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ID PMID Title PublicationDate abstract
22290392 A structural modulator of tumor necrosis factor type 1 receptor promotes bone formation un 2012 Mar 15 Recently an increase in the serum levels of a bone formation marker after anti-tumor necrosis factor (TNF)-α therapy in rheumatoid arthritis patients has been reported. However, there remains no direct evidence that TNF-α antagonist could accelerate bone formation under inflammatory condition. Cavity-induced allosteric modification (CIAM) compound, F002, is a newly developed-TNF-α antagonist, which was designed by using the structure of TNF type 1 receptor, thus preventing TNF-α-induced signaling. In this study, we examined whether the CIAM compound can promote bone formation under inflammatory condition induced by lipopolysaccharide (LPS). Thirty-six 10-week-old male mice (C57BL/6J) were used. Half of the mice received 10 mg/kg LPS, while the other half received PBS. Thereafter, incisor extraction was performed at 4 days after either LPS or PBS injection. Intraperitoneal injections of 2 mg/kg/day, 4 mg/kg/day CIAM, or vehicle (10% DMSO) were performed once a day from day 0 to day 7 after incisor tooth extraction. The mice were sacrificed at 21 days after the extraction. The regenerated bone mineral density (BMD) in the tooth socket, and the mineral apposition rate and the bone formation rate, direct evidences of bone formation, were significantly decreased in the LPS-injected group compared to the PBS-injected group. CIAM compound dose-dependently prevented the decrease of BMD under the LPS-injected condition, and promoted both the mineral apposition rate and the bone formation rate significantly compared to the LPS-injected group. We did not observe any significant differences among the PBS-injected groups. Taken together, TNF-α antagonist CIAM compound, was found to accelerate bone formation under LPS-induced inflammatory condition.
22223535 Concordance with guideline recommendations: previous and more recent nonsteroidal anti-inf 2012 Apr BACKGROUND: Clinical practice guidelines for appropriate nonsteroidal anti-inflammatory drug (NSAID) utilisation focus on preventing NSAID-related gastrointestinal (GI), cardiovascular (CV), congestive heart failure (CHF) and renal adverse events. We compared concordance of NSAID prescriptions with clinical practice guideline recommendations in Quebec, pre and post rofecoxib withdrawal from market. METHODS: Data were obtained from the Quebec Health Insurance Agency (RAMQ). All prescriptions for celecoxib and traditional NSAIDs (tNSAIDs) dispensed to patients ≥50 years of age were evaluated for concordance with clinical practice guidelines. Prescriptions were stratified by time period (pre and post rofecoxib withdrawal) and, GI, CV, CHF and renal risk factors at the dispensing date. Gastro-protective agent (GPA) co-prescriptions were also evaluated. RESULTS: We assessed 1,966,793 celecoxib and 1,743,481 tNSAIDs prescriptions. Of celecoxib prescriptions, 87.2% and 86.5% were appropriate in the post- and pre-periods, respectively, compared to 72.6% and 70.1% of tNSAIDs prescriptions, respectively. In logistic regression, 'appropriateness' of celecoxib prescriptions increased with age, rheumatoid arthritis and osteoarthritis (OA), and was higher in the post- versus pre-period (odds ratio 1.22, 95% confidence interval 1.18-1.26); it was lower in women and in patients with higher income. 'Appropriateness' of tNSAID prescriptions decreased in the post-period (0.92, 0.89-0.95), was lower in older persons and those with OA, and higher in women and in higher income patients. Of tNSAID prescriptions that should have received a GPA co-prescription, only 45.6% did. CONCLUSION: Concordance with guideline recommendations increased for celecoxib and decreased for tNSAIDs after rofecoxib withdrawal; GPA co-prescription with tNSAIDs remained suboptimal.
22088307 Synthesis and bio-evaluation of human macrophage migration inhibitory factor inhibitor to 2011 Dec 15 Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, is involved in the development of an array of inflammatory disorders including rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis and sepsis. The synthesis of MIF-inhibitor is a rationale approach to develop novel anti-inflammatory agent to treat multitude of inflammatory diseases. In this work, we have synthesized and evaluated MIF-inhibitory activity of a series of small molecules containing isoxazoline skeleton. Mode of binding of this inhibitor to human MIF (huMIF) was determined by docking studies. The synthesized molecules inhibit tautomerase activity of huMIF. The anti-inflammatory activity of the most active inhibitor, 4-((3-(4-hydroxy-3-methoxyphenyl)-4, 5-dihydroisoxazol-5-yl) methoxy) benzaldehyde (4b) was evaluated against huMIF-induced inflammation in a cellular model (RAW 264.7 cell). Compound 4b significantly inhibits huMIF-mediated NF-κB translocation to the nucleus, up-regulation of inducible nitric oxide synthase and nitric oxide production in RAW 264.7 cell which are the markers for inflammation. The compound 4b is not cytotoxic as evident from cell viability assay. Hence, the compound 4b has potential to be a novel anti-inflammatory agent.
21943244 Xenotropic murine leukemia virus-related virus is not associated with chronic fatigue synd 2011 Sep 24 BACKGROUND: In 2009, xenotropic murine leukemia virus-related virus (XMRV) was reported in 67% of patients with chronic fatigue syndrome (CFS) compared to 4% of controls. Since then numerous reports failed to detect XMRV in other cohorts of CFS patients, and some studies suggested that XMRV sequences in human samples might be due to contamination of these samples with mouse DNA. RESULTS: We determined the prevalence of XMRV in patients with CFS from similar areas in the United States as the original 2009 study, along with patients with chronic inflammatory disorders and healthy persons. Using quantitative PCR, we initially detected very low level signals for XMRV DNA in 15% of patients with CFS; however, the frequency of PCR positivity was no different between patients with CFS and controls. Repeated attempts to isolate PCR products from these reactions were unsuccessful. These findings were supported by our observations that PHA and IL-2 stimulation of peripheral blood mononuclear cells from patients with apparently low levels of XMRV, which induced virus replication in the 2009 report, resulted in the disappearance of the signal for XMRV DNA in the cells. Immunoprecipitation of XMRV-infected cell lysates using serum from patients from whom we initially detected low levels of XMRV DNA followed by immunoblotting with antibodies to XMRV gp70 protein failed to detect antibody in the patients, although one control had a weak level of reactivity. Diverse murine leukemia virus (MLV) sequences were obtained by nested PCR with a similar frequency in CFS patients and controls. Finally, we did not detect XMRV sequences in patients with several chronic inflammatory disorders including rheumatoid arthritis, Bechet's disease, and systemic lupus erythematosus. CONCLUSIONS: We found no definitive evidence for XMRV DNA sequences or antibody in our cohort of CFS patients, which like the original 2009 study, included patients from diverse regions of the United States. In addition, XMRV was not detected in a cohort of patients with chronic inflammatory disorders.
21843641 The non-antibiotic properties of tetracyclines: clinical potential in ophthalmic disease. 2011 Dec INTRODUCTION: Beyond their decades of long use as broad-spectrum antibiotics, tetracyclines and their derivatives have been shown to exhibit non-antimicrobial properties including their ability to interact with matrix metalloproteinases (MMP), tissue inhibitors of MMPs, growth factors and cytokines. As such, they are capable of affecting inflammation, immunomodulation, cell proliferation, and angiogenesis. Although they have been used to treat a variety of conditions including acne, cutaneous sarcoid, and rheumatoid arthritis, amongst others, their use in treating ophthalmologic disease is in its infancy. MATERIALS AND METHODS: A literature review on the role of non-antimicrobial properties of tetracyclines, semisynthetic tetracyclines, and chemically modified non-antibacterial tetracyclines (CMTs) and their clinical properties was performed. The effects of these compounds in relation to ophthalmic disease are presented. RESULTS: Due to their non-antimicrobial properties, tetracyclines and their derivatives are capable of influencing a wide variety of ocular diseases in animal models. By affecting expression of MMP-9 and tumor necrosis factor (TNF)-α, these compounds decrease corneal permeability, improve corneal smoothness, and reduce meibomian gland dysfunction; this improves the tear film which in turn restores the optical quality of the tear film and cornea. Sterile corneal ulceration may be inhibited via anticollagenase activity; this has been demonstrated in both animal models and case reports. CMTs suppress cataractogenesis in a diabetic rat model, possibly by affecting MMPs. With respect to retinal disease, tetracyclines can inhibit both microglial-mediated cell death and retinal cell apoptosis as well as prevent retinal capillary damage via caspase inhibition thus preventing retinal neovascularization. Experimental choroidal neovascularization is reduced by inhibition of MMP-2 and MMP-9, elevation of pigment epithelial derived growth factor (PEDF), and reduction of vascular endothelial growth factor (VEGF) expression via Fas ligand. DISCUSSION: Due to their non-antimicrobial properties, tetracyclines and their derivatives are capable of influencing a wide variety of ocular disease in animal models. Research suggests that they are able to reduce inflammation in the eyelid meibomian glands, improve optical clarity of the cornea, retard cataract formation, and limit ocular angiogenesis. They may have a role in treating the leading causes of vision loss: cataract, age-related macular degeneration, and diabetic retinopathy, all of which are anticipated to increase in incidence due to the aging population. CONCLUSIONS: Tetracyclines, semisynthetic tetracyclines, and CMTs may have a role in the treatment of several important ophthalmologic diseases; however, further research is required, including prospective multicenter clinical trials.
21735587 (64)Cu-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-MEDI-522. 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). A tripeptide sequence consisting of Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3). Various radiolabeled antagonists have been introduced for 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 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 cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (12). In addition to RGD peptides, a humanized anti-human integrin α(v)β(3) monoclonal antibody (MEDI-522) was identified to be unique in that it recognizes either the human α(v) or β(3) subunit. MEDI-522 cross-reacts with integrin α(v)β(3) from rabbits, chickens, and hamsters but not with integrin α(v)β(3) from mice or rats (13). MEDI-522 is being evaluated as an antiangiogenic agent for cancer therapy (14-16). Cai et al. (17) reported the development of (64)Cu-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-MEDI-522 ((64)Cu-DOTA-MEDI-522) for positron emission tomography (PET) imaging of α(v)β(3) receptors in nude mice bearing tumors.
21595127 (68)Ga-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Glu-[cyclo(Arg-Gly-Asp-D-Phe-L 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 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 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 cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (12). Janssen et al. (13) reported the development of (111)In-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Glu-[cyclo(Arg-Gly-Asp-D-Phe-Lys)](2) ((111)In-DOTA-E-[c(RGDfK)](2)) for single-photon emission computed tomography imaging α(v)β(3) receptors in nude mice bearing ovarian carcinoma tumors. Dijkgraaf et al. (14) also reported the evaluation of (68)Ga-DOTA-E-[c(RGDfK)](2) for positron emission tomography (PET) imaging α(v)β(3) receptors in tumor, which is the topic of this chapter.
23065964 Association between anti-TNF-α therapy and all-cause mortality. 2012 Dec PURPOSE: To compare mortality among patients with selected autoimmune diseases treated with anti-tumor necrosis factor alpha (TNF-α) agents with similar patients treated with non-biologic therapies. METHODS: Cohort study set within several large health care programs, 1998-2007. Autoimmune disease patients were identified using diagnoses from computerized healthcare data. Use of anti-TNF-α agents and comparison of non-biologic therapies were identified from pharmacy data, and mortality was identified from vital records and other sources. We compared new users of anti-TNF-α agents to new users of non-biologic therapies using propensity scores and Cox proportional hazards analysis to adjust for baseline differences. We also made head-to-head comparisons among anti-TNF-α agents. RESULTS: Among the 46 424 persons included in the analysis, 2924 (6.3%) had died by the end of follow-up, including 1754 (6.1%) of the 28 941 with a dispensing of anti-TNF-α agent and 1170 (6.7%) of the 17 483 who used non-biologic treatment alone. Compared to use of non-biologic therapies, use of anti-TNF-α therapy was not associated with an increased mortality in patients with rheumatoid arthritis (adjusted hazard ratio [aHR] 0.93 with 95% confidence intervals (CI) 0.85-1.03); psoriasis, psoriatic arthritis, or ankylosing spondylitis (combined aHR 0.81 with CI 0.61-1.06; or inflammatory bowel disease (aHR 1.12 with CI 0.85-1.46). Mortality rates did not differ to an important degree between patients treated with etanercept, adalimumab, or infliximab. CONCLUSION: Anti-TNF-α therapy was not associated with increased mortality among patients with autoimmune diseases.
21809421 Tumor necrosis factor inhibits mesenchymal stem cell differentiation into osteoblasts via 2011 Oct Patients with chronic inflammatory disorders, such as rheumatoid arthritis, often have osteoporosis due to a combination of Tumor necrosis factor-induced increased bone resorption and reduced bone formation. To test if TNF inhibits bone formation by affecting the commitment and differentiation of mesenchymal stem cells (MSCs) into osteoblasts, we examined the osteogenic potential of MSCs from TNF transgenic (TNF-Tg) mice, a model of chronic inflammatory arthritis. MSC-enriched cells were isolated from bone marrow stromal cells using negative selection with anti-CD45 antibody coated magnetic beads. The expression profile of MSC surface markers the osteogenic, chondrogenic, and adipogenic properties of CD45(-) cells were confirmed by FACS and cell differentiation assays. MSC-enriched CD45(-) cells from TNF-Tg mice formed significantly decreased numbers of fibroblast and ALP(+) colonies and had a decreased expression of osteoblast marker genes. As TNF may upregulate ubiquitin ligases, which negatively regulate osteoblast differentiation, we examined the expression levels of several ubiquitin ligases and found that Wwp1 expression was significantly increased in MSC-enriched CD45(-) cells of TNF-Tg mice. Wwp1 knockdown rescued impaired osteoblast differentiation of TNF-Tg CD45(-) cells. Wwp1 promotes ubiquitination and degradation of JunB, an AP-1 transcription factor that positively regulates osteoblast differentiation. Injection of TNF into wild-type mice resulted in decreased osteoblast differentiation of MSCs and increased JunB ubiquitination, which was completely blocked in Wwp1(-/-) mice. Thus, Wwp1 targets JunB for ubiquitination and degradation in MSCs after chronic exposure to TNF, and inhibition of Wwp1 in MSCs could be a new mechanism to limit inflammation-mediated osteoporosis by promoting their differentiation into osteoblasts.
21540203 Immunogenicity and safety of the 2009 non-adjuvanted influenza A/H1N1 vaccine in a large c 2011 Jun BACKGROUND: Despite the WHO recommendation that the 2010-2011 trivalent seasonal flu vaccine must contain A/California/7/2009/H1N1-like virus there is no consistent data regarding its immunogenicity and safety in a large autoimmune rheumatic disease (ARD) population. METHODS: 1668 ARD patients (systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic sclerosis, psoriatic arthritis (PsA), Behçet's disease (BD), mixed connective tissue disease, primary antiphospholipid syndrome (PAPS), dermatomyositis (DM), primary Sjögren's syndrome, Takayasu's arteritis, polymyositis and Granulomatosis with polyangiitis (Wegener's) (GPA)) and 234 healthy controls were vaccinated with a non-adjuvanted influenza A/California/7/2009(H1N1) virus-like strain flu. Subjects were evaluated before vaccination and 21 days post-vaccination. The percentage of seroprotection, seroconversion and the factor increase in geometric mean titre (GMT) were calculated. RESULTS: /st> After immunisation, seroprotection rates (68.5% vs 82.9% p<0.0001), seroconversion rates (63.4% vs 76.9%, p<0.001) and the factor increase in GMT (8.9 vs 13.2 p<0.0001) were significantly lower in ARD than controls. Analysis of specific diseases revealed that seroprotection significantly reduced in SLE (p<0.0001), RA (p<0.0001), PsA (p=0.0006), AS (p=0.04), BD (p=0.04) and DM (p=0.04) patients than controls. The seroconversion rates in SLE (p<0.0001), RA (p<0.0001) and PsA (p=0.0006) patients and the increase in GMTs in SLE (p<0.0001), RA (p<0.0001) and PsA (p<0.0001) patients were also reduced compared with controls. Moderate and severe side effects were not reported. CONCLUSIONS: The novel recognition of a diverse vaccine immunogenicity profile in distinct ARDs supports the notion that a booster dose may be recommended for diseases with suboptimal immune responses. This large study also settles the issue of vaccine safety. (ClinicalTrials.gov #NCT01151644).
21299443 Herp zoster at the site of infliximab infusion: case report. 2011 Sep Worldwide, many patients have been treated with tumor necrosis factor-α (TNF-α) antagonists for indications that include chronic inflammatory diseases such as rheumatoid and psoriatic arthritis, inflammatory bowel disease and others. Since their approval, concerns regarding safety have been raised. Increased susceptibility to bacterial infections, especially due to intracellular bacteria like Mycobacterium tuberculosis that is responsible for the most serious complications associated with this treatment. Viral infections are less frequently reported but probably relatively common, representing an important cause of morbidity to remember. Varicella zoster virus is one of the most frequently implicated viruses. We present the case of a 20-year-old man with Crohn's disease under infliximab treatment who developed herpes zoster at the site of infliximab's 7th and 9th infusion.
21792648 Prevalence and clinical presentations of hepatitis C virus among patients admitted to the 2012 Sep To study the prevalence of anti-HCV antibodies among patients admitted to the rheumatology department, Cairo University hospitals, in 6-month period as well as to determine whether chronic HCV infection was the primary cause of their admission or just a concomitant association with the rheumatic disease. One hundred and fifty-seven patients were included in this study. They represent all patients admitted to the rheumatology inpatient department of Cairo University hospitals during the study period. Preset questionnaire including detailed demographic data, cause of admission and clinical manifestations of their disease was obtained for every patient. All patients were screened for HCV antibodies using ELISA technique. Other laboratory and imaging investigations were done according to the patient's diagnosis. Twenty-nine patients (18.5%) were positive for HCV antibody. Eleven patients of them (38%) were admitted due to rheumatic manifestations directly related to chronic HCV infection, which represent 7% of all admitted patients (11/157). HCV antibodies were found in 17.6 and 6.7% among patients with rheumatoid and systemic lupus erythematosus. Arthritis, palpaple purpura, digital gangrene and mononeuritis multiplex were the most common causes of admission related to chronic HCV infection. HCV antibodies were found in 18.5% among admitted patients to the rheumatology ward. The rheumatic manifestations of chronic HCV represent the primary cause of admission in 7% of all admitted patients. HCV screening should be included in the routine investigations for patients presenting to rheumatology departments in countries with high prevalence of chronic HCV infection.
22864236 Distinct phenotypes in mixed connective tissue disease: subgroups and survival. 2012 Nov The aim of the present study was to assess the autoantibody profile, dominant clinical symptoms and cluster characteristics of different mixed connective tissue disease (MCTD phenotypes. Two-hundred-and-one patients with MCTD were followed-up longitudinally. Five clinical parameters, Raynaud's phenomenon, pulmonary artery hypertension (PAH), myositis, interstitial lung disease (ILD), erosive arthritis and five auto-antibodies besides anti-U1RNP, antiendothelial cell antibodies (AECA), anti-CCP, anti-cardiolipin (anti-CL), anti-SSA/SSB and IgM rheumatoid factor (RF) were selected for cluster analysis. The mean age of patients was 52.9 ± 12.4 years and the mean follow-up of the disease was 12.5 ± 7.2 years. Patients were classified into three cluster groups. Cluster 1 with 77 patients, cluster 2 with 79 patients and cluster 3 with 45 patients. In cluster 1 the prevalence of PAH (55.8%; p < 0.001), Raynaud's phenomenon (92.2%; p < 0.001) and livedo reticularis (24.6%, p < 0.001) was significantly greater than in cluster 2 and 3. In cluster 2, the incidence of ILD (98.7%; p < 0.001), myositis (77.2%; p < 0.001), and esophageal dysmotility (89.8%; p < 0.001) was significantly greater than that in cluster 1 and 3. In cluster 3, anti-CCP antibodies were present in 31 of 45 patients (68.8%) with erosions. Anti-CCP antibodies were present in 37 of 42 patients (88.0%) with erosions. PAH, angina, venous thrombosis was observed in cluster 1 and pulmonary fibrosis in cluster 2, musculosceletal damage, gastrointestinal symptoms and osteoporotic fractures were most frequent in cluster 3. Cumulative survival assessment indicated cluster 1 patients having the worst prognosis. Cluster analysis is valuable to differentiate among various subsets of MCTD and useful prognostic factor regarding the disease course.
23212446 Treatment with hydrogen molecule alleviates TNFα-induced cell injury in osteoblast. 2013 Jan Tumor necrosis factor-alpha (TNFα) plays a crucial role in inflammatory diseases such as rheumatoid arthritis and postmenopausal osteoporosis. Recently, it has been demonstrated that hydrogen gas, known as a novel antioxidant, can exert therapeutic anti-inflammatory effect in many diseases. In this study, we investigated the effect of treatment with hydrogen molecule (H(2)) on TNFα-induced cell injury in osteoblast. The osteoblasts isolated from neonatal rat calvariae were cultured. It was found that TNFα suppressed cell viability, induced cell apoptosis, suppressed Runx2 mRNA expression, and inhibited alkaline phosphatase activity, which was reversed by co-incubation with H(2). Incubation with TNFα-enhanced intracellular reactive oxygen species (ROS) formation and malondialdehyde production increased NADPH oxidase activity, impaired mitochondrial function marked by increased mitochondrial ROS formation and decreased mitochondrial membrane potential and ATP synthesis, and suppressed activities of antioxidant enzymes including SOD and catalase, which were restored by co-incubation with H(2). Treatment with H(2) inhibited TNFα-induced activation of NFκB pathway. In addition, treatment with H(2) inhibited TNFα-induced nitric oxide (NO) formation through inhibiting iNOS activity. Treatment with H(2) inhibited TNFα-induced IL-6 and ICAM-1 mRNA expression. In conclusion, treatment with H(2) alleviates TNFα-induced cell injury in osteoblast through abating oxidative stress, preserving mitochondrial function, suppressing inflammation, and enhancing NO bioavailability.
23134613 Divergence of the systemic immune response following oral infection with distinct strains 2012 Dec Periodontitis is a polymicrobial oral infection characterized by the destruction of tooth-supporting structures that can be linked to systemic diseases such as cardiovascular disease, diabetes or rheumatoid arthritis. Porphyromonas gingivalis, a bacterium implicated in the etiology of periodontitis, has shown variation in inducing T-cell responses among different strains. Therefore, in this study we investigated the strain-specific immune response using a murine experimental model of periodontitis. Periodontitis was induced by P. gingivalis strains A7A1-28, W83 and W50, and later confirmed by the presence of P. gingivalis in the oral microflora and by alveolar bone resorption. Splenocytes were evaluated for gene expression, cellular proteins and cytokine expression. Dendritic cells were stimulated in vitro for T helper cell-cytokine profiling. Results showed that P. gingivalis had the ability to alter the systemic immune response after bacterial exposure. Strains W50 and W83 were shown to induce alveolar bone loss, whereas the A7A1-28 strain did not significantly promote bone resorption in mice. Splenocytes derived from mice infected with strains W50 and W83 induced expression of high levels of interleukin-4 (IL-4) but A7A1-28 stimulated increased IL-10. Stimulation of dendritic cells in vitro showed a similar pattern of cytokine expression of IL-12p40, IL-6 and transforming growth factor-β among strains. A distinct systemic response in vivo was observed among different strains of P. gingivalis, with IL-10 associated with the least amount of alveolar bone loss. Evaluation of pathogen-driven systemic immune responses associated with periodontal disease pathogenesis may assist in defining how periodontitis may impact other diseases.
22935775 CAPE suppresses VEGFR-2 activation, and tumor neovascularization and growth. 2013 Feb The growth and metastasis of human solid tumors and the development of conditions such as diabetic retinopathy, rheumatoid arthritis, inflammatory psoriasis, and others are regulated by the balance between angiogenic stimulators and inhibitors released in the angiogenic-pathological microenvironment. Vascular endothelial growth factor (VEGF), an angiogenic factor, is a potent endothelial-specific mitogen that activates endothelial cells in pathological angiogenesis. Recently, we demonstrated that caffeic acid phenethyl ester (CAPE) inhibits tumor growth, invasion, and metastasis. However, the precise molecular mechanism underlying the inhibitory effect of CAPE on VEGF-mediated angiogenesis remains unknown. Here, we show that CAPE suppressed VEGF-induced proliferation, tube formation, migration, the formation of actin stress fibers and loss of VE-cadherin at cell-cell contacts in endothelial cells, indicating the inhibition of VEGF-mediated VEGF receptor-2 (VEGFR-2) and its downstream signal activation in vitro. CAPE blocked VEGF-stimulated neovascularization in the Matrigel plugs assay, and reduced vascular permeability in mouse skin capillaries in vivo. CAPE inhibited the growth and neovascularization of primary tumor cells in C57BL/6 and BALB/c mice inoculated with Lewis lung carcinoma, colon carcinoma, and melanoma cells. These results suggest that CAPE negatively modulates VEGF-induced angiogenesis by suppressing VEGFR-2 activation, and might be a therapeutic avenue for anti-angiogenesis.
22804104 Risk factors associated with a decrease ≥2 g/dL in haemoglobin and/or ≥10% haematocri 2012 Sep BACKGROUND: Nonsteroidal anti-inflammatory drugs are associated with gastrointestinal (GI) damage. The Celecoxib vs. Omeprazole and Diclofenac for At-Risk Osteoarthritis and Rheumatoid Arthritis Patients (CONDOR) trial showed that a haemoglobin drop ≥2 g/dL adjudicated as either of defined or presumed GI origin was the most frequent component/event for the composite GI primary end point. This adverse event is potentially clinically relevant in long-term NSAID treatment. AIM: To define potential risk factors associated with a decrease in haemoglobin/haematocrit. METHODS: Post hoc analysis of the CONDOR trial was conducted in the intention-to-treat population. Clinically significant blood loss was defined as: (i) a haemoglobin drop ≥2 g/dL and/or a haematocrit drop ≥10%; and (ii) blood loss adjudicated as either of defined or presumed GI origin. Fifteen risk factors were evaluated by stepwise logistic regression. Each factor had to be significant at <0.20 α to be included in the model. RESULTS: A total of 64/3774 (1.7%) osteoarthritis (OA) patients had decreased haemoglobin/haematocrit and were adjudicated to the GI endpoint. Significant risk factors, at the 0.20 α level found to be associated with clinically significant blood loss in OA patients included [odds ratio (80% CI)] baseline C-reactive protein (CRP) levels [2.27 (1.46-3.53)], history of gastritis and history of GI intolerance [1.55 (1.06-2.28)], positive Helicobacter pylori at screening [1.54 (1.07-2.22)], increasing age [1.17 (1.04-1.32)] and body mass index [BMI; 1.03 (1.00-1.06)]. CONCLUSIONS: Monitoring for decreases in haemoglobin should be considered for all OA patients and especially those with an increased age, BMI, history of gastritis and GI intolerance, CRP levels >1 mg/dL and/or positive H. pylori status, as this may affect their clinical management.
22521613 Licorice isoliquiritigenin suppresses RANKL-induced osteoclastogenesis in vitro and preven 2012 Jul Osteoclasts, bone-specialized multinucleated cells, are responsible for bone destructive diseases such as osteoporosis, periodontitis, and rheumatoid arthritis. Natural plant-derived products have received substantial attention given their potential therapeutic and preventive activities against human diseases. In the present study, we investigated the effects of isoliquiritigenin (ISL), a natural flavonoid isolated from licorice, on receptor activator of nuclear factor-κB ligand (RANKL)-induced in vitro osteoclastogenesis and inflammation-mediated bone destruction in vivo. We observed that ISL dose-dependently inhibited RANKL-induced osteoclast formation from RAW 264.7 and primary mouse bone marrow-derived macrophages (BMMs), as well as decreased the extent of lacunar resorption. Specifically, ISL targeted RANKL-induced osteoclastogenesis and F-actin rings formation at an early stage. The RANKL-stimulated mRNA expression of osteoclast-related genes and transcription factors were also diminished by ISL. Mechanistically, ISL blocked the RANKL-triggered RANK-TRAF6 association, phosphorylation of mitogen-activated protein kinases (MAPKs), inhibitor of κBα (IκBα) phosphorylation and degradation, nuclear factor-κB (NF-κB) p65 nuclear translocation, as well as activator protein (AP)-1 activation. ISL almost abrogated the nuclear factor of activated T cells (NFATc1) expression and inhibited its nuclear translocation specifically in pre-osteoclasts. Furthermore, the ectopic introduction of NFATc1 into osteoclast precursors almost reversed the ISL-elicited anti-osteoclastogenic effects. Consistent with the in vitro results, administration of ISL prevented inflammatory bone loss in mice by attenuating osteoclast activity. Taken together, our results demonstrated that ISL suppresses RANKL-induced osteoclastogenesis and inflammatory bone loss via RANK-TRAF6, MAPK, IκBα/NF-κB, and AP-1 signaling pathways. Therefore, ISL may be considered as a novel therapeutic and/or preventive strategy against lytic bone diseases.
22472925 Frequency of rheumatic diseases in Portugal: a systematic review. 2011 Oct OBJECTIVES: To describe the frequency of rheuma­tic diseases in Portugal through a systematic review of published literature, critically appraising available information and identifying data collection gaps. METHODS: We systematically reviewed the literature to retrieve data on the occurrence of rheumatic diseases in Portugal through MEDLINE and Índex das Revistas Médicas Portuguesas searches, PhD theses, and national health surveys reports. Original articles in English or Portuguese published between 1 January 2000 and 31 December 2010 were included. RESULTS: We retrieved information for the prevalence of rheumatic diseases, osteoarthritis, back pain, work-related musculoskeletal disorders (WRMDs), osteoporosis, fibromyalgia, rheumatoid arthritis, spondyloarthritis and other systemic rheumatic diseases and for the incidence of back pain, osteoporotic fracture and other systemic rheumatic diseases. The prevalence of rheumatic diseases ranged from 16.0% to 24.0% and the prevalence of osteoarthritis was 11.1% (95% confidence intervals (95%CI): 9.4-13.1) in the knee and 5.5% (95%CI: 4.3-7.0) in the hip. Regarding back pain, period prevalence ranged from 8.0% (95%CI: 6.1-10.1) to 29.5% (95%CI: 23.4-36.2) in children and from 12.3% (95%CI: 10.5-14.3) to 51.3% (95%CI: 48.6-53.9) in adults. The prevalence of WRMDs ranged from 5.9% to 84.2% (95%CI: 80.8-87.3). The yearly incidence of osteoporotic fracture (per 100 000) ranged from 93.3 to 481 (95%CI: 407-564) in women and from 31.9 to 154 (95%CI: 106-218) in men. The prevalence of osteoporosis in women ranged from 11.0% to 15.4% (95%CI: 13.4-17.6) and in men from 1.1% to 16.8% (95%CI: 12.2-22.3). The prevalence of fibromyalgia ranged from 3.6% (95%CI: 2.0-5.2) to 3.7% (95%CI: 2.0-5.4). The prevalence estimates of ankylosing spondylitis and of spondyloarthritis were 0.6% and 1.6% (95%CI: 0.8-2.7), respectively. The prevalence of systemic lupus erythematosus was estimated in 0.2% (95%CI: 0.1-0.8). CONCLUSIONS: There is a broad spectrum of information available that indicates an important burden of rheumatic diseases in the general Portuguese population. Gaps were identified particularly regarding inflammatory arthropathies and other systemic rheumatic diseases.
22359779 (64)Cu-1,4,7-Triazacyclononane,1-glutaric acid-4,7-acetic acid-cyclo(Arg-Gly-Asp-d-Phe-Lys 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. The α(v)β(3) antagonists are being studied as antitumor and antiangiogenic agents and the agonists are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). The peptide sequence Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3). Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). Most of the cyclic RGD peptides are composed of five amino acids. Various cyclic RGD peptides exhibit selective inhibition of binding to α(v)β(3) (50% inhibition concentration (IC(50)), 7–40 nM) but not to α(v)β(5) (IC(50), 600–4,000 nM) or α(IIb)β(3) (IC(50), 700–5,000 nM) integrins (11). Various radiolabeled cyclic RGD peptides and peptidomimetics have been found to have high accumulation in tumors in mice (12, 13). From these developments, [(18)F]galacto-c(RGDfK) has been evaluated in a number of clinical studies for imaging of α(v)β(3) in cancer patients (14-18). Knetsch et al. (19) reported the development of (68)Ga-1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid-cyclo(Arg-Gly-Asp-d-Phe-Lys) ((68)Ga-NODAGA-c(RGDfK)) for positron emission tomography (PET) imaging of α(v)β(3) receptors in nude mice bearing melanoma tumors. 1-(1-Carboxy-3-carbo-tert-butoxypropyl)-4,7-(carbo-tert-butoxymethyl)-1,4,7-triazacyclononane (NODAGA(tBu)(3)) was used to prepare (68)Ga-NODAGA-c(RGDfK). Dumont et al. (20) chelated NODAGA-c(RGDfK) with (64)Cu to form (64)Cu-NODAGA-c(RGDfK) for PET imaging of α(v)β(3) receptors in nude mice bearing human glioblastoma tumors.