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Repurposing the antipsychotic drug amisulpride for targeting synovial fibroblast activation in arthritis

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE229144 | GEO | 2023/04/06

REPOSITORIES: GEO

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Repurposing the antipsychotic drug amisulpride for targeting synovial fibroblast activation in arthritis II

Project description:Amisulpride, a known antipsychotic drug, was identified to target synovial fibroblasts activation in arthritis through novel identified targets.

2023-04-06 | GSE211137 | GEO

Repurposing the antipsychotic drug amisulpride for targeting synovial fibroblast activation in arthritis I

Project description:Amisulpride, a known antipsychotic drug, was identified to target synovial fibroblasts activation in arthritis through novel identified targets.

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Repurposing the antipsychotic drug amisulpride for targeting synovial fibroblast activation in arthritis

Project description:Repurposing the antipsychotic drug amisulpride for targeting synovial fibroblast activation in arthritis

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Repurposing the antipsychotic drug amisulpride for targeting synovial fibroblast activation in arthritis II

Project description:Repurposing the antipsychotic drug amisulpride for targeting synovial fibroblast activation in arthritis II

| PRJNA869078 | ENA

Repurposing the antipsychotic drug amisulpride for targeting synovial fibroblast activation in arthritis I

Project description:Repurposing the antipsychotic drug amisulpride for targeting synovial fibroblast activation in arthritis I

| PRJNA869070 | ENA

Repurposing of Amisulpride, a known antipsychotic drug, to target synovial fibroblasts activation in arthritis.

Project description:Synovial Fibroblasts (SFs) are key pathogenic drivers in arthritis and their in vivo activation by TNF is sufficient to orchestrate full arthritic pathogenesis in animal models. TNF blockade has been efficacious for a large percentage of Rheumatoid Arthritis (RA) patients, although characterized by a plethora of side effects. Novel therapeutic discoveries remain however challenging, especially in optimizing drug safety, side effects, longer-term responses, costs and administration routes. Aiming to find new potent therapeutics, we applied the L1000CDS2 search engine, in order to identify compounds that could potentially reverse the pathogenic expression signature of arthritogenic SFs, derived from the human TNF transgenic mouse model (hTNFtg). We identified a neuroleptic drug, namely Amisulpride, which was validated to reduce SFs’ inflammatory potential while decreasing the clinical score of hTNFtg polyarthritis. Notably, we found that Amisulpride did not exert its biological activities through its known targets Dopamine receptors 2 and 3 and Serotonin Receptor 7, nor through TNFTNFRI binding inhibition. By applying a click chemistry approach, novel potential targets of Amisulpride were identified, which were further validated to repress hTNFtg SFs’ inflammatory potential in vitro (Ascc3 and Sec62), while phosphoproteomics analysis revealed important fibroblast activation pathways, such as adhesion, to be altered upon treatment. Our data support that Amisulpride could provide an additive beneficial effect to patients suffering from RA and comorbid dysthymia, as it may reduce SFs pathogenicity in parallel with its antidepressive activity. Importantly, Amisulpride may also serve as a “lead” compound for the development of novel, more potent therapeutics against chronic inflammatory diseases

2023-04-06 | PXD036283 | Pride

Repurposing of a known antipsychotic drug to target arthritogenic synovial fibroblasts

Project description:We applied quantitative mass spectrometry (MS)-based proteomics to investigate the phosphoproteome of hTNF-stimulated and Amisulpride-treated synovial fibroblasts (SFs), as part of a study aiming to find new potent orally-administered therapeutics to reverse the pathogenic expression signature of arthritogenic SFs. Phosphoproteomics analysis were done by DIA-based phosphoproteomic profiling of synovial fibroblasts. Samples consisted of hTNF-induced WT SFs. Three different time points (5’, 15’, 30’) of hTNF induction were used and compared to cells pretreated with Amisulpride for 1h before being stimulated at similar time points with hTNF (5’, 15’, 30’).

2023-04-11 | PXD035230 | Pride

Profiling drugs for rheumatoid arthritis that inhibit synovial fibroblast activation.

Project description:Activation of synovial fibroblasts (SFs) contributes to rheumatoid arthritis (RA) by damaging synovial membranes and generating inflammatory cytokines that recruit immune cells to the joint. In this paper we profile cytokine secretion by primary human SFs from healthy tissues and from donors with RA and show that SF activation by TNF, IL-1α, and polyinosinic-polycytidylic acid (Poly(I:C)) cause secretion of multiple cytokines found at high levels in RA synovial fluids. We used interaction multiple linear regression to quantify therapeutic and countertherapeutic drug effects across activators and donors and found that the ability of drugs to block SF activation was strongly dependent on the identity of the activating cytokine. (5z)-7-oxozeaenol (5ZO), a preclinical drug that targets transforming growth factor-β-activated kinase 1 (TAK1), was more effective at blocking SF activation across all contexts than the approved drug tofacitinib, which supports the development of molecules similar to 5ZO for use as RA therapeutics.

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Succinate/NLRP3 Inflammasome Induces Synovial Fibroblast Activation: Therapeutical Effects of Clematichinenoside AR on Arthritis.

Project description:Clematichinenoside AR (C-AR) is a triterpene saponin isolated from the root of Clematis manshurica Rupr., which is a herbal medicine used in traditional Chinese medicine for the treatment of arthritis. C-AR exerts anti-inflammatory and immunosuppressive properties, but little is known about its action in the suppression of fibroblast activation. Low oxygen tension and transforming growth factor-β (TGF-β1) induction in the synovium contribute to fibrosis in arthritis. This study was designed to investigate the effect of C-AR on synovial fibrosis from the aspects of hypoxic TGF-β1 and hypoxia-inducible transcription factor-1α (HIF-1α) induction. In the synovium of rheumatoid arthritis (RA) rats, hypoxic TGF-β1 induction increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH) activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction. In response to NLRP3 inflammasome activation, the released IL-1β further increased TGF-β1 induction, suggesting the forward cycle between inflammation and fibrosis in myofibroblast activation. In the synovium of RA rats, C-AR inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome activation by inhibiting SDH activity, and thereby prevented myofibroblast activation by blocking the cross-talk between inflammation and fibrosis. Taken together, these results showed that succinate worked as a metabolic signaling, linking inflammation with fibrosis through NLRP3 inflammasome activation. These findings suggested that synovial succinate accumulation and HIF-1α induction might be therapeutical targets for the prevention of fibrosis in arthritis.

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Dynamic chromatin targeting of BRD4 stimulates cardiac fibroblast activation

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-02-25 | GSE127230 | GEO