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  • Doerr, Hans Wilhelm  (22)
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  • 1
    Language: English
    In: Current Molecular Medicine, March 2009, Vol.9(2), pp.131-151
    Description: Highly pathogenic H5N1 avian influenza virus can infect humans and is currently the most deadly influenza virus that has crossed the species barrier. As of December 2007, the spread of H5N1 virus from human to human has been rare. Nobody can predict if H5N1 may cause a pandemic. However, the number of human cases is continuously increasing and changes in virulence and epidemiology have been detected. There are specific pathogenic features of H5N1 infection. In contrast to human-adapted influenza A strains, H5N1 preferentially infects cells of the lower respiratory tract and may spread to tissues outside the respiratory tract in humans. Moreover, H5N1 replication is prolonged in target organs and results in higher viral loads and increased tissue damage. These features will have to be considered for therapeutic protocols for H5N1 infection in humans. Rapid genetic and antigenic changes observed in H5N1 virus isolates represent a challenge for the development of vaccines. In the present review, current knowledge about epidemiology, virulence factors and pathology of H5N1 infections in humans are summarised and discussed. Moreover, the possible roles of antiinfluenza drugs in the pandemic situation as well as the development of effective vaccines are subject of this overview.
    Keywords: Pathogenic H5n1 ; Avian Influenza ; Humans ; Of Chickens ; Epidemiology ; Epidemiology
    ISSN: 1566-5240
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  • 2
    Language: English
    In: The Journal of Infectious Diseases, 09/2000, Vol.182(3), pp.643-651
    Description: In fibroblasts, infection with human cytomegalovirus (HCMV) inhibits expression of the extracellular matrix proteins thrombospondin-1 and -2 (TSP-1 and TSP-2). These effects may depend on expression of HCMV immediate-early (IE) genes, which are activated by cellular transcription factor NF-kappaB. The influence of HCMV infection on TSP-1 and TSP-2 expression and the ability of different antiviral drugs to prevent these cellular changes in permissive cultures of human retinal glial cells were observed. Ganciclovir inhibited only HCMV late antigen (LA) expression, whereas antisense oligonucleotide ISIS 2922 and peptide SN50, inhibitors of HCMV IE expression and NF-kappaB activity, respectively, inhibited both IE and LA expression. ISIS 2922 and SN50, but not ganciclovir, prevented down-modulation of TSP-1 and TSP-2. The results showed that HCMV-induced down-modulation of TSP-1 and TSP-2 in retinal glial cells is prevented by inhibition of HCMV IE expression. These findings may be relevant to pathogenesis and treatment of HCMV retinitis.
    Keywords: Antiviral Agents -- Pharmacology ; Cytomegalovirus Retinitis -- Metabolism ; Neuroglia -- Metabolism ; Retina -- Metabolism ; Thrombospondin 1 -- Biosynthesis ; Thrombospondins -- Biosynthesis;
    ISSN: 0022-1899
    E-ISSN: 1537-6613
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  • 3
    Article
    Article
    In: Current Pharmaceutical Design, November 2007, Vol.13(33), pp.3378-3393
    Description: The short chain fatty acid valproic acid (VPA, 2-propylpetanoic acid) is approved for the treatment of epilepsia, bipolar disorders and migraine and clinically used for schizophrenia. In 1999, the first clinical anti-cancer trial using VPA was initiated. Currently, VPA is examined in numerous clinical trials for different leukaemias and solid tumour entities. In addition to clinical assessment, the experimental examination of VPA as anti-cancer drug is ongoing and many questions remain unanswered. Although other mechanisms may also contribute to VPA-induced anti-cancer effects, inhibition of histone deacetylases appears to play a central role. This review focuses on recent developments regarding the anti-cancer activity of VPA.
    Keywords: Hdac ; Differentiation ; Combination Therapy ; Clinical Studies ; Valproic Acid ; Angiogenesis
    ISSN: 1381-6128
    E-ISSN: 18734286
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  • 4
    Language: English
    In: Biochemical Pharmacology, 2010, Vol.79(2), pp.130-136
    Description: Artemisinin derivatives are well-tolerated anti-malaria drugs that also exert anti-cancer activity. Here, we investigated artemisinin and its derivatives dihydroartemisinin and artesunate in a panel of chemosensitive and chemoresistant human neuroblastoma cells as well as in primary neuroblastoma cultures. Only dihydroartemisinin and artesunate affected neuroblastoma cell viability with artesunate being more active. Artesunate-induced apoptosis and reactive oxygen species in neuroblastoma cells. Of 16 cell lines and two primary cultures, only UKF-NB-3(r)CDDP(1000) showed low sensitivity to artesunate. Characteristic gene expression signatures based on a previous analysis of artesunate resistance in the NC160 cell line panel clearly separated UKF-NB-3(r)CDDP(1000) from the other cell lines. L-Buthionine-S,R-sulfoximine, an inhibitor of GCL (glutamate-cysteine ligase), resensitised in part UKF-NB-3(r)CDDP(1000) cells to artesunate. This finding together with bioinformatic analysis of expression of genes involved in glutathione metabolism showed that this pathway is involved in artesunate resistance. These data indicate that neuroblastoma represents an artesunate-sensitive cancer entity and that artesunate is also effective in chemoresistant neuroblastoma cells. (C) 2009 Elsevier Inc. All rights reserved.
    Keywords: Neuroblastoma ; Artesunate ; Artemisinin ; Chemoresistance ; Cancer ; Chemotherapy ; Gamma-Glutamylcysteine Synthetase ; Traditional Chinese Medicine ; Amino-Acid-Sequence ; Ascites Tumor-Cells ; Cytotoxic Action ; Multidrug-Resistance ; Expression Profiles ; Falciparum-Malaria ; Oxidative Stress ; Leukemia-Cells
    ISSN: 0006-2952
    E-ISSN: 18732968
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  • 5
    Language: English
    In: Phytomedicine: International Journal of Phytotherapy & Phytopharmacology, March 15, 2011, Vol.18(5), p.384(3)
    Description: The Pelargonium sidoides extract EPs[super][registered] 7630 is an approved drug for the treatment of acute bronchitis in Germany. The postulated mechanisms underlying beneficial effects of EPs[super][registered] 7630 in bronchitis patients include immunomodulatory and cytoprotective effects, inhibition of interaction between bacteria and host cells, and increase of cilliary beat frequency on respiratory cells. Here, we investigated the influence of EPs[super][registered] 7630 on replication of a panel of respiratory viruses. Determination of virus-induced cytopathogenic effects and virus titres revealed that EPs[super][registered] 7630 at concentrations up to 100 [micro]g/ml interfered with replication of seasonal influenza A virus strains (H1N1, H3N2), respiratory syncytial virus, human coronavirus, parainfluenza virus, and coxsackie virus but did not affect replication of highly pathogenic avian influenza A virus (H5N1), adenovirus, or rhinovirus. Therefore, antiviral effects may contribute to the beneficial effects exerted by EPs[super][registered] 7630 in acute bronchitis patients.
    Keywords: Influenza -- Drug Therapy ; Influenza -- Research ; Virus Replication -- Research ; Herbal Medicine -- Health Aspects ; Herbal Medicine -- Research ; Geraniums -- Health Aspects ; Geraniums -- Research
    ISSN: 0944-7113
    E-ISSN: 1618095X
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  • 6
    Language: English
    In: PLoS ONE, May 17, 2011, Vol.6(5), p.e19705
    Description: Glycyrrhizin is known to exert antiviral and anti-inflammatory effects. Here, the effects of an approved parenteral glycyrrhizin preparation (Stronger Neo-Minophafen C) were investigated on highly pathogenic influenza A H5N1 virus replication, H5N1-induced apoptosis, and H5N1-induced pro-inflammatory responses in lung epithelial (A549) cells. Therapeutic glycyrrhizin concentrations substantially inhibited H5N1-induced expression of the pro-inflammatory molecules CXCL10, interleukin 6, CCL2, and CCL5 (effective glycyrrhizin concentrations 25 to 50 [micro]g/ml) but interfered with H5N1 replication and H5N1-induced apoptosis to a lesser extent (effective glycyrrhizin concentrations 100 [micro]g/ml or higher). Glycyrrhizin also diminished monocyte migration towards supernatants of H5N1-infected A549 cells. The mechanism by which glycyrrhizin interferes with H5N1 replication and H5N1-induced pro-inflammatory gene expression includes inhibition of H5N1-induced formation of reactive oxygen species and (in turn) reduced activation of NF[kappa]B, JNK, and p38, redox-sensitive signalling events known to be relevant for influenza A virus replication. Therefore, glycyrrhizin may complement the arsenal of potential drugs for the treatment of H5N1 disease.
    Keywords: Antiviral Agents -- Health Aspects ; Virus Replication -- Health Aspects ; Avian Influenza Viruses -- Health Aspects ; Avian Influenza -- Health Aspects ; Genes -- Health Aspects ; Apoptosis -- Health Aspects ; Gene Expression -- Health Aspects
    ISSN: 1932-6203
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  • 7
    Language: English
    In: Medical microbiology and immunology, 2011, Vol.200(1), pp.1-5
    Description: The question whether human cytomegalovirus may affect cancer diseases has been discussed (very controversially) for decades. There are convinced believers and strict opponents of the idea that HCMV might be able to play a role in the course of cancer diseases. In parallel, the number of published reports on the topic is growing. Recently published and presented (Ranganathan P, Clark P, Kuo JS, Salamat S, Kalejta RF. A Survey of Human Cytomegalovirus Genomic Loci Present in Glioblastoma Multiforme Tissue Samples. 35th Annual International Herpes Workshop, Salt Lake City, 2010) data on HCMV detection in glioblastoma tissues and colocalisation of HCMV proteins with cellular proteins known to be relevant for glioblastoma progression motivated us to recapitulate the current state of evidence. ; Includes references ; p. 1-5.
    Keywords: Neoplasms ; Cytomegalovirus ; Glioblastoma ; Tumour Virus ; Neuroblastoma ; Oncomodulation
    ISSN: 0300-8584
    E-ISSN: 14321831
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  • 8
    Language: English
    In: Biochemical Pharmacology, 2011, Vol.81(2), pp.251-258
    Description: Enzastaurin is a selective protein kinase Cβ inhibitor which is shown to have direct antitumor effect as well as suppress glycogen synthase kinase-3β (GSK-3β) phosphorylation (resulting in its activation) in both tumor tissues and peripheral blood mononuclear cells (PBMC). It is currently used in phase II trials for the treatment of colon cancer, refractory glioblastoma and diffuse large B cell lymphoma. In this study, the direct effect of enzastaurin on effector function of human natural killer (NK) cells was investigated. The results obtained showed that enzastaurin suppressed both natural and antibody-dependent cellular cytotoxicity (ADCC) of NK cells against different tumor targets. This inhibition was associated with a specific down-regulation of surface expression of NK cell activating receptor NKG2D and CD16 involved in natural cytotoxicity and ADCC respectively, as well as the inhibition of perforin release. Analysis of signal transduction revealed that enzastaurin activated GSK-3β by inhibition of GSK-3β phosphorylation. Treatment of NK cells with GSK-3β-specific inhibitor TDZD-8 prevented enzastaurin-induced inhibition of NK cell cytotoxicity. Apart from the known antitumor and antiangiogenic effects, these results demonstrate that enzastaurin suppresses NK cell activity and may therefore interfere with NK cell-mediated tumor control in enzastaurin-treated cancer patients. ; p. 251-258.
    Keywords: Patients ; Drugs ; Natural Killer Cells ; Glycogen ; Cytotoxicity ; Colorectal Neoplasms ; Protein Kinases ; Humans ; Signal Transduction ; Phosphorylation ; Lymphoma
    ISSN: 0006-2952
    E-ISSN: 18732968
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  • 9
    Language: English
    In: The American Journal of Pathology, 1999, Vol.155(1), pp.285-292
    Description: Thrombospondin-1 (TSP-1) is a potent inhibitor of angiogenesis. It has been shown that promoter sequences of the TSP-1 gene can be transactivated by the wild-type tumor suppressor protein p53. As human cytomegalovirus (HCMV) infection inactivates wild-type p53 of various cell types, we investigated whether HCMV infection is associated with reduced TSP-1 production. We found, in conjunction with accumulated p53, that TSP-1 mRNA and protein expression was significantly reduced in HCMV-infected cultured human fibroblasts. To determine whether the observed TSP-1 suppression depends on p53 inactivation, the p53-defective astrocytoma cell line U373MG was infected with HCMV. In these cells TSP-1 expression was also significantly reduced by HCMV infection whereas expression of the p53 mutant variant remained unaltered. In both cell lines the decreased expression of TSP-1 mRNA occurred early after infection (4 hours), indicating that HCMV inhibits TSP-1 transcription during the immediate-early phase of infection before HCMV DNA replication. Inhibition of HCMV DNA synthesis by ganciclovir did not influence TSP-1 reduction whereas the antisense oligonucleotide ISIS 2922, complementary to HCMV immediate-early mRNA, completely prevented the HCMV-mediated TSP-1 suppression. These findings strongly suggest a novel role for HCMV in the modulation of angiogenesis due to p53-independent down-regulation of TSP-1 expression.
    Keywords: Medicine
    ISSN: 0002-9440
    E-ISSN: 1525-2191
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  • 10
    Language: English
    In: Cellular and molecular life sciences CMLS, 2011, Vol.68(6), pp.1079-1090
    Description: Human cytomegalovirus (HCMV) is a major pathogen in immunocompromised individuals. Here, non-toxic concentrations of the anti-cancer kinase inhibitor sorafenib were shown to inhibit replication of different HCMV strains (including a ganciclovir-resistant strain) in different cell types. In contrast to established anti-HCMV drugs, sorafenib inhibited HCMV major immediate early promoter activity and HCMV immediate early antigen (IEA) expression. Sorafenib is known to inhibit Raf. Comparison of sorafenib with the MEK inhibitor U0126 suggested that sorafenib inhibits HCMV IEA expression through inhibition of Raf but independently of signaling through the Raf downstream kinase MEK 1/2. In concordance, siRNA-mediated depletion of Raf but not of MEK-reduced IEA expression. In conclusion, sorafenib diminished HCMV replication in clinically relevant concentrations and inhibited HCMV IEA expression, a pathophysiologically relevant event that is not affected by established anti-HCMV drugs. Moreover, we demonstrated for the first time that Raf activation is involved in HCMV IEA expression. ; Includes references ; p. 1079-1090.
    Keywords: Human Herpesvirus 5 ; Raf ; Antiviral Therapy ; Immediate Early Antigen ; Cancer Chemotherapy ; Kinase Inhibitor ; Sorafenib ; Oncomodulation
    ISSN: 1420-682X
    E-ISSN: 14209071
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