Sphingosine kills intracellular Pseudomonas aeruginosa and Staphylococcus aureus.

Sphingosine has been previously shown to kill many strains of pathogenic bacteria including Pseudomonas aeruginosa, Staphyloccus aureus, Acinetobacter, and atypical mycobacteria. However, these studies were performed on isolated or extracellular bacteria and it is unknown whether sphingosine also targets intracellular bacteria. Here, we demonstrate that exogenously-added sphingosine directly binds to extracellular P.

Caveolin-1 affects early mycobacterial infection and apoptosis in macrophages and mice.

Tuberculosis, caused by Mycobacterium tuberculosis, remains one of the deadliest infections in humans. Because Mycobacterium bovis Bacillus Calmette-Guérin (BCG) share genetic similarities with Mycobacterium tuberculosis, it is often used as a model to elucidate the molecular mechanisms of more severe tuberculosis infection. Caveolin-1 has been implied in many physiological processes and diseases, but it's role in mycobacterial infections has barely been studied.

Simultaneous targeting of mitochondrial Kv1.3 and lysosomal acid sphingomyelinase amplifies killing of pancreatic ductal adenocarcinoma cells in vitro and in vivo.

Pancreas ductal adenocarcinoma (PDAC) remains a malignant tumor with very poor prognosis and low 5-year overall survival. Here, we aimed to simultaneously target mitochondria and lysosomes as a new treatment paradigm of malignant pancreas cancer in vitro and in vivo. We demonstrate that the clinically used sphingosine analog FTY-720 together with PAPTP, an inhibitor of mitochondrial Kv1.

Sphingosine as a New Antifungal Agent against and spp.

This study investigated whether sphingosine is effective as prophylaxis against spp. and spp. In vitro experiments showed that sphingosine is very efficacious against and (formerly named ).

Mitochondrial Kv1.3 Channels as Target for Treatment of Multiple Myeloma.

Despite several new developments in the treatment of multiple myeloma, all available therapies are only palliative without curative potential and all patients ultimately relapse. Thus, novel therapeutic options are urgently required to prolong survival of or to even cure myeloma. Here, we show that multiple myeloma cells express the potassium channel Kv1.

Insight into the mechanism of cytotoxicity of membrane-permeant psoralenic Kv1.3 channel inhibitors by chemical dissection of a novel member of the family.

The potassium channel Kv1.3, involved in several important pathologies, is the target of a family of psoralen-based drugs whose mechanism of action is not fully understood. Here we provide evidence for a physical interaction of the mitochondria-located Kv1.

Characterization of the small molecule ARC39, a direct and specific inhibitor of acid sphingomyelinase in vitro.

Inhibition of acid sphingomyelinase (ASM), a lysosomal enzyme that catalyzes the hydrolysis of sphingomyelin into ceramide and phosphorylcholine, may serve as an investigational tool or a therapeutic intervention to control many diseases. Specific ASM inhibitors are currently not sufficiently characterized. Here, we found that 1-aminodecylidene bis-phosphonic acid (ARC39) specifically and efficiently (>90%) inhibits both lysosomal and secretory ASM in vitro.

Acid Sphingomyelinase Deficiency Ameliorates Farber Disease.

Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel acid ceramidase deficiency model that mirrors the human disease closely.

Pathological manifestations of Farber disease in a new mouse model.

Farber disease (FD) is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments are clinically available and affected patients have a severely shortened lifespan. Due to the low incidence, the pathogenesis of FD is still poorly understood.

Targeting the Potassium Channel Kv1.3 Kills Glioblastoma Cells.

Background/aims: Glioblastoma (GBM) is one of the most aggressive cancers, counting for a high number of the newly diagnosed patients with central nervous system (CNS) cancers in the United States and Europe. Major features of GBM include aggressive and invasive growth as well as a high resistance to treatment. Kv1.

Direct Pharmacological Targeting of a Mitochondrial Ion Channel Selectively Kills Tumor Cells In Vivo.

The potassium channel Kv1.3 is highly expressed in the mitochondria of various cancerous cells. Here we show that direct inhibition of Kv1.

Impaired glucose and lipid metabolism in ageing aryl hydrocarbon receptor deficient mice.

Disturbed homeostasis of glucose and lipid metabolism are dominant features of the so-called metabolic syndrome (MetS) and can increase the risk for the development of type 2 diabetes (T2D), a severe metabolic disease. T2D prevalence increases with age. The aryl hydrocarbon receptor (AHR) is a sensor of small molecules including dietary components.

Acid sphingomyelinase inhibition protects mice from lung edema and lethal Staphylococcus aureus sepsis.

Unlabelled: Pulmonary edema associated with increased vascular permeability is a severe complication of Staphylococcus aureus-induced sepsis and an important cause of human pathology and death. We investigated the role of the mammalian acid sphingomyelinase (Asm)/ceramide system in the development of lung edema caused by S. aureus.

The largest strongly connected component in the cyclical pedigree model of Wakeley et al.

We establish a link between Wakeley et al.'s (2012) cyclical pedigree model from population genetics and a randomized directed configuration model (DCM) considered by Cooper and Frieze (2004). We then exploit this link in combination with asymptotic results for the in-degree distribution of the corresponding DCM to compute the asymptotic size of the largest strongly connected component S(N) (where N is the population size) of the DCM resp.

Targeting a mitochondrial potassium channel to fight cancer.

Although chemotherapy is able to cure many patients with malignancies, it still also often fails. Therefore, novel approaches and targets for chemotherapeutic treatment of malignancies are urgently required. Recent studies demonstrated the expression of several potassium channels in the inner mitochondrial membrane.

Aryl hydrocarbon receptor is critical for homeostasis of invariant gammadelta T cells in the murine epidermis.

An immunoregulatory role of aryl hydrocarbon receptor (AhR) has been shown in conventional αβ and γδ T cells, but its function in skin γδ T cells (dendritic epidermal T cells [DETC]) is unknown. In this study, we demonstrate that DETC express AhR in wild-type mice, and are specifically absent in the epidermis of AhR-deficient mice (AhR-KO). We show that DETC precursors are generated in the thymus and home to the skin.

The aryl hydrocarbon receptor mediates UVB radiation-induced skin tanning.

Melanogenesis is the vital response to protect skin cells against UVB-induced DNA damage. Melanin is produced by melanocytes, which transfer it to surrounding keratinocytes. Recently, we have shown that the aryl hydrocarbon receptor (AhR) is part of the UVB-stress response in epidermal keratinocytes.

2,3,7,8-Tetrachlorodibenzo-p-dioxin impairs stable establishment of oral tolerance in mice.

The toxic environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent immunomodulatory chemical. TCDD activates the aryl hydrocarbon receptor (AhR) and suppresses peripheral humoral and cellular adaptive immune responses. Though the major route of uptake is via food, little is known until now on the immunotoxic effects of TCDD on the gut-associated lymphoid tissue.

Small molecules as friends and foes of the immune system.

Every organism is in contact with numerous small molecules (<1000 Da). Chemicals may cause or trigger adverse health effects, including diseases of the immune system. They may also be exploited as drugs.

Langerhans cell maturation and contact hypersensitivity are impaired in aryl hydrocarbon receptor-null mice.

Langerhans cells (LC) are professional APCs of the epidermis. Recently, it was suggested that they are tolerogenic and control adverse immune reactions, including against low molecular mass chemicals. The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, is involved in low molecular mass chemical metabolism and cell differentiation.

Development of a rapid, quantitative glucosyltransferase assay based on a screen-printed fructose enzyme electrode and application to optimization studies on gtfD expression in recombinant Escherichia coli.

A biosensor for fructose determination was used as basis of an assay for the determination of glucosyltransferase (GTF) activities and applied to monitoring recombinant enzyme production. GTFs catalyze the synthesis of glucans from sucrose leading to the release of fructose. Specific fructose determinations in the microM concentration range were achieved with a fructose electrode based on fructose dehydrogenase, which was immobilized on a screen-printed platinum electrode.

Biochemical analysis with microfluidic systems.

Microfluidic systems are capillary networks of varying complexity fabricated originally in silicon, but nowadays in glass and polymeric substrates. Flow of liquid is mainly controlled by use of electroosmotic effects, i.e.