Inflammatory responses in the rat superior colliculus after eye enucleation

Ocular enucleation induces profound morphological alterations in central visual areas. However, little is known about the response of glial cells and possible inflammatory processes in visual brain areas resulting from eye enucleation. In this study, immunoblotting and immunostaining assays revealed increased expression of astrocyte and microglia markers in the rat superior colliculus (SC) between 1 and 15 days after contralateral enucleation. A transient increase of neuronal COX-2 protein expression was also found in the SC. To evaluate the role of an anti-inflammatory drug in attenuating both COX-2 and glial cell activation, the synthetic glucocorticoid dexamethasone (DEX) was administered (1mg/kg i.p., for 3 days) to enucleated rats. Immunoblotting data revealed that DEX treatment significantly inhibited COX-2 protein expression. Postlesion immunostaining for astrocyte and microglia markers was also significantly reduced by DEX treatment. These findings suggest that the removal of retinal ganglion cell input generates inflammatory responses in central retinorecipient structures

Multifunctional nanocarriers encapsulating anti-Alzheimer drug for nasal delivery to central nervous system

Alzheimer's disease (AD) is a fatal neurodegenerative condition characterized clinically by progressive memory loss and irreversible cognitive deterioration. It has been shown that there is a progressive degeneration of the brain cholinergic neurons which leads to the appearance of cognitive symptoms of the disease. The aim of this work was the formulation of multifunctional nanocarriers for nasal administration of tacrine-HCl (THA). This route has many advantages; in particular is possible to convey the drug directly to the Central Nervous System, through the olfactory bulb. In particular, were prepared Albumin nanoparticles carrying beta cyclodextrin and two different beta cyclodextrin derivatives (hydroxypropyl beta cyclodextrin and sulphobutylether beta cyclodextrin), and Multifunctional liposomes, prepared using traditional excipients (cholesterol and phosphatidylcholine), partly enriched with α-tocopherol (Toc) and/or polyunsaturated fatty acids (eicosapentaenoic acid and docosahexaenoic acid) (Ω3). Both nanosystems were characterized in terms of size, Zeta potential and encapsulation efficiency. Were also evaluated their functional properties such as mucoadhesion and permeability, using an ex-vivo assay based on nasal sheep mucosa. On Liposomes were also assessed drug neuronal uptake, cell toxicity, antioxidant and, cytoprotective activity in the human neuronal cell line SH-SY5Y and finally tocopherol trans-membrane diffusion. Both the nanocarriers produced presented excellent properties and a high potential as new systems for CNS-delivery of anti-Alzheimer drugs via the nasal route.

Anti-inflammatory and immunosuppressive effects of the enaminone E121

Asthma is a chronic inflammatory disease of the airways. The treatment of asthma is far from optimal and hence the need for novel therapeutic agents exists. The purpose of this study was to assess the anti-asthma effects of an enaminone, E121, and also its effects on human peripheral blood mononuclear cell proliferation and cytokine release. The effects of E121 were assessed in an ovalbumin-induced model of airway inflammation and airway hyperresponsiveness. In addition, the effects of E121 on phytohemagglutinin (PHA), anti-CD3 monoclonal antibody and lipopolysaccharide (LPS)-induced human peripheral blood mononuclear cell proliferation and cytokine release, respectively, were assessed. Treatment of mice with E121 significantly decreased the ovalbumin-induced increase in airway total cell influx and eosinophil infiltration and this was associated with an inhibition of ovalbumin-induced airway hyperresponsiveness. Moreover, E121 reduced PHA and anti-CD3-induced human peripheral blood mononuclear cell proliferation in vitro. E121 also inhibited PHA, anti-CD3 monoclonal antibody and LPS-induced cytokine release from human peripheral blood mononuclear cell cultures. These findings indicate that E121 exhibits anti-inflammatory and immunosuppressive activities.

Clinical and antibacterial effect of an anti-inflammatory toothpaste formulation with Scutellaria baicalensis extract on experimental gingivitis

It was the aim of the study to evaluate the clinical and antibacterial effect of a dentifrice containing an anti-inflammatory plant extract (SB) versus a placebo (PLA) using an experimental gingivitis model. Forty subjects (20 per group) discontinued all oral hygiene measures for four teeth for a period of 21 days using a shield (to generate a possible gingivitis) while they could brush the other teeth normally. After brushing, the shield was removed and teeth were treated with the randomly assigned toothpaste slurry for 1 min. Löe and Silness gingival index (GI), Silness and Löe plaque index (PI), and biofilm vitality (VF%) were assessed at days 0, 14, and 21, respectively. Subjects of the PLA group developed a GI of 0.82?±?0.342 (day 14) and 1.585?±?0.218 (day 21), while the data of the SB group were significantly reduced (0.355?±?0.243 and 0.934?±?0.342, p?

A differential concentration-dependent effect of IVIg on neutrophil functions: relevance for anti-microbial and anti-inflammatory mechanisms

Background Polymorphonuclear neutrophils (PMN) play a key role in host defences against invading microorganisms but can also potentiate detrimental inflammatory reactions in case of excessive or misdirected responses. Intravenous immunoglobulins (IVIg) are used to treat patients with immune deficiencies and, at higher doses, in autoimmune, allergic and systemic inflammatory disorders. Methodology/Principal Findings We used flow cytometry to examine the effects of IVIg on PMN functions and survival, using whole-blood conditions in order to avoid artifacts due to isolation procedures. IVIg at low concentrations induced PMN activation, as reflected by decreased L-selectin and increased CD11b expression at the PMN surface, oxidative burst enhancement, and prolonged cell survival. In contrast, IVIg at higher concentrations inhibited LPS-induced CD11b degranulation and oxidative burst priming, and counteracted LPS-induced PMN lifespan prolongation. Conclusions/Significance IVIg appears to have differential, concentration-dependent effects on PMN, possibly supporting the use of IVIg as either an anti-microbial or an anti-inflammatory agent.

Atopic dermatitis: from new pathogenic insights toward a barrier-restoring and anti-inflammatory therapy

Recent published work on atopic dermatitis focusing on the pathogenesis and epidemiology, which have a direct effect on treatment, is presented.

Intracerebroventricularly delivered VEGF promotes contralesional corticorubral plasticity after focal cerebral ischemia via mechanisms involving anti-inflammatory actions

Vascular endothelial growth factor (VEGF) has potent angiogenic and neuroprotective effects in the ischemic brain. Its effect on axonal plasticity and neurological recovery in the post-acute stroke phase was unknown. Using behavioral tests combined with anterograde tract tracing studies and with immunohistochemical and molecular biological experiments, we examined effects of a delayed i.c.v. delivery of recombinant human VEGF(165), starting 3 days after stroke, on functional neurological recovery, corticorubral plasticity and inflammatory brain responses in mice submitted to 30 min of middle cerebral artery occlusion. We herein show that the slowly progressive functional improvements of motor grip strength and coordination, which are induced by VEGF, are accompanied by enhanced sprouting of contralesional corticorubral fibres that branched off the pyramidal tract in order to cross the midline and innervate the ipsilesional parvocellular red nucleus. Infiltrates of CD45+ leukocytes were noticed in the ischemic striatum of vehicle-treated mice that closely corresponded to areas exhibiting Iba-1+ activated microglia. VEGF attenuated the CD45+ leukocyte infiltrates at 14 but not 30 days post ischemia and diminished the microglial activation. Notably, the VEGF-induced anti-inflammatory effect of VEGF was associated with a downregulation of a broad set of inflammatory cytokines and chemokines in both brain hemispheres. These data suggest a link between VEGF's immunosuppressive and plasticity-promoting actions that may be important for successful brain remodeling. Accordingly, growth factors with anti-inflammatory action may be promising therapeutics in the post-acute stroke phase.

Neospora caninum: functional inhibition of protein disulfide isomerase by the broad-spectrum anti-parasitic drug nitazoxanide and other thiazolides

Nitazoxanide (NTZ) and several NTZ-derivatives (thiazolides) have been shown to exhibit considerable anti-Neospora caninum tachyzoite activity in vitro. We coupled tizoxanide (TIZ), the deacetylated metabolite, to epoxy-agarose-resin and performed affinity chromatography with N. caninum tachyzoite extracts. Two main protein bands of 52 and 43kDa were isolated. The 52kDa protein was readily recognized by antibodies directed against NcPDI, and mass spectrometry confirmed its identity. Poly-histidine-tagged NcPDI-cDNA was expressed in Escherichia coli and recombinant NcPDI (recNcPDI) was purified by Co2+-affinity chromatography. By applying an enzyme assay based on the measurement of insulin crosslinking activity, recNcPDI exhibited properties reminiscent for PDIs, and its activity was impaired upon the addition of classical PDI inhibitors such as bacitracin (1-2mM), para-chloromercuribenzoic acid (0.1-1mM) and tocinoic acid (0.1-1mM). RecNcPDI-mediated insulin crosslinking was inhibited by NTZ (5-100 microM) in a dose-dependent manner. In addition, the enzymatic activity of recNcPDI was inhibited by those thiazolides that also affected parasite proliferation. Thus, thiazolides readily interfere with NcPDI, and possibly also with PDIs from other microorganisms susceptible to thiazolides.

Sphingosylphosphorylcholine acts in an anti-inflammatory manner in renal mesangial cells by reducing interleukin-1beta-induced prostaglandin E2 formation

Sphingosylphosphorylcholine (SPC) is a bioactive lipid that binds to G protein-coupled-receptors and activates various signaling cascades. Here, we show that in renal mesangial cells, SPC not only activates various protein kinase cascades but also activates Smad proteins, which are classical members of the transforming growth factor-beta (TGFbeta) signaling pathway. Consequently, SPC is able to mimic TGFbeta-mediated cell responses, such as an anti-inflammatory and a profibrotic response. Interleukin-1beta-stimulated prostaglandin E(2) formation is dose-dependently suppressed by SPC, which is paralleled by reduced secretory phospholipase A(2) (sPLA(2)) protein expression and activity. This effect is due to a reduction of sPLA(2) mRNA expression caused by inhibited sPLA(2) promoter activity. Furthermore, SPC upregulates the profibrotic connective tissue growth factor (CTGF) protein and mRNA expression. Blocking TGFbeta signaling by a TGFbeta receptor kinase inhibitor causes an inhibition of SPC-stimulated Smad activation and reverses both the negative effect of SPC on sPLA(2) expression and the positive effect on CTGF expression. In summary, our data show that SPC, by mimicking TGFbeta, leads to a suppression of proinflammatory mediator production and stimulates a profibrotic cell response that is often the end point of an anti-inflammatory reaction. Thus, targeting SPC receptors may represent a novel therapeutic strategy to cope with inflammatory diseases.

Anti-inflammatory properties of alpha- and gamma-tocopherol

Natural vitamin E consists of four different tocopherol and four different tocotrienol homologues (alpha,beta, gamma, delta) that all have antioxidant activity. However, recent data indicate that the different vitamin E homologues also have biological activity unrelated to their antioxidant activity. In this review, we discuss the anti-inflammatory properties of the two major forms of vitamin E, alpha-tocopherol (alphaT) and gamma-tocopherol (gammaT), and discuss the potential molecular mechanisms involved in these effects. While both tocopherols exhibit anti-inflammatory activity in vitro and in vivo, supplementation with mixed (gammaT-enriched) tocopherols seems to be more potent than supplementation with alphaT alone. This may explain the mostly negative outcomes of the recent large-scale interventional chronic disease prevention trials with alphaT only and thus warrants further investigation.

Platelet GPIb complex as a target for anti-thrombotic drug development

Specific inhibition of platelet function is a major target of anti-thrombotic drug research. Platelet receptors are both accessible and specific but have multiple functions often linked to a wide range of ligands. GPIb complex is best known as a major platelet receptor for von Willebrand factor essential for platelet adhesion under high shear conditions found in arteries and in thrombosis. Recent animal studies have supported inhibition of GPIb as a good candidate for anti-thrombotic drug development with several classes of proteins showing important specific effects and the required discrimination between roles in haemostasis and thrombosis is important to protect against bleeding complications. These include antibodies, several classes of snake venom proteins, mutant thrombin molecules and peptides affecting subunit interactions. However, due to the nature of its receptor-ligand interactions involving large protein-protein interfaces, the possibility of developing classic pharmaceutical inhibitors for long term (and perhaps oral) treatment is still unclear, and additional information about structural interactions and signalling mechanisms is essential.

Brain edema and increased intracranial pressure in the pathophysiology of bacterial meningitis

A number of advances in our understanding of the pathophysiology of bacterial meningitis have been made in recent years. In vivo studies have shown that bacterial cell wall fragments and endotoxins are highly active components, independent of the presence of viable bacteria in the subarachnoid space. Their presence in the cerebrospinal fluid is associated with the induction of inflammation and with the development of brain edema and increased intracranial pressure. Antimicrobial therapy may cause an additional increase of harmful bacterial products in the cerebrospinal fluid and thereby potentiate these pathophysiological alterations. These changes may contribute to the development of brain damage during meningitis. Some promising experimental work has been directed toward counteracting the above phenomena with non-steroidal or steroidal anti-inflammatory agents as well as with monoclonal antibodies. Although considerable advances have been made, further research needs to be done in these areas to improve the prognosis of bacterial meningitis.

Association between burnout and circulating levels of pro- and anti-inflammatory cytokines in schoolteachers

OBJECTIVE: The burnout syndrome has been associated with an increased risk of cardiovascular disease. The physiological mechanisms potentially involved in this link are underexplored. Knowing that a chronic low-grade systemic inflammatory state contributes to atherosclerosis, we investigated circulating cytokine levels in relation to burnout symptoms. METHODS: We studied 167 schoolteachers (median, 48 years; range, 23-63 years; 67% women) who completed the Maslach Burnout Inventory with its three subscales emotional exhaustion (EE), lack of accomplishment (LA), and depersonalization (DP). Levels of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha and of the anti-inflammatory cytokines interleukin (IL)-4 and IL-10 were determined in fasting morning plasma samples. The TNF-alpha/IL-4 ratio and the TNF-alpha/IL-10 ratio were computed as two indices of increased inflammatory activity. Analyses were adjusted for demographic factors, medication, lifestyle factors (including sleep quality), metabolic factors, and symptoms of depression and anxiety. RESULTS: Higher levels of total burnout symptoms aggregating the EE, LA, and DP subscales independently predicted higher TNF-alpha levels (DeltaR(2)=.024, P=.046), lower IL-4 levels (DeltaR(2)=.021, P=.061), and a higher TNF-alpha/IL-4 ratio (DeltaR(2)=.040, P=.008). Higher levels of LA predicted decreased IL-4 levels (DeltaR(2)=.041, P=.008) and a higher TNF-alpha/IL-4 ratio (DeltaR(2)=.041, P=.007). The categorical dimensions of the various burnout scales (e.g., burnout yes vs. no) showed no independent relationship with any cytokine measure. CONCLUSION: Burnout was associated with increased systemic inflammation along a continuum of symptom severity rather than categorically. Given that low-grade systemic inflammation promotes atherosclerosis, our findings may provide one explanation for the increased cardiovascular risk previously observed in burned-out individuals.

Lipids as targets for novel anti-inflammatory therapies

Lipids serve important functions as membrane constituents and also as energy storing molecules. Besides these functions certain lipid species have now been recognized as signalling molecules that regulate a multitude of cellular responses including cell growth and death, and also inflammatory reactions. Bioactive lipids are generated by hydrolysis from membrane lipids mainly by phospholipases giving rise to fatty acids and lysophospholipids that either directly exert their function or are further converted to active mediators. This review will summarize the present knowledge about bioactive lipids that either promote or attenuate inflammatory reactions. These lipids include polyunsaturated fatty acids (PUFA), eicosanoids including the epoxyeicosatrienoic acids (EET), peroxisome proliferation activating receptor (PPAR) activators, cannabinoids and the sphingolipids ceramide, sphingosine 1-phosphate and sphingosylphosphorylcholine.