: The synthesis of nanometer and submicrometer hollow particles could be a motivating way to imprint new therapeutic properties into a chondroitin sulfate-based hydrogel formulation. The use of hollowed polymer structures as a formulation strategy is expected to have an impact in the effective therapy in the treatment of rheumatoid arthritis. METHODS: Chemical modification of the chondroitin sulfate with glycidyl methacrylate (GMA) was performed in water under thermal and acid stimuli. The hydrogel spheres were formed upon cross-linking reaction of modified chondroitin sulfate (CSM) in a water-in-benzyl alcohol nano-droplet emulsion. RESULTS: 1H NMR and 13C NMR spectra showed that the carbon-carbon pi-bonds coming from the GMA were incorporated onto backbones of CS. 13C-CP/MAS NMR spectra revealed that the formation of the CSM hydrogel spheres during the dispersion stage occurred by way of carbon-carbon pi-bonds on the CSM structure. The spherical shapes of the particles with diameters in the range of 20 microm to 500 nm were very clearly verified by SEM images where the dark center and edge of the hollow spheres could be identified easily. CONCLUSIONS: Nanometer- and submicrometer-sized hydrogel spheres with hollow interior were produced from chondroitin sulfate by using a new strategy of hydrogel synthesis.
18764781 The crystal structure of rabbit IgG-Fc. 2009 Jan 1 We report the structure of the Fc fragment of rabbit IgG at 1.95 A (1 A=0.1 nm) resolution. Rabbit IgG was the molecule for which Porter established the four-chain, Upsilon-shaped structure of the antibody molecule, and crystals of the Fc ('Fragment crystallisable') were first reported almost 50 years ago in this journal [Porter, R. R. (1959) Biochem. J. 73, 119-126]. This high-resolution analysis, apparently of the same crystal form, reveals several features of IgG-Fc structure that have not previously been described. More of the lower hinge region is visible in this structure than in others, demonstrating not only the acute bend in the IgG molecule that this region can mediate, as seen in receptor complexes, but also that this region has a tendency to adopt a bent structure even in the absence of receptor. As observed in other IgG-Fc structures, the Cgamma2 domains display greater mobility/disorder within the crystals than the Cgamma3 domains; unexpectedly the structure reveals partial cleavage of both Cgamma2 intra-domain disulphide bonds, whereas an alternative conformation for one of the cysteine residues in the intact bridge within the more ordered Cgamma3 domains is observed. The N-linked oligosaccharide chains at Asn(297) are well-defined and reveal two alternative conformations for the galactose units on each of the alpha(1-6)-linked branches. The presence of this galactose unit is important for stabilizing the structure of the entire branched carbohydrate chain, and its absence correlates with the severity of autoimmune conditions such as rheumatoid arthritis in both human clinical studies and in a rabbit model of the disease. Rabbit IgG, through this high-resolution structure of its Fc region, thus continues to offer new insights into antibody structure.
19799917 A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory di 2010 Aug 7 Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a key transcription factor that plays a central role in cellular defense against oxidative and electrophilic insults by timely induction of antioxidative and phase-2 detoxifying enzymes and related stress-response proteins. The 5'-flanking regions of genes encoding these cytoprotective proteins contain a specific consensus sequence termed antioxidant response element (ARE) to which Nrf2 binds. Recent studies have demonstrated that Nrf2-ARE signaling is also involved in attenuating inflammation-associated pathogenesis, such as autoimmune diseases, rheumatoid arthritis, asthma, emphysema, gastritis, colitis and atherosclerosis. Thus, disruption or loss of Nrf2 signaling causes enhanced susceptibility not only to oxidative and electrophilic stresses but also to inflammatory tissue injuries. During the early-phase of inflammation-mediated tissue damage, activation of Nrf2-ARE might inhibit the production or expression of pro-inflammatory mediators including cytokines, chemokines, cell adhesion molecules, matrix metalloproteinases, cyclooxygenase-2 and inducible nitric oxide synthase. It is likely that the cytoprotective function of genes targeted by Nrf2 may cooperatively regulate the innate immune response and also repress the induction of pro-inflammatory genes. This review highlights the protective role of Nrf2 in inflammation-mediated disorders with special focus on the inflammatory signaling modulated by this redox-regulated transcription factor.
19796214 Health-related quality of life of food allergic patients: comparison with the general popu 2010 Feb BACKGROUND: To date no studies have compared generic health-related quality of life (HRQL) of food allergic patients from childhood to adulthood with that of the general population or patients with other chronic diseases. The aim of this study was to compare generic HRQL of food allergic patients with the general population and other diseases. METHODS: Generic HRQL questionnaires (CHQ-CF87 and RAND-36) were completed by 79 children, 74 adolescents and 72 adults with food allergy. The generic HRQL scores were compared with scores from published studies on the general population and patients with asthma, irritable bowel syndrome (IBS), diabetes mellitus (DM) and rheumatoid arthritis (RA). RESULTS: Food allergic children and adolescents reported fewer limitations in school work due to behavioural problems (P < or = 0.013), but food allergic adolescents and adults reported more pain (P = 0.020), poorer overall health (P < 0.001), more limitations in social activities (P < 0.001) and less vitality (P = 0.002) than individuals from the general population. Food allergic patients reported poorer generic HRQL than patients with DM, but better generic HRQL than patients with RA, asthma and IBS. CONCLUSION: HRQL is impaired in food allergic adolescents and adults, compared to the general population, and it is intermediate in magnitude between DM and RA, asthma and IBS. Children show the least impact on generic HRQL from food allergy.
19725696 Prediction of plantar shear stress distribution by artificial intelligence methods. 2009 Sep Shear forces under the human foot are thought to be responsible for various foot pathologies such as diabetic plantar ulcers and athletic blisters. Frictional shear forces might also play a role in the metatarsalgia observed among hallux valgus (HaV) and rheumatoid arthritis (RA) patients. Due to the absence of commercial devices capable of measuring shear stress distribution, a number of linear models were developed. All of these have met with limited success. This study used nonlinear methods, specifically neural network and fuzzy logic schemes, to predict the distribution of plantar shear forces based on vertical loading parameters. In total, 73 subjects were recruited; 17 had diabetic neuropathy, 14 had HaV, 9 had RA, 11 had frequent foot blisters, and 22 were healthy. A feed-forward neural network (NN) and adaptive neurofuzzy inference system (NFIS) were built. These systems were then applied to a custom-built platform, which collected plantar pressure and shear stress data as subjects walked over the device. The inputs to both models were peak pressure, peak pressure-time integral, and time to peak pressure, and the output was peak resultant shear. Root-mean-square error (RMSE) values were calculated to test the models' accuracy. RMSE/actual shear ratio varied between 0.27 and 0.40 for NN predictions. Similarly, NFIS estimations resulted in a 0.28-0.37 ratio for local peak values in all subject groups. On the other hand, error percentages for global peak shear values were found to be in the range 11.4-44.1. These results indicate that there is no direct relationship between pressure and shear magnitudes. Future research should aim to decrease error levels by introducing shear stress dependent variables into the models.
19530995 Are B cells a potential target for therapeutic intervention in the classical T cell-mediat 2009 Jun Incidence of autoimmune diseases is rising rapidly in the developed world and treatment of such diseases will be a major burden on Government health resources of the future. Whether systemic or organ-specific, immune cell destruction of the target tissue normally requires co-operative interaction of a many distinct immune cells. Detailed knowledge of the cells and signal pathways involved in tissue destruction is paramount to the design of novel therapeutics. Several organ-specific autoimmune diseases e.g. multiple sclerosis, rheumatoid arthritis and type 1 diabetes have long been attributed to T cell-mediated destruction of the target tissue. However, recent reports from both murine models and man have suggested that B cells are principal players in these T cell-mediated diseases. In this review, we discuss the evidence that supports a link between B cells and the autoaggressive T cell response in type 1 diabetes and how accumulating evidence suggests targeting B cells may offer a novel therapeutic strategy for this autoimmune disease.
20176691 Identification and characterization of human UDP-glucuronosyltransferases responsible for 2010 Jun Daphnetin has been developed as an oral medicine for treatment of coagulation disorders and rheumatoid arthritis in China, but its in vitro metabolism remains unknown. In the present study, the UDP-glucuronosyltransferase (UGT) conjugation pathways of daphnetin were characterized. Two metabolites, 7-O-monoglucuronide daphnetin (M-1) and 8-O-monoglucuronide daphnetin (M-2), were identified by liquid chromatography/mass spectrometry and NMR when daphnetin was incubated, respectively, with liver microsomes from human (HLM), rat (RLM), and minipig (PLM) and human intestinal microsomes (HIM) in the presence of UDP-glucuronic acid. Screening assays with 12 human recombinant UGTs demonstrated that the formations of M-1 and M-2 were almost exclusively catalyzed by UGT1A9 and UGT1A6, whereas M-1 was formed to a minor extent by UGT1A3, 1A4, 1A7, 1A8, and 1A10 at a high substrate concentration. Kinetics studies, chemical inhibition, and correlation analysis were used to demonstrate that human UGT1A9 and UGT1A6 were major isoforms involved in the daphnetin glucuronidations in HLM and HIM. By in vitro-in vivo extrapolation of the kinetic data measured in HLM, the hepatic clearance and the corresponding hepatic extraction ratio were estimated to be 19.3 ml/min/kg b.wt. and 0.93, respectively, suggesting that human clearance of daphnetin via the glucuronidation is extensive. Chemical inhibition of daphnetin glucuronidation in HLM, RLM, and PLM showed large species differences although the metabolites were formed similarly among the species. In conclusion, the UGT conjugation pathways of daphnetin were fully elucidated and its C-8 phenol group was more selectively catalyzed by UGTs than by the C-7 phenol.
20161715 Eukaryotic DING proteins are endogenous: an immunohistological study in mouse tissues. 2010 Feb 8 BACKGROUND: DING proteins encompass an intriguing protein family first characterized by their conserved N-terminal sequences. Some of these proteins seem to have key roles in various human diseases, e.g., rheumatoid arthritis, atherosclerosis, HIV suppression. Although this protein family seems to be ubiquitous in eukaryotes, their genes are consistently lacking from genomic databases. Such a lack has considerably hampered functional studies and has fostered therefore the hypothesis that DING proteins isolated from eukaryotes were in fact prokaryotic contaminants. PRINCIPAL FINDINGS: In the framework of our study, we have performed a comprehensive immunological detection of DING proteins in mice. We demonstrate that DING proteins are present in all tissues tested as isoforms of various molecular weights (MWs). Their intracellular localization is tissue-dependant, being exclusively nuclear in neurons, but cytoplasmic and nuclear in other tissues. We also provide evidence that germ-free mouse plasma contains as much DING protein as wild-type. SIGNIFICANCE: Hence, data herein provide a valuable basis for future investigations aimed at eukaryotic DING proteins, revealing that these proteins seem ubiquitous in mouse tissue. Our results strongly suggest that mouse DING proteins are endogenous. Moreover, the determination in this study of the precise cellular localization of DING proteins constitute a precious evidence to understand their molecular involvements in their related human diseases.
20160715 Changes in liver biochemistry during methotrexate use for inflammatory bowel disease. 2010 Jul OBJECTIVES: We aimed to characterize the spectrum of liver enzyme test (LET) abnormalities that occur while using methotrexate for inflammatory bowel disease (IBD). METHODS: A retrospective review was undertaken of subjects using methotrexate for IBD at a single center. The clinical and epidemiological parameters, and hepatotoxicity risk factors, were recorded. Subjects were excluded if cumulative methotrexate doses could not be ascertained, if they had a diagnosis of rheumatoid arthritis or psoriasis, or if baseline and follow-up LETs were not available. Also noted were the cumulative methotrexate dose during the peak LET increase, severity of LET increase, and whether normalization occurred. RESULTS: Eighty-seven subjects were included (Crohn's disease, n=67; UC, n=17; indeterminate colitis n=3). The mean therapy duration was 81 weeks (3- to 364-week range), and the cumulative average dose was 1,813 mg (25-8,255-mg range). Thirty-seven (43%) subjects received a cumulative dose >1,500 mg. Sixty-seven (77%) had normal LETs, and in 51 (76%) LETs remained normal throughout methotrexate therapy. In the 16 (24%) who developed LET abnormalities, seven (44%) had underlying risk factor(s) for liver disease. Normalization (without dose reduction) occurred in 14 (88%) while continuing methotrexate. Of 20 subjects with abnormal LETs at baseline, nine (45%) subsequently normalized while continuing methotrexate, whereas nine (45%) worsened. Seventeen liver biopsies were performed in 11 and were classified as Roenigk's grade I in 15 (88%) subjects. Roenigk IIIb or IV was not seen. CONCLUSIONS: Methotrexate is commonly associated with LET abnormalities, but these frequently normalize while still on therapy, and in only 5% will drug discontinuation be necessary. Liver biopsies rarely have substantive abnormalities.
19951375 Anti-infliximab IgE and non-IgE antibodies and induction of infusion-related severe anaphy 2010 May BACKGROUND: Infliximab is a chimeric monoclonal antibody against TNF-alpha useful in the treatment of many chronic inflammatory diseases. Severe anaphylaxis has been reported during therapy, although the exact mechanism has not been fully defined. The reactions have been related to the infliximab immunogenicity and development of specific antibodies. AIMS OF THE STUDY: Evaluation of the development of IgE and non-IgE antibodies to infliximab and their relationship with infusion reaction. METHODS: Seventy-one patients (11 reactives, 11 therapeutically nonresponders, and 49 unreactive therapeutically responders) and 20 non-infliximab-exposed control subjects (ten rheumatoid arthritis, five spondyloarthropathies, five vasculitis) were evaluated for the presence of IgE (ImmunoCAP assay), IgM, and non-isotype-specific (ELISA assays) anti-infliximab antibodies. Sera were obtained at baseline and during the course of treatment, before each infliximab infusion. RESULTS: Eleven out of 71 patients had a hypersensitivity reaction to infliximab. Non-isotype-specific anti-infliximab antibodies were detected in eight reactive and two nonresponder patients. Three patients with severe reactions displayed anti-infliximab IgE antibodies and positive skin testing. Detectable levels of anti-infliximab IgM antibodies were shown in three additional IgE- and skin testing-negative patients. IgE and IgM antibodies to infliximab were not detectable in the two nonresponder patients. Antibodies developed before the 2nd and the 3rd infusion, and their appearance was strictly related to the timing of the reaction. CONCLUSIONS: This report indicates that in some patients with infliximab-related severe reactions, IgE or IgM antibodies against infliximab were detectable. The majority of reactions could be predicted by the appearance of anti-infliximab antibodies.
19788859 Inhibition of methionine sulfoxide reduction by dimethyl sulfoxide. 2009 Sep 30 Dimethyl sulfoxide (DMSO) is widely used in chemistry and biology as a solvent and as a cryoprotectant. It is also used as a pharmaceutical agent for the treatment of interstitial cystitis and rheumatoid arthritis. Previous reports described DMSO as being reduced by methionine-S-sulfoxide reductase (MsrA). However, little is known about the DMSO reduction capability of methionine-R-sulfoxide reductase (MsrB) or its effect on the catalysis of methionine sulfoxide reduction. We show that mammalian MsrB2 and MsrB3 were unable to reduce DMSO. This compound inhibited MsrB2 activity but did not inhibit MsrB3 activity. We further determined that DMSO functions as an inhibitor of MsrA and MsrB2 in the reduction of methionine sulfoxides via different inhibition mechanisms. DMSO competitively inhibited MsrA activity but acted as a non-competitive inhibitor of MsrB2 activity. Our study also demonstrated that DMSO inhibits in vivo methionine sulfoxide reduction in yeast and mammalian cells. [BMB reports 2009; 42(9): 580-585].
19697966 Cytokine antagonists for the treatment of asthma: progress to date. 2009 Asthma is a disease of the airways in which several cytokines such as interleukin (IL)-4, IL-5, IL-13 and tumor necrosis factor-alpha (TNFalpha) play a major role in the development and progression of inflammation, airway hyperresponsiveness, mucus production, and airway remodeling. The conventional anti-inflammatory therapies, represented by inhaled corticosteroids and antileukotrienes, are not always able to provide optimal disease control and it is therefore hoped that cytokine antagonists could achieve this goal in such situations. Anticytokine therapies have been tested in preclinical studies and some have entered clinical trials. Anti-IL-4 therapies have been tested in animal models of allergy-related asthma, but because of unclear efficacy their development was discontinued. However, IL-4/IL-13 dual antagonists and IL-13-specific blocking agents are more promising, as they exhibit more sustained anti-inflammatory effects. IL-5 antagonists have been found to be of limited efficacy in clinical studies but might be useful in conditions characterized by severe hypereosinophilia, and in which asthma is one of the disease manifestations. Unlike other chronic inflammatory conditions, such as rheumatoid arthritis, the use of anti-TNFalpha therapies in asthma might be limited by the unfavorable risk/benefit ratio associated with long-term use. The identification of so-called asthma TNFalpha phenotypes and perhaps the use of a less aggressive treatment regimen might address this important aspect. Other cytokine antagonists (for example for IL-9 or IL-25) are currently being evaluated in the asthma setting, and could open new therapeutic perspectives based on their efficacy and safety.