There are differences in the pharmacological properties of phenylhistamines and histaprodifens between guinea pig histamine H 1 receptor (gpH 1 R) and human histamine H 1 receptor (hH 1 R). The aim of this study was to analyze species differences in more detail, focusing on histaprodifen derivatives and including the bovine histamine H 1 receptor (bH 1 R) and rat histamine H 1 receptor (rH 1 R). H 1 R species isoforms were coexpressed with the regulator of G protein signaling RGS4 in Sf9 insect cells. We performed [3 H]mepyramine binding assays and steady-state GTPase assays. For a novel class of histaprodifens, the chiral histaprodifens, unique species differences between hH 1 R, bH 1 R, rH 1 R, and gpH 1 R were observed. The chiral histaprodifens 8R and 8S were both partial agonists at gpH 1 R, but only 8R was a partial agonist at the other H 1 R species isoforms. An additional phenyl group in chiral histaprodifens 10R and 10S, respectively, resulted in a switch from agonism at gpH 1 R to antagonism at hH 1 R, bH 1 R, and rH 1 R. In general, histaprodifens showed the order of potency hH 1 R Ͻ bH 1 R Ͻ rH 1 R Ͻ gpH 1 R. An active-state model of gpH 1 R was generated with molecular dynamics simulations. Dimeric histaprodifen was docked into the binding pocket of gpH 1 R. Hydrogen bonds and electrostatic interactions were detected between dimeric histaprodifen and . We conclude the following: 1) chiral histaprodifens interact differentially with H 1 R species isoforms; 2) gpH 1 R and rH 1 R, on one hand, and hH 1 R and bH 1 R, on the other hand, resemble each other structurally and pharmacologically; and 3) histaprodifens interact with H 1 R at multiple sites.

Epigenetic modifiers of the histone deacetylase (HDAC) family contribute to autoimmunity, cancer, HIV infection, inflammation, and neurodegeneration. Hence, histone deacetylase inhibitors (HDACi), which alter protein acetylation, gene expression patterns, and cell fate decisions, represent promising new drugs for the therapy of these diseases. Whereas pan-HDACi inhibit all 11 Zn-dependent histone deacetylases (HDACs) and cause a broad spectrum of side effects, specific inhibitors of histone deacetylase 6 (HDAC6i) are supposed to have less side effects. We present the synthesis and biological evaluation of Marbostats, novel HDAC6i that contain the hydroxamic acid moiety linked to tetrahydro-β-carboline derivatives. Our lead compound Marbostat-100 is a more potent and more selective HDAC6i than previously established well-characterized compounds in vitro as well as in cells. Moreover, Marbostat-100 is well tolerated by mice and effective against collagen type II induced arthritis. Thus, Marbostat-100 represents a most selective known HDAC6i and the possibility for clinical evaluation of a HDAC isoform-specific drug.

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Aim of the study was to develop a standardized model system to investigate endodontic irrigation techniques and assess the efficiency of different activation methods on the removal of hard tissue debris in complex root canal systems. Mesial roots of mandibular molars were firstly scanned by micro-computed tomography (µCT) and allocated to three groups of irrigant activation: sonic activation (EDDY, VDW, Munich, Germany), laser activation (AutoSWEEPS, FOTONA, Ljubljana, Slovenia) and conventional needle irrigation (control). Roots were fixed in individual 3D-printed holders to facilitate root canal enlargement under constant irrigation with NaOCl (5%). To enable standardized quantification of remaining debris, BaSO4-enriched dentine powder was compacted into the canals, followed by another µCT-scan. The final irrigation was performed using 17% ethylenediaminetetraacetic acid (EDTA) and 5% sodium hypochlorite (NaOCl) with the respective activation method, and the volume of remaining artificial debris was quantified after a final µCT-scan. The newly developed model system allowed for reliable, reproducible and standardized assessment of irrigation methods. Activation of the irrigant proved to be significantly more effective than conventional needle irrigation regarding the removal of debris, which persisted particularly in the apical third of the root canal in the control group. The efficiency of irrigation was significantly enhanced with laser- and sonic-based activation, especially in the apical third.

The purpose of this study was to evaluate the quality of surface contouring of chondromalacic cartilage by bipolar radio frequency energy using different treatment patterns in an animal model, as well as examining the impact of the treatment onto chondrocyte viability by two different methods. Our experiments were conducted on 36 fresh osteochondral sections from the tibia plateau of slaughtered 6-month-old pigs, where the thickness of the cartilage is similar to that of human wrist cartilage. An area of 1 cm2 was first treated with emery paper to simulate the chondromalacic cartilage. Then, the treatment with RFE followed in 6 different patterns. The osteochondral sections were assessed for cellular viability (live/dead assay, caspase (cell apoptosis marker) staining, and quantitative analysed images obtained by fluorescent microscopy). For a quantitative characterization of none or treated cartilage surfaces, various roughness parameters were measured using confocal laser scanning microscopy (Olympus LEXT OLS 4000 3D). To describe the roughness, the Root-Mean-Square parameter (Sq) was calculated. A smoothing effect of the cartilage surface was detectable upon each pattern of RFE treatment. The Sq for native cartilage was Sq=3.8±1.1 μm. The best smoothing pattern was seen for two RFE passes and a 2-second pulsed mode (B2p2) with an Sq=27.3±4.9 μm. However, with increased smoothing, an augmentation in chondrocyte death up to 95% was detected. Using bipolar RFE treatment in arthroscopy for small joints like the wrist or MCP joints should be used with caution. In the case of chondroplasty, there is a high chance to destroy the joint cartilage.