Selective Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibition by the SCH772984 Compound Attenuates In Vitro and In Vivo Inflammatory Responses and Prolongs Survival in Murine Sepsis Models

Kopczyński, Michał; Rumieńczyk, Izabela; Kulecka, Maria; Statkiewicz, Małgorzata; Pyśniak, Kazimiera; Sandowska-Markiewicz, Zuzanna; Wójcik-Trechcińska, Urszula; Goryca, Krzysztof; Pyziak, Karolina; Majewska, Eliza; Masiejczyk, Magdalena; Wójcik-Jaszczyńska, Katarzyna; Rzymski, Tomasz; Bomsztyk, Karol; Ostrowski, Jerzy; Mikula, Michał

doi:10.3390/ijms221910204

Cited by 11 publications

(9 citation statements)

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“…Several large-scale transcriptomic and proteomic studies have been performed with macrophages challenged with LPS with the aim of exploring different aspects of the TLR4 signaling and its impact on mucosal protection [ 40 , 41 ]. In this work, we carried out a transcriptomic study to evaluate the response of murine macrophages to the activation of TLR4 and in line with several other studies [ 51 , 52 ], we found that RAW macrophages mount a complex transcriptomic response characterized by changes in the expression of hundreds of genes with diverse immunological functions. Of note, the most remarkable changes in RAW macrophages after the stimulation with LPS were found in expression of cytokines, chemokines and surface markers genes.…”

Section: Discussionsupporting

confidence: 63%

Lactiplantibacillus plantarum LOC1 Isolated from Fresh Tea Leaves Modulates Macrophage Response to TLR4 Activation

Suzuki

Albarracín

Tsujikawa³

et al. 2022

Foods

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Previously, we demonstrated that Lactiplantibacillus plantarum LOC1, originally isolated from fresh tea leaves, was able to improve epithelial barrier integrity in in vitro models, suggesting that this strain is an interesting probiotic candidate. In this work, we aimed to continue characterizing the potential probiotic properties of the LOC1 strain, focusing on its immunomodulatory properties in the context of innate immunity triggered by Toll-like receptor 4 (TLR4) activation. These studies were complemented by comparative and functional genomics analysis to characterize the bacterial genes involved in the immunomodulatory capacity. We carried out a transcriptomic study to evaluate the effect of L. plantarum LOC1 on the response of murine macrophages (RAW264.7 cells) to the activation of TLR4. We demonstrated that L. plantarum LOC1 exerts a modulatory effect on lipopolysaccharide (LPS)-induced inflammation, resulting in a differential regulation of immune factor expression in macrophages. The LOC1 strain markedly reduced the LPS-induced expression of some inflammatory cytokines (IL-1β, IL-12, and CSF2) and chemokines (CCL17, CCL28, CXCL3, CXCL13, CXCL1, and CX3CL1), while it significantly increased the expression of other cytokines (TNF-α, IL-6, IL-18, IFN-β, IFN-γ, and CSF3), chemokines (IL-15 and CXCL9), and activation markers (H2-k1, H2-M3, CD80, and CD86) in RAW macrophages. Our results show that L. plantarum LOC1 would enhance the intrinsic functions of macrophages, promoting their protective effects mediated by the stimulation of the Th1 response without affecting the regulatory mechanisms that help control inflammation. In addition, we sequenced the LOC1 genome and performed a genomic characterization. Genomic comparative analysis with the well-known immunomodulatory strains WCSF1 and CRL1506 demonstrated that L. plantarum LOC1 possess a set of adhesion factors and genes involved in the biosynthesis of teichoic acids and lipoproteins that could be involved in its immunomodulatory capacity. The results of this work can contribute to the development of immune-related functional foods containing L. plantarum LOC1.

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Section: Discussionsupporting

confidence: 63%

Lactiplantibacillus plantarum LOC1 Isolated from Fresh Tea Leaves Modulates Macrophage Response to TLR4 Activation

Suzuki

Albarracín

Tsujikawa³

et al. 2022

Foods

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“…43 Previous research has reported that the effective dose range of SCH772984 in mouse models is 10-20 mg/kg. [44][45][46] In conclusion, 1 mg/kg psilocin counteracted METH-induced hy-…”

Section: Discussionmentioning

confidence: 82%

“…SCH772984 is a selective ERK1/2 inhibitor that binds to unphosphorylated and inactive ERK1/2 and effectively inhibits ERK1/2 phosphorylation 43 . Previous research has reported that the effective dose range of SCH772984 in mouse models is 10–20 mg/kg 44–46 …”

Section: Discussionmentioning

confidence: 99%

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Psilocin suppresses methamphetamine‐induced hyperlocomotion and acquisition of conditioned place preference via D2R‐mediated ERK signaling

et al. 2023

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Aim Psilocin is an active metabolite form of psilocybin and exerts psychoactive effects. Recent studies suggest that psilocin may have regulatory effects on abuse drugs, but the mechanisms remain unclear. In this study, we want to explore the effects of psilocin on methamphetamine (METH)‐induced alterations of behavior in mice and its molecular mechanisms. Methods Acute METH administration model and conditioned place preference (CPP) model were used to investigate the effects of psilocin on METH‐induced alterations of behavior. Western blot was used to detect the expression of proteins. Results In the acute 2 mg/kg METH administration model, 1 mg/kg psilocin counteracted METH‐induced elevation of activity. In the 1 mg/kg METH‐induced CPP model, 1 mg/kg psilocin inhibited CPP formation during the acquisition phase. However, psilocin did not impact METH extinction and relapse. Molecular results showed that the regulatory effect of psilocin on METH was underscored by altered expression of dopamine 2 receptor (D2R) and phosphorylated extra‐cellular signal‐regulated kinase (p‐ERK) in the prefrontal cortex (PFC), nucleus accumbens (NAc), and ventral tegmental area (VTA). Trifluoperazine (TFP)‐2HCl is a D2R inhibitor, and SCH772984 is a selective extra‐cellular signal‐regulated kinase (ERK) inhibitor that effectively inhibits ERK1/2 phosphorylation. The results indicated that 2 mg/kg TFP‐2HCl and 10 mg/kg SCH772984 blocked METH‐induced hyperactivity and acquisition of METH‐induced CPP. Conclusion Psilocin has regulatory effects on METH‐induced alterations of behavior in mice via D2R‐mediated signal regulation of ERK phosphorylation.

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“…Reactome PK buffer and TRIzol RNA-seq data analysis of LPS-induced DEGs for each organ identified nearly identical pathways well described in models of sepsis (48,50,58). This included such pathways as cytokine signaling in the immune system, neutrophil degranulation, signaling by interleukins, platelets degranulation and several others ( Fig.8C ).…”

Section: Resultsmentioning

confidence: 90%

CryoGrid-PIXUL-RNA: High throughput RNA isolation platform for tissue transcript analysis

Schactler

Scheuerman

Lius

et al. 2022

Preprint

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Disease molecular complexity requires high throughput workflows to map disease pathways through analysis of vast tissue repositories. Great progress has been made in life sciences analytical technologies. To match the high throughput of these advanced analytical platforms, we have previously developed a multipurpose microplate sonicator, PIXUL, that can be used in multiple workflows to extract analytes from cultured cells and tissue fragments for various downstream molecular assays. And yet, the sample preparation devices, such as PIXUL, along with the downstream analytical capabilities have not been fully exploited to interrogate tissues because storing and sampling of such specimens remain, in comparison, inefficient. To mitigate this bottleneck, we have developed a low-cost user-friendly system, the CryoGrid, that consists of CryoBlock, thermometer/thermocouple, and QR coded CryoTrays to freeze and store frozen tissue fragments, and hand-held CryoCore tool for tissue sampling supported by iPad and Google apps to display tissues, direct coring and share metadata. RNA is one of the most studied analytes. There is a decades-long history of developing methods to isolate and analyze RNA. Still, the throughput of sampling and RNA extraction from tissues has not matched that of the high throughput transcriptome analytical platforms. To address this need, we have integrated the CryoGrid system with PIXUL-based methods to isolate RNA for gene-specific qPCR and genome-wide transcript analyses. TRIzol is commonly used to isolate RNA but it is labor-intensive, hazardous, requires fume-hoods, and is an expensive reagent. We developed a PIXUL-based TRIzol-free RNA isolation fast protocol that uses a buffer containing proteinase K (PK). Virtually every disease (and often therapeutic agents' toxicity) is a systemic syndrome but often only one organ is examined. CryoGrid-PIXUL, integrated with either TRIzol or PK buffer RNA isolation protocols, yielded similar RNA profiles in a multiorgan (brain, heart, kidney and liver) mouse model of sepsis. Thus, RNA isolation using the CryoGrid-PIXUL system combined with the PK buffer offers an inexpensive user-friendly workflow to study transcriptional responses in tissues in health and disease as well as in therapeutic interventions.

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Selective Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibition by the SCH772984 Compound Attenuates In Vitro and In Vivo Inflammatory Responses and Prolongs Survival in Murine Sepsis Models

Cited by 11 publications

References 65 publications

Lactiplantibacillus plantarum LOC1 Isolated from Fresh Tea Leaves Modulates Macrophage Response to TLR4 Activation

Lactiplantibacillus plantarum LOC1 Isolated from Fresh Tea Leaves Modulates Macrophage Response to TLR4 Activation

Psilocin suppresses methamphetamine‐induced hyperlocomotion and acquisition of conditioned place preference via D2R‐mediated ERK signaling

CryoGrid-PIXUL-RNA: High throughput RNA isolation platform for tissue transcript analysis

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