Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Metalloproteases in Pain Generation and Persistence: A Possible Target?

ABSTRACT: Matrix metalloproteinases (MMPs) are a large family of zinc-dependent proteolytic enzymes associated with extracellular matrix protein turnover and tissue degradation. They participate to many different physiological reactions but are also hyperactivated in several diseases. Various literature studies have documented that MMPs play a role in the modulation of neuropathic and nociceptive pain. The heterogeneity of clinical and pre-clinical data is an important issue in this experimental context. Despite the presence of a good number of studies on MMP inhibitors, these drugs showed scarce efficacy and relevant side effects. In the present manuscript, we reviewed studies in the literature that define a possible role of MMPs in pain and the effects of their modulation.

SUBMITTER: Marciano G

PROVIDER: S-EPMC9953417 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Metalloproteases in Pain Generation and Persistence: A Possible Target?

Marcianò Gianmarco G Vocca Cristina C Rania Vincenzo V Citraro Rita R De Sarro Giovambattista G Gallelli Luca L

Biomolecules 20230131 2

Matrix metalloproteinases (MMPs) are a large family of zinc-dependent proteolytic enzymes associated with extracellular matrix protein turnover and tissue degradation. They participate to many different physiological reactions but are also hyperactivated in several diseases. Various literature studies have documented that MMPs play a role in the modulation of neuropathic and nociceptive pain. The heterogeneity of clinical and pre-clinical data is an important issue in this experimental context. ...[more]

PMID: 36830637

Similar Datasets

Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain.

Project description:Treatment of neuropathic pain, triggered by multiple insults to the nervous system, is a clinical challenge because the underlying mechanisms of neuropathic pain development remain poorly understood. Most treatments do not differentiate between different phases of neuropathic pain pathophysiology and simply focus on blocking neurotransmission, producing transient pain relief. Here, we report that early- and late-phase neuropathic pain development in rats and mice after nerve injury require different matrix metalloproteinases (MMPs). After spinal nerve ligation, MMP-9 shows a rapid and transient upregulation in injured dorsal root ganglion (DRG) primary sensory neurons consistent with an early phase of neuropathic pain, whereas MMP-2 shows a delayed response in DRG satellite cells and spinal astrocytes consistent with a late phase of neuropathic pain. Local inhibition of MMP-9 by an intrathecal route inhibits the early phase of neuropathic pain, whereas inhibition of MMP-2 suppresses the late phase of neuropathic pain. Further, intrathecal administration of MMP-9 or MMP-2 is sufficient to produce neuropathic pain symptoms. After nerve injury, MMP-9 induces neuropathic pain through interleukin-1beta cleavage and microglial activation at early times, whereas MMP-2 maintains neuropathic pain through interleukin-1beta cleavage and astrocyte activation at later times. Inhibition of MMP may provide a novel therapeutic approach for the treatment of neuropathic pain at different phases.

| S-EPMC2279180 | biostudies-literature

Persistence of pain and cognitive impairment in older adults.

Project description:BackgroundNo studies have examined the longitudinal association between the persistence of pain and its relationship to cognitive problems in older adults. The objective of this study was to examine how the persistent of pain associates with cognitive performance, cognitive impairment, and subjective memory decline.MethodsAcross 10 biennial waves, 8515 adults ages 65 and over were assessed from the Health and Retirement Study (Mage = 74.17, SD = 6.87, 59.2% female). At each wave, individuals were asked to report on pain presence, and if present, rate its intensity and interference with daily activities such as housework or chores. Using running frequencies or averages, we calculated the persistence of pain using these three pain measures. Cognition was assessed using cognitive performance and different cognitive impairment cutoffs. Incident subjective memory decline was additionally measured as new self-reported memory change in the last 2 years. General estimating equations examined concurrent associations between persistence of pain and cognitive variables, adjusting for demographics, depressive symptoms, and medical comorbidities.ResultsPersistence of pain presence was associated with an increased risk of cognitive impairment. Only persistence of pain interference, not pain intensity, was significantly associated with poorer cognitive performance or being classified as cognitively impaired. For every 2 years, persistence of pain interference was associated with 21% increased odds of cognitive impairment. Only one of three pain variables was related to incident subjective memory decline.ConclusionsPersistence of pain is associated with poorer cognitive performance in community-dwelling older adults, especially when involving ongoing interference in chores and work. Facilitating pain management might be important for helping to maintain later-life cognition and reduce dementia risk.

| S-EPMC8821128 | biostudies-literature

Persistence of pain quality in community-dwelling older adults with chronic non-cancer pain.

Project description:Longitudinal assessment of chronic geriatric pain is complicated by an age-associated plateau in pain severity and increase in widespread pain, calling for innovative measures such as pain quality descriptors that characterize how pain may feel. We characterized persistence of pain quality and its relation to severity, activity interference and distribution of sites, in a population-based sample of adults aged≥70 years with chronic pain (n = 398). Persistent pain quality was defined as reporting descriptors within the same category: sensory, cognitive/affective, or neuropathic at baseline and 18 months. A count variable indicated number of persistent categories. Pain quality was highly persistent. Adjusted for baseline covariates, individuals endorsing 3 persistent categories were 2-2.5x more likely to experience more widespread pain at 18 months compared to fewer persistent categories. No associations were noted in changes in pain severity or interference. A comprehensive pain assessment that includes diverse pain quality descriptors may improve individualized pain management.

| S-EPMC6076861 | biostudies-literature

Monobodies as possible next-generation protein therapeutics - a perspective.

Project description:Over the past two decades, hundreds of new somatic mutations have been identified in tumours, and a few dozen novel cancer therapeutics that selectively target these mutated oncoproteins have entered clinical practice. This development has resulted in clinical breakthroughs for a few tumour types, but more commonly patients' overall survival has not improved because of the development of drug resistance. Furthermore, only a very limited number of oncoproteins, largely protein kinases, are successfully targeted, whereas most non-kinase oncoproteins inside cancer cells remain untargeted. Engineered small protein inhibitors offer great promise in targeting a larger variety of oncoproteins with better efficacy and higher selectivity. In this article, I focus on a promising class of synthetic binding proteins, termed monobodies, that we have shown to inhibit previously untargetable protein-protein interactions in different oncoproteins. I will discuss the great promise alongside the technical challenges inherent in converting monobodies from potent pre-clinical target validation tools to next-generation protein-based therapeutics.

| S-EPMC7316567 | biostudies-literature

Large mutational target size for rapid emergence of bacterial persistence.

Project description:Phenotypic heterogeneity displayed by a clonal bacterial population permits a small fraction of cells to survive prolonged exposure to antibiotics. Although first described over 60 y ago, the molecular mechanisms underlying this behavior, termed persistence, remain largely unknown. To systematically explore the genetic basis of persistence, we selected a library of transposon-mutagenized Escherichia coli cells for survival to multiple rounds of lethal ampicillin exposure. Application of microarray-based genetic footprinting revealed a large number of loci that drastically elevate persistence frequency through null mutations and domain disruptions. In one case, the C-terminal disruption of methionyl-tRNA synthetase (MetG) results in a 10,000-fold higher persistence frequency than wild type. We discovered a mechanism by which null mutations in transketolase A (tktA) and glycerol-3-phosphate (G3P) dehydrogenase (glpD) increase persistence through metabolic flux alterations that increase intracellular levels of the growth-inhibitory metabolite methylglyoxal. Systematic double-mutant analyses revealed the genetic network context in which such persistent mutants function. Our findings reveal a large mutational target size for increasing persistence frequency, which has fundamental implications for the emergence of antibiotic tolerance in the clinical setting.

| S-EPMC3411964 | biostudies-literature

Phospholipase C{beta}3 in mouse and human dorsal root ganglia and spinal cord is a possible target for treatment of neuropathic pain.

Project description:Treatment of neuropathic pain is a major clinical problem. This study shows expression of phospholipase ss3 (PLCss3) in mouse and human DRG neurons, mainly in small ones and mostly with a nonpeptidergic phenotype. After spared nerve injury, the pain threshold was strongly reduced, and systemic treatment of such animals with the unselective PLC inhibitor U73122 caused a rapid and long-lasting (48-h) increase in pain threshold. Thus, inhibition of PLC may provide a way to treat neuropathic pain.

| S-EPMC2604939 | biostudies-literature

The selectivity of galardin and an azasugar-based hydroxamate compound for human matrix metalloproteases and bacterial metalloproteases.

Project description:Inhibitors targeting bacterial enzymes should not interfere with enzymes of the host, and knowledge about structural determinants for selectivity is important for designing inhibitors with a therapeutic potential. We have determined the binding strengths of two hydroxamate compounds, galardin and compound 1b for the bacterial zinc metalloproteases, thermolysin, pseudolysin and auerolysin, known to be bacterial virulence factors, and the two human zinc metalloproteases MMP-9 and MMP-14. The active sites of the bacterial and human enzymes have huge similarities. In addition, we also studied the enzyme-inhibitor interactions by molecular modelling. The obtained Ki values of galardin for MMP-9 and MMP-14 and compound 1b for MMP-9 are approximately ten times lower than previously reported. Compound 1b binds stronger than galardin to both MMP-9 and MMP-14, and docking studies indicated that the diphenyl ether moiety of compound 1b obtains more favourable interactions within the S´1-subpocket than the 4-methylpentanoyl moiety of galardin. Both compounds bind stronger to MMP-9 than to MMP-14, which appears to be due to a larger S´1-subpocket in the former enzyme. Galardin, but not 1b, inhibits the bacterial enzymes, but the galardin Ki values were much larger than for the MMPs. The docking indicates that the S´1-subpockets of the bacterial proteases are too small to accommodate the diphenyl ether moiety of 1b, while the 4-methylpentanoyl moiety of galardin enters the pocket. The present study indicates that the size and shape of the ligand structural moiety entering the S´1-subpocket is an important determinant for selectivity between the studied MMPs and bacterial MPs.

| S-EPMC6075749 | biostudies-literature

Gene expression changes in astrocytes by pulsed radiofrequency: a possible mechanism of neuropathic pain improvement

Project description:We investigated genomic effects of pulsed radiofrequency (PRF) on mouse cultured astrocyte cell line, C8D1A cells, using microarray analysis. PRF increased 2,431 genes and decreased 209 genes. Among these genes, 435 genes were upregulated with more than 10-fold, 89 genes with more than 30-fold, while there was no gene with 10-fold decrease. From the gene ontology analysis using the list of 10-fold upregulated genes, PRF treatment activated immune response. From pathway analysis using Kyoto Encyclopedia of Gene and Genomes using the same list, 7 pathways related with neuropathic pain were detected.

2019-05-31 | GSE130755 | GEO

PDGF/PDGFR: A Possible Molecular Target in Scleroderma Fibrosis.

Project description:Systemic sclerosis (SSc) is a clinically heterogeneous disorder of the connective tissue characterized by vascular alterations, immune/inflammatory manifestations, and organ fibrosis. SSc pathogenesis is complex and still poorly understood. Therefore, effective therapies are lacking and remain nonspecific and limited to disease symptoms. In the last few years, many molecular and cellular mediators of SSc fibrosis have been described, providing new potential options for targeted therapies. In this review: (i) we focused on the PDGF/PDGFR pathway as key signaling molecules in the development of tissue fibrosis; (ii) we highlighted the possible role of stimulatory anti-PDGFRα autoantibodies in the pathogenesis of SSc; (iii) we reported the most promising PDGF/PDGFR targeting therapies.

| S-EPMC8999630 | biostudies-literature

Catalytic domain architecture of metzincin metalloproteases.

Project description:Metalloproteases cleave proteins and peptides, and deregulation of their function leads to pathology. An understanding of their structure and mechanisms of action is necessary to the development of strategies for their regulation. Among metallopeptidases are the metzincins, which are mostly multidomain proteins with approximately 130-260-residue globular catalytic domains showing a common core architecture characterized by a long zinc-binding consensus motif, HEXXHXXGXX(H/D), and a methionine-containing Met-turn. Metzincins participate in unspecific protein degradation such as digestion of intake proteins and tissue development, maintenance, and remodeling, but they are also involved in highly specific cleavage events to activate or inactivate themselves or other (pro)enzymes and bioactive peptides. Metzincins are subdivided into families, and seven such families have been analyzed at the structural level: the astacins, ADAMs/adamalysins/reprolysins, serralysins, matrix metalloproteinases, snapalysins, leishmanolysins, and pappalysins. These families are reviewed from a structural point of view.

| S-EPMC2708831 | 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