Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit (ZAFES)
Refine
Year of publication
Document Type
- Article (92)
- Preprint (3)
- Conference Proceeding (2)
- Doctoral Thesis (1)
Has Fulltext
- yes (98)
Is part of the Bibliography
- no (98)
Keywords
- Inflammation (4)
- Pre-analytics (3)
- inflammation (3)
- neuropathic pain (3)
- pain (3)
- spinal cord (3)
- Gene Regulation (2)
- Interleukin (2)
- Lipidomics (2)
- MLL (2)
- Metabolomics (2)
- PGE2 (2)
- Pain (2)
- apoptosis (2)
- cytotoxicity (2)
- differentiation (2)
- extracellular matrix (2)
- migration (2)
- prostaglandin (2)
- prostaglandins (2)
- 11q23/MLL rearrangements (1)
- 15-PGDH (1)
- 2-Arachidonoyl glycerol (1)
- 3-hydroxyanthranilic acid (1)
- 5-lipoxygenase (1)
- 5-lipoxygenase; (1)
- ADAM10 (1)
- AF4 (1)
- ARID5B (1)
- Anandamide (1)
- B16 cells (1)
- Best-practice model (1)
- Biglycan (1)
- Biomarker Discovery Study (1)
- Biomarkers & Diagnostic Imaging (1)
- Blood sample handling (1)
- Blood sampling (1)
- CD3 (1)
- CEBPE (1)
- CXCL10 (1)
- CXCL16 (1)
- CXCR3 (1)
- Case management (1)
- Crohn’s disease (1)
- Cyclosporin A (1)
- Cytokines Induction (1)
- DNA G-quadruplex (1)
- DNA pulldown (1)
- DNA-protein-interactions (1)
- Decorin (1)
- Dendritic Cells (1)
- Dendritic cells (1)
- Diabetic nephropathy (1)
- Doubling time (1)
- Endocannabinoid (1)
- Endocannabinoids (1)
- FTY720 (1)
- Fibrosis (1)
- Fingolimod (1)
- Gene/Regulation (1)
- Glomerulonephritis (1)
- HDAC (1)
- HIV-1 (1)
- HODE (1)
- Highwire (1)
- IDO1 (1)
- IKK epsilon (1)
- IKKε (1)
- IKZF1 (1)
- IL-12 (1)
- IL-18 binding protein (1)
- Immunosuppression (1)
- Infant leukemia (1)
- Innate Immunity (1)
- Innate immunity (1)
- Interleukin-1 (1)
- Interleukin-22 (1)
- Interleukin-36 (1)
- Ischemia-reperfusion injury (1)
- K3EDTA plasma sampling (1)
- Kidney disease (1)
- LC-MS-Based Clinical Research (1)
- Lumican (1)
- MLL-Baby (1)
- MLV (1)
- MMP9 (1)
- MRP4 (1)
- MTT (1)
- MYCBP2 (1)
- Macrophage (1)
- Macrophages (1)
- Metabolism (1)
- NADPH oxidase (1)
- NF-кB (1)
- Neuron (1)
- Nuclear factor kappa B (1)
- Nuklearfaktor Kappa B (1)
- Oral anticoagulation (1)
- PAM (1)
- PHR1 (1)
- Plasma (1)
- RNA-templated DNA repair (1)
- RNA/MicroRNA (1)
- Receptors/Nuclear (1)
- S1P lyase (1)
- SAMHD1 knockout mouse (1)
- SAMHD1 phosphorylation (1)
- SERS (1)
- STAT1 (1)
- Sampling protocol (1)
- Schmerz (1)
- Schmerzforschung (1)
- Serum (1)
- Sphingosine 1-phosphate (1)
- Sphingosine-1-phosphate (1)
- T Cell Biology (1)
- T-bet (1)
- TBK1 (1)
- TEM (1)
- TRP Channels (1)
- Toll-like receptor (1)
- Trafficking (1)
- Ubiquitin Ligase (1)
- Wilms tumor (1)
- acute leukemia (1)
- adipose-derived stem cells (ASCs) (1)
- age (1)
- amlexanox (1)
- analgesics (1)
- antifibrotic therapy (1)
- autoantigen (1)
- autoimmunity (1)
- autophagy (1)
- back pain (1)
- biglycan (1)
- cPLA2 (1)
- cadherin (1)
- calcitriol (1)
- cancer (1)
- cell adhesion (1)
- cell proliferation (1)
- combination therapy (1)
- cortisol (1)
- costimulation (1)
- cyclooxygenase (1)
- decorin (1)
- diabetic nephropathy (1)
- eicosanoids (1)
- epigenetics (1)
- epithelial‐mesenchymal transition (1)
- fibrocytes (1)
- fibromodulin (1)
- fibrosis (1)
- fluorescence confocal laser scanning microscopy (1)
- fluorescent ligand (1)
- flurbiprofen (1)
- genetic rearrangements (1)
- glycosaminoglycan (1)
- growth factor (1)
- histone deacetylase (1)
- human histamine H3 receptor (1)
- hyperalgesia (1)
- idiopathic pulmonary fibrosis (1)
- immunoglobulin superfamily (1)
- infants (1)
- insulitis (1)
- integrin (1)
- interferon-γ (1)
- interleukin-10 (1)
- interleukin-22 (1)
- intervertebral disc (1)
- invasion (1)
- junctional adhesion molecule (1)
- kynureninase (1)
- kynurenine (1)
- labelfree quantitative mass spectrometry (1)
- leukemia; solid tumors (1)
- leukotriene (1)
- linoleic acid metabolites (1)
- lipids inflammatory pain (1)
- lipoproteins (1)
- liver (1)
- liver fibrosis (1)
- lumican (1)
- mPGES-1 (1)
- macrophage (1)
- macrophage polarization (1)
- macrophages (1)
- melanoma (1)
- miRNA let-7e (1)
- microenvironment (1)
- microglia (1)
- mitogenic effects (1)
- nerve injury (1)
- neuroinflammation (1)
- neuropathy (1)
- nociception (1)
- non-classical adhesion molecule (1)
- p38 MAPK (1)
- pain, dorsal root ganglia (1)
- perfusion (1)
- phagocytosis (1)
- pharmacological tool (1)
- podocytes (1)
- polymorphism (1)
- premature transcript termination (1)
- primary tubular cells (1)
- prostaglandin E (1)
- proteoglycan (1)
- reactive oxygen species (1)
- recurrent chromosomal translocations (1)
- selectin (1)
- signal transducer and activator of transcription (1)
- smooth muscle cells (1)
- sphingosine-1-phosphate (1)
- transient receptor potential channels (1)
- treatment outcome (1)
- tryptophan (1)
- tumor growth (1)
- type I interferons (1)
- vascular biology (1)
- дети первого года жизни (1)
- исходы терапии (1)
- острые лейкозы (1)
- перестройки 11q23/MLL (1)
Institute
The transient receptor potential (TRP) ankyrin type 1 (TRPA1) channel is highly expressed in a subset of sensory neurons where it acts as an essential detector of painful stimuli. However, the mechanisms that control the activity of sensory neurons upon TRPA1 activation remain poorly understood. Here, using in situ hybridization and immunostaining, we found TRPA1 to be extensively co-localized with the potassium channel Slack (KNa1.1, Slo2.2, or Kcnt1) in sensory neurons. Mice lacking Slack globally (Slack−/−) or conditionally in sensory neurons (SNS-Slack−/−) demonstrated increased pain behavior after intraplantar injection of the TRPA1 activator allyl isothiocyanate. By contrast, pain behavior induced by the TRP vanilloid 1 (TRPV1) activator capsaicin was normal in Slack-deficient mice. Patch-clamp recordings in sensory neurons and in a HEK cell line transfected with TRPA1 and Slack revealed that Slack-dependent potassium currents (IKS) are modulated in a TRPA1-dependent manner. Taken together, our findings highlight Slack as a modulator of TRPA1-mediated, but not TRPV1-mediated, activation of sensory neurons.
Keywords: TRPA1; slack; dorsal root ganglia; pain; mice
The SARS-CoV-2 pandemic has challenged researchers at a global scale. The scientific community’s massive response has resulted in a flood of experiments, analyses, hypotheses, and publications, especially in the field of drug repurposing. However, many of the proposed therapeutic compounds obtained from SARS-CoV-2 specific assays are not in agreement and thus demonstrate the need for a singular source of COVID-19 related information from which a rational selection of drug repurposing candidates can be made. In this paper, we present the COVID-19 PHARMACOME, a comprehensive drug-target-mechanism graph generated from a compilation of 10 separate disease maps and sources of experimental data focused on SARS-CoV-2 / COVID-19 pathophysiology. By applying our systematic approach, we were able to predict the synergistic effect of specific drug pairs, such as Remdesivir and Thioguanosine or Nelfinavir and Raloxifene, on SARS-CoV-2 infection. Experimental validation of our results demonstrate that our graph can be used to not only explore the involved mechanistic pathways, but also to identify novel combinations of drug repurposing candidates.
Type 1 diabetes (T1D) is mainly precipitated by the destruction of insulin-producing β-cells in the pancreatic islets of Langerhans by autoaggressive T cells. The etiology of the disease is still not clear, but besides genetic predisposition the exposure to environmental triggers seems to play a major role. Virus infection of islets has been demonstrated in biopsies of T1D patients, but there is still no firm proof that such an infection indeed results in islet-specific autoimmunity. However, virus infection results in a local inflammation with expression of inflammatory factors, such as cytokines and chemokines that attract and activate immune cells, including potential autoreactive T cells. Many chemokines have been found to be elevated in the serum and expressed by islet cells of T1D patients. In mouse models, it has been demonstrated that β-cells express chemokines involved in the initial recruitment of immune cells to the islets. The bulk load of chemokines is however released by the infiltrating immune cells that also express multiple chemokine receptors. The result is a mutual attraction of antigen-presenting cells and effector immune cells in the local islet microenvironment. Although there is a considerable redundancy within the chemokine ligand-receptor network, a few chemokines, such as CXCL10, seem to play a key role in the T1D pathogenesis. Studies with neutralizing antibodies and investigations in chemokine-deficient mice demonstrated that interfering with certain chemokine ligand-receptor axes might also ameliorate human T1D. However, one important aspect of such a treatment is the time of administration. Blockade of the recruitment of immune cells to the site of autoimmune destruction might not be effective when the disease process is already ongoing. By that time, autoaggressive cells have already arrived in the islet microenvironment and a blockade of migration might even hold them in place leading to accelerated destruction. Thus, an anti-chemokine therapy makes most sense in situations where the cells have not yet migrated to the islets. Such situations include treatment of patients at risk already carrying islet-antigen autoantibodies but are not yet diabetic, islet transplantation recipients, and patients that have undergone a T cell reset as occurring after anti-CD3 antibody treatment.
Sphingosine‐1‐phosphate lyase 1 (S1P lyase or SGPL1) is an essential sphingosine‐1‐phosphate‐degrading enzyme. Its manipulation favors onset and progression of colorectal cancer and others in vivo. Thus, SGPL1 is an important modulator of cancer initiation. However, in established cancer, the impact of retrospective SGPL1 modulation is elusive. Herein, we analyzed how SGPL1 siRNA affects malignancy of the human colorectal cancer cells DLD‐1 and found that in parallel to the reduction of SGPL1 expression levels, migration, invasion, and differentiation status changed. Diminished SGPL1 expression was accompanied with reduced cell migration and cell invasion in scratch assays and transwell assays, whereas metabolic activity and proliferation was not altered. Decreased migration was attended by increased cell–cell‐adhesion through upregulation of E‐cadherin and formation of cadherin‐actin complexes. Spreading cell islets showed lower vimentin abundance in border cells. Furthermore, SGPL1 siRNA treatment induced expression of epithelial cell differentiation markers, such as intestinal alkaline phosphatase and cytokeratin 20. Hence, interference with SGPL1 expression augmented a partial redifferentiation of colorectal cancer cells toward normal colon epithelial cells. Our investigation showed that SGPL1 siRNA influenced tumorigenic activity of established colorectal cancer cells. We therefore suggest SGPL1 as a target for lowering malignant potential of already existing cancer.
Inflammation is a highly regulated biological response of the immune system that is triggered by assaulting pathogens or endogenous alarmins. It is now well established that some soluble extracellular matrix constituents, such as small leucine-rich proteoglycans (SLRPs), can act as danger signals and trigger aseptic inflammation by interacting with innate immune receptors. SLRP inflammatory signaling cascade goes far beyond its canonical function. By choosing specific innate immune receptors, coreceptors, and adaptor molecules, SLRPs promote a switch between pro- and anti-inflammatory signaling, thereby determining disease resolution or chronification. Moreover, by orchestrating signaling through various receptors, SLRPs fine-tune inflammation and, despite their structural homology, regulate inflammatory processes in a molecule-specific manner. Hence, the overarching theme of this review is to highlight the molecular and functional specificity of biglycan-, decorin-, lumican-, and fibromodulin-mediated signaling in inflammatory and autoimmune diseases.
Pain is the most frequent cause triggering patients to visit a physician. The worldwide incidence of chronic pain is in the range of 20% of adults, and chronic pain conditions are frequently associated with several comorbidities and a drastic decrease in patients’ quality of life. Although several approved analgesics are available, such therapy is often not satisfying due to insufficient efficacy and/or severe side effects. Therefore, novel strategies for the development of safe and highly efficacious pain killers are urgently needed. To reach this goal, it is necessary to clarify the causes and signal transduction cascades underlying the onset and progression of the different types of chronic pain. The papers in this Special Issue cover a wide variety of mechanisms involved in different pain types such as inflammatory, neuropathic or cancer pain. Therefore, the results summarized here might contribute to a better understanding of the mechanisms in chronic pain and thereby to the development of novel therapeutic strategies for pain patients.
5‐Lipoxygenase (5‐LO) is the initial enzyme in the biosynthesis of leukotrienes, which are mediators involved in pathophysiological conditions such as asthma and certain cancer types. Knowledge of proteins involved in 5‐LO pathway regulation, including gene regulatory proteins, is needed to evaluate all options for therapeutic intervention in these diseases. Here, we present a mass spectrometric screening of ALOX5 promoter‐interacting proteins, obtained by DNA pulldown and label‐free quantitative mass spectrometry. Protein preparations from myeloid and B‐lymphocytic cell lines were screened for promoter DNA interactors. Through statistical analysis, 66 proteins were identified as specific ALOX5 promotor binding proteins. Among those, the 15 most likely candidates for a prominent role in ALOX5 gene regulation are the known ALOX5 interactors Sp1 and Sp3, the related factor Sp2, two Krüppel‐like factors (KLF13 and KLF16) and six other zinc finger proteins (MAZ, PRDM10, VEZF1, ZBTB7A, ZNF281 and ZNF579). Intriguingly, we also identified two helicases (BLM and DHX36) and the proteins hnRNPD and hnRNPK, which are, together with the protein MAZ, known to interact with DNA G‐quadruplex structures. As G‐quadruplexes are implicated in gene regulation, spectroscopic and antibody‐based methods were used to confirm their presence within the GC‐rich sequence of the ALOX5 promoter. In summary, we have systematically characterized the interactome of the ALOX5 promoter, identifying several zinc finger proteins as novel potential ALOX5 gene regulators. Further, we have shown that the ALOX5 promoter can form DNA G‐quadruplex structures, which may play a functional role in ALOX5 gene regulation.
Цель: Оценить влияние локализации точки разрыва в геномной ДНК гена MLL на прогноз острых лейкозов (ОЛ) у детей первого года жизни.
Методы: В исследование было включено 68 детей первого года жизни (29 мальчиков и 39 девочек с медианой возраста 4,8 мес.) с MLL-позитивными острым лимфобластным лейкозом (ОЛЛ) (n = 46), острым миелоидным лейкозом (ОМЛ) (n = 20) и ОЛ смешанной линейности (n = 2).
Результаты: 5-летняя бессобытийная выживаемость (БСВ) детей первого года жизни с ОЛЛ, включенных в исследование MLL-Baby, с точкой разрыва в интроне 11 ДНК гена MLL (n = 29) была статистически значимо ниже, чем у пациентов c локализацией точек разрыва, начиная с интрона 7 по экзон 11 (n = 17; 0,16 ± 0,07 и 0,38 ± 0,14; p = 0,039), а кумулятивная вероятность развития рецидива была значительно выше в группе с точкой разрыва в интроне 11 (0,74 ± 0,09 и 0,52 ± 0,17; p = 0,045). В то же время многофакторный анализ показал, что единственным значимым фактором, связанным с неблагоприятным прогнозом, остается сохранение минимальной остаточной болезни (МОБ) в точке наблюдения 4 протокола MLL-Baby (отношение опасности 5,994; 95%-й доверительный интервал 2,209–16,263; p < 0,001). У 22 пациентов с ОМЛ связи между прогнозом и локализацией точки разрыва в ДНК гена MLL не выявлено.
Заключение: Наличие точки разрыва в интроне 11 гена MLL у детей первого года жизни с ОЛЛ, получавших лечение по протоколу MLL-Baby, вело к статистически значимо более низким показателям БСВ и более высокой кумулятивной вероятности развития рецидива. Однако в многофакторной модели риска это нивелировалось сохранением МОБ в точке наблюдения 4. У детей первого года жизни с ОМЛ взаимосвязи между локализацией точки разрыва в ДНК гена MLL и прогнозом не выявлено.
Inhibitor-kappaB kinase epsilon (IKKε) and TANK-binding kinase 1 (TBK1) are non-canonical IκB kinases, both described as contributors to tumor growth and metastasis in different cancer types. Several hints indicate that they are also involved in the pathogenesis of melanoma; however, the impact of their inhibition as a potential therapeutic measure in this “difficult-to-treat” cancer type has not been investigated so far. We assessed IKKε and TBK1 expression in human malignant melanoma cells, primary tumors and the metastasis of melanoma patients. Both kinases were expressed in the primary tumor and in metastasis and showed a significant overexpression in tumor cells in comparison to melanocytes. The pharmacological inhibition of IKKε/TBK1 by the approved drug amlexanox reduced cell proliferation, migration and invasion. Amlexanox did not affect the cell cycle progression nor apoptosis induction but significantly suppressed autophagy in melanoma cells. The analysis of potential functional downstream targets revealed that NF-кB and ERK pathways might be involved in kinase-mediated effects. In an in vivo xenograft model in nude mice, amlexanox treatment significantly reduced tumor growth. In conclusion, amlexanox was able to suppress tumor progression potentially by the inhibition of autophagy as well as NF-кB and MAP kinase pathways and might therefore constitute a promising candidate for melanoma therapy.
The widely varying therapeutic response of patients with inflammatory bowel disease (IBD) continues to raise questions regarding the unclarified heterogeneity of pathological mechanisms promoting disease progression. While biomarkers for the differentiation of Crohn’s disease (CD) versus ulcerative colitis (UC) have been suggested, specific markers for a CD subclassification in ileal CD versus colonic CD are still rare. Since an altered signature of the tryptophan metabolism is associated with chronic inflammatory disease, we sought to characterize potential biomarkers by focusing on the downstream enzymes and metabolites of kynurenine metabolism. Using immunohistochemical stainings, we analyzed and compared the mucosal tryptophan immune metabolism in bioptic samples from patients with active inflammation due to UC or CD versus healthy controls. Localization-specific quantification of immune cell infiltration, tryptophan-metabolizing enzyme expression and mucosal tryptophan downstream metabolite levels was performed. We found generally increased immune cell infiltrates in the tissue of all patients with IBD. However, in patients with CD, significant differences were found between regulatory T cell and neutrophil granulocyte infiltration in the ileum compared with the colon. Furthermore, we observed decreased kynurenine levels as well as strong kynureninase (KYNU) expression specifically in patients with ileal CD. Correspondingly, significantly elevated levels of the kynurenine metabolite 3-hydroxyanthranilic acid were detected in the ileal CD samples. Highlighting the heterogeneity of the different phenotypes of CD, we identified KYNU as a potential mucosal biomarker allowing the localization-specific differentiation of ileal CD versus colonic CD.