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Biomedical subjects

A Laich

Publications and source records attributed to A Laich.

12 recordsLinked to original sources
PubMed2003

Atorvastatin suppresses interferon-gamma -induced neopterin formation and tryptophan degradation in human peripheral blood mononuclear cells and in monocytic cell lines.

Inhibitors of 3-hydroxy-3methylglutaryl-co-enzyme A (HMG-CoA) reductase, so-called statins, are used in medical practice because of their lipid-lowering effect and to reduce the risk of coronary heart disease. Recent findings indicate that statins also have anti-inflammatory properties and can modulate the immune response. In vitro, we investigated the effect of atorvastatin on the T cell/macrophage system in peripheral blood mononuclear cells (PBMC) and in the human monocytic cell lines THP-1 and MonoMac6. We monitored neopterin production and tryptophan degradation in PBMC after treatment with 10 micro m and 100 micro m atorvastatin in the presence or absence of 100 U/ml IFN-gamma, 10 micro g/ml phytohaemagglutinin (PHA) or 10 micro g/ml concanavalin A (ConA) and in monocytic cell lines THP-1 and MonoMac6 with or without stimulation with 100 U/ml IFN-gamma or 10 ng/ml to 1 micro g/ml lipopolysaccharide (LPS). In stimulated PBMC 100 micro m atorvastatin inhibited neopterin formation and tryptophan degradation completely, whereas 10 micro m atorvastatin was only partially effective. Also in monocytic cell lines THP-1 and MonoMac6, atorvastatin was able to suppress IFN-gamma- and LPS-induced formation of neopterin and degradation of tryptophan. Our data from PBMC agree well with previous investigations that statins inhibit T cell activation within the cellular immune response. In addition we demonstrate that atorvastatin directly inhibits IFN-gamma-mediated pathways in monocytic cells, suggesting that both immunoreactivity of T cells and of monocyte-derived macrophages are down-regulated by this statin.

Atorvastatin↗
PubMed2002

Moderate hyperhomocysteinaemia and immune activation in Parkinson's disease.

Moderate hyperhomocysteinaemia has been linked to an increased risk for cardiovascular diseases. Increased homocysteine concentrations may follow folate depletion due to insufficient dietary intake of the vitamin, but there is also some indication that immune activation could play a role. In this preliminary study, homocysteine, folate, and vitamin B(12) concentrations were measured in 19 patients with Parkinson's disease, 61-90 years of age, and compared to a healthy control group of similar age and to neopterin concentrations as an indicator of immune activation. A subgroup of patients presented with increased homocysteine and low folate concentrations. Homocysteine levels correlated inversely with vitamins folate and B(12) and positively with neopterin concentrations. Disturbed homocysteine metabolism in Parkinson's disease may be associated with vitamin deficiency and with immune system activation which may underlie folate depletion.

Aged↗
PubMed2002

Hyperhomocysteinemia, pteridines and oxidative stress.

Tetrahydrofolate is an essential cofactor for the conversion of homocysteine to methionine, and hyperhomocysteinemia is considered as a risk factor for cardiovascular and cerebrovascular diseases. In subjects with hyperhomocysteinemia usually an inverse relationship exists to folic acid levels, and supplementation with folic acid is able to lower homocysteine concentrations. The pathogenesis of most if not all diseases which are accompanied with moderate hyperhomocysteinemia involves cellular immune activation and therefore in patients very often exists also a positive correlation between homocysteine concentrations and the degree of immune activation which is indicated, e.g. by increased neopterin concentrations. Since neopterin concentrations also serves as an estimate of oxidative stress merging from immune system activation, this association suggests that cellular immune activation and oxidative stress could be involved in the development of hyperhomocysteinemia. Because tetrahydrofolate is very susceptible to oxidation, an increased oxidative degradation of tetrahydrofolates may become relevant under oxidative stress conditions. In this way folate deficiency may develop despite normal dietary intake of the vitamin. In our patients, hyperhomocysteinemia is considered as an indirect consequence of hyperconsumption of antioxidant vitamins during prolonged states of immune activation.

Animals↗
PubMed2001

Complement C4bC2 complex formation: an investigation by surface plasmon resonance.

Complex formation between the human complement proteins C4b and C2 was investigated by surface plasmon resonance. C4b was immobilised and C2 was used in the fluid phase to measure interaction at different ionic strengths (30-830 mM NaCl) and in the absence and presence of MgCl2. Maximum binding was observed at 30 mM NaCl, and was negligible above 300 mM NaCl. Binding was not greatly influenced by variation in Mg(2+) in the range of 2.5-15 mM. C4bC2 affinity (Kd) was determined by steady-state analysis to be 7.2x10(-8) M in physiological conditions (10 mM Hepes, 2.5 mM MgCl2, 0.75 mM CaCl2 and 140 mM NaCl, pH 7.4). For C4(H2O)C2 complex formation, a Kd of 4.0x10(-8) M was calculated. As far as detected by the applied method, complex formation does not involve conformational changes of one of the binding partners. Consistent with previous reports, C4bC2 binding takes place as a multiple-site binding event in the presence of Mg2+. C4bC2 complex formation in 10 mM Hepes, 2.5 mM EDTA and 140 mM NaCl (pH 7.4) was also observed and the interaction showed characteristics of a single-site binding event. Kd was 1.5x10(-8) M. Complement factor B (FB) was also tested for its binding to immobilised C4b. Weak interaction was observed at FB concentrations in the physiological range (500-1000 nM). Kd was 1.2x10(-6) M, indicating possible cross-reactivity between classical and alternative pathways of the activation of the complement system.

Complement C4↗
PubMed2000

The gastric H,K-ATPase blocker lansoprazole is an inhibitor of chloride channels.

1. It was postulated that swelling dependent chloride channels are involved in the proton secretion of parietal cells. Since omeprazole, lansoprazole and its acid activated sulphenamide form AG2000 are structurally related to phenol derivatives known to block swelling dependent chloride channels, we set out to test, whether these substances--which are known to block the H,K-ATPase--could also lead to an inhibition of swelling-dependent chloride channels. Swelling-dependent chloride channels--characterized in many different cell types--show highly conserved biophysical and pharmacological features, therefore we investigated the effect of omeprazole, lansoprazole and its acid activated sulphenamide form AG2000 on swelling-dependent chloride channels elicited in fibroblasts, after the reduction of the extracellular osmolarity. 2. Omeprazole, lansoprazole and its acid activated sulphenamide form AG2000 are able to block swelling-dependent chloride channels (IClswell). 3. Lansoprazole and its protonated metabolite AG2000 act on at least two different sites of the IClswell protein: on an extracellular site which seems to be in a functional proximity to the nucleotide binding site, and on an intracellular site which allows the formation of disulfide-bridges. 4. The inhibition of the proton pump and the simultaneous blocking of chloride channels by omeprazole, lansoprazole and its acid activated sulphenamide form AG2000, as described here could be an effective mode to restrict proton secretion in parietal cells.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2000

Serine proteases of the complement system.

The complement system in blood plasma is a major mediator of innate immune defence. The function of complement is to recognize, then opsonize or lyse, particulate materials, including bacteria, yeasts and other microrganisms, host cell debris and altered host cells. Recognition occurs by binding of complement proteins to charge or saccharide arrays. After recognition, a series of serine proteases is activated, culminating in the assembly of complex unstable proteases called C3/C5 convertases. These activate the complement protein C3, which acts as an opsonin. The complement serine proteases include the closely related C1r, C1s, MASPs 1-3 (80-90 kDa), C2 and Factor B (100 kDa), Factor D (25 kDa) and Factor I (85 kDa). Each of these has unusually restricted specificity and low enzymic activity. The C1r, C1s and MASP group occur as proenzymes. When activated, they are regulated, like many plasma serine proteases, by a serpin, C1-inhibitor. C2 and Factor B, however, have complex multiple regulation by a group of complement proteins called the Regulation of Complement Activation (or RCA) proteins, whereas Factors I and D appear to have no natural inhibitors. Advances in structure determination and protein-protein interaction properties are leading to a more detailed understanding of the complement-system proteases, and are indicating possible new routes for potential therapeutic control of complement.

Animals↗
PubMed1999

Structure and expression of the human small cytokine B subfamily member 11 (SCYB11/formerly SCYB9B, alias I-TAC) gene cloned from IFN-gamma-treated human monocytes (THP-1).

Among CXC chemokines, monokine induced by interferon-gamma (IFN-gamma) (MIG) and IGN-gamma-inducible protein, 10 kDa (INP10), constitute a distinct group because of their sequence and function. We studied genomic structure and expression of a third, recently identified member of this group named small inducible cytokine B subfamily member 11 (SCYB11, formerly SCYB9B) or IFN-inducible T cell alpha chemoattractant (I-TAC). The cDNA (1445 bp) for this 94 amino acid protein (Mr 10,364) was cloned from IFN-gamma-treated human myelomonocytic cells (THP-1). The reading frame of SCYB11 is distributed to 4 exons spanning 1197 bp of the genomic sequence. In vitro transcription/translation yielded a single protein of about 10 kDa, indicating that the deduced reading frame is translated by eukaryotic ribosomes. The recombinant 73 amino acid mature protein overexpressed in Escherichia coli was chemotactic for interleukin-2 (IL-2)-selected T memory cells. Studying various cytokines and lipopolysaccharide in THP-1 cells identified IFN-gamma as the major stimulus for SCYB11 mRNA expression, followed by IFN-alpha and IFN-beta, which were about 25 times less effective. Of a panel of different human cells tested, SCYB11 mRNA was also induced in umbilical vein endothelial cells, dermal fibroblasts, and tumor cell lines from various organs, whereas it was not found in T lymphocytes activated via anti-CD3 antibodies or via IL-2.

Amino Acid Sequence↗
PubMed1996

ICln: a chloride channel paramount for cell volume regulation.

Cell volume regulation is a ubiquitous cell regulatory mechanism based on meticulously controlled ion transport mechanisms. Keeping the absolute volume constant seems to be of the highest priority for most cells and is achieved at the expense of altered intracellular ion concentrations. We have been able to demonstrate that ICln, a chloride channel cloned from epithelial cells, is paramount for the ability of swollen cells to regulate their volume back to that under resting conditions. A unique feature of ICln is the distinct sensitivity of these channels for nucleotides and nucleoside analogues added to the extracellular fluid. In addition, cromolyn sodium and nedocromil sodium, drugs used by patients with asthma, are able to impede the function of these channels.

Animals↗
PubMed1995

Antiviral drugs from the nucleoside analog family block volume-activated chloride channels.

BACKGROUND: The antiviral drugs AZT and acyclovir are generally used in the treatment of infections with human immunodeficiency virus (HIV) and herpes simplex virus (HSV). These substances are known to impede virus replication by premature nucleic acid chain termination. It is not yet clear, however, if this is the sole mechanism responsible for the antiviral and/or the numerous side effects observed in patients treated with these agents. We investigated the swelling-induced chloride current in fibroblasts, which we demonstrated is closely related or identical to a cloned epithelial chloride channel, ICln: This chloride channel can be blocked by nucleotides. MATERIALS AND METHODS: Electrophysiological, fluorescence optical, and volume measurements were made to determine the effect of nucleoside analogs on the swelling-dependent chloride current (ICl) in NIH 3T3 fibroblasts and in human T cell lymphoma (H9) cells and the cAMP-dependent chloride current in CaCo cells. RESULTS: AZT and acyclovir block the swelling-dependent chloride current and the chloride flux in fibroblasts, and the regulatory volume decrease (RVD) and ICl in H9 cells. This immediate effect can be substantially reduced by the simultaneous incubation of the cells with thymidine-5'-diphosphate (TDP) or uridine, both of which are by themselves unable to affect ICl. CONCLUSIONS: We show here a novel molecular mechanism by which antiviral drugs of the nucleoside analog family could lead to impairments of the kidney, bone marrow, gastrointestinal, and neuronal functions, and how these side effects could possibly be restricted by the presence of TDP or uridine.

3T3 Cells↗