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  1. Article ; Online: Immunomodulatory oligonucleotides inhibit neutrophil migration by decreasing the surface expression of interleukin-8 and leukotriene B4 receptors.

    Admyre, Charlotte / Axelsson, Lars-Göran / von Stein, Oliver / Zargari, Arezou

    Immunology

    2014  Volume 144, Issue 2, Page(s) 206–217

    Abstract: Neutrophils play important roles in many inflammatory diseases. The migration of neutrophils to the inflammatory site is tightly regulated by specific chemokines, of which interleukin-8 (IL-8) and leukotriene B4 (LTB4 ) constitute key mediators by ... ...

    Abstract Neutrophils play important roles in many inflammatory diseases. The migration of neutrophils to the inflammatory site is tightly regulated by specific chemokines, of which interleukin-8 (IL-8) and leukotriene B4 (LTB4 ) constitute key mediators by binding to the surface receptors CXCR1/2 and BLT1, respectively. Oligonucleotides (ODN) containing CpG motifs mediate potent immunomodulatory effects through binding to Toll-like receptor 9. So far, knowledge on how ODN can affect neutrophil migration during inflammation is lacking. This study demonstrates that several novel CpG ODN significantly down-regulate the surface expression of CXCR1/2 and BLT1. In addition, the ODN significantly blocked IL-8-induced and LTB4 -induced neutrophil migration in vitro, as well as leucocyte migration in vivo demonstrated in mice by intravital microscopy and in a model of airway inflammation. The down-regulation of CXCR1 is rapid, occurring 15 min after ODN stimulation, and can be mediated through an endosomally independent mechanism. Inhibition of the IL-8 and LTB4 pathways may provide new opportunities of therapeutic intervention using ODN to reduce neutrophil infiltration during inflammation.
    MeSH term(s) Animals ; Chemotaxis, Leukocyte/drug effects ; Chemotaxis, Leukocyte/immunology ; CpG Islands/genetics ; Down-Regulation/immunology ; Female ; Humans ; Immunologic Factors/pharmacology ; Immunomodulation ; Inflammation/drug therapy ; Inflammation/immunology ; Interleukin-8/antagonists & inhibitors ; Interleukin-8/biosynthesis ; Interleukin-8/immunology ; Macrophage-1 Antigen/immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Neutrophil Infiltration/drug effects ; Neutrophil Infiltration/immunology ; Neutrophils/drug effects ; Neutrophils/immunology ; Oligonucleotides/pharmacology ; Ovalbumin ; Receptors, Interleukin-8A/biosynthesis ; Receptors, Interleukin-8B/biosynthesis ; Receptors, Leukotriene B4/antagonists & inhibitors ; Receptors, Leukotriene B4/biosynthesis ; Receptors, Leukotriene B4/immunology ; Toll-Like Receptor 9/immunology ; Tumor Necrosis Factor-alpha/immunology
    Chemical Substances Immunologic Factors ; Interleukin-8 ; Macrophage-1 Antigen ; Oligonucleotides ; Receptors, Interleukin-8A ; Receptors, Interleukin-8B ; Receptors, Leukotriene B4 ; Toll-Like Receptor 9 ; Tumor Necrosis Factor-alpha ; Ovalbumin (9006-59-1)
    Language English
    Publishing date 2014-08-07
    Publishing country England
    Document type Journal Article
    ZDB-ID 80124-0
    ISSN 1365-2567 ; 0019-2805 ; 0953-4954
    ISSN (online) 1365-2567
    ISSN 0019-2805 ; 0953-4954
    DOI 10.1111/imm.12368
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Biomarkers can predict potential clinical responders to DIMS0150 a toll-like receptor 9 agonist in ulcerative colitis patients.

    Kuznetsov, Nikolai V / Zargari, Arezou / Gielen, Alexander W / von Stein, Oliver D / Musch, Eugen / Befrits, Ragnar / Lofberg, Robert / von Stein, Petra

    BMC gastroenterology

    2014  Volume 14, Page(s) 79

    Abstract: Background: Glucocorticoids (GCS) remain one of the mainstay treatments in the management of ulcerative colitis (UC) but up to a third of patients will ultimately fail to respond and progress to a more severe and difficult to manage disease state. ... ...

    Abstract Background: Glucocorticoids (GCS) remain one of the mainstay treatments in the management of ulcerative colitis (UC) but up to a third of patients will ultimately fail to respond and progress to a more severe and difficult to manage disease state. Previous clinical studies suggest that the Toll-Like Receptor 9 (TLR9) agonist DIMS0150 not only induces production of key anti-inflammatory cytokines as IL-10 but interestingly also enhances steroid sensitivity in steroid refractory UC patients. We investigated, in the context of a clinical study, whether a pre-selection of steroid response genes could identify steroid refractory UC subjects most likely to respond to DIMS0150 treatment.
    Methods: In a non-interventional pilot study, blood from steroid refractory UC patients and healthy volunteers was taken and thirty-four previously described steroid response genes were analysed by real time PCR analysis. To establish clinical utility of the identified biomarkers, a placebo controlled, randomized, double blinded study in active steroid dependent and steroid resistant UC patients on concomitant steroid therapies was used (EudraCT number: 2006-001846-15).
    Results: We identified three potential biomarkers CD163, TSP-1 and IL-1RII whose response to steroids was significantly enhanced when DIMS0150 was applied. Thirty-four subjects were randomized to receive a single rectal administration of placebo or 30 mg of DIMS0150. Blood derived PBMCs were obtained prior to dosing and assayed for evidence of a steroid enhancing effect following steroid incubation in the presence of DIMS0150. Comparison to established steroid sensitivity marker IL-6 confirmed that clinical responders are steroid refractory UC patients. Upon study completion and un-blinding, the biomarker assay correctly predicted a clinical response in over 90% of the patients.
    Conclusion: Using specific steroid response biomarkers, GCS refractory UC patients most likely to benefit from DIMS0150 treatment could be identified and illustrates the usefulness of a personalized treatment approach.
    MeSH term(s) Administration, Rectal ; Adult ; Aged ; Antigens, CD/genetics ; Antigens, Differentiation, Myelomonocytic/genetics ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics ; Biomarkers ; Case-Control Studies ; Colitis, Ulcerative/drug therapy ; Colitis, Ulcerative/genetics ; DNA/therapeutic use ; Double-Blind Method ; Female ; Glucocorticoids/therapeutic use ; Humans ; Immunologic Factors/therapeutic use ; Male ; Middle Aged ; Polymerase Chain Reaction ; Prognosis ; Receptors, Cell Surface/genetics ; Receptors, Interleukin-1 Type II/genetics ; Toll-Like Receptor 9/agonists ; Treatment Outcome ; Young Adult
    Chemical Substances Antigens, CD ; Antigens, Differentiation, Myelomonocytic ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ; Biomarkers ; CD163 antigen ; DIMS0150 ; Glucocorticoids ; IL1R2 protein, human ; Immunologic Factors ; Receptors, Cell Surface ; Receptors, Interleukin-1 Type II ; SPZ1 protein, human ; TLR9 protein, human ; Toll-Like Receptor 9 ; DNA (9007-49-2)
    Language English
    Publishing date 2014-04-23
    Publishing country England
    Document type Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial
    ISSN 1471-230X
    ISSN (online) 1471-230X
    DOI 10.1186/1471-230X-14-79
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Topical treatment with the Toll-like receptor agonist DIMS0150 has potential for lasting relief of symptoms in patients with chronic active ulcerative colitis by restoring glucocorticoid sensitivity.

    Musch, Eugen / Lutfi, Tamim / von Stein, Petra / Zargari, Arezou / Admyre, Charlotte / Malek, Mouhamad / Löfberg, Robert / von Stein, Oliver D

    Inflammatory bowel diseases

    2011  Volume 19, Issue 2, Page(s) 283–292

    Abstract: Background: Patients with chronic active ulcerative colitis (UC) are regarded as treatment failures and represent an area of high unmet medical need, as normally the only remaining option is colectomy.: Methods: We treated a total of eight chronic ... ...

    Abstract Background: Patients with chronic active ulcerative colitis (UC) are regarded as treatment failures and represent an area of high unmet medical need, as normally the only remaining option is colectomy.
    Methods: We treated a total of eight chronic active severe UC outpatients with the immunomodulatory agent DIMS0150 as an add-on to current therapies. Seven patients received a single topical dose of 30 mg and one special case subject received three doses with 4 weeks between dosing occasions. All patients were classed as treatment failures and were elected for colectomy. Efficacy evaluation was determined in terms of colitis activity index, endoscopic improvement, and histologic disease activity assessed primarily at week 12 with a follow-up period of over 2 years. Glucocorticoid sensitivity was assayed by in vitro measurement of interleukin 6.
    Results: All patients demonstrated a pronounced and rapid reduction in their colitis activity index within 1 week following a single intracolonic administration via colonoscope of the agent DIMS0150. Further improvements were evident at week 4, resulting in a clinical response rate for the single-dose treatment of 71%, with 43% in clinical remission. By week 12 the clinical response and remission rates had reached 82% and 71%, respectively. A follow-up period of over 2 years posttreatment indicated that all but one of the treated patients had avoided the need for colectomy, with the longest patient being in symptom-free remission for over 27 months. Treatment with DIMS0150 restored glucocorticoid sensitivity.
    Conclusions: DIMS0150 may have the potential to be an effective agent to treat chronic active UC patients with the prospect to avoid colectomy on a long-term basis and is currently the subject of a clinical phase III study (EudraCT number: 2011-003130-14).
    MeSH term(s) Administration, Topical ; Adult ; Aged ; Biomarkers/blood ; Colitis, Ulcerative/drug therapy ; Colitis, Ulcerative/metabolism ; Colon/metabolism ; Colonoscopy ; DNA/therapeutic use ; Drug Administration Schedule ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Glucocorticoids/therapeutic use ; Humans ; Immunologic Factors/therapeutic use ; Interleukin-6/blood ; Male ; Middle Aged ; Prednisolone/therapeutic use ; Prospective Studies ; Toll-Like Receptor 9/metabolism ; Treatment Outcome
    Chemical Substances Biomarkers ; DIMS0150 ; Glucocorticoids ; IL6 protein, human ; Immunologic Factors ; Interleukin-6 ; TLR9 protein, human ; Toll-Like Receptor 9 ; DNA (9007-49-2) ; Prednisolone (9PHQ9Y1OLM)
    Language English
    Publishing date 2011-08-29
    Publishing country England
    Document type Clinical Trial ; Journal Article
    ZDB-ID 1340971-2
    ISSN 1536-4844 ; 1078-0998
    ISSN (online) 1536-4844
    ISSN 1078-0998
    DOI 10.1002/ibd.23019
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4530: Show issues Location:
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  4. Article ; Online: Multigene analysis can discriminate between ulcerative colitis, Crohn's disease, and irritable bowel syndrome.

    von Stein, Petra / Lofberg, Robert / Kuznetsov, Nikolai V / Gielen, Alexander W / Persson, Jan-Olov / Sundberg, Rolf / Hellstrom, Karin / Eriksson, Anders / Befrits, Ragnar / Ost, Ake / von Stein, Oliver D

    Gastroenterology

    2008  Volume 134, Issue 7, Page(s) 1869–81; quiz 2153–4

    Abstract: Background & aims: Inflammatory bowel diseases (IBDs) and the irritable bowel syndrome (IBS) are heterogeneous disorders of the gastrointestinal tract and can profoundly affect the quality of life. Because many of the symptoms of IBD are similar to ... ...

    Abstract Background & aims: Inflammatory bowel diseases (IBDs) and the irritable bowel syndrome (IBS) are heterogeneous disorders of the gastrointestinal tract and can profoundly affect the quality of life. Because many of the symptoms of IBD are similar to those of IBS, the former may be misdiagnosed. In addition, the 2 major forms of IBD, ulcerative colitis (UC) and Crohn's disease (CD), have overlapping nonspecific, pathologic features leading to difficulties in assessing colonic inflammation and hence the term IBD unclassified has been proposed. The aim of this study was to identify and assess the utility of a certain set of marker genes that could help to distinguish IBS from IBD, and further to discriminate between UC and CD.
    Methods: Subtractive suppression hybridization was used to identify IBD-specific genes in colonic mucosal biopsy specimens. In quantitative polymerase chain reaction experiments, the differential expressions of identified genes then were analyzed using a classification algorithm and the possible clinical value of these marker genes was evaluated in a total of 301 patients in 3 stepwise studies.
    Results: Seven marker genes were identified as differentially expressed in IBD, making it possible to discriminate between patients suffering from UC, CD, or IBS with area under the receiver-operating characteristic curves ranging from 0.915 to 0.999 (P < .0001) using the clinical diagnosis as gold standard.
    Conclusions: Expression profiling of relevant marker genes in colonic biopsy specimens from patients with IBD/IBS-like symptoms may enable swift and reliable determination of diagnosis, ultimately improving disease management.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Algorithms ; Colitis, Ulcerative/diagnosis ; Colitis, Ulcerative/genetics ; Colitis, Ulcerative/pathology ; Colon/chemistry ; Colon/pathology ; Crohn Disease/diagnosis ; Crohn Disease/genetics ; Crohn Disease/pathology ; DNA, Complementary/analysis ; Diagnosis, Differential ; Female ; Gene Expression Profiling/methods ; Genetic Markers ; Genetic Predisposition to Disease ; Genetic Testing ; Genotype ; Humans ; Intestinal Mucosa/chemistry ; Intestinal Mucosa/pathology ; Irritable Bowel Syndrome/diagnosis ; Irritable Bowel Syndrome/genetics ; Irritable Bowel Syndrome/pathology ; Male ; Middle Aged ; Oligonucleotide Array Sequence Analysis ; Phenotype ; Pilot Projects ; Predictive Value of Tests ; Prospective Studies ; RNA/analysis ; ROC Curve ; Reproducibility of Results ; Retrospective Studies ; Reverse Transcriptase Polymerase Chain Reaction
    Chemical Substances DNA, Complementary ; Genetic Markers ; RNA (63231-63-0)
    Language English
    Publishing date 2008-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80112-4
    ISSN 1528-0012 ; 0016-5085
    ISSN (online) 1528-0012
    ISSN 0016-5085
    DOI 10.1053/j.gastro.2008.02.083
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Ui V Zs.44: Show issues Location:
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    Zs.MO 572: Show issues

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  5. Article: Identification of a new WASP and FKBP-like (WAFL) protein in inflammatory bowel disease: a potential marker gene for ulcerative colitis.

    Viklund, Ing-Marie / Kuznetsov, Nikolai V / Löfberg, Robert / Daperno, Marco / Sostegni, Raffaello / Astegiano, Marco / Rizzetto, Mario / von Stein, Oliver / D'Amato, Mauro / von Stein, Petra / Pettersson, Sven

    International journal of colorectal disease

    2008  Volume 23, Issue 10, Page(s) 921–930

    Abstract: Background and aims: Inflammatory bowel disease (IBD) is a complex inflammatory disease of the gastrointestinal tract with unknown cause that lacks molecular markers for diagnosis. Crohn's disease (CD) and ulcerative colitis (UC) are the two major forms ...

    Abstract Background and aims: Inflammatory bowel disease (IBD) is a complex inflammatory disease of the gastrointestinal tract with unknown cause that lacks molecular markers for diagnosis. Crohn's disease (CD) and ulcerative colitis (UC) are the two major forms of IBD. The aim of this study was to investigate gene expression patterns in UC and characterize newly identified marker genes potentially linked to disease pathogenesis of UC.
    Materials and methods: Biopsies were taken from eight UC patients, from inflamed and non-inflamed parts of the colon. Gene expression was investigated by subtractive suppression hybridization (SSH), and further study of a selected gene was performed by Northern blot, immunohistochemistry, immunocytochemistry, and in vitro monocyte differentiation.
    Results: Three hundred thirty-one differentially expressed genes were found and classified into functional groups. In this paper, we report one gene with unknown function to be differentially expressed in UC but not Crohn's disease by real-time reverse transcriptase polymerase chain reaction. Due to its predicted protein architecture, we call this gene Wiskott-Aldrich syndrome protein and FKBP-like (WAFL). Initial pilot experiments suggest WAFL to participate in innate immune functions.
    Conclusion: The SSH result supports the current view of UC to be a chronic inflammatory disorder with aberrant expression of epithelial barrier proteins, cell fate-related factors, and disturbed metabolism. The new gene, WAFL, reported in this study, appears to be conditionally regulated in myeloid cells. This indicates that WAFL may be connected to innate immune-host responses. As such, it represents an interesting, hitherto unknown player in IBD where there is a need for further elucidation on the molecular and cellular level.
    MeSH term(s) Adult ; Aged ; Biomarkers ; Biopsy ; Blotting, Northern ; Cells, Cultured ; Colitis, Ulcerative/genetics ; Colitis, Ulcerative/metabolism ; Colitis, Ulcerative/pathology ; Female ; Gene Expression ; Humans ; Immunohistochemistry ; Inflammatory Bowel Diseases/genetics ; Inflammatory Bowel Diseases/metabolism ; Inflammatory Bowel Diseases/pathology ; Male ; Middle Aged ; Pilot Projects ; RNA/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Tacrolimus Binding Proteins/genetics ; Tacrolimus Binding Proteins/metabolism ; Wiskott-Aldrich Syndrome Protein/genetics ; Wiskott-Aldrich Syndrome Protein/metabolism ; Young Adult
    Chemical Substances Biomarkers ; Wiskott-Aldrich Syndrome Protein ; RNA (63231-63-0) ; Tacrolimus Binding Proteins (EC 5.2.1.-)
    Language English
    Publishing date 2008-07-25
    Publishing country Germany
    Document type Comparative Study ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
    ZDB-ID 84975-3
    ISSN 1432-1262 ; 0179-1958
    ISSN (online) 1432-1262
    ISSN 0179-1958
    DOI 10.1007/s00384-008-0527-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 2121: Show issues Location:
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