s100a8 a9 inhibitor  (TargetMol)

Journal: Journal of Inflammation Research

Article Title: S100A8/A9 Inhibition Reduces Neutrophil Extracellular Trap Formation and Mitigates Sepsis-Related Liver Injury

doi: 10.2147/JIR.S609689

Figure Lengend Snippet: Baseline Characteristics of Healthy Controls (HCs), Patients Without Sepsis-Related Liver Injury (SRLI), or Patients Without Sepsis-Related Liver Injury (Non-SRLI)

Article Snippet: To investigate the effect of S100A8/A9 on SRLI, wild-type mice were intraperitoneally injected with the S100A8/A9 inhibitor paquinimod (MedChemExpress, Monmouth Junction, NJ, USA) at a dose of 10 mg/kg 24 h before CLP or sham surgery.

Techniques:

Journal: Journal of Inflammation Research

Article Title: S100A8/A9 Inhibition Reduces Neutrophil Extracellular Trap Formation and Mitigates Sepsis-Related Liver Injury

doi: 10.2147/JIR.S609689

Figure Lengend Snippet: Receiver Operating Characteristic (ROC) Curve Analysis Results of S100A8/A9 on Patients Without Sepsis-Related Liver Injury (SRLI)

Article Snippet: To investigate the effect of S100A8/A9 on SRLI, wild-type mice were intraperitoneally injected with the S100A8/A9 inhibitor paquinimod (MedChemExpress, Monmouth Junction, NJ, USA) at a dose of 10 mg/kg 24 h before CLP or sham surgery.

Techniques:

Journal: Theranostics

Article Title: Single-cell RNA sequencing reveals that myeloid S100A8/A9 is a novel regulator of the transition from adaptive hypertrophy to heart failure after pressure overload

doi: 10.7150/thno.118369

Figure Lengend Snippet: S100A9 is upregulated during cardiac hypertrophy and heart failure. (A) Protein concentrations of S100A8/A9 heterodimer in human plasma (n = 119 for normal and n = 143 for HF). (B) Association between S100A8/A9 heterodimer and plasma BNP in patients with HF. (C) mRNA levels of S100A8/A9 in sham- or TAC-treated hearts (n = 6). (D) Representative immunoblots of the S100A8 and S100A9 cardiac signaling proteins and the GAPDH loading control (left). The right panel shows the quantification of these proteins (n = 6). (E) Protein levels of S100A8/A9 heterodimer in mouse plasma (n = 10). (F) A schematic representation of the single-cell workflow based on a public dataset ( GSE122930 ). Samples were isolated from the hearts of TAC- or sham-operated C57BL6/J male mice 1 or 4 weeks after surgery in duplicate. Hearts were digested, and live CD45 + cells were FACS-sorted and loaded for scRNA-seq. (G) Two-dimensional t-distributed stochastic neighbor embedding (tSNE) visualization of 17853 cardiac CD45 + (immune) cells identified 8 distinct cell types that were classified into 19 clusters after unsupervised clustering. Each point depicts a single cell, which is colored according to cluster designation. (H) t-SNE plots showing the expression of the S100A8 and S100A9 genes. The expression levels of the genes are indicated by blue color intensity. (l) Violin plots showing the expression levels of the S100A8 and S100A9 genes in all cell types. (J) Volcano plots showing differentially expressed genes in neutrophils and macrophages between the TAC (1- and 4-week) and sham groups. The values are presented as the means ± SDs (n = number of humans or animals). *p < 0.05, **p < 0.01 and ***p < 0.001 vs. the normal control or sham group.

Article Snippet: WT mice received daily intraperitoneal injections of the S100A8/A9 inhibitor ABR-238901 (E1134, MedChemExpress) at 30 mg/kg/day for four consecutive weeks.

Techniques: Clinical Proteomics, Western Blot, Control, Isolation, Expressing

Journal: Theranostics

Article Title: Single-cell RNA sequencing reveals that myeloid S100A8/A9 is a novel regulator of the transition from adaptive hypertrophy to heart failure after pressure overload

doi: 10.7150/thno.118369

Figure Lengend Snippet: S100A8/A9 expression is upregulated in cardiac neutrophils at one week post TAC in mice. (A) t-SNE plot of the two neutrophil subpopulations (Mature_Neu_1 and Immature_Neu_2). (B) Dot plots of signature genes confirming the subpopulation identities. (C) Monocle analyses showing the ordering of neutrophil cells along pseudotime trajectories. The minute dots in the illustration signify cells, with diverse colors denoting distinct clusters or states. (D) Violin plots showing the expression levels of the S100A8 and S100A9 genes in all neutrophils from the TAC and Sham groups at 1 week. (E) Violin plots showing the expression levels of the S100A8 and S100A9 genes in the two neutrophil subgroups between the TAC and sham groups at 1 week. (F) Top 10 Gene Ontology (GO) pathways associated with genes upregulated in the neutrophils from the TAC group versus those from the Sham group at 1 week. (G) The top 10 enriched KEGG pathways associated with the genes whose expression was upregulated in neutrophils from the TAC group versus those from the sham group at 1 week. (H) Lollipop plot showing the expression levels of differentially expressed inflammatory factors. (I) S100A9-KO and WT mice were subjected to TAC for one week to assess cardiac dysfunction and hypertrophy. Representative immunoblots of the phosphorylated (p)-p38, p38, p-JNK, JNK, p-c-Jun, c-Jun, p-c-Fos, and c-Fos cardiac signaling proteins, as well as the GAPDH loading control (upper). The lower panel shows the quantification of these proteins (n = 4). (J) Cardiac qPCR analyses of CCL2 and CCL6 (n = 6). The values are presented as the means ± SDs (n = number of animals). **p < 0.01 and ***p < 0.001 vs. the WT + sham group; # p < 0.05, ## p < 0.01 and ### p < 0.001 vs. the WT + TAC 1-week group.

Article Snippet: WT mice received daily intraperitoneal injections of the S100A8/A9 inhibitor ABR-238901 (E1134, MedChemExpress) at 30 mg/kg/day for four consecutive weeks.

Techniques: Expressing, Western Blot, Control

Journal: Theranostics

Article Title: Single-cell RNA sequencing reveals that myeloid S100A8/A9 is a novel regulator of the transition from adaptive hypertrophy to heart failure after pressure overload

doi: 10.7150/thno.118369

Figure Lengend Snippet: S100A8/A9 expression is upregulated in cardiac macrophages at four weeks post TAC in mice. (A) t-SNE plot of the three macrophage subpopulations (OSM + CCR2 + M1, CCR2 - M2, and CCR2 - M1). (B) Dot plots of signature genes confirming the subpopulation identities. (C) Monocle analyses showing the ordering of macrophages along pseudotime trajectories. The minute dots in the illustration signify cells, with diverse colors denoting distinct clusters or states. (D) Percentages of the macrosubpopulations in the sham and TAC groups. (E) Violin plots showing the expression levels of the S100A8 and S100A9 genes in three types of neutrophils in the TAC and sham groups at 4 weeks. (F) Differential gene expression in the OSM2 + CCR2 + M1 macrophage subgroup. Volcano plots displaying all differentially expressed genes in OSM2 + CCR2 + macrophages from the TAC group versus the sham group at 4 weeks. S100A8 and S100A9 were the top two genes whose expression was most significantly upregulated in the TAC group. (G) Gene Ontology (GO) pathway enrichment results for 300 genes upregulated in OSM2 + CCR2 + M1 macrophages from the TAC group compared with the sham group at 4 weeks. (H) KEGG pathways associated with 300 upregulated genes in OSM2 + CCR2 + M1 macrophages from the TAC group compared with those from the sham group at 4 weeks. (I) S100A9-KO and WT mice were subjected to TAC for 4 weeks to assess cardiac dysfunction and hypertrophy. Representative images of H&E-stained cardiac tissue. (J) Cardiac immunofluorescence staining with Mac-2 antibody (left, red) and quantification of the results (right, n = 10). (K) Cardiac qPCR analyses of IL-1β and TNF-α (n = 8). (L) Representative immunoblots of the p-p65, p65, and NLRP3 proteins, as well as the GAPDH loading control (left). The right panel shows the quantification of the results (n = 4). The values are presented as the means ± SDs (n = number of animals). **p < 0.01 and ***p < 0.001 vs. the WT + sham group; ## p < 0.01 and ### p < 0.001 vs. the WT + TAC 4-week group.

Article Snippet: WT mice received daily intraperitoneal injections of the S100A8/A9 inhibitor ABR-238901 (E1134, MedChemExpress) at 30 mg/kg/day for four consecutive weeks.

Techniques: Expressing, Gene Expression, Staining, Immunofluorescence, Western Blot, Control

Journal: Theranostics

Article Title: Single-cell RNA sequencing reveals that myeloid S100A8/A9 is a novel regulator of the transition from adaptive hypertrophy to heart failure after pressure overload

doi: 10.7150/thno.118369

Figure Lengend Snippet: The S100A9-specific inhibitor ABR-238901 attenuates TAC-induced cardiac hypertrophy and dysfunction. (A) Molecular structure of the S100A9-specific antagonist ABR-238901. (B) WT mice were treated with ABR-238901 at a dosage of 30 mg/kg/day and subjected to TAC for 4 weeks. (C) Representative echocardiographic images (left) and quantified EF% (right, n = 10). (D) Ratio of LW to TL (n =10). (E) Representative images of H&E-stained cardiac tissue (left) and the HW/TL ratio (right, n = 10). (F) Representative images of cardiac tissue subjected to WGA staining (left) and the relative area of cardiomyocytes (right, n = 10). (G) Representative images of cardiac tissue subjected to Masson's staining (left) and the quantified fibrotic area (right, n = 10). (H) Cardiac immunohistochemical staining with an α-SMA antibody (left) and quantification of the results (right, n = 10). (I) Cardiac immunofluorescence staining with a COL3A1 antibody (left, green) and quantification of the results (right, n = 10). (J) Cardiac qPCR analyses of ANP, BNP, α-SMA and COL1A1 (n = 10). (K) Cardiac immunofluorescence staining with Mac-2 antibody (left, red) and quantification of the results (right, n = 10). (L) Cardiac qPCR analyses of IL-1β and TNF-α (n = 10). (M) Representative immunoblots of the p-AKT, AKT, CaNA, TGF-β, p-Smad2, Smad2, p-p65, p65, and NLRP3 proteins, as well as the GAPDH loading control (left). The right panel shows the quantification of these proteins (n = 4). The values are presented as the means ± SDs (n = number of animals). ***p < 0.001 vs. the vehicle + sham group; # p < 0.05, ## p < 0.01 and ### p < 0.001 vs. the vehicle + TAC group.

Article Snippet: WT mice received daily intraperitoneal injections of the S100A8/A9 inhibitor ABR-238901 (E1134, MedChemExpress) at 30 mg/kg/day for four consecutive weeks.

Techniques: Staining, Immunohistochemical staining, Immunofluorescence, Western Blot, Control

Journal: Theranostics

Article Title: Single-cell RNA sequencing reveals that myeloid S100A8/A9 is a novel regulator of the transition from adaptive hypertrophy to heart failure after pressure overload

doi: 10.7150/thno.118369

Figure Lengend Snippet: Schematic diagram of the proposed model. TAC induces early neutrophil infiltration, characterized by high expression of S100A8/A9. This response triggers inflammation and adaptive cardiac hypertrophy via the p38 MAPK/JNK/AP-1 axis, which induces release of CCL2 and CCL6. These secreted chemokines subsequently promote infiltration of the BM-derived CCR2 + macrophages, which also present elevated S100A8/A9 expression. Mechanistically, S100A8/A9 activates ER stress/NF-κB/NLRP3 signaling, which promotes the polarization of macrophages toward the M1 phenotype, while concurrently stimulating the AKT/Calcineurin A and TGF-β/Smad2/3 pathways. This cascade ultimately exacerbates maladaptive cardiac hypertrophy and accelerates HF progression.

Article Snippet: WT mice received daily intraperitoneal injections of the S100A8/A9 inhibitor ABR-238901 (E1134, MedChemExpress) at 30 mg/kg/day for four consecutive weeks.

Techniques: Expressing, Derivative Assay