Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Thinking outside the box: non-canonical targets in multiple sclerosis.

ABSTRACT: Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system that causes demyelination, axonal degeneration and astrogliosis, resulting in progressive neurological disability. Fuelled by an evolving understanding of MS immunopathogenesis, the range of available immunotherapies for clinical use has expanded over the past two decades. However, MS remains an incurable disease and even targeted immunotherapies often fail to control insidious disease progression, indicating the need for new and exceptional therapeutic options beyond the established immunological landscape. In this Review, we highlight such non-canonical targets in preclinical MS research with a focus on five highly promising areas: oligodendrocytes; the blood-brain barrier; metabolites and cellular metabolism; the coagulation system; and tolerance induction. Recent findings in these areas may guide the field towards novel targets for future therapeutic approaches in MS.

SUBMITTER: Bierhansl L

PROVIDER: S-EPMC9169033 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Thinking outside the box: non-canonical targets in multiple sclerosis.

Bierhansl Laura L Hartung Hans-Peter HP Aktas Orhan O Ruck Tobias T Roden Michael M Meuth Sven G SG

Nature reviews. Drug discovery 20220606 8

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system that causes demyelination, axonal degeneration and astrogliosis, resulting in progressive neurological disability. Fuelled by an evolving understanding of MS immunopathogenesis, the range of available immunotherapies for clinical use has expanded over the past two decades. However, MS remains an incurable disease and even targeted immunotherapies often fail to control insidious disease progression, indicating the ...[more]

PMID: 35668103

Similar Datasets

Thinking outside the Ischemia Box: Advancements in the Use of Multiple Sclerosis Drugs in Ischemic Stroke.

Project description:Ischemic stroke (IS) is a major cause of death and disability, despite early intervention. Thrombo-inflammation, the inflammatory process triggered by ischemia, is a concept that ties IS with multiple sclerosis (MS), under the wider 'umbrella' of neuroinflammation, i.e., the inflammation of the nervous tissue. Drawing from this, numerous studies have explored the potential of MS disease-modifying drugs in the setting of IS. In this review, we present the available studies and discuss their potential in ameliorating IS outcomes. Based on our search, the vast majority of the studies have been conducted on animals, yielding mostly positive results. Two clinical trials involving natalizumab showed that it does not confer any benefits, but four human studies regarding fingolimod have showcased its potential in improving recovery prospects. However, concerns on safety and other issues are raised, and basic questions still need to be answered.

| S-EPMC7914575 | biostudies-literature

The PCNA interaction motifs revisited: thinking outside the PIP-box.

Project description:Proliferating cell nuclear antigen (PCNA) is a cellular hub in DNA metabolism and a potential drug target. Its binding partners carry a short linear motif (SLiM) known as the PCNA-interacting protein-box (PIP-box), but sequence-divergent motifs have been reported to bind to the same binding pocket. To investigate how PCNA accommodates motif diversity, we assembled a set of 77 experimentally confirmed PCNA-binding proteins and analyzed features underlying their binding affinity. Combining NMR spectroscopy, affinity measurements and computational analyses, we corroborate that most PCNA-binding motifs reside in intrinsically disordered regions, that structure preformation is unrelated to affinity, and that the sequence-patterns that encode binding affinity extend substantially beyond the boundaries of the PIP-box. Our systematic multidisciplinary approach expands current views on PCNA interactions and reveals that the PIP-box affinity can be modulated over four orders of magnitude by positive charges in the flanking regions. Including the flanking regions as part of the motif is expected to have broad implications, particularly for interpretation of disease-causing mutations and drug-design, targeting DNA-replication and -repair.

| S-EPMC6881253 | biostudies-literature

Thinking outside the CaaX-box: an unusual reversible prenylation on ALDH9A1

Project description:Protein lipidation is a post-translational modification that confers hydrophobicity on protein substrates to control their cellular localization, mediate protein trafficking, and regulate protein function. In particular, protein prenylation is a C-terminal modification on proteins bearing canonical motifs catalyzed by prenyltransferases. Prenylated proteins have been of interest due to their numerous associations with various diseases. Chemical proteomic approaches have been pursued over the last decade to define prenylated proteomes (prenylome) and probe their responses to perturbations in various cellular systems. Here, we describe the discovery of prenylation of a non-canonical prenylated protein, ALDH9A1, which lacks any apparent prenylation motif. This enzyme was initially identified through chemical proteomic profiling of prenylomes in various cell lines. Metabolic labeling with an isoprenoid probe using overexpressed ALDH9A1 revealed that this enzyme can be prenylated inside cells but does not respond to inhibition by prenyltransferase inhibitors. Site-directed mutagenesis of the key residues involved in ALDH9A1 activity indicates that the catalytic C288 bears the isoprenoid modification likely through an NAD+-dependent mechanism. Furthermore, the isoprenoid modification is also susceptible to hydrolysis, indicating a reversible modification. We hypothesize that this modification originates from endogenous farnesal or geranygeranial, the established degradation products of prenylated proteins and results in a thioester form that accumulates. This novel reversible prenoyl modification on ALDH9A1 expands the current paradigm of protein prenylation by illustrating a potentially new type of protein–lipid modification that may also serve as a novel mechanism for controlling enzyme function

2023-11-06 | PXD036365 | Pride

Thinking outside the "Blue Box": from molecular to supramolecular pH-responsiveness.

Project description:We present herein the development of a new polycationic cyclophane: the "red box", second in a series of hydrazone-based analogues of the well-known organic receptor cyclobis(paraquat-p-phenylene)cyclophane ("blue box"). The macrocycle has been prepared in an excellent yield in aqueous media, and shows both a remarkable pH-responsiveness and unusual hydrolytic stability of the two hydrazone C[double bond, length as m-dash]N bonds, associated with charge delocalization of the amine lone pair. Whilst in aqueous media the "red box" is able to complex a variety of aromatic substrates, both in its acidic and basic form, in organic media the cyclophane is only able to capture those in the acidic form, resulting in supramolecular pH-responsiveness.

| S-EPMC7069232 | biostudies-literature

Thinking outside the CaaX-box: an unusual reversible prenylation on ALDH9A1.

Project description:Protein lipidation is a post-translational modification that confers hydrophobicity on protein substrates to control their cellular localization, mediate protein trafficking, and regulate protein function. In particular, protein prenylation is a C-terminal modification on proteins bearing canonical motifs catalyzed by prenyltransferases. Prenylated proteins have been of interest due to their numerous associations with various diseases. Chemical proteomic approaches have been pursued over the last decade to define prenylated proteomes (prenylome) and probe their responses to perturbations in various cellular systems. Here, we describe the discovery of prenylation of a non-canonical prenylated protein, ALDH9A1, which lacks any apparent prenylation motif. This enzyme was initially identified through chemical proteomic profiling of prenylomes in various cell lines. Metabolic labeling with an isoprenoid probe using overexpressed ALDH9A1 revealed that this enzyme can be prenylated inside cells but does not respond to inhibition by prenyltransferase inhibitors. Site-directed mutagenesis of the key residues involved in ALDH9A1 activity indicates that the catalytic C288 bears the isoprenoid modification likely through an NAD+-dependent mechanism. Furthermore, the isoprenoid modification is also susceptible to hydrolysis, indicating a reversible modification. We hypothesize that this modification originates from endogenous farnesal or geranygeranial, the established degradation products of prenylated proteins and results in a thioester form that accumulates. This novel reversible prenoyl modification on ALDH9A1 expands the current paradigm of protein prenylation by illustrating a potentially new type of protein-lipid modification that may also serve as a novel mechanism for controlling enzyme function.

| S-EPMC10619140 | biostudies-literature

Antifungal drug screening: thinking outside the box to identify novel antifungal scaffolds.

Project description:Invasive fungal infections are responsible for a significant disease burden worldwide. Drugs to treat these infections are limited to only four unique classes, and despite these available treatments, mortality rates remain unacceptably high. In this review, we will discuss antifungal drug screening and how the approach to identifying novel compounds needs move away from traditional growth-based assays in order to meet the demand for new drugs. We highlight specific examples of creative screening strategies that increase the likelihood of identifying compounds with desired activities and provide perspective to inspire development of novel screens for the identification of first-in-class antifungals.

| S-EPMC7652037 | biostudies-literature

Thinking Outside the Box: Developing Dynamic Data Visualizations for Psychology with Shiny.

Project description:The study of human perception has helped psychologists effectively communicate data rich stories by converting numbers into graphical illustrations and data visualization remains a powerful means for psychology to discover, understand, and present results to others. However, despite an exponential rise in computing power, the World Wide Web, and ever more complex data sets, psychologists often limit themselves to static visualizations. While these are often adequate, their application across professional psychology remains limited. This is surprising as it is now possible to build dynamic representations based around simple or complex psychological data sets. Previously, knowledge of HTML, CSS, or Java was essential, but here we develop several interactive visualizations using a simple web application framework that runs under the R statistical platform: Shiny. Shiny can help researchers quickly produce interactive data visualizations that will supplement and support current and future publications. This has clear benefits for researchers, the wider academic community, students, practitioners, and interested members of the public.

| S-EPMC4664644 | biostudies-literature

Thinking Outside the Euclidean Box: Riemannian Geometry and Inter-Temporal Decision-Making.

Project description:Inter-temporal decisions involves assigning values to various payoffs occurring at different temporal distances. Past research has used different approaches to study these decisions made by humans and animals. For instance, considering that people discount future payoffs at a constant rate (e.g., exponential discounting) or at variable rate (e.g., hyperbolic discounting). In this research, we question the widely assumed, but seldom questioned, notion across many of the existing approaches that the decision space, where the decision-maker perceives time and monetary payoffs, is a Euclidean space. By relaxing the rigid assumption of Euclidean space, we propose that the decision space is a more flexible Riemannian space of Constant Negative Curvature. We test our proposal by deriving a discount function, which uses the distance in the Negative Curvature space instead of Euclidean temporal distance. The distance function includes both perceived values of time as well as money, unlike past work which has considered just time. By doing so we are able to explain many of the empirical findings in inter-temporal decision-making literature. We provide converging evidence for our proposal by estimating the curvature of the decision space utilizing manifold learning algorithm and showing that the characteristics (i.e., metric properties) of the decision space resembles those of the Negative Curvature space rather than the Euclidean space. We conclude by presenting new theoretical predictions derived from our proposal and implications for how non-normative behavior is defined.

| S-EPMC4809573 | biostudies-literature

Bicaval Valve Implantation for Severe Tricuspid Regurgitation: Thinking Outside the Valve Box.

Project description: Not available

| S-EPMC8289099 | biostudies-literature

<i>Return to 1616</i>: Multispecies Fauna Reconstruction Requires Thinking Outside the Box.

Project description:Conservation translocations have become increasingly popular for 'rewilding' areas that have lost their native fauna. These multispecies translocations are complex and need to consider the requirements of each individual species as well as the influence of likely interactions among them. The Dirk Hartog Island National Park Ecological Restoration Project, Return to 1616, aspires to restore ecological function to Western Australia's largest island. Since 2012, pest animals have been eradicated, and conservation translocations of seven fauna species have been undertaken, with a further six planned. Here, we present a synthesis of the innovative approaches undertaken in restoring the former faunal assemblage of Dirk Hartog Island and the key learnings gathered as the project has progressed.

| S-EPMC10486414 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data