ABSTRACT
Teachers with poor neuroliteracy fail to distinguish scientific evidence from neuromyths (NM), which might lead to the implementation of pseudoscientific educational methods. The prevalence of NM and general knowledge about the brain (GKAB) among in-service and pre-service teachers has been assessed in multiple countries, but no such study has been performed in Hungary. The aims of this study were to (1) assess the neuroliteracy of pre-service teachers, (2) compare the results with those of previous studies and (3) analyze the factors influencing neuroliteracy. Our sample included 822 pre-service teachers from 12 Hungarian universities. We developed a survey including 10 NM and 13 GKAB statements, adapted from a widely used questionnaire. The average rate of incorrect answers to NM was 56.9%, whereas the average rate of correct answers to GKAB was 70.9%. Male gender and frequency of using Facebook as the primary information source about neuroscience were the only predictors of NM acceptance. In comparison with other studies, the Hungarian pre-service teachers had the second highest endorsement of NM. The most prevalent NM were linked to motor functions, which might be related to the widespread use and promotion of motor therapies in Hungary.
ABSTRACT
Bruton's tyrosine kinase (BTK) is a member of the TEC kinase family and is selectively expressed in a subset of immune cells. It is a key regulator of antigen receptor signaling in B cells and of Fc receptor signaling in mast cells and macrophages. A BTK inhibitor will likely have a positive impact on autoimmune diseases which are caused by autoreactive B cells and immune-complex driven inflammation. We report the design, optimization, and characterization of potent and selective covalent BTK inhibitors. Starting from the selective reversible inhibitor 3 binding to an inactive conformation of BTK, we designed covalent irreversible compounds by attaching an electrophilic warhead to reach Cys481. The first prototype 4 covalently modified BTK and showed an excellent kinase selectivity including several Cys-containing kinases, validating the design concept. In addition, this compound blocked FcγR-mediated hypersensitivity in vivo. Optimization of whole blood potency and metabolic stability resulted in compounds such as 8, which maintained the excellent kinase selectivity and showed improved BTK occupancy in vivo.
ABSTRACT
Starting from a weak screening hit, potent and selective inhibitors of the MALT1 protease function were elaborated. Advanced compounds displayed high potency in biochemical and cellular assays. Compounds showed activity in a mechanistic Jurkat T cell activation assay as well as in the B-cell lymphoma line OCI-Ly3, which suggests potential use of MALT1 inhibitors in the treatment of autoimmune diseases as well as B-cell lymphomas with a dysregulated NF-κB pathway. Initially, rat pharmacokinetic properties of this compound series were dominated by very high clearance which could be linked to amide cleavage. Using a rat hepatocyte assay a good in vitro-in vivo correlation could be established which led to the identification of compounds with improved PK properties.
Subject(s)
Antineoplastic Agents/pharmacology , Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein/antagonists & inhibitors , Piperidines/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Hepatocytes/drug effects , Humans , Jurkat Cells , Microsomes/drug effects , Molecular Structure , Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein/metabolism , Piperidines/chemical synthesis , Piperidines/chemistry , Proteolysis/drug effects , Rats , Structure-Activity RelationshipABSTRACT
MAP-activated protein kinase 2 (MK2) plays an important role in the regulation of innate immune response as well as in cell survival upon DNA damage. Despite its potential for the treatment of inflammation and cancer, to date no MK2 low molecular weight inhibitors have reached the clinic, mainly due to inadequate absorption, distribution, metabolism, and excretion (ADME) properties. We describe here an approach based on specifically placed fluorine within a recently described pyrrole-based MK2 inhibitor scaffold for manipulation of its physicochemical and ADME properties. While preserving target potency, the novel fluoro-derivatives showed greatly improved permeability as well as enhanced solubility and reduced in vivo clearance leading to significantly increased oral exposure.
ABSTRACT
We applied ancient DNA methods to shed light on the origin of ancient Hungarians and their relation to modern populations. Hungarians moved into the Carpathian Basin from the Eurasian Pontic steppes in the year 895 AD as a confederation of seven tribes, but their further origin remains obscure. Here, we present 17 mtDNA haplotypes and four Y-chromosome haplogroups, which portray the genetic composition of an entire small cemetery of the first generation Hungarians. Using novel algorithms to compare these mitochondrial DNA haplogroups with other ancient and modern Eurasian data, we revealed that a significant portion of the Hungarians probably originated from a long ago consolidated gene pool in Central Asia-South Siberia, which still persists in modern Hungarians. Another genetic layer of the early Hungarians was obtained during their westward migrations by admixing with various populations of European origin, and an important component of these was derived from the Caucasus region. Most of the modern populations, which are genetically closest relatives of ancient Hungarians, today speak non-Indo-European languages. Our results contribute to our understanding of the peopling of Europe by providing ancient DNA data from a still genetically poorly studied period of medieval human migrations.
Subject(s)
Chromosomes, Human, Y/genetics , DNA, Mitochondrial/genetics , Haplotypes , White People/genetics , Algorithms , Archaeology , Cemeteries , Female , Genetics, Medical/methods , Genetics, Population , Genome, Human , Human Migration , Humans , Hungary , Male , PhylogenyABSTRACT
PURPOSE: The purpose of this study was to create a physical education (PE) attitude scale and examine how it is associated with aerobic capacity (AC). METHOD: Participants (n = 961, aged 15-20 years) were randomly selected from 26 Hungarian high schools. AC was estimated from performance on the Progressive Aerobic Cardiovascular and Endurance Run test, and the attitude scale had 31 items measured on a Likert scale that ranged from 1 to 5. Principal component analysis was used to examine the structure of the questionnaire while several 2-way analyses of variance and multiple linear regression (MLR) were computed to examine trends in AC and test the association between component scores obtained from the attitude scale and AC, respectively. RESULTS: Five components were identified: health orientation in PE (C1), avoid failure in PE (C2), success orientation in PE (C3), attitude toward physical activity (C4), and cooperation and social experience in PE (C5). There was a statistically significant main effect for sex on C3 (p < .05), C4 (p < .001), and C5 (p < .05) indicating that boys' scores were higher than girls. The Sex × Age interaction was also statistically significant (p < .05) and follow-up comparisons revealed sex differences in C5 for 15-year-old participants. Girls showed statistically significant higher values than boys in C5 at the age of 16 years. MLR results revealed that component scores were significantly associated with AC (p < .05). Statistically significant predictors included C1, C2, C3, and C4 for boys and C2 and C4 for girls. CONCLUSION: The 5-component scale seems to be suitable for measuring students' attitudes toward PE. The design of the study does not allow for direct associations between attitudes and AC but suggests that these 2 might be related.
Subject(s)
Attitude , Cardiovascular Physiological Phenomena , Physical Education and Training , Physical Fitness , Students/psychology , Adolescent , Age Factors , Female , Humans , Hungary , Male , Oxygen Consumption , Schools , Sex Factors , Surveys and Questionnaires , Young AdultABSTRACT
Spirocyclopropane- and spiroazetidine-substituted tetracycles 13D-E and 16A are described as orally active MK2 inhibitors. The spiroazetidine derivatives are potent MK2 inhibitors with IC(50)<3 nM and inhibit the release of TNFalpha (IC(50)<0.3 microM) from hPBMCs and hsp27 phosphorylation in anisomycin stimulated THP-1 cells. The spirocyclopropane analogues are less potent against MK2 (IC(50)=0.05-0.23 microM), less potent in cells (IC(50)<1.1 microM), but show good oral absorption. Compound 13E (100mg/kg po; bid) showed oral activity in rAIA and mCIA, with significant reduction of swelling and histological score.
Subject(s)
Azetidinecarboxylic Acid/chemistry , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Administration, Oral , Animals , Azetidinecarboxylic Acid/chemical synthesis , Azetidinecarboxylic Acid/pharmacology , Azetidines/chemistry , Binding Sites , Cell Line , Crystallography, X-Ray , Cyclopropanes/chemistry , Cyclopropanes/pharmacology , HSP27 Heat-Shock Proteins/metabolism , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/metabolism , Spiro Compounds/chemistry , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Pyrrolo[2,3-f]isoquinoline based amino acids, tetracyclic lactams and cyclic ketone analogues are described as novel MK2 inhibitors with IC(50) as low as 5nM and good selectivity profiles against a number of related kinases including ERK, p38alpha and JNKs. TNFalpha release was suppressed from human peripheral blood mononuclear cells (hPBMCs), and a representative compound inhibited LPS induced TNFalpha release in mice illustrating the potential of this series to provide orally active MK2 inhibitors.
Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemistry , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Administration, Oral , Amino Acids/chemical synthesis , Amino Acids/chemistry , Amino Acids/pharmacology , Animals , Binding Sites , Crystallography, X-Ray , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Isoquinolines/chemistry , Ketones/chemical synthesis , Ketones/chemistry , Ketones/pharmacology , Lactams/chemical synthesis , Lactams/chemistry , Lactams/pharmacology , Mice , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/metabolism , Pyrroles/chemistry , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Recent reports have suggested critical roles of myeloid cells in tumor invasion and metastasis, although these findings have not led to therapeutics. Using a mouse model for liver dissemination, we show that mouse and human colon cancer cells secrete CC-chemokine ligands CCL9 and CCL15, respectively, and recruit CD34(+) Gr-1(-) immature myeloid cells (iMCs). They express CCL9/15 receptor CCR1 and produce matrix metalloproteinases MMP2 and MMP9. Lack of the Ccr1, Mmp2, or Mmp9 gene in the host dramatically suppresses outgrowths of disseminated tumors in the liver. Importantly, CCR1 antagonist BL5923 blocks the iMC accumulation and metastatic colonization and significantly prolongs the survival of tumor-bearing mice. These results suggest that CCR1 antagonists can provide antimetastatic therapies for patients with disseminated colon cancer in the liver.
Subject(s)
Cell Differentiation , Colonic Neoplasms/pathology , Liver Neoplasms/secondary , Myeloid Cells/pathology , Receptors, CCR1/metabolism , Animals , Chemokines, CC/metabolism , Colonic Neoplasms/metabolism , Disease Models, Animal , Humans , Ligands , Liver/metabolism , Liver/pathology , Liver Neoplasms/enzymology , Liver Neoplasms/pathology , Macrophage Inflammatory Proteins/metabolism , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Mice , Myeloid Cells/metabolism , Receptors, CCR1/antagonists & inhibitors , Signal Transduction , Survival AnalysisABSTRACT
New, selective 3-aminopyrazole based MK2-inhibitors were discovered by scaffold hopping strategy. The new derivatives proved to inhibit intracellular phosphorylation of hsp27 as well as LPS-induced TNFalpha release in cells. In addition, selected derivative 14e also inhibited LPS-induced TNFalpha release in vivo.
Subject(s)
Drug Discovery , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrazoles/chemistry , Cell Line, Tumor , Cells, Cultured , Crystallography, X-Ray , Drug Discovery/methods , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Protein Conformation , Protein Serine-Threonine Kinases/metabolism , Pyrazoles/metabolism , Pyrazoles/pharmacologyABSTRACT
Pyrrolo-pyrimidones of the general structure 1 were synthesized and evaluated for their potential as MK2 inhibitors. Potent derivatives were discovered which inhibit MK2 in the nanomolar range and show potent inhibition of cytokine release from LPS-stimulated monocytes. These derivatives were shown to inhibit phosphorylation of hsp27, a downstream target of MK2 and are modestly selective in a panel of 28 kinases.
Subject(s)
Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Arthritis, Rheumatoid/drug therapy , Combinatorial Chemistry Techniques , Cytokines/metabolism , Dose-Response Relationship, Drug , Drug Design , HSP27 Heat-Shock Proteins/antagonists & inhibitors , HSP27 Heat-Shock Proteins/metabolism , Humans , Leukocytes, Mononuclear/drug effects , Lipopolysaccharides/pharmacology , Molecular Structure , Monocytes/drug effects , Phosphorylation , Pyrimidinones/chemistry , Pyrroles/chemistry , Tumor Necrosis Factor-alpha/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitorsABSTRACT
Diabetic nephropathy is associated with interstitial macrophage infiltrates, but their contribution to disease progression is unclear. We addressed this question by blockade of chemokine receptor (CCR)1 because CCR1 mediates the macrophage recruitment to the renal interstitium. In fact, when CCR1 was blocked with BL5923, a novel orally available CCR1 antagonist, the interstitial recruitment of ex vivo labeled macrophages was markedly decreased in uninephrectomized male db/db mice with advanced diabetic nephropathy. Likewise, BL5923 (60 mg/kg, twice a day) orally administered from months 5 to 6 of life reduced the numbers of interstitial macrophages in uninephrectomized db/db mice. This was associated with reduced numbers of Ki-67 proliferating tubular epithelial and interstitial cells, tubular atrophy, and interstitial fibrosis in uninephrectomized db/db mice. Glomerular pathology and proteinuria were not affected by the CCR1 antagonist. BL5923 reduced renal mRNA expression of Ccl2, Ccr1, Ccr2, Ccr5, transforming growth factor-beta1, and collagen I-alpha1 when compared with untreated uninephrectomized male db/db mice of the same age. Thus, we identified a previously unrecognized role for interstitial macrophages for tubulointerstitial injury, loss of peritubular microvasculature, interstitial inflammation, and fibrosis in type 2 diabetic db/db mice. These data identify oral treatment with the CCR1 antagonist BL5923 as a potential therapy for late-stage diabetic nephropathy.
Subject(s)
Diabetes Mellitus, Type 2/complications , Diabetic Neuropathies/pathology , Kidney/drug effects , Macrophages/pathology , Administration, Oral , Animals , Antigens, Differentiation/analysis , Cell Line , Cells, Cultured , Diabetic Neuropathies/etiology , Gene Expression/drug effects , Immunohistochemistry , Kidney/metabolism , Kidney/pathology , Kidney Glomerulus/drug effects , Kidney Glomerulus/metabolism , Kidney Glomerulus/pathology , Kidney Tubules/drug effects , Kidney Tubules/metabolism , Kidney Tubules/pathology , Macrophages/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Microscopy, Fluorescence , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, CCR1 , Receptors, CCR2 , Receptors, Chemokine/antagonists & inhibitors , Receptors, Chemokine/genetics , Receptors, Chemokine/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Transforming Growth Factor beta1/geneticsABSTRACT
The design, synthesis, and the biological evaluation of 2-benzamido-pyrimidines as novel IKK inhibitors are described. By optimization of the lead compound 3, compounds 16 and 24 are identified as good inhibitors of IKK2 with IC(50) values of 40 and 25 nM, respectively. Compound 16 also demonstrated significant in vivo activity in an acute model of cytokine release.
Subject(s)
Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , I-kappa B Kinase/antagonists & inhibitors , Pyrimidines/chemical synthesis , Cytokines/metabolism , Dose-Response Relationship, Drug , Drug Design , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Inhibitory Concentration 50 , Models, Chemical , Pyrimidines/chemistry , Pyrimidines/pharmacology , Structure-Activity RelationshipABSTRACT
A test library with three novel p38alpha inhibitory scaffolds and a narrow set of substituents was prepared. Appropriate combination of substituent and scaffold generated potent p38alpha inhibitors, for example, pyrazolo[3,4-b]pyridine 9, pyrazolo[3,4-d]pyrimidine 18a and pyrazolo[3,4-b]pyrazine 23b with potent in vivo activity upon oral administration in animal models of rheumatoid arthritis.
Subject(s)
Arthritis, Experimental/drug therapy , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Pyrazines/administration & dosage , Pyrazoles/administration & dosage , Pyridines/administration & dosage , Pyrimidines/administration & dosage , Administration, Oral , Animals , Disease Models, Animal , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Mice , Molecular Structure , Pyrazines/chemical synthesis , Pyrazines/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Cinnamides as novel CCR1 antagonist chemotypes are described with high affinity to human and rodent receptors. A1B1 and A4B7 showed oral activity in the mouse collagen induced arthritis.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Arthritis, Experimental/drug therapy , Receptors, Chemokine/antagonists & inhibitors , Administration, Oral , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Humans , Mice , Rats , Receptors, CCR1 , Structure-Activity RelationshipABSTRACT
A library of trisubstituted oxazoles, thiazoles, imidazoles (1,2,4- and 2,4,5-substituted) and imidazo[1,2-b]pyridines was prepared and evaluated in vitro as p38alpha inhibitors and in vivo in several models of rheumatoid arthritis. Four structures--32, 37, 45 and 59--were identified as potent inhibitors of p38alpha with high efficacy in the LPS induced TNFalpha release model in the mouse, the adjuvant induced arthritis and the collagen induced arthritis in the rat with ED50s between 1.0 and 9.5 mg/kg p.o.
Subject(s)
Antirheumatic Agents/chemical synthesis , Pyridines/chemical synthesis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Antirheumatic Agents/pharmacology , Antirheumatic Agents/therapeutic use , Arthritis, Experimental/chemically induced , Arthritis, Experimental/drug therapy , Collagen , Disease Models, Animal , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Imidazoles/chemistry , Lipopolysaccharides/pharmacology , Mice , Oxazoles/chemistry , Pyridines/pharmacology , Pyridines/therapeutic use , Rats , Structure-Activity Relationship , Thiazoles/chemistry , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Benzoylpyridines and benzophenones were synthesized and evaluated in vitro as p38alpha inhibitors and in vivo in several models of rheumatoid arthritis. Oral activity was found to depend upon substitution: 1,1-dimethylpropynylamine substituted benzophenone 10b (IC50: 14 nM) and pyridinoyl substituted benzimidazole 17b (IC50: 21 nM) showed highest efficacy and selectivity with ED50s of 9.5 and 8.6 mg/kg p.o. in CIA.
Subject(s)
Benzophenones/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Mouth/metabolism , Pyridines/chemical synthesis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Arthritis, Experimental/chemically induced , Arthritis, Experimental/drug therapy , Benzophenones/pharmacology , Benzophenones/therapeutic use , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Inhibitory Concentration 50 , Pyridines/pharmacology , Pyridines/therapeutic use , Rats , Structure-Activity RelationshipABSTRACT
We recently described a new model to study non-invasively with magnetic resonance imaging (MRI) the effects of compounds to prevent and/or resolve airway inflammation induced by ovalbumin in the lungs of actively sensitised rats. We report here the effects of 4-(4-fluorophenyl)-2-(1-methylpiperidin-4-yl)-5-(2-(1-(S)-phenylethyl)amino-4-pyridinyl)thiazole fumarate (Compound 1), which exhibits inhibitory activity against p38alpha and p38beta2 and residual activity on c-Jun amino-terminal kinase (JNK)2 mitogen-activated protein (MAP) kinases, on the oedematous signals detected by MRI and generated by antigen challenge in the lungs of sensitized rats. Compound 1 (10 mg kg(-1)) given orally 1 h prior to allergen challenge significantly reduced the oedematous signal measured at 24 h. Similar effects were seen with a synthetic corticosteroid, mometasone furoate (0.3 mg kg(-1)), given intratracheally 3 h prior to challenge. For both compounds, inhibition of the oedematous signal was accompanied by reductions in the inflammatory parameters in the bronchoalveolar lavage fluid measured 24 h after challenge with ovalbumin. Compound 1 (10 mg kg(-1)) administered 24 h after challenge with ovalbumin did not change the rate of resolution of the signal detected by MRI in the lungs. In contrast, mometasone furoate (0.3 mg kg(-1)) significantly increased resolution of these signals, which was evident 3 h after drug administration and maintained to 48 h post challenge. Collectively, our data suggest that the p38 MAP kinase inhibitor Compound 1 shows a different profile than glucocorticosteroids since its ability to resolve existing inflammation is limited.
Subject(s)
Enzyme Inhibitors/therapeutic use , Magnetic Resonance Imaging/methods , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Pneumonia/drug therapy , Pneumonia/enzymology , Animals , Enzyme Inhibitors/pharmacology , Humans , Male , Mitogen-Activated Protein Kinases/metabolism , Rats , Rats, Inbred BNABSTRACT
2,6-Diamino-3,5-difluoropyridinyl substituted pyridinylimidazoles, -pyrroles, -oxazoles, -thiazoles and -triazoles have been identified as novel p38alpha inhibitors. Pyridinylimidazole 11 potently inhibited LPS-induced TNFalpha in mice, showed good efficacy in the established rat adjuvant (ED(50): 10 mg/kg po b.i.d.) and collagen induced arthritis (ED(50): 5 mg/kg po b.i.d.) with disease modifying properties based on histological analysis of the joints.