Impact of Linker Composition on VHL PROTAC Cell Permeability.

The discovery of cell permeable and orally bioavailable von Hippel-Lindau (VHL) proteolysis targeting chimeras (PROTACs) is challenging as their structures locates them at, or beyond, the outer limits of oral druggable space. We have designed a set of nine VHL PROTACs and found that the linker had a profound impact on passive cell permeability. Determination of the solution ensembles in a nonpolar solvent revealed that high permeability was correlated to the ability of the PROTACs to adopt folded conformations that have a low solvent accessible 3D polar surface area.

Bioactive abietenolide diterpenes from Suregada procera.

The phytochemical investigation of the leaves and the roots of Suregada procera afforded the new ent-abietane diterpenoid sureproceriolide A (1) along with the known secondary metabolites 8,14β:11,12α-diepoxy-13(15)-abietane-16,12-olid (2), jolkinolide A (3), jolkinolide E (4), ent-pimara-8(14),15-dien-19-oic acid (5), sitosterol (6), oleana-9(11):12-dien-3β-ol (7), and oleic acid (8). Their structures were elucidated by NMR spectroscopic and mass spectrometric analyses, and the structure of jolkinolide A (3) was confirmed by single-crystal X-ray diffraction analysis. Sureproceriolide A (1) showed modest activity against the Gram-positive bacterium Staphylococcus lugdunensis (MIC = 31.

Antimicrobial Dihydroflavonols and Isoflavans Isolated from the Root Bark of .

Three new dihydroflavonols, gloverinols A-C (-), a new flavon-3-ol, gloverinol D (), two new isoflavans, gloveriflavan A () and B (), and seven known compounds were isolated from the root bark of . The structures of the isolates were elucidated by using NMR, ECD, and HRESIMS data analyses. Among the isolated compounds, gloverinol B (), gloveriflavan B (), and 1-(2,4-dihydroxyphenyl)-3-hydroxy-3-(4-hydroxyphenyl)-1-propanone () were the most active against , with MIC values of 9.

Mild Hyperthermia-Induced Thermogenesis in the Endoplasmic Reticulum Defines Stress Response Mechanisms.

Previous studies reported that a mild, non-protein-denaturing, fever-like temperature increase induced the unfolded protein response (UPR) in mammalian cells. Our dSTORM super-resolution microscopy experiments revealed that the master regulator of the UPR, the IRE1 (inositol-requiring enzyme 1) protein, is clustered as a result of UPR activation in a human osteosarcoma cell line (U2OS) upon mild heat stress. Using ER thermo yellow, a temperature-sensitive fluorescent probe targeted to the endoplasmic reticulum (ER), we detected significant intracellular thermogenesis in mouse embryonic fibroblast (MEF) cells.

The Influence of Disulfide, Thioacetal and Lanthionine-Bridges on the Conformation of a Macrocyclic Peptide.

Cyclisation of peptides by forming thioether (lanthionine), disulfide (cystine) or methylene thioacetal bridges between side chains is established as an important tool to stabilise a given structure, enhance metabolic stability and optimise both potency and selectivity. However, a systematic comparative study of the effects of differing bridging modalities on peptide conformation has not previously been carried out. In this paper, we have used the NMR deconvolution algorithm, NAMFIS, to determine the conformational ensembles, in aqueous solution, of three cyclic analogues of angiotensin(1-7), incorporating either disulfide, or non-reducible thioether or methylene thioacetal bridges.

Triggered cagedSTORM microscopy.

In standard SMLM methods, the photoswitching of single fluorescent molecules and the data acquisition processes are independent, which leads to the detection of single molecule blinking events on several consecutive frames. This mismatch results in several data points with reduced localization precision, and it also increases the possibilities of overlapping. Here we discuss how the synchronization of the fluorophores' ON state to the camera exposure time increases the average intensity of the captured point spread functions and hence improves the localization precision.

Taming Molecular Folding: Anion-Templated Foldamers with Tunable Quaternary Structures.

Higher-order foldamers represent a unique class of supramolecules at the forefront of molecular design. Herein we control quaternary folding using a novel approach that combines halogen bonding (XBing) and hydrogen bonding (HBing). We present the first anion-templated double helices induced by halogen bonds (XBs) and stabilized by "hydrogen bond enhanced halogen bonds" (HBeXBs).

Elucidating the Binding Mode of Sulfur- and Selenium-Based Cationic Chalcogen-Bond Donors.

For a comparison of the interaction modes of various chalcogen-bond donors, 2-chalcogeno-imidazolium salts have been designed, synthesized, and studied by single crystal X-ray diffraction, solution NMR and DFT as well as for their ability to act as activators in an S1-type substitution reaction. Their interaction modes in solution were elucidated based on NMR diffusion and chemical shift perturbation experiments, which were supported by DFT-calculations. Our finding is that going from lighter to the heavier chalcogens, hydrogen bonding plays a less, while chalcogen bonding an increasingly important role for the coordination of anions.

Antiviral Rotenoids and Isoflavones Isolated from ssp. .

Three new (-) and six known rotenoids (-), along with three known isoflavones (-), were isolated from the leaves of ssp. . A new glycosylated isoflavone (), four known isoflavones (-), and one known chalcone () were isolated from the root wood extract of the same plant.

Curcumin mitigates ochratoxin A-induced oxidative stress and alters gene expression in broiler chicken liver and kidney.

The study aimed to evaluate the effect of curcumin (CURC) supplementation on broiler chickens exposed to ochratoxin A (OTA), by examining biochemical parameters and the expression of glutathione redox system genes and their regulation. OTA reduced glutathione content in the liver while increasing glutathione peroxidase activity. CURC showed no significant effects.

The Effects of T-2 Toxin, Deoxynivalenol, and Fumonisin B1 on Oxidative Stress-Related Genes in the Kidneys of Laying Hens.

In the context of nephrotoxic risks associated with environmental contaminants, this study focused on the impact of mycotoxin exposure on the renal health of laying hens, with particular attention to oxidative stress pathways. Sixty laying hens were assigned to three groups-a control group (CON), a low-dose mycotoxin group (LOW), and a high-dose mycotoxin group (HIGH)-and monitored for 72 h. Mycotoxin contamination involved T-2/HT-2 toxin, DON/3-AcDON/15-AcDON, and FB1 at their EU-recommended levels (low mix) and at double doses (high mix).

Direct interaction of Su(var)2-10 via the SIM-binding site of the Piwi protein is required for transposon silencing in Drosophila melanogaster.

Nuclear Piwi/Piwi-interacting RNA complexes mediate co-transcriptional silencing of transposable elements by inducing local heterochromatin formation. In Drosophila, sumoylation plays an essential role in the assembly of the silencing complex; however, the molecular mechanism by which the sumoylation machinery is recruited to the transposon loci is poorly understood. Here, we show that the Drosophila E3 SUMO-ligase Su(var)2-10 directly binds to the Piwi protein.

Fluorinated captopril analogues inhibit metallo-β-lactamases and facilitate structure determination of NDM-1 binding pose.

Bacterial resistance to the majority of clinically used β-lactam antibiotics is a global health threat and, consequently, the driving force for the development of metallo-β-lactamase (MBL) inhibitors. The rapid evolution of new MBLs calls for new strategies and tools for inhibitor development. In this study, we designed and developed a series of trifluoromethylated captopril analogues as probes for structural studies of enzyme-inhibitor binding.

Is Simultaneous Binding to DNA and Gyrase Important for the Antibacterial Activity of Cystobactamids?

Cystobactamids are aromatic oligoamides that exert their natural antibacterial properties by inhibition of bacterial gyrases. Such aromatic oligoamides were proposed to inhibit α-helix-mediated protein-protein interactions and may serve for specific recognition of DNA. Based on this suggestion, we designed new derivatives that have duplicated cystobactamid triarene units as model systems to decipher the specific binding mode of cystobactamids to double stranded DNA.

Peripheral thickening of the sarcomeres and pointed end elongation of the thin filaments are both promoted by SALS and its formin interaction partners.

During striated muscle development the first periodically repeated units appear in the premyofibrils, consisting of immature sarcomeres that must undergo a substantial growth both in length and width, to reach their final size. Here we report that, beyond its well established role in sarcomere elongation, the Sarcomere length short (SALS) protein is involved in Z-disc formation and peripheral growth of the sarcomeres. Our protein localization data and loss-of-function studies in the Drosophila indirect flight muscle strongly suggest that radial growth of the sarcomeres is initiated at the Z-disc.

Reduction of intracellular oxidative stress with a copper-incorporated layered double hydroxide.

Biocompatible Cu(II)-doped layered double hydroxide (CMA) nanoparticles were developed to combat reactive oxygen species. The 2-dimensional nanozymes showed both superoxide dismutase- and catalase-like activities in chemical assays, while proving as efficient antioxidants in the reduction of intracellular oxidative stress. The results indicate the great promise of CMA in antioxidant therapies.

Molecular chameleons in drug discovery.

Molecular chameleons possess a flexibility that allows them to dynamically shield or expose polar functionalities in response to the properties of the environment. Although the concept of molecular chameleons was introduced already in 1970, interest in them has grown considerably since the 2010s, when drug discovery has focused to an increased extent on new chemical modalities. Such modalities include cyclic peptides, macrocycles and proteolysis-targeting chimeras, all of which reside in a chemical space far from that of traditional small-molecule drugs.

Halogen Bonds of Halogen(I) Ions─Where Are We and Where to Go?

Halenium ions, X, are particularly strong halogen-bond donors that interact with two Lewis bases simultaneously to form linear [D···X···D]-type halonium complexes. Their three-center, four-electron halogen bond is both fundamentally interesting and technologically valuable as it tames the reactivity of halogen(I) ions, opening up new horizons in a variety of fields including synthetic organic and supramolecular chemistry. Understanding this bonding situation enables the development of improved halogen(I) transfer reactions and of advanced functional materials.

Multi-Fusarium mycotoxin exposure activates Nrf2 and Ahr pathway in the liver of laying hens.

This study investigates gene expression changes in laying hens exposed to trichothecene mycotoxins, known to induce oxidative stress and affect xenobiotic transformation and antioxidants. A 3-day feeding trial tested low and high doses of T-2/HT-2 toxin, DON/3-AcDON/15-AcDON, and FB1 in hen feed. Results showed increased expression of AHR, AHRR, HSP90, and CYP1A2 genes on days 2 and 3, suggesting a response to mycotoxin exposure.

α-Aminophosphonate inhibitors of metallo-β-lactamases NDM-1 and VIM-2.

The upswing of antibiotic resistance is an escalating threat to human health. Resistance mediated by bacterial metallo-β-lactamases is of particular concern as these enzymes degrade β-lactams, our most frequently prescribed class of antibiotics. Inhibition of metallo-β-lactamases could allow the continued use of existing β-lactam antibiotics, such as penicillins, cephalosporins and carbapenems, whose applicability is becoming ever more limited.

Do non-coordinating polymers function as host materials for solid polymer electrolytes? The case of PVdF-HFP.

In the search for novel solid polymer electrolytes (SPEs), primarily targeting battery applications, a range of different polymers is currently being explored. In this context, the non-coordinating poly(vinylidene fluoride--hexafluoropropylene) (PVdF-HFP) polymer is a frequently utilized system. Considering that PVdF-HFP should be a poor solvent for cation salts, it is counterintuitive that this is a functional host material for SPEs.

Phase-separated ribosome-nascent chain complexes in genotoxic stress response.

Assemblysomes are EDTA- and RNase-resistant ribonucleoprotein (RNP) complexes of paused ribosomes with protruding nascent polypeptide chains. They have been described in yeast and human cells for the proteasome subunit Rpt1, and the disordered amino-terminal part of the nascent chain was found to be indispensable for the accumulation of the Rpt1-RNP into assemblysomes. Motivated by this, to find other assemblysome-associated RNPs we used bioinformatics to rank subunits of protein complexes according to their amino-terminal disorder propensity.

Effects of Short- and Medium-Chain Fatty Acids on Production, Meat Quality, and Microbial Attributes-A Review.

The non-therapeutic use of antimicrobials in poultry production contributes to the spread of drug-resistant pathogens in both birds and humans. Antibiotics are known to enhance feed efficiency and promote the growth and weight gain of poultry. New regulatory requirements and consumer preferences have led to a reduced use of antibiotics in poultry production and to the discovery of natural alternatives to antibiotic growth promoters.