Paradoxical effect of anti-inflammatory drugs on IL-6 mRNA expression in patients with PTSD during treatment.

The pathophysiology of posttraumatic stress disorder (PTSD) is associated with the activation of the innate immune system, including cytokines like interleukin 6 (IL-6). However, the role of IL-6 in the etiology and treatment of PTSD still remains elusive. We conducted a prospective controlled trial to investigate the development of IL-6 during psychosomatic treatment in individuals with PTSD in comparison with individuals without PTSD. We assessed IL-6 mRNA expression before and after 2 months of psychosomatic treatment in individuals with and without PTSD. Severities of PTSD and depressive symptoms were assessed in parallel. Linear mixed regression was applied for statistical analysis, including the factors diagnosis PTSD and pre-post treatment after subgrouping for intake of anti-inflammatory drugs. The development of IL-6 mRNA expression during treatment was affected by the use of anti-inflammatory drugs. In the subgroup without intake of anti-inflammatory drugs, no significant statistical treatment effect in individuals with and without PTSD emerged. In the subgroup of individuals taking anti-inflammatory drugs, a significant interaction effect of the factors pre-post treatment and diagnosis PTSD was observed. Whereas IL-6 mRNA expression in individuals without PTSD decreased according to amelioration of symptoms, IL-6 mRNA expression in individuals with PTSD increased significantly during treatment, in opposite direction to symptom severity. Anti-inflammatory drugs might affect IL-6 mRNA expression in individuals with PTSD in a paradoxical way. This study offers a further piece of evidence that IL-6 could be involved in the pathophysiology of PTSD and PTSD-specific immunologic molecular mechanisms.

Immunotherapy targeting plasma ASM is protective in a mouse model of Alzheimer's disease.

Acid sphingomyelinase (ASM) has been implicated in neurodegenerative disease pathology, including Alzheimer's disease (AD). However, the specific role of plasma ASM in promoting these pathologies is poorly understood. Herein, we explore plasma ASM as a circulating factor that accelerates neuropathological features in AD by exposing young APP/PS1 mice to the blood of mice overexpressing ASM, through parabiotic surgery. Elevated plasma ASM was found to enhance several neuropathological features in the young APP/PS1 mice by mediating the differentiation of blood-derived, pathogenic Th17 cells. Antibody-based immunotherapy targeting plasma ASM showed efficient inhibition of ASM activity in the blood of APP/PS1 mice and, interestingly, led to prophylactic effects on neuropathological features by suppressing pathogenic Th17 cells. Our data reveals insights into the potential pathogenic mechanisms underlying AD and highlights ASM-targeting immunotherapy as a potential strategy for further investigation.

Breaking strength and bone microarchitecture in osteoporosis: a biomechanical approximation based on load tests in 104 human vertebrae from the cervical, thoracic, and lumbar spines of 13 body donors.

BACKGROUND: The purpose of the study was to investigate associations between biomechanical resilience (failure load, failure strength) and the microarchitecture of cancellous bone in the vertebrae of human cadavers with low bone density with or without vertebral fractures (VFx). METHODS: Spines were removed from 13 body donors (approval no. A 2017-0072) and analyzed in regard to bone mineral density (BMD), Hounsfield units (HU), and fracture count (Fx) with the aid of high-resolution CT images. This was followed by the puncture of cancellous bone in the vertebral bodies of C2 to L5 using a Jamshidi™ needle. The following parameters were determined on the micro-CT images: bone volume fraction (BVF), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp), degree of anisotropy (DA), trabecular number (Tb.N), trabecular pattern factor (Tb.Pf), and connectivity density (Conn.D). The axial load behavior of 104 vertebral specimens (C5, C6, T7, T8, T9, T12, L1, L3) was investigated with a servohydraulic testing machine. RESULTS: Individuals with more than 2 fractures had a significantly lower trabecular pattern factor (Tb.Pf), which also proved to be an important factor for a reduced failure load in the regression analysis with differences between the parts of the spine. The failure load (FL) and endplate sizes of normal vertebrae increased with progression in the craniocaudal direction, while the HU was reduced. Failure strength (FS) was significantly greater in the cervical spine than in the thoracic or lumbar spine (p < 0.001), independent of sex. BVF, Tb.Th, Tb.N, and Conn.D were significantly higher in the cervical spine than in the other spinal segments. In contrast, Tb.Sp and Tb.Pf were lowest in the cervical spine. BVF was correlated with FL (r = 0.600, p = 0.030) and FS (r = 0.763, p = 0.002). Microarchitectural changes were also detectable in the cervical spine at lower densities. CONCLUSIONS: Due to the unique microarchitecture of the cervical vertebrae, fractures occur much later in this region than they do in the thoracic or lumbar spine. Trial registration Approval no. A 2017-0072.

Bulboma: A Benign Keratosis With Differentiation Toward the Lower Segment of the Hair Follicle.

ABSTRACT: Bulboma is an appellation proposed to designate a distinctive solitary keratosis exhibiting differentiation toward the bulb of the lower segment of the hair follicle. Bulboma is composed of a papillated proliferation of epithelial cells beneath which is a broad front of interconnected follicular papillae. Overlying these coalescing follicular papillae are follicular germinative cells ascending into matrical cells and supramatrical cells. Cells demonstrating differentiation toward Huxley's and Henle's layer of the inner root sheath at the level of the bulb are present including strikingly bright eosinophilic trichohyalin granules and the blue-grey corneocytes of the stem. There is overlying hypergranulosis and orthokeratosis. The clinical and histopathological findings in 4 cases of bulboma, a rare, benign solitary keratosis are presented.

Primary Cutaneous Atypical Spindle Cell Lipomatous Tumor.

This report documents an exophytic, pedunculated nodule in a 74-year-old man that upon histopathological examination revealed an atypical spindle cell/pleomorphic lipomatous tumor (ASPLT) confined to the papillary and reticular dermis, representing the fourth documented case within the skin. Despite the overt pleomorphic changes present histologically, the patient is free of metastasis or recurrence five years after surgery.

Visual stimulation with food pictures in the regulation of hunger hormones and nutrient deposition, a potential contributor to the obesity crisis.

Food cues affect hunger and nutritional choices. Omnipresent stimulation with palatable food contributes to the epidemics of obesity. The objective of the study was to investigate the impact of food cues on appetite-related hormones and to assess the functionality of the secreted hormones on macronutrient uptake in healthy subjects. Additionally, we aimed at verifying differences in the response of total and active ghrelin to stimulation with food pictures and to a meal followed by the stimulation. We were also interested in the identification of factors contributing to response to food cues. We recruited healthy, non-obese participants for two independent cross-over studies. During the first study, the subjects were presented random non-food pictures on the first day and pictures of foods on the second day of the study. Throughout the second study, following the picture session, the participants were additionally asked to drink a milkshake. Concentrations of blood glucose, triglycerides and hunger-related hormones were measured. The results showed that concentrations of several hormones measured in the blood are interdependent. In the case of ghrelin and gastric inhibitory peptide (GIP) as well as ghrelin and glucagon-like peptide-1 (GLP-1), this co-occurrence relies on the visual cues. Regulation of total ghrelin concentration following food stimulation is highly individual and responders showed upregulated total ghrelin, while the concentration of active ghrelin decreases following a meal. Protein content and colour intensity of food pictures reversely correlated with participants' rating of the pictures. We conclude that observation of food pictures influences the concentration of several appetite-related hormones. The close link of visual clues to physiological responses is likely of clinical relevance. Additionally, the protein content of displayed foods and green colour intensity in pictures may serve as a predictor of subjective attractiveness of the presented meal.

P2X7 Receptor Stimulation Is Not Required for Oxalate Crystal-Induced Kidney Injury.

Oxalate crystal-induced renal inflammation is associated with progressive kidney failure due to activation of the NLRP3/CASP-1 inflammasome. It has been suggested previously that purinergic P2X7 receptor signaling is critical for crystal-induced inflammasome activation and renal injury. Therefore, we investigated the role of the P2X7 receptor in response to crystal-induced cytokine release, inflammation, and kidney failure using in vitro and in vivo models. Dendritic cells and macrophages derived from murine bone marrow and human peripheral blood mononucleated cells stimulated with calcium-oxalate crystals, monosodium urate crystals, or ATP lead to the robust release of interleukin-1beta (IL-1ß). Treatment with the P2X7 inhibitor A740003 or the depletion of ATP by apyrase selectively abrogated ATP-induced, but not oxalate and urate crystal-induced IL-1ß release. In line with this finding, dendritic cells derived from bone marrow (BMDCs) from P2X7-/- mice released reduced amounts of IL-1ß following stimulation with ATP, while oxalate and urate crystal-induced IL-1ß release was unaffected. In sharp contrast, BMDCs from Casp1-/- mice exhibited reduced IL-1ß release following either of the three stimulants. In addition, P2X7-/- mice demonstrated similar degrees of crystal deposition, tubular damage and inflammation when compared with WT mice. In line with these findings, increases in plasma creatinine were no different between WT and P2X7-/- mice. In contrast to previous reports, our results indicate that P2X7 receptor is not required for crystal-induced CKD and it is unlikely to be a suitable therapeutic target for crystal-induced progressive kidney disease.

Acid sphingomyelinase - a regulator of canonical transient receptor potential channel 6 (TRPC6) activity.

Recent investigations propose the acid sphingomyelinase (ASM)/ceramide system as a novel target for antidepressant action. ASM catalyzes the breakdown of the abundant membrane lipid sphingomyelin to the lipid messenger ceramide. This ASM-induced lipid modification induces a local shift in membrane properties, which influences receptor clustering and downstream signaling. Canonical transient receptor potential channels 6 (TRPC6) are non-selective cation channels located in the cell membrane that play an important role in dendritic growth, synaptic plasticity and cognition in the brain. They can be activated by hyperforin, an ingredient of the herbal remedy St. John's wort for treatment of depression disorders. Because of their role in the context of major depression, we investigated the crosstalk between the ASM/ceramide system and TRPC6 ion channels in a pheochromocytoma cell line 12 neuronal cell model (PC12 rat pheochromocytoma cell line). Ca2+ imaging experiments indicated that hyperforin-induced Ca2+ influx through TRPC6 channels is modulated by ASM activity. While antidepressants, known as functional inhibitors of ASM activity, reduced TRPC6-mediated Ca2+ influx, extracellular application of bacterial sphingomyelinase rebalanced TRPC6 activity in a concentration-related way. This effect was confirmed in whole-cell patch clamp electrophysiology recordings. Lipidomic analyses revealed a decrease in very long chain ceramide/sphingomyelin molar ratio after ASM inhibition, which was connected with changes in the abundance of TRPC6 channels in flotillin-1-positive lipid rafts as visualized by western blotting. Our data provide evidence that the ASM/ceramide system regulates TRPC6 channels likely by controlling their recruitment to specific lipid subdomains and thereby fine-tuning their physical properties.

Chronic Psychosocial Stress in Mice Is Associated With Increased Acid Sphingomyelinase Activity in Liver and Serum and With Hepatic C16:0-Ceramide Accumulation.

Chronic psychosocial stress adversely affects human morbidity and is a risk factor for inflammatory disorders, liver diseases, obesity, metabolic syndrome, and major depressive disorder (MDD). In recent studies, we found an association of MDD with an increase of acid sphingomyelinase (ASM) activity. Thus, we asked whether chronic psychosocial stress as a detrimental factor contributing to the emergence of MDD would also affect ASM activity and sphingolipid (SL) metabolism. To induce chronic psychosocial stress in male mice we employed the chronic subordinate colony housing (CSC) paradigm and compared them to non-stressed single housed control (SHC) mice. We determined Asm activity in liver and serum, hepatic SL concentrations as well as hepatic mRNA expression of genes involved in SL metabolism. We found that hepatic Asm activity was increased by 28% (P = 0.006) and secretory Asm activity by 47% (P = 0.002) in stressed mice. C16:0-Cer was increased by 40% (P = 0.008). Gene expression analysis further revealed an increased expression of tumor necrosis factor (TNF)-α (P = 0.009) and of several genes involved in SL metabolism (Cers5, P = 0.028; Cers6, P = 0.045; Gba, P = 0.049; Gba2, P = 0.030; Ormdl2, P = 0.034; Smpdl3B; P = 0.013). Our data thus provides first evidence that chronic psychosocial stress, at least in mice, induces alterations in SL metabolism, which in turn might be involved in mediating the adverse health effects of chronic psychosocial stress and peripheral changes occurring in mood disorders.

Association between bullous pemphigoid and malignancy: A meta-analysis.

It has been suggested that bullous pemphigoid is associated with an increased risk of malignancy, but the evidence is inconsistent. Therefore, a meta-analysis was conducted to explore this association. PUBMED and Embase were searched for studies investigating the association between bullous pemphigoid and malignancy. This meta-analysis included 16 studies with a total of 9398 cases of bullous pemphigoid. The rate of malignancy in patients with bullous pemphigoid was 11% (95% CI: 9-14, P < 0.001); 9% (95% CI: 6-13, P < 0.003) for women and 13% (95% CI: 9-18, P < 0.03) for men, with a statistically insignificant higher risk in men (OR = 1.30, 95% CI: 0.99-1.71, P = 0.06). The event rate was 9% (95% CI: 5-14, P < 0.001) in the Asian population and 13% (95% CI: 10-17, P < 0.001) in the European population, with a statistically significant lower risk in the Asians population (OR = 0.69, 95% CI: 0.57-0.84; P < 0.001). The event rate of malignancy was higher in patients with bullous pemphigoid than in matched controls (OR = 2.08, 95% CI: 1.22-3.55; P = 0.005). The overall event rate of malignancy was higher in the bullous pemphigoid group than in matched controls. Caution is required when interpreting these results, as potential confounding variables were not controlled for.

Enhanced Acid Sphingomyelinase Activity Drives Immune Evasion and Tumor Growth in Non-Small Cell Lung Carcinoma.

The lipid hydrolase enzyme acid sphingomyelinase (ASM) is required for the conversion of the lipid cell membrane component sphingomyelin into ceramide. In cancer cells, ASM-mediated ceramide production is important for apoptosis, cell proliferation, and immune modulation, highlighting ASM as a potential multimodal therapeutic target. In this study, we demonstrate elevated ASM activity in the lung tumor environment and blood serum of patients with non-small cell lung cancer (NSCLC). RNAi-mediated attenuation of SMPD1 in human NSCLC cells rendered them resistant to serum starvation-induced apoptosis. In a murine model of lung adenocarcinoma, ASM deficiency reduced tumor development in a manner associated with significant enhancement of Th1-mediated and cytotoxic T-cell-mediated antitumor immunity. Our findings indicate that targeting ASM in NSCLC can act by tumor cell-intrinsic and -extrinsic mechanisms to suppress tumor cell growth, most notably by enabling an effective antitumor immune response by the host. Cancer Res; 77(21); 5963-76. ©2017 AACR.

Kdm6b and Pmepa1 as Targets of Bioelectrically and Behaviorally Induced Activin A Signaling.

The transforming growth factor-ß (TGF-ß) family member activin A exerts multiple neurotrophic and protective effects in the brain. Activin also modulates cognitive functions and affective behavior and is a presumed target of antidepressant therapy. Despite its important role in the injured and intact brain, the mechanisms underlying activin effects in the CNS are still largely unknown. Our goal was to identify the first target genes of activin signaling in the hippocampus in vivo. Electroconvulsive seizures, a rodent model of electroconvulsive therapy in humans, were applied to C57BL/6J mice to elicit a strong increase in activin A signaling. Chromatin immunoprecipitation experiments with hippocampal lysates subsequently revealed that binding of SMAD2/3, the intracellular effectors of activin signaling, was significantly enriched at the Pmepa1 gene, which encodes a negative feedback regulator of TGF-ß signaling in cancer cells, and at the Kdm6b gene, which encodes an epigenetic regulator promoting transcriptional plasticity. Underlining the significance of these findings, activin treatment also induced PMEPA1 and KDM6B expression in human forebrain neurons generated from embryonic stem cells suggesting interspecies conservation of activin effects in mammalian neurons. Importantly, physiological stimuli such as provided by environmental enrichment proved already sufficient to engender a rapid and significant induction of activin signaling concomitant with an upregulation of Pmepa1 and Kdm6b expression. Taken together, our study identified the first target genes of activin signaling in the brain. With the induction of Kdm6b expression, activin is likely to gain impact on a presumed epigenetic regulator of activity-dependent neuronal plasticity.

Hippocampal structure and function are maintained despite severe innate peripheral inflammation.

Chronic peripheral inflammation mediated by cytokines such as TNFα, IL-1ß, and IL-6 is associated with psychiatric disorders like depression and anxiety. However, it remains elusive which distinct type of peripheral inflammation triggers neuroinflammation and affects hippocampal plasticity resulting in depressive-like behavior. We hypothesized that chronic peripheral inflammation in the human TNF-α transgenic (TNFtg) mouse model of rheumatoid arthritis spreads into the central nervous system and induces depressive state manifested in specific behavioral pattern and impaired adult hippocampal neurogenesis. TNFtg mice showed severe erosive arthritis with increased IL-1ß and IL-6 expression in tarsal joints with highly elevated human TNF-α levels in the serum. Intriguingly, IL-1ß and IL-6 mRNA levels were not altered in the hippocampus of TNFtg mice. In contrast to the pronounced monocytosis in joints and spleen of TNFtg mice, signs of hippocampal microgliosis or astrocytosis were lacking. Furthermore, locomotion was impaired, but there was no locomotion-independent depressive behavior in TNFtg mice. Proliferation and maturation of hippocampal neural precursor cells as well as survival of newly generated neurons were preserved in the dentate gyrus of TNFtg mice despite reduced motor activity and peripheral inflammatory signature. We conclude that peripheral inflammation in TNFtg mice is mediated by chronic activation of the innate immune system. However, severe peripheral inflammation, though impairing locomotor activity, does not elicit depressive-like behavior. These structural and functional findings indicate the maintenance of hippocampal immunity, cellular plasticity, and behavior despite peripheral innate inflammation.

Secretion of acid Sphingomyelinase is affected by its polymorphic signal peptide.

BACKGROUND: Acid sphingomyelinase (ASM) catalyses the hydrolysis of sphingomyelin into ceramide, which acts as a lipid messenger that regulates important cellular functions. Deregulated ASM activity has been reported for different common diseases, but the mechanisms regulating ASM activity are still debated. ASM contains an exceptional signal peptide which is polymorphic due to a variable number of a hexanucleotide sequence that determines the length of the hydrophobic core. We investigated the impact of the signal peptide polymorphism on the regulation of ASM activity and secretion in vivo and in vitro. METHODS AND RESULTS: Subjects homozygous for the rare 4-repeat allele displayed significantly lower secreted ASM activity than subjects homozygous for the common 6-repeat allele. In vitro, overexpression of ASM variants encoded by 2, 8 or 9 repeats resulted in a significantly lowered ASM secretion rate. Treatment of ASM-overexpressing cells with tumour necrosis factor α induced secretion of ASM, and the secretion rate was highest for the most common ASM variant encoding 6 repeats compared to other naturally occurring variants. CONCLUSION: We provide evidence that the polymorphic ASM signal peptide regulates ASM secretion. It might be an evolutionary mechanism to increase ASM secretion potential, whereas an increase in lysosomal ASM activity is limited due to deleterious cellular effects.

Identification of novel functional inhibitors of acid sphingomyelinase.

We describe a hitherto unknown feature for 27 small drug-like molecules, namely functional inhibition of acid sphingomyelinase (ASM). These entities named FIASMAs (Functional Inhibitors of Acid SphingoMyelinAse), therefore, can be potentially used to treat diseases associated with enhanced activity of ASM, such as Alzheimer's disease, major depression, radiation- and chemotherapy-induced apoptosis and endotoxic shock syndrome. Residual activity of ASM measured in the presence of 10 µM drug concentration shows a bimodal distribution; thus the tested drugs can be classified into two groups with lower and higher inhibitory activity. All FIASMAs share distinct physicochemical properties in showing lipophilic and weakly basic properties. Hierarchical clustering of Tanimoto coefficients revealed that FIASMAs occur among drugs of various chemical scaffolds. Moreover, FIASMAs more frequently violate Lipinski's Rule-of-Five than compounds without effect on ASM. Inhibition of ASM appears to be associated with good permeability across the blood-brain barrier. In the present investigation, we developed a novel structure-property-activity relationship by using a random forest-based binary classification learner. Virtual screening revealed that only six out of 768 (0.78%) compounds of natural products functionally inhibit ASM, whereas this inhibitory activity occurs in 135 out of 2028 (6.66%) drugs licensed for medical use in humans.

Biomechanics of postoperative shoes: plantar pressure distribution, wearing characteristics and design criteria: a preliminary study.

BACKGROUND: Modern concepts in the postoperative treatment of first metatarsal osteotomies include special shoes that should decrease stress in the forefoot region. The purpose of this study was to determine plantar pressure distribution, wearing characteristics and stress-reducing effectiveness of five different types of commonly used postoperative shoes. Additionally, we wanted to modify the shoe that revealed the most favourable results in a way that improves forefoot relief as well as provides comfort to the patients. METHODS: Eight persons consented to participate in the study. Plantar pressure distribution in five different types of postoperative shoes (Rathgeber(®) normal, Rathgeber(®) modified, 4. Darco(®) flat, Darco(®) VFE, Wocker(®)) was assessed using Mediologic(®) insoles. Also, subjective criteria considering wearing comfort, stability and rolling characteristics were evaluated. Based on the postoperative shoe revealing the most favourable results, further prototypes were developed. Each new model was targeted to meet the given requirements, minimal forefoot pressure, in a different way. RESULTS: The Rathgeber(®) modified model revealed the most favourable results concerning plantar pressure distribution as well as subjective wearing characteristics. Therefore, it was chosen for further modifications. After adding an extra layer of high elastic and springy material for shock absorption at the hallux region, forefoot relief and wearing characteristics showed improved results. CONCLUSION: The results of the present study indicate that damping material in the hallux region of postoperative shoes minimises stress in this region and improves patient's comfort.

Functional Inhibitors of Acid Sphingomyelinase (FIASMAs): a novel pharmacological group of drugs with broad clinical applications.

Acid sphingomyelinase (ASM) is an important lipid-metabolizing enzyme cleaving sphingomyelin to ceramide, mainly within lysosomes. Acid ceramidase (AC) further degrades ceramide to sphingosine which can then be phosphorylated to sphingosine-1-phosphate. Ceramide and its metabolite sphingosine-1-phosphate have been shown to antagonistically regulate apoptosis, cellular differentiation, proliferation and cell migration. Inhibitors of ASM or AC therefore hold promise for a number of new clinical therapies, e.g. for Alzheimer's disease and major depression on the one hand and cancer on the other. Inhibitors of ASM have been known for a long time. Cationic amphiphilic substances induce the detachment of ASM protein from inner lysosomal membranes with its consecutive inactivation, thereby working as functional inhibitors of ASM. We recently experimentally identified a large number of hitherto unknown functional inhibitors of ASM and determined specific physicochemical properties of such cationic amphiphilic substances that functionally inhibit ASM. We propose the acronym "FIASMA" (Functional Inhibitor of Acid SphingoMyelinAse) for members of this large group of compounds with a broad range of new clinical indications. FIASMAs differ markedly with respect to molecular structure and current clinical indication. Most of the available FIASMAs are licensed for medical use in humans, are minimally toxic and may therefore be applied for disease states associated with increased activity of ASM.

A novel approach to simulate Hodgkin-Huxley-like excitation with COMSOL Multiphysics.

A proof of concept for the evaluation of external nerve and muscle fiber excitation with the finite element software COMSOL Multiphysics, formerly known as FEMLAB, is presented. This software allows the simultaneous solution of fiber excitation by 1D models of the Hodgkin-Huxley type which are embedded in a volume conductor where the electric field is mainly dominated by the electrode currents. This way the presented bidomain model includes the interaction between electrode currents and transmembrane currents during the excitation process. Especially for direct muscle fiber stimulation (cardiac muscle, denervated muscle) the effects from secondary currents from large populations of excited fibers seem to be significant. The method has many applications, for example, the relation between stimulus parameters and fiber recruitment can be analyzed.

Identification of new functional inhibitors of acid sphingomyelinase using a structure-property-activity relation model.

Some organic weak bases induce a detachment from inner lysosomal membranes and subsequent inactivation of acid sphingomyelinase (ASM) and thus work as functional ASM inhibitors. The aim of the present investigation was to develop a structure-property-activity relation (SPAR) model in order to specify the structural and physicochemical characteristics of probes capable of functionally inhibiting ASM. High p K a and high log P values are necessary but not sufficient preconditions for functional inhibition of ASM. The experimental data supported the requirement of an additional factor, which is necessary for functional inhibition of ASM. This factor k is related to the steric hindrance of the most basic nitrogen atom and presumably modulates the free presentation of a protonated nitrogen atom at the inner lysosomal surface. During the course of the study, we characterized 26 new functional ASM inhibitors, including doxepine 63, fluoxetine 104, maprotiline 109, nortriptyline 114, paroxetine 118, sertraline 124, suloctidil 125, and terfenadine 127.

The peroxisome proliferator-activated receptor-gamma agonist troglitazone inhibits transforming growth factor-beta-mediated glioma cell migration and brain invasion.

Gliomas are the most common primary tumors of the central nervous system, with glioblastomas as the most malignant entity. Rapid proliferation and diffuse brain invasion of these tumors are likely to determine the unfavorable prognosis. Considering its promigratory properties, the transforming growth factor-beta (TGF-beta) signaling pathway has become a major therapeutic target. Analyses of resected glioma tissues revealed an intriguing correlation between tumor grade and the expression of TGF-beta(1-3) as well as their receptors I and II. Here, we analyzed the effects of peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists on glioma proliferation, migration, and brain invasion. Using an organotypic glioma invasion model, we show that micromolar doses of the PPAR-gamma activator troglitazone blocked glioma progression without neurotoxic damage to the organotypic neuronal environment observed. This intriguing antiglioma property of troglitazone seems to be only partially based on its moderate cytostatic effects. We identified troglitazone as a potent inhibitor of glioma cell migration and brain invasion, which occurred in a PPAR-gamma-independent manner. The antimigratory property of troglitazone was in concordance with the transcriptional repression of TGF-beta(1-3) and their receptors I and II and associated with reduced TGF-beta release. Due to its capacity to counteract TGF-beta release and glioma cell motility and invasiveness already at low micromolar doses, troglitazone represents a promising drug for adjuvant therapy of glioma and other highly migratory tumor entities.