Visual loss in acute optic neuritis is typically attributed to axonal conduction block due to inflammatory demyelination, but the mechanisms remain unclear. Recent research has highlighted tissue hypoxia as an important cause of neurological deficits and tissue damage in both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) and, here, we examine whether the optic nerves are hypoxic in experimental optic neuritis induced in Dark Agouti rats. At both the first and second peaks of disease expression, inflamed optic nerves labelled significantly for tissue hypoxia (namely, positive for hypoxia inducible factor-1α (HIF1α) and intravenously administered pimonidazole). Acutely inflamed nerves were also labelled significantly for innate markers of oxidative and nitrative stress and damage, including superoxide, nitric oxide and 3-nitrotyrosine. The density and diameter of capillaries were also increased. We conclude that in acute optic neuritis, the optic nerves are hypoxic and come under oxidative and nitrative stress and damage. Tissue hypoxia can cause mitochondrial failure and thus explains visual loss due to axonal conduction block. Tissue hypoxia can also induce a damaging oxidative and nitrative environment. The findings indicate that treatment to prevent tissue hypoxia in acute optic neuritis may help to restore vision and protect from damaging reactive oxygen and nitrogen species.

• MeSH
• encefalomyelitida autoimunitní experimentální * metabolismus   MeSH
• hypoxie metabolismus   MeSH
• imunologické faktory metabolismus   MeSH
• krysa rodu rattus MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nervus opticus metabolismus   MeSH
• zánět zrakového nervu * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• abnormality vyvolané léky epidemiologie   prevence a kontrola   MeSH
• imunologické faktory metabolismus   terapeutické užití   MeSH
• interferon beta metabolismus   terapeutické užití   MeSH
• kojenec MeSH
• kojení MeSH
• komplikace těhotenství etiologie   farmakoterapie   MeSH
• lidé MeSH
• mateřské mléko MeSH
• monoklonální protilátky metabolismus   terapeutické užití   MeSH
• nežádoucí účinky léčiv MeSH
• progrese nemoci MeSH
• roztroušená skleróza * farmakoterapie   MeSH
• těhotenství MeSH
• trimestry těhotenství účinky léků   MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• přehledy MeSH

Selective inhibition of histone deacetylase 6 (HDAC6) is being recognized as a therapeutic approach for cancers. In this study, we designed a new HDAC6 inhibitor, named Suprastat, using in silico simulations. X-ray crystallography and molecular dynamics simulations provide strong evidence to support the notion that the aminomethyl and hydroxyl groups in the capping group of Suprastat establish significant hydrogen bond interactions, either direct or water-mediated, with residues D460, N530, and S531, which play a vital role in regulating the deacetylase function of the enzyme and which are absent in other isoforms. In vitro characterization of Suprastat demonstrates subnanomolar HDAC6 inhibitory potency and a hundred- to a thousand-fold HDAC6 selectivity over the other HDAC isoforms. In vivo studies reveal that a combination of Suprastat and anti-PD1 immunotherapy enhances antitumor immune response, mediated by a decrease of protumoral M2 macrophages and increased infiltration of antitumor CD8+ effector and memory T-cells.

• MeSH
• fenylmočovinové sloučeniny chemická syntéza   metabolismus   terapeutické užití   MeSH
• histondeacetylasa 6 antagonisté a inhibitory   metabolismus   MeSH
• imunologické faktory chemická syntéza   metabolismus   terapeutické užití   MeSH
• imunoterapie MeSH
• inhibitory histondeacetylas chemická syntéza   metabolismus   terapeutické užití   MeSH
• jaterní mikrozomy metabolismus   MeSH
• krysa rodu rattus MeSH
• krystalografie rentgenová MeSH
• kyseliny hydroxamové chemická syntéza   metabolismus   terapeutické užití   MeSH
• lidé MeSH
• melanom farmakoterapie   terapie   MeSH
• myši inbrední C57BL MeSH
• nádorové buněčné linie MeSH
• racionální návrh léčiv MeSH
• simulace molekulární dynamiky MeSH
• vazba proteinů MeSH
• vodíková vazba MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Candida glabrata is a second most common human opportunistic pathogen which causes superficial but also life-threatening systemic candidosis. According to the localisation of mannans and mannoproteins in the outermost layer of the cell wall, mannan detection could be one of the first steps in the cell recognition of Candida cells by the host innate immune system. Mannans from the cell wall provide important immunomodulatory activities, comprising stimulation of cytokine production, induction of dendritic cells (DCs) maturation and T-cell immunity. The model of DCs represents a promising tool to study immunomodulatory interventions throughout the vaccine development. Activated DCs induce, activate and polarise T-cell responses by expression of distinct maturation markers and cytokines regulating the adaptive immune responses. In addition, they are uniquely adept at decoding the fungus-associated information and translate it in qualitatively different T helper responses. We find out, that C. glabrata mannan is able to induce proliferation of splenocytes and to increase the production of TNF-α and IL-4. Next, increased the expression of co-stimulatory molecules CD80 and CD86 and the proportion of CD4+CD25+ and CD4+CD28+ T cells during in vitro stimulation of splenocytes. Reported results provide C. glabrata mannan capability to modulate cytokine production, DCs activation and antigen presentation activity, influencing T-cell phenotype in response to stimulation.

• MeSH
• Candida glabrata imunologie   MeSH
• cytokiny metabolismus   MeSH
• dendritické buňky imunologie   MeSH
• imunologické faktory metabolismus   MeSH
• kultivované buňky MeSH
• mannany metabolismus   MeSH
• myši MeSH
• přirozená imunita * MeSH
• proliferace buněk účinky léků   MeSH
• T-lymfocyty imunologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Stem cells have the capability of self-renewal and can differentiate into different cell types that might be used in regenerative medicine. Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) currently lack effective treatments. Although stem cell therapy is still on the way from bench to bedside, we consider that it might provide new hope for patients suffering with neurodegenerative diseases. In this article, we will give an overview of recent studies on the potential therapeutic use of mesenchymal stem cells (MSCs), neural stem cells (NSCs), embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and perinatal stem cells to neurodegenerative disorders and we will describe their immunomodulatory mechanisms of action in specific therapeutic modalities.

• MeSH
• biologické modely MeSH
• imunologické faktory metabolismus   MeSH
• kmenové buňky metabolismus   MeSH
• lidé MeSH
• neurodegenerativní nemoci terapie   MeSH
• transplantace kmenových buněk * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Antimicrobial and immunomodulatory potential of various Lactobacillus reuteri strains is closely connected to their metabolite production profile under given cultivation conditions. We determined the in vitro production of antimicrobial substances such as organic acids, ethanol, and reuterin by four strains of L. reuteri (L. reuteri E, L. reuteri KO5, L. reuteri CCM 3625, and L. reuteri ATCC 55730). All studied L. reuteri strains showed the ability to produce lactic acid, acetic acid, and ethanol with concominant consumption of glucose and together with phenyllactic acid-a potent antifungal compound-with concominant consumption of phenylalanine. The reuterin production from glycerol was confirmed for all analyzed lactobacilli strains except L. reuteri CCM 3625. Production of organic acids, ethanol, and reuterin is significantly involved in antimicrobial activity of lactobacilli which was determined using the dual-culture overlay diffusion method against six indicator bacteria and five indicator moulds. In comparison to the referential L. reuteri ATCC 55730, the highest inhibition potential was observed against Escherichia coli CCM 3988 and Pseudomonas aeruginosa CCM 3955. Among analyzed indicators of moulds, the growth of Alternaria alternata CCM F-128 was the most inhibited by all four analyzed L. reuteri strains. Finally, the immunomodulatory potential of analyzed lactobacilli were proven by the determination of the in vitro production of biogenic amines histamine and tyramine. L. reuteri CCM 3625 was able to produce tyramine, and L. reuteri E and L. reuteri KO5 were able to produce histamine under given cultivation conditions.

• MeSH
• antibakteriální látky analýza   metabolismus   farmakologie   MeSH
• Escherichia coli účinky léků   MeSH
• fermentace MeSH
• imunologické faktory analýza   metabolismus   farmakologie   MeSH
• kyselina mléčná analýza   metabolismus   farmakologie   MeSH
• kyselina octová analýza   metabolismus   farmakologie   MeSH
• Limosilactobacillus reuteri chemie   metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH

Severe meconium aspiration syndrome (MAS) in newborns is often treated by exogenous surfactant. Because its efficacy is reduced by meconium-induced inflammation, glucocorticoid budesonide was added into surfactant preparation Curosurf to enhance efficacy of the surfactant therapy in experimental model of MAS. Oxygen-ventilated rabbits were intratracheally given meconium (25 mg/ml, 4 ml/kg) to induce respiratory failure. Thirty minutes later, animals were treated by intratracheal budesonide (0.25 mg/kg) or surfactant lung lavage (10 ml/kg, 5 mg phospholipids/ml) repeated twice, followed by undiluted Curosurf (100 mg phospholipids/kg) or by the above mentioned surfactant treatment with the last surfactant dose fortified with budesonide (0.25 mg/kg) or were untreated. Animals were ventilated for additional 5 hours and respiratory parameters were measured regularly. After sacrificing animals, wet-dry lung weight ratio was evaluated and plasma levels of interleukins (IL)-1beta, -6, -8, and TNF-alpha were measured by ELISA method. Efficacy of the given therapies to enhance lung functions and to diminish lung edema formation and inflammation increased from budesonide-only and surfactant-only therapy to surfactant+budesonide therapy. Combined therapy improved gas exchange from 30 min of administration, and showed a longer-lasting effect than surfactant-only therapy. In conclusions, budesonide additionally improved the effects of exogenous surfactant in experimental MAS.

• MeSH
• antiflogistika aplikace a dávkování   MeSH
• biologické přípravky aplikace a dávkování   MeSH
• bronchodilatancia aplikace a dávkování   MeSH
• budesonid aplikace a dávkování   MeSH
• fixní kombinace léků MeSH
• fosfolipidy aplikace a dávkování   MeSH
• imunologické faktory metabolismus   MeSH
• králíci MeSH
• mechanika dýchání účinky léků   MeSH
• plicní surfaktanty MeSH
• prasata MeSH
• syndrom aspirace mekonia diagnóza   farmakoterapie   patofyziologie   MeSH
• synergismus léků MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Type I interferons (IFN-α and IFN-β) are crucial determinants of the host immune response and tick saliva modulates this response, thus facilitating the transmission of tickborne pathogens. The current study therefore examines the effect of Ixodes ricinus tick saliva on IFN-β signalling in murine dendritic cells using lipopolysaccharide (LPS) and Borrelia afzelii spirochaetes as inducers. Activated dendritic cells secret IFN that activates Signal Transducer and Activator of Transcription 1 (STAT-1). Our results show that Borrelia-induced activation of STAT-1 was suppressed by tick saliva. As the amount of secreted IFN-β was not influenced by tick saliva, the results indicated that saliva affected the interferon pathway at the IFN receptor or downstream of it. By using recombinant IFN-β, we show that tick saliva attenuates IFN-triggered STAT-1 activation. Tick saliva also inhibited LPS-induced IFN-β production suggesting that saliva interferes with the activation of the pathway that mediates IFN-β induction. Our data indicate that I. ricinus tick saliva may modulate the host immune response by attenuating the initial signal transduction pathway of type I IFN.

• MeSH
• Borrelia burgdorferi komplex patogenita   MeSH
• dendritické buňky imunologie   MeSH
• imunologické faktory imunologie   metabolismus   MeSH
• interferon typ I antagonisté a inhibitory   imunologie   MeSH
• klíště imunologie   MeSH
• kultivované buňky MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• sliny imunologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Dendritic cells are a sentinel in defending against pathogens and tick saliva facilitates transmission of tick-borne pathogens by modulating the host immune response. The maturation of dendritic cells is inhibited by tick saliva. To elucidate the mechanism of this inhibition, we tested the impact of Ixodes ricinus tick saliva on signalling pathways activated by Toll-like receptor (TLR-2) ligand and Borrelia afzelii in spleen dendritic cells. The activation of nuclear factor-κB (NF-κB) p65 and phosphatidylinositol-3 kinase (PI3K)/Akt pathways was decreased by tick saliva upon both TLR-2 and Borrelia stimulation. Among the mitogen-activated protein kinases (MAPK), the activation of extracellular matrix-regulated kinase (Erk1/2) was suppressed by tick saliva, but not p38. In response to spirochaetes, the amount of TNF-α decreased in the presence of tick saliva which was mediated by selective suppression of Erk1/2, NF-κB and Akt as tick saliva mimicked the effect of their specific inhibitors, UO126, IKK-IV and LY294002, respectively. Saliva-induced enhancement of IL-10 was not observed in the presence of specific inhibitor of Protein Kinase A (PKA), H-89, suggesting the involvement of PKA pathway in IL-10 production. Our cumulative data show that tick saliva interferes with several signalling pathways, thus modulating the immune functions of dendritic cells.

• MeSH
• 1-fosfatidylinositol-3-kinasa metabolismus   MeSH
• Borrelia burgdorferi komplex imunologie   MeSH
• dendritické buňky imunologie   MeSH
• imunologické faktory metabolismus   MeSH
• interleukin-10 sekrece   MeSH
• klíště patogenita   MeSH
• mitogenem aktivované proteinkinasy metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• sliny metabolismus   MeSH
• TNF-alfa sekrece   MeSH
• toll-like receptor 2 imunologie   MeSH
• transkripční faktor RelA metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Obesity is a known high-risk factor for the development of vascular diseases and chronic kidney disease (CKD). In this study we aimed to elucidate the impact of adipose tissue on the inflammatory state in CDK patients with obesity. PATIENTS AND METHODS: A cohort of 40 patients with CKD (stages 3-4) with mild proteinuria (2.3-3.5 g/day) were analyzed in a prospective cross-sectional study: single blood samples and visceral and subcutaneous samples of adipose tissue were taken from 20 patients with obesity and 20 without obesity (control group) during elective abdominal surgery (laparoscopic cholecystectomy). Serum concentrations of asymmetric dimethylarginine (ADMA), adiponectin, C-reactive protein, interleukin-6, tumor necrosis factor-alpha, pentosidine and monocyte chemoattractant protein-1 were measured. Messenger RNA expression of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, adiponectin receptors 1 and 2, and immunocompetent cell marker CD68 was measured in subcutaneous and visceral fat samples using real-time PCR. Adipose tissue was examined immunohistochemically for CD68-positive cells. Other biochemical parameters (insulin, glycated hemoglobin, cholesterol, LDL cholesterol, and triglycerides) were assessed in the two groups of patients at the same time. RESULTS: Serum concentrations of ADMA, C-reactive protein, pentosidine, interleukin-6, tumor necrosis factor-alpha and monocyte chemoattractant protein-1 were significantly higher in obese CKD patients than in the control group; adiponectin was lower in the obese group. Subcutaneous and visceral mRNA expressions of tumor necrosis factor-alpha, CD68, adiponectin receptor-1, and monocyte chemoattractant protein-1 were significantly increased in the obese patients, whereas expression of adiponectin, interleukin-6, and adiponectin receptor-2 did not significantly differ between the patient groups. In general, mRNA expressions were higher in visceral than in subcutaneous samples (P < 0.01 vs. P < 0.05). Increased infiltration of subcutaneous and visceral adipose tissue by CD68-positive immunocompetent cells was found in the obese CKD group. With respect to lipid metabolism parameters, a small but significant increase in levels was found in the obese patients (P < 0.02). Changes in triglycerides were more marked in this group (P < 0.01) and a similar increase was noted in insulin and HbA1c levels (P < 0.02). CONCLUSION: Increased expression of proinflammatory cytokines and increased infiltration by immunocompetent cells were found in adipose tissue of obese patients with CKD stages 3-4. This upregulated inflammation may contribute to the induction of a systemic proinflammatory state in patients with CKD and could accelerate the progression of renal dysfunction.

• MeSH
• chronická renální insuficience * komplikace   metabolismus   MeSH
• cytokiny * metabolismus   MeSH
• imunologické faktory metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• obezita * komplikace   metabolismus   MeSH
• tkáňová distribuce MeSH
• tuková tkáň * metabolismus   MeSH
• zánět * komplikace   metabolismus   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH