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ID PMID Title PublicationDate abstract
21279300 Ultraviolet light-induced Köbner phenomenon contributes to the development of skin erupti 2011 Mar Multicentric reticulohistiocytosis is a rare systemic disease of unknown aetiology characterized by erosive arthritis and cutaneous lesions consisting of multiple reddish-brown papules and nodules, mainly involving the face and distal upper extremities. It has been suggested that skin eruptions in multicentric reticulohistiocytosis are associated with Köbner phenomenon due to their characteristic distribution, such as on the dorsal aspects of the hands and fingers. We report here a case of a Japanese woman with multicentric reticulohistiocytosis, in whom erythematous macules and papules were widely distributed over the face, ears, neck and the V-area of the chest. Notably, repeated irradiation of ultraviolet (UV) B on the uninvolved back skin resulted in the induction of erythematous macules with infiltration of reticulohistiocytes, indicating the association of UVB-induced Köbner phenomenon with the development of skin lesions, especially on the sun-exposed area. This is the first known report demonstrating the contribution of UV-light-induced Köbner phenomenon for the development of skin eruptions in patients with multicentric reticulo-histiocytosis.
22028728 Polymerized-type I collagen induces upregulation of Foxp3-expressing CD4 regulatory T cell 2012 Previous studies showed that polymerized-type I collagen (polymerized collagen) exhibits potent immunoregulatory properties. This work evaluated the effect of intramuscular administration of polymerized collagen in early and established collagen-induced arthritis (CIA) in mice and analyzed changes in Th subsets following therapy. Incidence of CIA was of 100% in mice challenged with type II collagen. Clinimorphometric analysis showed a downregulation of inflammation after administration of all treatments (P < 0.05). Histological analysis showed that the CIA-mice group had extensive bone erosion, pannus and severe focal inflammatory infiltrates. In contrast, there was a remarkable reduction in the severity of arthritis in mice under polymerized collagen, methotrexate or methotrexate/polymerized collagen treatment. Polymerized Collagen but not methotrexate induced tissue joint regeneration. Polymerized Collagen and methotrexate/polymerized collagen but not methotrexate alone induces downregulation of CD4(+)/IL17A(+) T cells and upregulation of Tregs and CD4(+)/IFN-γ(+) T cells. Thus, Polymerized Collagen could be an effective therapeutic agent in early and established rheumatoid arthritis by exerting downregulation of autoimmune inflammation.
22955878 Tumour necrosis factor-alpha inhibitor-induced hepatic injury in patients with rheumatoid 2013 Nov Tumour necrosis factor-alpha (TNF-α) inhibitors are widely used in the management of patients with rheumatoid arthritis (RA) and spondylarthritides. However, TNF-α inhibition may lead to adverse events, including liver injury. The RA patients are frequently treated with several potentially hepatotoxic drugs concomitantly; hence, a causative link between TNF-α inhibitors and liver injury is usually difficult to establish. We report two cases of RA patients who developed histologically manifest liver injury shortly after the introduction of treatment with two different TNF-α inhibitors. Furthermore, we present the analysis of the laboratory data from the BioRx.si registry (the Slovenian national registry of rheumatologic patients treated with biologicals) and provide evidence that elevated levels of serum aminotransferase can be observed in patients treated with TNF-α inhibitors. Additionally, our analysis suggests no significant differences between the impact of adalimumab and etanercept on aminotransferase levels. Although the use of TNF-alpha inhibitors is safe and efficient, we suggest that continuous careful monitoring of aminotransferase levels in patients treated with these agents is probably warranted.
22002809 Model-based determination of abatacept exposure in support of the recommended dose for Jap 2011 Dec The objective of this study was to provide support for a body weight-tiered dosing regimen by characterizing abatacept pharmacokinetics (PK) and the relationship between exposure and the ACR20 (American College of Rheumatology criteria for 20% improvement) response in Japanese patients with rheumatoid arthritis (RA). A population PK model was developed using NONMEM with 2,535 samples from 344 Japanese RA patients in two clinical trials. The exposure-response relationship was characterized using a Generalized Estimating Equation (GEE) logistic regression model, with time-varying actual trough concentrations and ACR20 responder rates over 6 months in a randomized, placebo-controlled phase 2 trial for stable methotrexate. Abatacept exposure was well characterized using a linear, two-compartment model, in which body weight and the empirically calculated glomerular filtration rate were significant covariates for clearance. The ACR20 response model was developed by examining the quasi-likelihood information criterion, and the cumulative logit in the final model was specified by the log-transformed trough concentration. The predicted ACR20 responder rate was consistent with the actual values in the clinical trial and this model revealed trough concentrations higher than the recommended body weight-tiered dose are unlikely to result in substantial increases in clinical efficacy. Considering that ACR20 is a longitudinal binary variable and the response to RA treatment is delayed, the GEE model was useful for predicting the probability of an ACR20 response. In conclusion, the same dosing regimen as non-Japanese patients is recommended because a body weight-tiered dosing regimen achieves similar exposures across the wide range of body weight.
21248776 CIITA is not associated with risk of developing rheumatoid arthritis. 2011 Apr The major histocompatibility complex (MHC) class II transactivator gene (CIITA) encodes an important transcription factor regulating genes required for human leukocyte antigen (HLA) class II MHC-restricted antigen presentation. MHC genes, particularly HLA class II, are strongly associated with risk of developing rheumatoid arthritis (RA). Given the strong biological relationship between CIITA and HLA class II genes, a comprehensive investigation of CIITA variation in RA was conducted. This study tested 31 CIITA single-nucleotide polymorphisms in 2542 RA cases and 3690 controls (N=6232). All individuals were of European ancestry, as determined by ancestry informative genetic markers. No evidence for association between CIITA variation and RA was observed after a correction for multiple testing was applied. This is the largest study to fully characterize common genetic variation in CIITA, including an assessment of haplotypes. Results exclude even a modest role for common CIITA polymorphisms in susceptibility to RA.
22280236 The IL23/Th17 pathway as a therapeutic target in chronic inflammatory diseases. 2012 Apr IL-23 is a pro-inflammatory cytokine belonging to the IL-12 cytokine family. IL-23 is essential for the differentiation of Th17 lymphocytes, a subtype of T lymphocyte implicated in chronic inflammatory/autoimmune mediated diseases. IL-23 and Th17 correspond to a new axis that drives immune activation and chronic inflammation through the differentiation and activation of Th17 cells. Animal models of chronic inflammatory diseases such as chronic joint diseases, inflammatory bowel diseases and demyelinating diseases strongly suggest the involvement of this cytokine pathway. Thus, IL-23/Th17 is considered as a relevant therapeutic target in autoimmune driven diseases, and biological agents blocking IL-23 or IL-17 are currently being developed. Ustekinumab is a monoclonal antibody targeting the common p40 subunit of IL-12 and IL-23. This treatment has demonstrated its efficacy over placebo in randomized placebo controlled trials and is currently licensed for the treatment of psoriasis. It has also demonstrated its efficacy in psoriatic arthritis. Results for Crohn's disease were less evident, while ustekinumab was ineffective in multiple sclerosis. Secukinumab is an IL-17A monoclonal antibody that is under development and preliminary results have suggested its efficacy in inflammatory mediated diseases such as psoriasis and ankylosing spondylitis. Several other IL-23 or IL-17 neutralizing agents are being evaluated in clinical trials. The biological properties of the IL-23/Th17/IL-17 axis and the clinical applications of the drugs that aim to block its functions are reviewed here. Targeting the IL-23/Th17 axis seems to be a relevant and realistic therapeutic approach and these new agents pave the way for additive and alternative treatments to currently available biologics in chronic inflammatory diseases.
22833377 Concomitant iguratimod therapy in patients with active rheumatoid arthritis despite stable 2013 May OBJECTIVES: To investigate the efficacy and safety of iguratimod (T-614) in Japanese patients with active rheumatoid arthritis who had inadequate response to stable background methotrexate (MTX) alone. METHODS: In this multicenter, double-blind, controlled trial, a total of 253 patients were randomized at 2:1 ratio to either the iguratimod group or the placebo group. Iguratimod was orally administered at dosages of 25 mg/day for the first 4 weeks (25 mg once daily) and 50 mg/day for the subsequent 20 weeks (25 mg twice daily). MTX at dosage of 6 or 8 mg/week was administered to patients in both groups. RESULTS: The rate of 20 % improvement in American College of Rheumatology criteria (ACR20) at week 24 was 69.5 % in the iguratimod group compared with 30.7 % in the placebo group (P < 0.001). Significant improvements in the ACR50, ACR70, Health Assessment Questionnaire Disability Index, Disease Activity Score 28 <3.2, and rheumatoid factor were also observed. The most commonly reported adverse events (AEs) were blood iron decrease, nasopharyngitis, and lymphocyte decrease. These AEs were mild or moderate in severity. No deaths occurred. CONCLUSION: The study results suggest that iguratimod in combination with MTX was efficacious and had a manageable safety profile.
22079753 Do rheumatoid arthritis patients have equal access to treatment with new medicines?: tumou 2012 Jan PURPOSE: To explore the use of the biological tumour necrosis factor alpha (TNFalpha) inhibitors used in the treatment of rheumatoid arthritis as a measure of access to treatment with new medicines. In addition, characteristics both related to national health systems and spending will be assessed to explore possible differences in international utilisation. METHODS: Data from four European countries were included: Ireland, The Netherlands, Norway and Portugal. Annual utilisation rates of TNFalpha inhibitors (2003-2007) were expressed as defined daily doses (DDDs)/1000 inhabitants/day. Qualitative data such as country characteristics, national health policy characteristics, guidelines were obtained from the literature. In addition, interviews were held with leading rheumatologists of each country to put obtained results into (cultural) context. RESULTS: Utilisation of TNFalpha inhibitors varied widely from 0.32 (Portugal) to 1.89 (Norway) DDDs/1000 inhabitants/day (2007). A major driver for the utilisation of TNFalpha inhibitors seemed to be the country's total health expenditure (R(2)=0.81). When the use of TNFalpha inhibitors became more established, the association seemed stronger. Differences in health expenditure were nevertheless not the only determinant of usage. Cultural aspects such as difference in recognition of guidelines also come into play when looking at differences in TNFalpha utilisation between countries. CONCLUSIONS: The prospects of patients receiving TNFalpha inhibitor treatment depend on the country where they are living. In case uniformity of management and treatment would be considered to provide health benefits, the extent and the causes of variation should feature prominently on future public health agendas.
22070546 Signs of cross-seeding: aortic medin amyloid as a trigger for protein AA deposition. 2011 Dec The highly diverse deposition pattern displayed by systemic amyloidoses, sometimes within the same amyloid disease, remains unexplained. The localized medin (AMed) amyloidosis develops from the precursor protein lactadherin and deposits in the media of the thoracic aorta in almost all individuals above 50 years of age. Given its high prevalence in the population, and the fact that systemic amyloidoses also deposit in the aorta, led us to investigate whether AMed amyloid could influence the tissue distribution of serum amyloid A derived (AA) amyloidosis. Seven aortas from patients with diagnosed systemic AA amyloidosis were investigated. Four displayed partial co-localization between medin and AA aggregates when examined with double-labeling immunofluorescence. Furthermore, in vitro studies showed that AMed amyloid-like fibrils promote the aggregation of protein AA into fibrils. The findings indicate that the highly frequent "senile" amyloidoses may have the potential to initiate fibril formation of the more uncommon amyloidoses by a cross-seeding mechanism.
22664142 Microarray-based gene expression profiling reveals the mediators and pathways involved in 2012 Aug Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints. The prolonged use of non-steroidal anti-inflammatory drugs and other newer drugs is associated with severe adverse reactions. Therefore, there is a need for newer anti-arthritic agents. Celastrol, a bioactive component of the Chinese herb Celastrus, possesses anti-arthritic activity as tested in the adjuvant arthritis (AA) model of rheumatoid arthritis (RA). However, the mechanism of action of Celastrol has not been fully defined. We reasoned that microarray analysis of the lymphoid cells of Celastrol-treated arthritic animals might provide vital clues in this regard. We isolated total RNA of the draining lymph node cells (LNCs) of Celastrol-treated (Tc) and vehicle-treated (Tp) arthritic Lewis rats that were restimulated in vitro with the disease-related antigen, mycobacterial heat-shock protein 65 (Bhsp65), and tested it using microarray gene chips. Also tested was RNA from LNCs of control arthritic rats just before any treatment (Tâ‚€). Seventy six genes involved in various biological functions were differentially regulated by Bhsp65 in LNCs of Tp group, and 19 genes among them were shared by the Tc group. Furthermore, a group of 14 genes was unique to Tc. When Tc and Tp were compared, many of the Bhsp65-induced genes were related to the immune cells, cellular proliferation and inflammatory responses. Our results revealed 10 differentially expressed genes and 14 pathways that constituted the "Celastrol Signature". Our results would help identify novel targets for RA therapy.
23092598 [Non oncologic applications of molecular targeted therapies]. 2012 Oct Significant improvements in the knowledge of cancer biology have permitted the development of new molecular targeted therapies. Meanwhile, a better understanding of the physiology of various non-cancerous diseases has allowed developing these agents in other areas. This review intends to illustrate these perspectives through examples corresponding to different strategies of molecular-targeted therapies : use of a monoclonal antibody binding a receptor (rituximab and rheumatoid arthritis) or a ligand (bevacizumab and age-related macular degeneration), tyrosine kinase inhibitor (imatinib and systemic sclerosis) or inhibitor of cytoplasmic signal transduction pathways (immunosuppressive and antiproliferative effects of mammalian target of rapamycin [mTOR] inhibitors). Clinical results can draw today what could become molecular medicine of tomorrow.
23218628 Subvastus versus medial parapatellar approach in total knee arthroplasty: meta-analysis. 2012 Dec The subvastus and medial parapatellar approaches are 2 commonly performed techniques in total knee arthroplasty, but the optimal approach for total knee arthroplasty remains controversial. The purpose of this study was to compare the effectiveness and safety of the subvastus vs medial parapatellar approach.The PubMed, Embase, Cochrane Library, Inter-Services Intelligence Web of Knowledge, and Chinese Biomedical Literature databases were searched for eligible quasi-randomized, controlled and randomized, controlled trials. Two authors independently extracted data and assessed the methodological quality of the included studies according to the Cochrane handbook version 5.1.0. Statistical analysis was performed using Review Manager version 5.1 software. Eight randomized, controlled trials and 1 quasi-randomized, controlled trial involving 940 primary total knee arthroplasties were included for meta-analysis. Meta-analysis revealed significant differences favoring the subvastus group in Knee Society Score in terms of function at 4 to 6 weeks (weighted mean difference [WMD]=5.09; 95% confidence interval [CI], 3.08 to 7.09; P<.01) and knee score at 12 months (WMD=2.17; 95% CI, 0.01 to 4.34; P=.05) and lateral retinacular release (odds ratio=0.34; 95% CI, 0.14 to 0.79; P=.01) when compared with the medial parapatellar approach. However, both groups showed similar results in range of motion (P>.05), operative time (WMD=2.15; 95% CI, -3.61 to 7.35; P=.42), blood loss (WMD= -31.07; 95% CI, -91.89 to 29.75; P=.32), hospital stay (WMD= -0.18; 95% CI, -0.67 to 0.31; P=.47), and postoperative complications (P>.05).
21873689 A large-scale association study identified multiple HLA-DRB1 alleles associated with ACPA- 2011 Dec BACKGROUND: HLA-DRB1 is associated with rheumatoid arthritis (RA). However, it has recently been suggested that HLA-DRB1 is only associated with patients with RA who have anticitrullinated peptide/protein antibodies (ACPA), which are specific to RA. OBJECTIVE: To elucidate whether specific HLA-DR alleles are associated with ACPA-negative RA development. METHODS: HLA-DRB1 typing was carried out in 368 Japanese ACPA-negative patients with RA and 1508 healthy volunteers as the first set, followed by HLA-DRB1 typing of 501 cases and 500 controls as the second set. The HLA-DRB1 allele frequency and diplotype frequency were compared in each group, and the results of the two studies were combined to detect HLA-DRB1 alleles or diplotypes associated with ACPA-negative RA. RESULTS: HLA-DRB1*12:01 was identified as a novel susceptibility allele for ACPA-negative RA (p=0.000088, OR=1.72, 95% CI 1.31 to 2.26). HLA-DRB1*04:05 and *14:03 showed moderate associations with ACPA-negative RA (p=0.0063, OR=1.26, 95% CI 1.07 to 1.49 and p=0.0043, OR=1.81, 95% CI 1.20 to 2.73, respectively). The shared epitope was weakly associated with ACPA-negative RA, but no dosage effect was detected (p=0.016, OR=1.17, 95% CI 1.03 to 1.34). A combination of HLA-DRB1*12:01 and DRB1*09:01 showed a strong association with susceptibility to ACPA-negative RA (p=0.00013, OR=3.62, 95% CI 1.79 to 7.30). Homozygosity for HLA-DR8 was significantly associated with ACPA-negative RA (p=0.0070, OR=2.16, 95% CI 1.22 to 3.82). It was also found that HLA-DRB1*15:02 and *13:02 were protective against ACPA-negative RA (p=0.00010, OR=0.68, 95% CI 0.56 to 0.83 and p=0.00059, OR=0.66, 95% CI 0.52 to 0.84, respectively). CONCLUSIONS: In this large-scale association study multiple alleles and diplotypes were found to be associated with susceptibility to, or protection against, ACPA-negative RA.
22302395 Influence of MIF, CD40, and CD226 polymorphisms on risk of rheumatoid arthritis. 2012 Jun Macrophage migration inhibitory factor (MIF) is a key pro-inflammatory mediator. It plays an important role part in the pathogenesis of several inflammatory and immune diseases. A functional single nucleotide polymorphism (SNP) of MIF -173 G/C is known to influence MIF promoter activity in T lymphoblast cell lines and is associated with a higher serum MIF level. The CD40 is also crucial for some relevant functions of the immune system and may be related to rheumatoid arthritis (RA). And CD226 is an important cell-surface receptor molecule involved in the adhesion and activation of T-cell. We hypothesized that these polymorphisms may contribute to RA susceptibility. We studied MIF -173 G/C, CD40, and CD226 gene polymorphisms in 214 patients with RA and 478 controls in a Chinese population. Genotyping was done by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). When the MIF -173 GG homozygote genotype was used as the reference group, the CC genotype was associated with a significantly increased risk for RA. In the recessive model, when the MIF -173 GG/GC genotypes were used as the reference group, the CC homozygote genotype was associated with a significant 1.56-fold increased susceptibility to RA. None of the CD40 rs1883832 C/T and CD226 rs763361 C/T polymorphisms achieved a significant difference in genotype distributions between cases and controls. In the stratification analyzes, a significantly increased risk for RA associated with the MIF -173 CC genotype was evident among CRP-negative patients compared with the MIF -173 GG/GC genotype. For the CD40 rs1883832 C/T variant, the risk effects of CD40 rs1883832 TT versus CD40 rs1883832 CC/CT were significant in men. These findings suggested that the functional SNP MIF -173 G/C variant allele was associated with the development of RA. However, CD40 and CD226 gene polymorphisms may not be associated with RA susceptibility. Due to the limitation of sample size, this study should be considered preliminary.
23631533 Odontogenic osteomyelitis or bisphosphonate-related osteonecrosis of mandible of patient w 2012 Nov The key to appropriate treatment of odontogenic osteomyelitis or bisphosphonate-related osteonecrosis of the mandible in patients with autoimmune diseases lies in making the correct diagnosis based on meticulous review of signs and symptoms. As this complex case involving a patient with multiple comorbidities illustrates, diagnosis can be difficult, because these conditions may overlap or be mistaken for other conditions. However, prompt treatment is essential to limit the progression, which can be devastating for these medically complex patients. It is, therefore, important to understand local and systemic conditions that can weaken the immune system and predispose patients to chronic bone infection, meticulously go through signs and symptoms, and have a complete medical history, including patient medications.
22147649 A phase II, randomized, double-blind, placebo-controlled study evaluating the efficacy and 2012 Jun OBJECTIVE: CXCL10 (also known as interferon-γ-inducible 10-kd protein [IP-10]) is a chemokine that potentially plays a role in the immunopathogenesis of rheumatoid arthritis (RA). We undertook this phase II study to evaluate the efficacy and safety of MDX-1100, a fully human, anti-CXCL10 (anti-IP-10) monoclonal antibody, in RA patients whose disease responded inadequately to methotrexate (MTX). METHODS: Patients with active RA receiving stable doses of MTX (10-25 mg weekly) were randomized to receive intravenous doses of 10 mg/kg MDX-1100 (n = 35) or placebo (n = 35) every other week. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) on day 85, and patients were followed up for safety to day 141. RESULTS: The ACR20 response rate was significantly higher among MDX-1100-treated patients than among placebo-treated patients (54% versus 17%; P = 0.0024). Statistically significant differences in the ACR20 response rate between treatments were observed starting on day 43 (P < 0.05). The ACR50 and ACR70 response rates on day 85 did not differ between the groups. Overall, 51.4% of MDX-1100-treated patients and 30.3% of placebo-treated patients experienced at least 1 adverse event (AE). No study drug-related serious AEs were reported. CONCLUSION: MDX-1100 was well tolerated and demonstrated clinical efficacy in RA patients whose disease responded inadequately to MTX. This is the first study to demonstrate clinical efficacy of a chemokine inhibitor in RA and supports the notion of a potential role of IP-10 in the immunopathogenesis of RA.
22863637 Letter: Lichenoid eruption induced by etanercept. 2012 Jul 15 Lichenoid drug eruption is an uncommon, but previously reported, side effect of anti-tumor necrosis factor therapy. The majority of these adverse events relate to infliximab. We report a patient who developed a lichenoid eruption on the back of her hands during etanercept therapy. She improved with topical treatment and discontinuation of the drug was not necessary. The physiopathological link between anti-TNF treatment and lichenoid eruptions remains unclear. It is important to realize that a lichenoid reaction pattern may occur during anti-TNF agent treatment.
22238071 Interferon-γ release assay versus tuberculin skin test prior to treatment with golimumab, 2012 Jul OBJECTIVE: To evaluate the performance of an interferon-γ release assay (IGRA) versus the standard tuberculin skin test (TST) as a screening tool for latent tuberculosis (TB) infection prior to the initiation of anti-tumor necrosis factor therapy in patients with autoimmune inflammatory diseases. METHODS: This integrated analysis involved screening of patients with rheumatoid arthritis, those with psoriatic arthritis, and those with ankylosing spondylitis from phase III trials of golimumab. The IGRA used to screen for latent TB was the QuantiFERON-TB Gold In-Tube test. RESULTS: In this pooled analysis, 2,282 patients underwent both IGRA and TST screening prior to golimumab treatment. Among these patients, 13.8% had at least one test yielding positive findings for latent TB, including 9.4% with positive results by TST, 7.0% with positive results by IGRA, and 2.6% with positive results on both tests. The rate of indeterminate results for TB on IGRA was 1.8%. Agreement between the TST and IGRA results, measured by the kappa coefficient, was 0.22 (95% confidence interval 0.157-0.279; P=0.021). Among the patients with positive IGRA findings, 36.9% had positive TST findings. Among the patients with positive TST findings, 27.4% had positive IGRA findings. Overall, 781 (34.2%) of the 2,282 patients had previously received the bacillus Calmette-Guérin (BCG) vaccine; among this vaccinated group, the rate of positivity for latent TB by TST was 15.2% (119 of 781), compared to a rate of positivity of 9.1% (71 of 781) by IGRA (P=0.0002). Among patients who had not received the BCG vaccine, the rate of positivity by TST was 5.0% (62 of 1,248) and the rate of positivity by IGRA was 5.8% (72 of 1,248) (P=0.3745). When the IGRA was repeated in patients whose results were initially indeterminate, the rate of indeterminate IGRA findings for latent TB was much lower than has been previously reported. CONCLUSION: In the absence of a true gold standard test for latent TB infection, results of this comparison of IGRA and TST in a large cohort of patients with rheumatic diseases suggest that the IGRA provides greater specificity and possibly greater sensitivity than the TST.
22480655 [Mild stress as a means to modulate aging: from fly to human?]. 2012 Mar Hormesis is the phenomenon by which adaptive responses to low doses of otherwise harmful conditions improve the functional ability of organisms. Some mild stresses have beneficial effects on longevity, aging and resistance to strong stresses (heat or cold shocks, infection) in Drosophila flies. Studies on rodents are indeed scarce but mild stress seems to be effective in humans because, for instance, patients suffering from angina have a higher survival when confronted with a heart attack. A few studies, in less tragic situations however, suggest that mild stress could have positive effects in elderly people. Performing more experiments on the effects of mild stress in humans would help to know whether it could be used in therapy or to improve healthspan of elderly.
19859713 The anti-malaria agent artesunate inhibits expression of vascular endothelial growth facto 2011 Jan Increasing evidence indicates that the anti-malarial agent artemisinin and its derivatives may exert anti-angiogenic effect. In the present study, we explored the effect of artesunate, a artemisinin derivative, on TNFα- and hypoxia-induced expression of hypoxia inducible factor-1α (HIF-1α) and secretion of vascular endothelial growth factor (VEGF) and inteleukin-8 (IL-8) in human rheumatoid arthritis fibroblast-like synoviocytes (RA FLS), and further investigated the signal mechanism by which this compound modulates HIF-1α, VEGF and IL-8 expression. RA FLS obtained from patients with active rheumatoid arthritis were pretreated with artesunate, and then stimulated with TNFα and hypoxia. Production of VEGF and IL-8 was measured by ELISA. Nuclear location of HIF-1α was measured by confocal fluorescence microscopy. HIF-1α and other signal transduction proteins expression was measured by Western blot. Artesunate decreased the secretion of VEGF and IL-8 from TNFα- or hypoxia-stimulated RA FLS in a dose-dependent manner. Artesunate also inhibited TNFα- or hypoxia-induced nuclear expression and translocation of HIF-1α. We also showed that artesunate prevented Akt phosphorylation, but did not find evidence that phosphorylation of p38 and ERK was affected. TNFα- or hypoxia-induced secretion of VEGF and IL-8 and expression of HIF-1α were hampered by treatment with the PI3 kinase inhibitor LY294002, suggesting that inhibition of PI3 kinase/Akt activation might inhibit VEGF and IL-8 secretion and HIF-1α expression induced by TNFα or hypoxia. Our results suggest that artesunate inhibits angiogenic factor expression in RA FLS, and provide novel evidence that, as a low-cost agent, artesunate may have therapeutic potential for RA.