Small RNAs Possess Dephospho-CoA 5'-Caps, but No CoAlation Marks.

Novel features of coenzyme A (CoA) and its precursor, 3'-dephospho-CoA (dpCoA), recently became evident. dpCoA was found to attach to 5'-ends of small ribonucleic acids (dpCoA-RNAs) in two bacterial species ( and ). Furthermore, CoA serves, in addition to its well-established coenzymatic roles, as a ubiquitous posttranslational protein modification ('CoAlation'), thought to prevent the irreversible oxidation of cysteines.

Discovery of potent benzoxaborole inhibitors against SARS-CoV-2 main and dengue virus proteases.

The RNA viruses SARS-CoV-2 and dengue pose a major threat to human health worldwide and their proteases (M; NS2B/NS3) are considered as promising targets for drug development. We present the synthesis and biological evaluation of novel benzoxaborole inhibitors of these two proteases. The most active compound achieves single-digit micromolar activity against SARS-CoV-2 M in a biochemical assay.

Corona versus Dengue: Distinct Mechanisms for Inhibition of Polyprotein Processing by Antiviral Drugs.

Inhibitors interfering with processing of the viral polyprotein are used successfully for the control of extremely important viral pathogens, such as HIV and most recently SARS-CoV-2. This Viewpoint provides a mechanistic evaluation of a promising antiviral lead compound against dengue virus, JNJ-A07, 4-(3-((1-(4-chlorophenyl)-2-oxo-2-(6-(trifluoromethoxy)indolin-1-yl)ethyl)amino)-5-methoxyphenoxy)butanoic acid. The antiviral effect of JNJ-A07 appears, in our opinion, to be connected to an interference with the function of the viral protease.

Antibody-drug conjugates: What drives their progress?

Antibody-drug conjugates (ADCs) are on the brink of widespread use for the targeted treatment of cancer. ADCs manage the toxicity of drugs with unacceptable narrow therapeutic windows by guiding highly toxic compounds to the target cells, thereby sparing healthy cells. In this review, we describe approved ADCs and discuss their modes of action, together with medicinal chemical aspects, to evaluate the potential for improvement and to combat tumor-acquired resistance.

Curcuminoids for Metabolic Syndrome: Meta-Analysis Evidences Toward Personalized Prevention and Treatment Management.

The metabolic syndrome (MS) is a multifactorial syndrome associated with a significant economic burden and healthcare costs. MS management often requires multiple treatments (polydrug) to ameliorate conditions such as diabetes mellitus, insulin resistance, obesity, cardiovascular diseases, hypertension, and non-alcoholic fatty liver disease (NAFLD). However, various therapeutics and possible drug-drug interactions may also increase the risk of MS by altering lipid and glucose metabolism and promoting weight gain.

Late-Stage Functionalisation of Peptides on the Solid Phase by an Iodination-Substitution Approach.

The functionalisation of peptides at a late synthesis stage holds great potential, for example, for the synthesis of peptide pharmaceuticals, fluorescent biosensors or peptidomimetics. Here we describe an on-resin iodination-substitution reaction sequence on homoserine that is also suitable for peptide modification in a combinatorial format. The reaction sequence is accessible to a wide range of sulfur nucleophiles with various functional groups including boronic acids, hydroxy groups or aromatic amines.

APPsα Rescues Tau-Induced Synaptic Pathology.

Alzheimer's disease (AD) is histopathologically characterized by Aβ plaques and the accumulation of hyperphosphorylated Tau species, the latter also constituting key hallmarks of primary tauopathies. Whereas Aβ is produced by amyloidogenic APP processing, APP processing along the competing nonamyloidogenic pathway results in the secretion of neurotrophic and synaptotrophic APPsα. Recently, we demonstrated that APPsα has therapeutic effects in transgenic AD model mice and rescues Aβ-dependent impairments.

Metabolomic, Lipidomic and Proteomic Characterisation of Lipopolysaccharide-induced Inflammation Mouse Model.

Neuroinflammation is an important feature in the pathogenesis and progression of central nervous system (CNS) diseases including Alzheimer's disease (AD). One of the widely used animal models of peripherally induced neuroinflammation and neurodegeneration is a lipopolysaccharide (LPS)-induced inflammation mouse model. An acute LPS administration has been widely used for investigation of inflammation-associated disease and testing inflammation-targeting drug candidates.

Focal structural variants revealed by whole genome sequencing disrupt the histone demethylase KDM4C in B-cell lymphomas.

Histone methylation-modifiers, such as EZH2 and KMT2D, are recurrently altered in B-cell lymphomas. To comprehensively describe the landscape of alterations affecting genes encoding histone methylation-modifiers in lymphomagenesis we investigated whole genome and transcriptome data of 186 mature B-cell lymphomas sequenced in the ICGC MMML-Seq project. Besides confirming common alterations of KMT2D (47% of cases), EZH2 (17%), SETD1B (5%), PRDM9 (4%), KMT2C (4%), and SETD2 (4%), also identified by prior exome or RNA-sequencing studies, we here found recurrent alterations to KDM4C in chromosome 9p24, encoding a histone demethylase.

MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis.

Aberrant expression of MYC transcription factor family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYCN induces massive lipid peroxidation on depletion of cysteine, the rate-limiting amino acid for glutathione (GSH) biosynthesis, and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death.

Altered protein expression of membrane transporters in isolated cerebral microvessels and brain cortex of a rat Alzheimer's disease model.

There is growing evidence that membrane transporters expressed at the blood-brain barrier (BBB) and brain parenchymal cells play an important role in Alzheimer's disease (AD) development and progression. However, quantitative information about changes in transporter protein expression at neurovascular unit cells in AD is limited. Here, we studied the changes in the absolute protein expression of five ATP-binding cassette (ABC) and thirteen solute carrier (SLC) transporters in the isolated brain microvessels and brain cortical tissue of TgF344-AD rats compared to age-matched wild-type (WT) animals using liquid chromatography tandem mass spectrometry based quantitative targeted absolute proteomic analysis.

Computational Prediction of Phosphoinositide Binding to Hyperpolarization-Activated Cyclic-Nucleotide Gated Channels.

Protein-lipid interactions are key regulators of ion channel function. Numerous ion channels, including hyperpolarization-activated cyclic-nucleotide gated (HCN) channels have been shown to be regulated by phosphoinositides (PIPs), with important implications in cardiac and neuronal function. Specifically, PIPs have been shown to enhance HCN activation.

Phytochemical Profiling of the Leaf Extract of var. and Its Antioxidant, Antibacterial, and Antiaging Activities and in : A Cosmeceutical and Dermatological Approach.

We previously annotated the phytochemical constituents of a root extract from var. and highlighted its hepatoprotective and hypoglycemic properties. We here extended our study on the leaf extract and identified its phytoconstituents using HPLC-PDA-ESI-MS/MS.

Targeting Transporters for Drug Delivery to the Brain: Can We Do Better?

Limited drug delivery to the brain is one of the major reasons for high failure rates of central nervous system (CNS) drug candidates. The blood-brain barrier (BBB) with its tight junctions, membrane transporters, receptors and metabolizing enzymes is a main player in drug delivery to the brain, restricting the entrance of the drugs and other xenobiotics. Current knowledge about the uptake transporters expressed at the BBB and brain parenchymal cells has been used for delivery of CNS drugs to the brain via targeting transporters.

Current Understanding of Modes of Action of Multicomponent Bioactive Phytochemicals: Potential for Nutraceuticals and Antimicrobials.

Plants produce a diversity of plant secondary metabolites (PSMs), which function as defense chemicals against herbivores and microorganisms but also as signal compounds. An individual plant produces and accumulates mixtures of PSMs with different structural features using different biosynthetic pathways. Almost all PSMs exert one or several biological activities that can be useful for nutrition and health.

Real-time monitoring of immediate drug response and adaptation upon repeated treatment in a microfluidic chip system.

Microfluidic tissue culture and organ-on-a-chip models provide efficient tools for drug testing in vivo and are considered to become the basis of in vitro test systems to analyze drug response, drug interactions and toxicity to complement and reduce animal testing. A major limitation is the efficient recording of drug action. Here we present an efficient experimental setup that allows long-term cultivation of cells in a microfluidic system in combination with continuous recording of luciferase reporter gene expression.

Antioxidant and anti-aging effects of Warburgia salutaris bark aqueous extract: Evidences from in silico, in vitro and in vivo studies.

Ethnopharmacological Relevance: The genus Warburgia (family Canellaceae) is widely distributed over Afrotropical and Neotropical realms. Traditionally, W. salutaris (G.

Synthesis and Characterization of Biodegradable Poly(butyl cyanoacrylate) for Drug Delivery Applications.

Poly(butyl cyanoacrylate) (PBCA) is a biodegradable and biocompatible homopolymer which is used as a carrier matrix for drug delivery systems in the pharmaceutical industry. Typically, polymerization is carried out under aqueous conditions and results in molecular weights are mostly lower than 3000 g/mol due to the instability of the high molecular weight PBCA. However, the stability of polymer excipients is a major prerequisite for drug product development in the pharmaceutical industry.

Postweaning positive modulation of α5GABAA receptors improves autism-like features in prenatal valproate rat model in a sex-specific manner.

Autism spectrum disorder (ASD), as a common neurodevelopmental disorder that encompasses impairments in social communication and interaction, as well as repetitive and restrictive behavior, still awaits an effective treatment strategy. The involvement of GABAergic neurotransmission, and especially a deficit of GABA receptors that contain the α5 subunits, were implicated in pathogenesis of ASD. Therefore, we tested MP-III-022, a positive allosteric modulator (PAM) selective for α5GABAA receptors, in Wistar rats prenatally exposed to valproic acid, as an animal model useful for studying ASD.

Ellagic Acid: A Review on Its Natural Sources, Chemical Stability, and Therapeutic Potential.

Ellagic acid (EA) is a bioactive polyphenolic compound naturally occurring as secondary metabolite in many plant taxa. EA content is considerable in pomegranate ( L.) and in wood and bark of some tree species.

Impact of Linker Modification and PEGylation of Vancomycin Conjugates on Structure-Activity Relationships and Pharmacokinetics.

As multidrug-resistant bacteria represent a concerning burden, experts insist on the need for a dramatic rethinking on antibiotic use and development in order to avoid a post-antibiotic era. New and rapidly developable strategies for antimicrobial substances, in particular substances highly potent against multidrug-resistant bacteria, are urgently required. Some of the treatment options currently available for multidrug-resistant bacteria are considerably limited by side effects and unfavorable pharmacokinetics.

Metabolomics-Based Profiling of (Lamiaceae) Leaves Using LC/ESI/MS-MS and In Vivo Evaluation of Its Antioxidant Activity Using Model.

We investigated the antioxidant activity of the total methanol extract of leaves (CST), the ethyl acetate (CSE), and the remaining aqueous (CSR) fractions in vitro, in vivo using model, and in silico. LC-ESI-MS/MS analysis was employed for metabolic profiling of CST. ADME/TOPAKT prediction was performed to determine the potential pharmacokinetic, pharmacodynamic, and toxicity properties of the major identified phytoconstituents.

Spatially modulated illumination microscopy: application perspectives in nuclear nanostructure analysis.

Thousands of genes and the complex biochemical networks for their transcription are packed in the micrometer sized cell nucleus. To control biochemical processes, spatial organization plays a key role. Hence the structure of the cell nucleus of higher organisms has emerged as a main topic of advanced light microscopy.

Structured illumination ophthalmoscope: super-resolution microscopy on the living human eye.

In this paper, we present the prototype of an ophthalmoscope that uses structured illumination microscopy (SIM) to enable super-resolved imaging of the human retina, and give first insights into clinical application possibilities. The SIM technique was applied to build a prototype that uses the lens of the human eye as an objective to 'super-resolve' the retina of a living human. In our multidisciplinary collaboration, we have adapted this well-established technique in ophthalmology and successfully imaged a human retina using significantly lower light intensity than a state-of-the-art ophthalmoscope.

Transcriptome signature changes in the liver of a migratory passerine.

The liver plays a principal role in avian migration. Here, we characterised the liver transcriptome of a long-distance migrant, the Northern Wheatear (Oenanthe oenanthe), sampled at different migratory stages, looking for molecular processes linked with adaptations to migration. The analysis of the differentially expressed genes suggested changes in the periods of the circadian rhythm, variation in the proportion of cells in G1/S cell-cycle stages and the putative polyploidization of this cell population.