Hydrogen sulfide inhibits endothelial nitric oxide formation and receptor ligand-mediated Ca(2+) release in endothelial and smooth muscle cells.

Background: In the vascular system, ATP-sensitive K(+)-channels are a target for H2S. Recent evidence suggests that H2S may also modulate Na(+)- and Ca(2+)-permeable channels and intracellular Ca(2+) stores, but the influence of H2S on endothelial Ca(2+) dynamics and Ca(2+)-dependent activation of endothelial nitric oxide synthase (eNOS) is unclear. In this study, we investigated the effects of H2S on Ca(2+) signaling in endothelial and smooth muscle cells with special emphasis given to the role of H2S in modulating endothelial NO formation.

Enhanced Antiproliferative and Pro-apoptotic Activities of a Novel Curcumin-related Compound in Jurkat Leukemia T-Cells.

Background/aim: Inhibition of arachidonic acid metabolism by curcumin has been suggested to be a key mechanism for its anti-carcinogenic action. Recently, we reported on the synthesis of curcumin analogues and their evaluation as selective COX1 inhibitors. Two compounds (HP109/HP102) were selected for evaluation of their anti-proliferative and pro-apoptotic potential in Jurkat T-cells.

Hydrogen sulphide decreases IL-1β-induced activation of fibroblast-like synoviocytes from patients with osteoarthritis.

Balneotherapy employing sulphurous thermal water is still applied to patients suffering from diseases of musculoskeletal system like osteoarthritis (OA) but evidence for its clinical effectiveness is scarce. Since the gasotransmitter hydrogen sulphide (H2 S) seems to affect cells involved in degenerative joint diseases, it was the objective of this study to investigate the effects of exogenous H2 S on fibroblast-like synoviocytes (FLS), which are key players in OA pathogenesis being capable of producing pro-inflammatory cytokines and matrix degrading enzymes. To address this issue primary FLS derived from OA patients were stimulated with IL-1β and treated with the H2 S donor NaHS.

Dimethyl sulphoxide and dimethyl sulphone are potent inhibitors of IL-6 and IL-8 expression in the human chondrocyte cell line C-28/I2.

Aims: Reactive oxygen species (ROS) are highly diffusable and reactive molecules which modulate gene transcription, particularly of pro-inflammatory cytokines which play a crucial role in the nascency and progression of chronic inflammatory diseases such as rheumatoid arthritis (RA) and osteoarthritis (OA). Since thiols could be potent inhibitors of the production of cytokines, the effects of dimethyl sulphoxide (DMSO) and dimethyl sulphone (DMS) on constitutive and IL-1β-induced IL-6 and IL-8 expression in the human chondrocyte cell line C-28/I2 were evaluated.

Main Methods: C-28/I2 cells were incubated for 12h with different concentrations of DMSO or DMS.

Inhibitors of p38 and ERK1/2 MAPkinase and hydrogen sulphide block constitutive and IL-1β-induced IL-6 and IL-8 expression in the human chondrocyte cell line C-28/I2.

Mitogen-activated protein kinases (MAPKs) play a central role in inflammatory processes, and their blockage represents pharmacological approaches in the treatment of autoimmune diseases like rheumatoid arthritis (RA). Alternatively, H(2)S has long been used in sulphur bath therapy for patients suffering from different types of rheumatic disorders, but reports about the beneficial effects of this form of therapy are controversial, rare and of poor scientific quality. The human chondrocyte cell line C-28/I2 was treated with two different MAPK inhibitors (SB203580 and U0126) or with various concentrations of the H(2)S donor Natrium hydrogen sulphide (NaHS).

H2S transiently blocks IL-6 expression in rheumatoid arthritic fibroblast-like synoviocytes and deactivates p44/42 mitogen-activated protein kinase.

Sulfur bath therapy represents the oldest form of treatment for patients with different types of rheumatic disorders. However, scientific reports about the beneficial effects of this form of therapy are controversial, rare and of poor scientific quality. Also, little is known about the role and underlying molecular mechanisms of H2S.

NF-kappaB independent activation of a series of proinflammatory genes by hydrogen sulfide.

A stress response has the potential to induce greater resistance to subsequent stress damage. We tested whether hydrogen sulfide (H(2)S), an important signaling molecule, also used therapeutically, and known for detrimental effects, might induce a protective stress response. Therefore, the response of fibroblast-like synoviocytes (FLS) treated with sodium hydrosulfide and mice exposed to H(2)S were examined.

Short term hyperthermia prevents the activation of mitogen-activated protein kinase p38.

We demonstrated earlier that hyperthermia (HT), a form of balneotherapy, suppresses transcription and translation of a number of pro-inflammatory genes. Here we show that short term HT not only acts by preventing the activation of NF-kappaB, but also by blocking the activation of the MAPK p38. Data are presented that show that the effects of HT on p38 are clearly independent of HT effects on NF-kappaB.

Systemic lupus erythematosus patients exhibit functional deficiencies of endothelial progenitor cells.

Objective: SLE is characterized by an increased cardiovascular risk. Since endothelial progenitor cells (EPCs) have been described to serve as a biomarker for the CV risk and are known to be depleted in various diseases, we were interested if SLE would also be associated with altered peripheral EPC levels or functional abnormalities of these cells.

Methods: EPCs were quantified in 31 female SLE patients with different disease activity and in age-matched healthy controls (HCs) by FACS analysis and by colony forming unit (CFU) assay.

Hyaluronan production in synoviocytes as a consequence of viral infections: HAS1 activation by Epstein-Barr virus and synthetic double- and single-stranded viral RNA analogs.

One of the hallmarks of arthritis is swollen joints containing unusually high quantities of hyaluronan. Intact hyaluronan molecules facilitate cell migration by acting as ligands for CD44. Hyaluronan degradation products, readily formed at sites of inflammation, also fuel inflammatory processes.

Differential diagnosis of tuberculous and malignant pleural effusions: what is the role of adenosine deaminase?

The objective of this study was to evaluate the utility of invasive and noninvasive diagnostic procedures in tuberculous pleurisy (TPE) in an area with intermediate incidence of tuberculosis. The aim was to determine the cutoff value for adenosine deaminase (ADA) and the sensitivity and specificity of ADA and evaluate pleural fluid cytology and pleural biopsy in the differential diagnosis of malignant and tuberculous pleurisy. The study included 121 patients.

Apis mellifera venom and melittin block neither NF-kappa B-p50-DNA interactions nor the activation of NF-kappa B, instead they activate the transcription of proinflammatory genes and the release of reactive oxygen intermediates.

Many alternative treatment approaches, originating from Asia, are becoming increasingly popular in the Western hemisphere. Recently, an article published in a renowned journal reported that venom of apis mellifera (bee venom (BV)) and melittin mediate immune-modulating effects by blocking the activation of the transcription factor NF-kappaB. Such a modus operandi would corroborate the many claims of beneficial effects of BV treatment and give immediate credit to this form of therapy.

Aspects of the biology of hyaluronan, a largely neglected but extremely versatile molecule.

HA takes part in a surprisingly large number of biological processes such as embryogenesis, angiogenesis, cell motility, wound healing and cell adhesion. While substantial progress in HA research has indeed been made over the last years, many important questions have not yet been answered. One of the most pertinent questions awaiting an answer is the quest for functional differences of HA synthesized by the three HAS genes.

The anti-rheumatic gold salt aurothiomalate suppresses interleukin-1beta-induced hyaluronan accumulation by blocking HAS1 transcription and by acting as a COX-2 transcriptional repressor.

Gold compounds are among the oldest disease-modifying drugs and are still widely used today for treating rheumatoid arthritis. Despite decades of use, little is known about the mode of action of this class of drugs. Here we have demonstrated that aurothiomalate (AuTM) suppresses hyaluronan accumulation by blocking interleukin (IL)-1beta-induced hyaluronan synthase-1 transcription.

Prostaglandin E2: a potent activator of hyaluronan synthase 1 in type-B-synoviocytes.

We demonstrated earlier that the gene HAS1 is inactive in resting type-B-synoviocytes but can be readily activated by a series of proinflammatory cytokines including IL-1beta. Here we show that in type-B-synoviocytes mRNA levels for the gene COX-2 increase more than 200-fold in response to IL-1beta treatment, whereas COX-1 mRNA levels remain virtually unchanged. We tested a series of eicosanoids and demonstrate that PGE(2) is a very potent activator of HAS1 in synoviocytes.

Quinacrine but not chloroquine inhibits PMA induced upregulation of matrix metalloproteinases in leukocytes: quinacrine acts at the transcriptional level through a PLA2-independent mechanism.

Objective: Macrophages play an important role in rheumatoid arthritis (RA). RA is a disease characterized by the successive accumulation of leukocytes resulting in subsequent destruction of affected joints. Activation of matrix metalloproteinases (MMP) is essential for many physiological as well as many pathological events owing to the essential role of MMP in cell migration.

Adenovirus-mediated gene transfer of mutated IkappaB kinase and IkappaBalpha reveal NF-kappaB-dependent as well as NF-kappaB-independent pathways of HAS1 activation.

It has become increasingly clear that hyaluronan is more than the simple matrix molecule it was once thought to be but instead takes part in a multitude of biological functions. Three genes encode for hyaluronan synthases (HAS). We demonstrated earlier that HAS2 and HAS3 are constitutively activated in type-B synoviocytes (fibroblast-like synoviocytes) and, furthermore, that the only gene that readily responds to stimulation with a series of proinflammatory cytokines is HAS1.

Effects of leflunomide on hyaluronan synthases (HAS): NF-kappa B-independent suppression of IL-1-induced HAS1 transcription by leflunomide.

Despite evidence that points to unfettered hyaluronic acid (HA) production as a culprit in the progression of rheumatic disorders, little is known about differences in regulation and biological functions of the three hyaluronan synthase (HAS) genes. Testing the effects of drugs with proven anti-inflammatory effects could help to clarify biological functions of these genes. In this study, we demonstrate that leflunomide suppresses HA release in fibroblast-like synoviocytes (FLS) in a dose-dependent manner.

Mepacrine inhibits matrix metalloproteinases-1 (MMP-1) and MMP-9 activation in human fibroblast-like synoviocytes.

Objective: Matrix metalloproteinases (MMP) are enzymes known to be involved in normal physiological and in many pathological conditions. Rheumatic diseases are among the ailments where MMP have been shown to exert detrimental effects. Mepacrine is used alone or in combination with other drugs to treat lupus and other rheumatic diseases.

Differential effect of transforming growth factor beta (TGF-beta) on the genes encoding hyaluronan synthases and utilization of the p38 MAPK pathway in TGF-beta-induced hyaluronan synthase 1 activation.

Unfettered hyaluronan (HA) production is a hallmark of rheumatoid arthritis. The discovery of three genes encoding hyaluronan synthases (HASs) allows for the investigation of the signaling pathways leading to the activation of these genes. Our objective is to further understanding of the regulation of these genes as well as to find ways to prevent undesired gene activation.

Fast, simultaneous, and sensitive detection of staphylococci.

Aims: Bacterial infections are common and are involved in many forms of disease, ranging from arthritis to food poisoning. Of much concern are nosocomial infections, especially the increasing resistance of bacteria to methicillin. A prerequisite for the successful treatment of bacterial infections is a specific and sensitive method of detecting microorganisms.

Glucocorticoids inhibit induced and non-induced mRNA accumulation of genes encoding hyaluronan synthases (HAS): hydrocortisone inhibits HAS1 activation by blocking the p38 mitogen-activated protein kinase signalling pathway.

Objective: Glucocorticoids are still a mainstay in the treatment of rheumatoid arthritis (RA). Unfettered hyaluronan release is a hallmark of RA. The discovery of three genes encoding hyaluronan synthase (HAS) led us to investigate the effect of hydrocortisone and dexamethasone on the activation of these genes at the molecular level and, at least in part, the mode of action of these drugs.

Antioxidant protein 2 prevents methemoglobin formation in erythrocyte hemolysates.

Antioxidant protein 2 (AOP2) is a member of a family of thiol-specific antioxidants, recently renamed peroxiredoxins, that evolved as part of an elaborate system to counteract and control detrimental effects of oxygen radicals. AOP2 is found in endothelial cells, erythrocytes, monocytes, T and B cells, but not in granulocytes. AOP2 was found solely in the cytoplasm and was not associated with the nuclear or membrane fractions; neither was it detectable in plasma.

Effects of quinacrine on endothelial cell morphology and transcription factor-DNA interactions.

Quinacrine has been used for decades and the beneficial effects of this drug are as numerous as its toxic effects. Since endothelial cells (EC) are in many cases the first cells coming in contact with drugs, the effect of quinacrine on certain aspects of EC biology were studied. The presented data demonstrate that quinacrine can have a marked impact on the integrity on EC monolayer without grossly interfering with cell viability.