Browse
Submit Data
Databases
API
Help

Dataset Information

31 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Emerging Therapeutic Potential of SIRT6 Modulators.

ABSTRACT: Sirtuin 6 (SIRT6) is an NAD⁺-dependent protein deacylase and mono-ADP-ribosyltransferase of the sirtuin family with a wide substrate specificity. In vitro and in vivo studies have indicated that SIRT6 overexpression or activation has beneficial effects for cellular processes such as DNA repair, metabolic regulation, and aging. On the other hand, SIRT6 has contrasting roles in cancer, acting either as a tumor suppressor or promoter in a context-specific manner. Given its central role in cellular homeostasis, SIRT6 has emerged as a promising target for the development of small-molecule activators and inhibitors possessing a therapeutic potential in diseases ranging from cancer to age-related disorders. Moreover, specific modulators allow the molecular details of SIRT6 activity to be scrutinized and further validate the enzyme as a pharmacological target. In this Perspective, we summarize the current knowledge about SIRT6 pharmacology and medicinal chemistry and describe the features of the activators and inhibitors identified so far.

SUBMITTER: Fiorentino F

PROVIDER: S-EPMC8389836 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Endogenous Metabolic Modulators: Emerging Therapeutic Potential of Amino Acids.

Project description:Multifactorial disease pathophysiology is complex and incompletely addressed by existing targeted pharmacotherapies. Amino acids (AAs) and related metabolites and precursors are a class of endogenous metabolic modulators (EMMs) that have diverse biological functions and, thus, have been explored for decades as potential multifactorial disease treatments. Here, we review the literature on this class of EMMs in disease treatment, with a focus on the emerging clinical studies on AAs and related metabolites and precursors as single- and combination-agents targeted to a single biology. These clinical research insights, in addition to increasing understanding of disease metabolic profiles and combinatorial therapeutic design principles, highlight an opportunity to develop EMM compositions with AAs and related metabolites and precursors to target multifactorial disease biology. EMM compositions are uniquely designed to enable a comprehensive approach, with potential to simultaneously and safely target pathways underlying multifactorial diseases and to regulate biological processes that promote overall health.

| S-EPMC7569218 | biostudies-literature

Emerging roles of SIRT6 in human diseases and its modulators.

Project description:The biological functions of sirtuin 6 (SIRT6; e.g., deacetylation, defatty-acylation, and mono-ADP-ribosylation) play a pivotal role in regulating lifespan and several fundamental processes controlling aging such as DNA repair, gene expression, and telomeric maintenance. Over the past decades, the aberration of SIRT6 has been extensively observed in diverse life-threatening human diseases. In this comprehensive review, we summarize the critical roles of SIRT6 in the onset and progression of human diseases including cancer, inflammation, diabetes, steatohepatitis, arthritis, cardiovascular diseases, neurodegenerative diseases, viral infections, renal and corneal injuries, as well as the elucidation of the related signaling pathways. Moreover, we discuss the advances in the development of small molecule SIRT6 modulators including activators and inhibitors as well as their pharmacological profiles toward potential therapeutics for SIRT6-mediated diseases.

| S-EPMC7906922 | biostudies-literature

A fluorogenic assay for screening Sirt6 modulators.

Project description:A fluorogenic high-throughput assay suitable for screening Sirt6 modulators is developed based on the recently discovered efficient activity of Sirt6 to hydrolyze myristoyl lysine. Sirt6 modulators will be useful in investigating the function of Sirt6 and protein lysine fatty acylation.

| S-EPMC3756594 | biostudies-literature

Emerging peptide antibiotics with therapeutic potential.

Project description:This review covers some of the recent progress in the field of peptide antibiotics with a focus on compounds with novel or established mode of action and with demonstrated efficacy in animal infection models. Novel drug discovery approaches, linear and macrocyclic peptide antibiotics, lipopeptides like the polymyxins as well as peptides addressing targets located in the plasma membrane or in the outer membrane of bacterial cells are discussed.

| S-EPMC7773004 | biostudies-literature

Cell-Derived Nanoparticles are Endogenous Modulators of Sepsis With Therapeutic Potential.

Project description:Cell-derived nanoparticles (CDNPs) containing cytosolic proteins and RNAs/DNAs can be isolated from stressed eukaryotic cells. Previously, CDNPs isolated from cultured cells exerted immunomodulatory activities in different infections. Here, we sought to elucidate the role of CDNPs using a murine model of cecal ligation and puncture (CLP). We hypothesized that CDNPs influence the immune response at the site of infection, where severe cellular stress occurs. We observed early CDNP accumulation in the peritoneum after 4 h and continued CDNP presence 24 h after CLP. To determine whether CDNPs influence the host response to sepsis, we isolated CDNPs from a murine fibroblast cell line stressed by nutrient-deprivation, and injected them into septic mice. CDNP-treated mice demonstrated decreased peritoneal interleukin 6 levels and an approximately 2-log lower bacterial load compared with control mice 24 h after CLP. Additionally, a 20% CFU reduction was observed when incubating CDNPs with Pseudomona aeroginosa, indicating that CDNPs are bactericidal. To identify CDNP-responsive cells, CFSE-labeled CDNPs were injected into mice at the time of CLP. We observed that CDNPs were preferentially ingested by F4/80 macrophages, and to a lesser degree, associated with inflammatory monocytes and neutrophils. Strikingly, CDNP-ingesting cells demonstrated elevated CD11b and MHCII expression compared with control cells. Altogether, our data indicate that CDNPs enhance the immune response at the site of infection and promote bacterial clearance, by direct bacterial killing and increasing phagocyte activation. Thus, CDNPs represent a novel, unexplored endogenous sepsis modulator with therapeutic potential.

| S-EPMC5555790 | biostudies-literature

Therapeutic potential of N-methyl-D-aspartate receptor modulators in psychiatry.

Project description:N-methyl-D-aspartate (NMDA) receptors mediate a slow component of excitatory synaptic transmission, are widely distributed throughout the central nervous system, and regulate synaptic plasticity. NMDA receptor modulators have long been considered as potential treatments for psychiatric disorders including depression and schizophrenia, neurodevelopmental disorders such as Rett Syndrome, and neurodegenerative conditions such as Alzheimer's disease. New interest in NMDA receptors as therapeutic targets has been spurred by the findings that certain inhibitors of NMDA receptors produce surprisingly rapid and robust antidepressant activity by a novel mechanism, the induction of changes in the brain that well outlast the presence of drug in the body. These findings are driving research into an entirely new paradigm for using NMDA receptor antagonists in a host of related conditions. At the same time positive allosteric modulators of NMDA receptors are being pursued for enhancing synaptic function in diseases that feature NMDA receptor hypofunction. While there is great promise, developing the therapeutic potential of NMDA receptor modulators must also navigate the potential significant risks posed by the use of such agents. We review here the emerging pharmacology of agents that target different NMDA receptor subtypes, offering new avenues for capturing the therapeutic potential of targeting this important receptor class.

| S-EPMC10700609 | biostudies-literature

BRCA1 and microRNAs: emerging networks and potential therapeutic targets.

Project description:BRCA1 is a well-known tumor suppressor implicated in familial breast and ovarian cancer. Since its cloning in 1994, numerous studies have established BRCA1's role in diverse cellular and biochemical processes, such as DNA damage repair, cell cycle control, and transcriptional regulation as well as ubiquitination. In addition, a number of recent studies have functionally linked this tumor suppressor to another important cellular regulator, microRNAs, which are short (19-22 nt) RNAs that were discovered in the nematode in 1993. Soon their presence and function were validated in mammals, and since then, the role of microRNAs has been actively investigated in almost all biological processes, including cancer. In this review, we will describe recent progress in the understanding of the BRCA1 function through microRNAs and the role of microRNAs in regulating BRCA1, with emphasis on the implication of these processes on the development and progression of cancer. We will also discuss the therapeutic potential of microRNA mimics or inhibitors of microRNAs to affect BRCA1 function.

| S-EPMC3887789 | biostudies-literature

The therapeutic potential of ROR? modulators in the treatment of human disease.

Project description:Nuclear receptors (NR) are ligand-regulated transcription factors that bind DNA in proximity to their target genes and exert their effects as a result of binding by small molecule ligands such as sterols, lipids, fatty acids, retinoids, and steroid hormones. The retinoic acid receptor-related orphan receptors or RORs (NR1F1-NR1F3) are nuclear receptors that regulate multiple cellular processes, including metabolism, cellular differentiation, and apoptosis, in a range of tissues and organs. These receptors bind as monomers to ROR response elements commonly called ROREs present in promoter regions of target genes and tether chromatin remodeling enzymes, facilitating recruitment of transcription machinery. Several recent reports have highlighted the potential role for RORs in human disease, and more importantly, studies have demonstrated that these receptors can be modulated by exogenous synthetic ligands, paving the way for development of novel therapeutics. Here we review the current status of synthetic ligand development as well as the structural aspects governing modulation of ROR signaling pathways as they relate to metabolic diseases and autoimmune disorders.

| S-EPMC4863310 | biostudies-literature

Realising the therapeutic potential of neuroactive steroid modulators of the GABAA receptor.

Project description:In the 1980s particular endogenous metabolites of progesterone and of deoxycorticosterone were revealed to be potent, efficacious, positive allosteric modulators (PAMs) of the GABAA receptor (GABAAR). These reports were followed by the discovery that such steroids may be synthesised not only in peripheral endocrine glands, but locally in the central nervous system (CNS), to potentially act as paracrine, or autocrine "neurosteroid" messengers, thereby fine tuning neuronal inhibition. These discoveries triggered enthusiasm to elucidate the physiological role of such neurosteroids and explore whether their levels may be perturbed in particular psychiatric and neurological disorders. In preclinical studies the GABAAR-active steroids were shown to exhibit anxiolytic, anticonvulsant, analgesic and sedative properties and at relatively high doses to induce a state of general anaesthesia. Collectively, these findings encouraged efforts to investigate the therapeutic potential of neurosteroids and related synthetic analogues. However, following over 30 years of investigation, realising their possible medical potential has proved challenging. The recent FDA approval for the natural neurosteroid allopregnanolone (brexanolone) to treat postpartum depression (PPD) should trigger renewed enthusiasm for neurosteroid research. Here we focus on the influence of neuroactive steroids on GABA-ergic signalling and on the challenges faced in developing such steroids as anaesthetics, sedatives, analgesics, anticonvulsants, antidepressants and as treatments for neurodegenerative disorders.

| S-EPMC7231973 | biostudies-literature

FYN: emerging biological roles and potential therapeutic targets in cancer.

Project description:Src family protein kinases (SFKs) play a key role in cell adhesion, invasion, proliferation, survival, apoptosis, and angiogenesis during tumor development. In humans, SFKs consists of eight family members with similar structure and function. There is a high level of overexpression or hyperactivity of SFKs in tumor, and they play an important role in multiple signaling pathways involved in tumorigenesis. FYN is a member of the SFKs that regulate normal cellular processes. Additionally, FYN is highly expressed in many cancers and promotes cancer growth and metastasis through diverse biological functions such as cell growth, apoptosis, and motility migration, as well as the development of drug resistance in many tumors. Moreover, FYN is involved in the regulation of multiple cancer-related signaling pathways, including interactions with ERK, COX-2, STAT5, MET and AKT. FYN is therefore an attractive therapeutic target for various tumor types, and suppressing FYN can improve the prognosis and prolong the life of patients. The purpose of this review is to provide an overview of FYN's structure, expression, upstream regulators, downstream substrate molecules, and biological functions in tumors.

| S-EPMC9901160 | 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