Cinnamaldehyde is a natural essential oil suggested to possess anti-bacterial and anti-inflammatory properties; and to activate transient receptor potential ankyrin 1 (TRPA1) channels expressed on neuronal and non-neuronal cells. Here, we investigated the immunomodulatory effects of cinnamaldehyde in an in vivo model of systemic inflammatory response syndrome (SIRS) induced by lipopolysaccharide. Swiss mice received a single oral treatment with cinnamaldehyde 1 h before LPS injection. To investigate whether cinnamaldehyde effects are dependent on TRPA1 activation, animals were treated subcutaneously with the selective TRPA1 antagonist HC-030031 5 min prior to cinnamaldehyde administration. Vehicle-treated mice were used as controls. Cinnamaldehyde ameliorated SIRS severity in LPS-injected animals. Diminished numbers of circulating mononuclear cells and increased numbers of peritoneal mononuclear and polymorphonuclear cell numbers were also observed. Cinnamaldehyde augmented the number of peritoneal Ly6C(high) and Ly6C(low) monocyte/macrophage cells in LPS-injected mice. Reduced levels of nitric oxide, plasma TNFα and plasma and peritoneal IL-10 were also detected. Additionally, IL-1β levels were increased in the same animals. TRPA1 antagonism by HC-030031 reversed the changes in the number of circulating and peritoneal leukocytes in cinnamaldehyde-treated animals, whilst increasing the levels of peritoneal IL-10 and reducing peritoneal IL-1β. Overall, cinnamaldehyde modulates SIRS through TRPA1-dependent and independent mechanisms.
This article reports the anti-inflammatory effect of Blutaparon portulacoides (B. portulacoides), specifically the ethanolic extract of its aerial parts, on the edema formation and leukocyte influx caused by Bothrops jararacussu (B. jararacussu) snake venom and Bothropstoxin-I and II (BthTX-I and II) isolated from this venom as an alternative treatment for Bothrops snakebites. The antiinflammatory effect of B. portulacoides ethanolic extract was compared with an animal group pretreated with dexamethasone. B. portulacoides ethanolic extract significantly inhibited paw edema induced by B. jararacussu venom and by BthTX-I and II. Also, results demonstrated that the extract caused a reduction of the leukocyte influx induced by BthTX-I. However, the extract was not capable of inhibiting the leukocyte influx induced by the venom and by BthTX-II. In conclusion, these results suggest that the ethanolic extract of this plant possess components able to inhibit or inactivate toxins present in B. jararacussu venom, including its myotoxins, responsible for the edema formation. However, the leukocyte migration caused by the venom and BthTX-II was not inhibited by the plant, probably due to the different mechanisms involved in the edema formation and leukocyte influx. This is the first report of B. portulacoides extract as anti-inflammatory against snake venoms and isolated toxins.
Thioredoxin plays an essential role in bacterial antioxidant machinery and virulence; however, its regulatory actions in the host are less well understood. Reduced human Trx activates transient receptor potential canonical 5 (TRPC5) in inflammation, but there is no evidence of whether these receptors mediate bacterial thioredoxin effects in the host. Importantly, TRPC5 can form functional complexes with other subunits such as TRPC4. Herein, E. coli-derived thioredoxin induced mortality in lipopolysaccharide- (LPS-) injected mice, accompanied by reduction of leukocyte accumulation, regulation of cytokine release into the peritoneum, and impairment of peritoneal macrophage-mediated phagocytosis. Dual TRPC4/TRPC5 blockade by ML204 increased mortality and hypothermia in thioredoxin-treated LPS mice but preserved macrophage's ability to phagocytose. TRPC5 deletion did not alter body temperature but promoted additional accumulation of peritoneal leukocytes and inflammatory mediator release in thioredoxin-administered LPS mice. Thioredoxin diminished macrophage-mediated phagocytosis in wild-type but not TRPC5 knockout animals. TRPC5 ablation did not affect LPS-induced responses. However, ML204 caused mortality associated with exacerbated hypothermia and decreased peritoneal leukocyte numbers and cytokines in LPS-injected mice. These results suggest that bacterial thioredoxin effects under LPS stimuli are mediated by TRPC4 and TRPC5, shedding light on the additional mechanisms of bacterial virulence and on the pathophysiological roles of these receptors.
Rheumatoid arthritis is a chronic disease of the joints, which causes joint pain and disability. Anaemia is a frequent extra-articular manifestation in rheumatoid arthritis, affecting 30-70% of the patients; presenting a negative impact on patient´s quality of life. Some of the drugs used in rheumatoid arthritis treatment improve anaemia; but little is known on the beneficial effects of the anti-rheumatic leflunomide or the anti-TNFα adalimumab, in this parameter. We investigated the incidence of anaemia in rheumatoid arthritis patients treated or not with leflunomide or adalimumab. We also assessed whether anaemia correlates with disease activity. Anaemia was present in patients who had just been diagnosed with rheumatoid arthritis and had never taken disease modifying agents or biologicals (non-specific therapy group), but not in those taking either leflunomide or adalimumab. The erythrocyte sedimentation rate was increased in patients with non-specific therapy in comparison with those taking either leflunomide or adalimumab. Anaemia correlated with increased erythrocyte sedimentation rate. We suggest that leflunomide and adalimumab may be useful in treating anaemia in patients with rheumatoid arthritis.
BackgroundHerpes Zoster has been reported with increased frequency in association with rheumatic diseases and biologic therapy.ObjectivesTo study herpes zoster (HZ) in patients with rheumatic diseases included in the Brazilian Register for monitoring of biologic therapies in rheumatic diseases - BiobadaBrasil,MethodsBiobadaBrasi is a prospective observational cohort study, part of an international initiative (biobadaAmerica) in collaboration with BiobadaSer. Patients with rheumatic diseases are enrolled at the moment of introduction of their first biologic therapy; a comparison cohort of patients with active RA receiving traditional disease-modifying antirheumatic drugs (DMARDs) was recruited in parallel in each center. This register was established in 2009 and is an ongoing study ran by the Brazilian Society of Rheumatology comprising 32 centers (30 public, located at academic centres, 2 private) in almost all states of the country. Data quality is under constant monitoring (online, by phone and “in situ”). In this report all biologic administered to more than a hundred patients were included: abatacept, adalimumab, etanercept, infliximab, rituximab and tocilizumab. Data was expressed as mean (SD); crude incidence rates (IR) were calculated as number of HZ episodes per 1000 patient-years- IR (1000 patient-years).ResultsUp to January 2016, 2715 patients were included in the register, 70% female, mean age 51 (14.3) yrs, submitted to 3770 treatments; 1721 patients with diagnosis of RA; $54 with AS and APs=181.61 HZ episodes were related including only one relapse reported in a 44years-old female patient with AR and in use of rituximab. The crude IR (95% CI) of HZ in the study population (biologic agentes) was 8.3 (1000 patient-years) vs 4.45 (1000 patient-years) in the control population (traditional DMARds), (p=0,7 95%CI-3,7–4,7). Only 6 cases were considered severe by the investigators, two of them were HZ ophthalmicus, one periorbital and all lead to some impairment. These patients were taking different biologic agents (etanercept, adalimumab, infliximab – 2 patients) and one was using traditional DMARDS.Treatment with steroids (HR 1.99; 95%CI 1.092–3.6) was the only factor associated with zoster development. There was no difference in age, sex, specific disease or biologic agent associated with HZ episodes.ConclusionsIn our database, the risk of HZ was significantly increased in association with corticosteroid treatment but neither with biologic agents nor with inflammatory rheumatic diseases.Acknowledgementfor monitor P Cabral, for contribution to the BiobadaBrasil registry, L.Barbosa, W.Chahade, A.Hayata, A.Kakehasi, M.Pinheiro, A.Ranzolin, M.Scheinberg, F.Sztajnbok, I.SilveiraDisclosure of InterestNone declared
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