Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Pharmacol Exp Ther ; 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849143

RESUMO

While acute inflammation serves essential functions in maintaining tissue homeostasis, chronic inflammation is causally linked to many diseases. Macrophages are a major cell-type that orchestrates inflammatory processes. During inflammation, macrophages undergo polarization and activation, thereby mobilizing pro-inflammatory and anti-inflammatory transcriptional programs that regulate ensuing macrophage functions. Fatty acid binding protein 5 (FABP5) is a lipid chaperone highly expressed in macrophages. FABP5 deletion is implicated in driving macrophages towards an anti-inflammatory phenotype, yet signaling pathways regulated by macrophage-FABP5 have not been systematically profiled. We leveraged proteomic and phosphoproteomic approaches to characterize pathways modulated by FABP5 in M1 and M2 polarized bone marrow derived macrophages (BMDMs). Stable isotope labeling by amino acids (SILAC) based analysis of M1 and M2 polarized wild-type (WT) and FABP5 knockout (KO) BMDMs revealed numerous differentially regulated proteins and phosphoproteins. FABP5 deletion impacted downstream pathways associated with inflammation, cytokine production, oxidative stress, and kinase activity. Toll-like receptor 2 (TLR2) emerged as a novel target of FABP5 and pharmacological FABP5 inhibition blunted TLR2-mediated activation of downstream pathways, ascribing a novel role for FABP5 in TLR2 signaling. This study represents a comprehensive characterization of the impact of FABP5 deletion upon the proteomic and phosphoproteomic landscape of M1 and M2 polarized BMDMs. Loss of FABP5 altered pathways implicated in inflammatory responses, macrophage function, and TLR2 signaling. This work provides a foundation for future studies seeking to investigate the therapeutic potential of FABP5 inhibition in pathophysiological states resulting from dysregulated inflammatory signaling. Significance Statement This work employed quantitative proteomic and phosphoproteomic approaches to characterize the proteomic profiles of bone marrow derived macrophages obtained from wild-type and fatty acid binding protein 5 (FABP5) knockout mice. Our findings revealed multiple differentially regulated pathways in M1 and M2 polarized FABP5 knockout macrophages compared to wild-type controls, notably those related to inflammation. These results expand our understanding of FABP5 function in macrophages and support recent studies highlighting the therapeutic potential of targeting macrophage FABP5 to treat inflammatory diseases.

2.
Osteoarthritis Cartilage ; 32(3): 266-280, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38035977

RESUMO

OBJECTIVE: Osteoarthritis (OA) is often accompanied by debilitating pain that is refractory to available analgesics due in part to the complexity of signaling molecules that drive OA pain and our inability to target these in parallel. Fatty acid binding protein 5 (FABP5) is a lipid chaperone that regulates inflammatory pain; however, its contribution to OA pain has not been characterized. DESIGN: This combined clinical and pre-clinical study utilized synovial tissues obtained from subjects with end-stage OA and rats with monoiodoacetate-induced OA. Cytokine and chemokine release from human synovia incubated with a selective FABP5 inhibitor was profiled with cytokine arrays and ELISA. Immunohistochemical analyses were conducted for FABP5 in human and rat synovium. The efficacy of FABP5 inhibitors on pain was assessed in OA rats using incapacitance as an outcome. RNA-seq was then performed to characterize the transcriptomic landscape of synovial gene expression in OA rats treated with FABP5 inhibitor or vehicle. RESULTS: FABP5 was expressed in human synovium and FABP5 inhibition reduced the secretion of pronociceptive cytokines (interleukin-6 [IL6], IL8) and chemokines (CCL2, CXCL1). In rats, FABP5 was upregulated in the OA synovium and its inhibition alleviated incapacitance. The transcriptome of the rat OA synovium exhibited >6000 differentially expressed genes, including the upregulation of numerous pronociceptive cytokines and chemokines. FABP5 inhibition blunted the upregulation of the majority of these pronociceptive mediators. CONCLUSIONS: FABP5 is expressed in the OA synovium and its inhibition suppresses pronociceptive signaling and pain, indicating that FABP5 inhibitors may constitute a novel class of analgesics to treat OA.


Assuntos
Citocinas , Osteoartrite , Humanos , Ratos , Animais , Citocinas/metabolismo , Osteoartrite/metabolismo , Dor/metabolismo , Quimiocinas/metabolismo , Membrana Sinovial/metabolismo , Analgésicos , Proteínas de Ligação a Ácido Graxo/genética
3.
Res Sq ; 2023 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-37790380

RESUMO

Background: While acute inflammation serves essential functions in maintaining tissue homeostasis, chronic inflammation is causally linked to many diseases. Macrophages are a major cell-type that orchestrates inflammatory processes. During inflammation, macrophages undergo polarization and activation, thereby mobilizing pro-inflammatory and anti-inflammatory transcriptional programs that regulate ensuing macrophage functions. Fatty acid binding protein 5 (FABP5) is a lipid chaperone that is highly expressed in macrophages. FABP5 deletion is implicated in driving macrophages towards an anti-inflammatory phenotype, yet the signaling pathways regulated by macrophage FABP5 have not been systematically profiled. Herein, we leveraged proteomic and phosphoproteomic approaches to characterize pathways modulated by FABP5 in M1 and M2 polarized bone marrow derived macrophages (BMDMs). Results: Stable isotope labeling by amino acids (SILAC) based analysis of M1 and M2 polarized wild-type (WT) and FABP5 knockout (KO) BMDMs revealed numerous differentially regulated proteins and phosphoproteins. FABP5 deletion impacted several downstream pathways associated with inflammation, cytokine production, oxidative stress, and kinase activity. Kinase enrichment analysis based on phosphorylated sites revealed key kinases, including members of the GRK family, that were altered in FABP5 KO BMDMs. Reactive oxygen species (ROS) levels were elevated in M1 polarized KO macrophages, consistent with the differential protein expression profiles. Conclusions: This study represents a comprehensive characterization of the impact of FABP5 deletion upon the proteomic and phosphoproteomic landscape of M1 and M2 polarized BMDMs. Loss of FABP5 altered multiple pathways implicated in inflammatory responses and macrophage function. This work provides a foundation for future studies seeking to investigate the therapeutic potential of FABP5 inhibition in pathophysiological states resulting from dysregulated inflammatory signaling.

4.
Bioorg Med Chem ; 94: 117464, 2023 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-37708641

RESUMO

Fatty acid binding proteins (FABPs) are intracellular chaperones that deliver bioactive lipids to cytosolic enzymes and nuclear receptors, thereby regulating diverse biological functions. FABP5 is a member of the FABP family that mediates endocannabinoid transport and inactivation, with pharmacological or genetic FABP5 inhibition conferring antinociceptive effects. Consequently, FABP5 inhibitors have emerged as promising analgesics and demonstrate antinociceptive activity in models of pain. Recently developed FABP5 inhibitors based upon the α-truxillic acid monoester (TAME) scaffold demonstrate high affinities for FABP5 but are commonly accompanied by reduced selectivity against related FABPs, notably FABP3 that is expressed in the heart, highlighting the need to identify additional scaffolds that afford enhanced selectivity while maintaining FABP5 potency. Here, we describe the synthesis and biological evaluation of truxillic acid monoamides (TAMADs) as potent, selective, and efficacious FABP5 inhibitors. Combining in silico molecular docking and in vitro binding assay approaches, our findings demonstrate that TAMADs exhibit exceptional selectivity against FABP3 and several compounds attain high FABP5 affinities. Examination of antinociceptive activity revealed that TAMADs and their corresponding TAMEs demonstrate comparable efficacy and temporal activity profiles in vivo. These results position TAMAD as a suitable scaffold for the development of FABP5 inhibitors with diminished FABP3 cross-reactivity.


Assuntos
Analgésicos , Proteínas de Ligação a Ácido Graxo , Humanos , Simulação de Acoplamento Molecular , Proteínas de Ligação a Ácido Graxo/metabolismo , Analgésicos/química , Dor/tratamento farmacológico , Proteína 3 Ligante de Ácido Graxo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...