Virtual Screening Approaches to Identify Promising Multitarget-Directed Ligands for the Treatment of Autism Spectrum Disorder.

Autism spectrum disorder is a complex neurodevelopmental disorder. The available medical treatment options for autism spectrum disorder are very limited. While the etiology and pathophysiology of autism spectrum disorder are still not fully understood, recent studies have suggested that wide alterations in the GABAergic, glutamatergic, cholinergic, and serotonergic systems play a key role in its development and progression.

Aggregation of adult parasitic nematodes in sex-mixed groups analysed by transient anomalous diffusion formalism.

Intestinal parasitic worms are widespread throughout the world, causing chronic infections in humans and animals. However, very little is known about the locomotion of the worms in the host gut. We studied the movement of naturally infecting mice, and used as an animal model for roundworm infections.

Integration of MUTZ-Langerhans cells into a 3D full-thickness skin equivalent and influences of serum reduction and undefined medium supplements on differentiation.

The MUTZ-3 cell line is a surrogate for Langerhans cells (LCs) employed in New Approach Methodologies for assessing the skin sensitizing potential of chemicals. However, MUTZ-3 cells must first be differentiated to achieve the LC-typical phenotype. As all protocols use high fetal calf serum (FCS) concentrations, we aimed at reducing, or even replacing FCS, while maintaining MUTZ-LC characteristics.

Histamine H receptor antagonist/nitric oxide donors as novel promising therapeutic hybrid-tools for glaucoma and retinal neuroprotection.

Glaucoma is a degenerative optic neuropathy in which the degeneration of optic nerve and blindness occur. The main cause is a malfunction of ciliary processes (protrusions of the ciliary bodies) resulting in increased intraocular pressure (IOP). Ocular hypertension (OHT) causes ischemic events leading to retinal ganglion cell (RGC) depletion and blindness.

Bis(benzimidazol-2-yl)amine-Based DPP-4 Inhibitors Potentially Suitable for Combating Diabetes and Associated Nervous System Alterations.

Bis(benzimidazol-2-yl)amine scaffold is not present in dipeptidyl peptidase-4 (DPP-4) inhibitors published so far. Herein, the inhibitory potential of bis(benzimidazol-2-yl)amine derivatives against DPP-4 was evaluated. In non-competitive inhibition mode, three representatives 5, 6, and 7 inhibited DPP-4 in vitro with IC values below 50 μM.

The stimulation of TH2 cells results in increased IL-5 and IL-13 production via the H receptor.

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease resulting in decreased quality of life. Histamine and specifically the H receptor play a key role in the inflammatory process in AD and serve as targets for novel therapeutic approaches.

Objective: In the present study we aimed to elucidate the immunopathological mechanisms with which the H receptor impacts TH2 cells and contributes to AD pathophysiology.

Structural insights into the cross-exon to cross-intron spliceosome switch.

Early spliceosome assembly can occur through an intron-defined pathway, whereby U1 and U2 small nuclear ribonucleoprotein particles (snRNPs) assemble across the intron. Alternatively, it can occur through an exon-defined pathway, whereby U2 binds the branch site located upstream of the defined exon and U1 snRNP interacts with the 5' splice site located directly downstream of it. The U4/U6.

Aromatic linker variations in novel dopamine D and D receptor ligands.

Dopamine D-like receptors, especially D and D receptor subtypes, are important targets of antipsychotic agents. Many of these antipsychotics share an aliphatic linker element between a protonable amine group and an acyl-like moiety. Here, we have modified this aliphatic linker into phenylmethyl and phenylethyl linkers substituted in different positions.

Novel 4-nitroimidazole analogues: synthesis, biological evaluation, studies, and molecular dynamics simulation.

A new series of 4-nitroimidazole bearing aryl piperazines , tetrazole and 1,3,4-thiadiazole derivatives was synthesized. All derivatives were screened for their anticancer activity against eight diverse human cancer cell lines (Capan-1, HCT-116, LN229, NCI-H460, DND-41, HL-60, K562, and Z138). Compound proved the most potent compound of the series inhibiting proliferation of most of the selected human cancer cell lines with IC values in the low micromolar range.

Steering droplets on substrates with plane-wave wettability patterns and deformations.

Motivated by strategies for targeted microfluidic transport of droplets, we investigate how sessile droplets can be steered toward a preferred direction using travelling waves in substrate wettability or deformations of the substrate. To perform our numerical study, we implement the boundary-element method to solve the governing Stokes equations for the fluid flow field inside the moving droplet. In both cases we find two distinct modes of droplet motion.

4-Oxypiperidine Ethers as Multiple Targeting Ligands at Histamine H Receptors and Cholinesterases.

This study examines the properties of a novel series of 4-oxypiperidines designed and synthesized as histamine HR antagonists/inverse agonists based on the structural modification of two lead compounds, viz., and . The products are intended to maintain a high affinity for HR while simultaneously inhibiting AChE or/and BuChE enzymes.

Cryo-EM analyses of dimerized spliceosomes provide new insights into the functions of B complex proteins.

The B complex is a key intermediate stage of spliceosome assembly. To improve the structural resolution of monomeric, human spliceosomal B (hB) complexes and thereby generate a more comprehensive hB molecular model, we determined the cryo-EM structure of B complex dimers formed in the presence of ATP S. The enhanced resolution of these complexes allows a finer molecular dissection of how the 5' splice site (5'ss) is recognized in hB, and new insights into molecular interactions of FBP21, SNU23 and PRP38 with the U6/5'ss helix and with each other.

Discovery of a Small Molecule Activator of Slack (Kcnt1) Potassium Channels That Significantly Reduces Scratching in Mouse Models of Histamine-Independent and Chronic Itch.

Various disorders are accompanied by histamine-independent itching, which is often resistant to the currently available therapies. Here, it is reported that the pharmacological activation of Slack (Kcnt1, K1.1), a potassium channel highly expressed in itch-sensitive sensory neurons, has therapeutic potential for the treatment of itching.

Controlling active turbulence by activity patterns.

By patterning activity in space, one can control active turbulence. To show this, we use Doi's hydrodynamic equations of a semidilute solution of active rods. A linear stability analysis reveals the resting isotropic fluid to be unstable above an absolute pusher activity.

Reconstruction of a fatty acid synthesis cycle from acyl carrier protein and cofactor structural snapshots.

Fatty acids (FAs) play a central metabolic role in living cells as constituents of membranes, cellular energy reserves, and second messenger precursors. A 2.6 MDa FA synthase (FAS), where the enzymatic reactions and structures are known, is responsible for FA biosynthesis in yeast.

Dual Piperidine-Based Histamine H and Sigma-1 Receptor Ligands in the Treatment of Nociceptive and Neuropathic Pain.

In search of new dual-acting histamine H/sigma-1 receptor ligands, we designed a series of compounds structurally based on highly active ligands previously studied and described by our team. However, we kept in mind that within the previous series, a pair of closely related compounds, and , differing only in the piperazine/piperidine moiety in the structural core showed a significantly different affinity at sigma-1 receptors (σRs). Therefore, we first focused on an in-depth analysis of the protonation states of piperazine and piperidine derivatives in the studied compounds.

Ceramides and ceramide synthases in cancer: Focus on apoptosis and autophagy.

Different studies corroborate a role for ceramide synthases and their downstream products, ceramides, in modulation of apoptosis and autophagy in the context of cancer. These mechanisms of regulation, however, appear to be context dependent in terms of ceramides' fatty acid chain length, subcellular localization, and the presence or absence of their downstream targets. Our current understanding of the role of ceramide synthases and ceramides in regulation of apoptosis and autophagy could be harnessed to pioneer the development of new treatments to activate or inhibit a single type of ceramide synthase, thereby regulating the apoptosis induction or cross talk of apoptosis and autophagy in cancer cells.

Optimal navigation of a smart active particle: directional and distance sensing.

We employ Q learning, a variant of reinforcement learning, so that an active particle learns by itself to navigate on the fastest path toward a target while experiencing external forces and flow fields. As state variables, we use the distance and direction toward the target, and as action variables the active particle can choose a new orientation along which it moves with constant velocity. We explicitly investigate optimal navigation in a potential barrier/well and a uniform/ Poiseuille/swirling flow field.

Guanidines: Synthesis of Novel Histamine HR Antagonists with Additional Breast Anticancer Activity and Cholinesterases Inhibitory Effect.

This study examines the properties of novel guanidines, designed and synthesized as histamine HR antagonists/inverse agonists with additional pharmacological targets. We evaluated their potential against two targets viz., inhibition of MDA-MB-231, and MCF-7 breast cancer cells viability and inhibition of AChE/BuChE.

Trisubstituted 1,3,5-Triazines as Histamine H Receptor Antagonists with Promising Activity In Vivo.

Pain is a very unpleasant experience that makes life extremely uncomfortable. The histamine H receptor (HR) is a promising target for the treatment of inflammatory and immune diseases, as well as pain. HR ligands have demonstrated analgesic effects in a variety of pain models, including inflammatory pain.

Thiazole derivatives as dual inhibitors of deoxyribonuclease I and 5-lipoxygenase: A promising scaffold for the development of neuroprotective drugs.

A library of 43 thiazole derivatives, including 31 previously and 12 newly synthesized in the present study, was evaluated in vitro for their inhibitory properties against bovine pancreatic DNase I. Nine compounds (including three newly synthesized) inhibited the enzyme showing improved inhibitory properties compared to that of the reference crystal violet (IC = 346.39 μM).