icg-001 and Inflammation

Liver fibrosis is the common pathological basis of all chronic liver diseases, and is the necessary stage for the progression of chronic liver disease to cirrhosis. As one of pathogenic factors, inflammation plays a predominant role in liver fibrosis

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Hepatic Stellate Cells; Hepatocytes; Humans; Imidazoles; Inflammation; Inflammation Mediators; Liver; Liver Cirrhosis; Molecular Targeted Therapy; Protein Kinase Inhibitors; Pyrimidinones; Signal Transduction; Sulfoxides; Ursodeoxycholic Acid

In heart failure (HF) caused by hypertension, the myocyte size increases, and the cardiac wall thickens. A low-molecular-weight compound called ICG001 impedes β-catenin-mediated gene transcription, thereby protecting both the heart and kidney. However, the HF-preventive mechanisms of ICG001 remain unclear. Hence, we investigated how ICG001 can prevent cardiac hypertrophy and fibrosis induced by transverse aortic constriction (TAC). Four weeks after TAC, ICG001 attenuated cardiac hypertrophy and fibrosis in the left ventricular wall. The TAC mice treated with ICG001 showed a decrease in the following: mRNA expression of brain natriuretic peptide (Bnp), Klf5, fibronectin, β-MHC, and β-catenin, number of cells expressing the macrophage marker CD68 shown in immunohistochemistry, and macrophage accumulation shown in flow cytometry. Moreover, ICG001 may mediate the substrates in the glycolysis pathway and the distinct alteration of oxidative stress during cardiac hypertrophy and HF. In conclusion, ICG001 is a potential drug that may prevent cardiac hypertrophy and fibrosis by regulating KLF5, immune activation, and the Wnt/β-catenin signaling pathway and inhibiting the inflammatory response involving macrophages.

Topics: Animals; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; Cardiomegaly; Cardiomyopathies; Fibrosis; Glycolysis; Heart Failure; Inflammation; Kruppel-Like Transcription Factors; Macrophages; Membrane Proteins; Mice; Myocardium; Oxidative Stress; Phosphoproteins; Pyrimidinones; Wnt Signaling Pathway

The transcription factor β-catenin is able to induce tolerogenic/anti-inflammatory features in different types of dendritic cells (DCs). Monocyte-derived dendritic cells (moDCs) have been widely used in dendritic cell-based cancer therapy, but so far with limited clinical efficacy. We wanted to investigate the hypothesis that aberrant differentiation or induction of dual pro- and anti-inflammatory features may be β-catenin dependent in moDCs. β-catenin was detectable in both immature and lipopolysaccharide (LPS)-stimulated DCs. The β-catenin inhibitor ICG-001 dose-dependently increased the pro-inflammatory signature cytokine IL-12p70 and decreased the anti-inflammatory signature molecule IL-10. The β-catenin activator 6-bromoindirubin-3'-oxime (6-BIO) dose-dependently increased total and nuclear β-catenin, and this was associated with decreased IL-12p70, increased IL-10, and reduced surface expression of activation markers, such as CD80 and CD86, and increased expression of inhibitory markers, such as PD-L1. 6-BIO and ICG-001 competed dose-dependently regarding these features. Genome-wide mRNA expression analyses further underscored the dual development of pro- and anti-inflammatory features of LPS-matured moDCs and suggest a role for β-catenin inhibition in production of more potent therapeutic moDCs.

Topics: B7-H1 Antigen; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; Cell Differentiation; Cells, Cultured; Dendritic Cells; Gene Expression Regulation; Humans; Immune Tolerance; Indoles; Inflammation; Interleukin-10; Interleukin-12; Lipopolysaccharides; Monocytes; Oximes; Pyrimidinones

It is a great challenge to absorb and conduct biophysicochemical interactions at the nano-bio interface. Peptides are emerging as versatile materials whose function can be programmed to perform specific tasks. Peptides combined nanoparticles might be utilized as a new approach of treatment. Human β-defensin 3 (hBD3), possesses both antimicrobial and proregeneration properties. Gold nanoparticles (AuNPs) have shown promising applications in the field of tissue engineering. However, the coordinating effects of AuNPs and hBD3 on human periodontal ligament cells (hPDLCs) remain unknown. In this study, we systematically investigated whether AuNPs and hBD3 would be able to coordinate and enhance the osteogenic differentiation of hPDLCs in inflammatory microenvironments, and the underlying mechanisms was explored.. The present study demonstrated that hBD3 combined AuNPs could significantly promote the osteogenic differentiation of hPDLCs in inflammatory microenvironments via activating the Wnt/β-catenin signaling pathway.

Topics: Alkaline Phosphatase; beta Catenin; beta-Defensins; Bridged Bicyclo Compounds, Heterocyclic; Calcification, Physiologic; Cell Differentiation; Cell Survival; Cells, Cultured; Cellular Microenvironment; Core Binding Factor Alpha 1 Subunit; Escherichia coli; Gene Expression Regulation; Gold; Humans; Inflammation; Lipopolysaccharides; Metal Nanoparticles; Osteogenesis; Periodontal Ligament; Pyrimidinones; Real-Time Polymerase Chain Reaction; Wnt Signaling Pathway

Beta-catenin signaling has recently been tied to the emergence of tolerogenic dendritic cells (DCs). In this article, we demonstrate a novel role for beta-catenin in directing DC subset development through IFN regulatory factor 8 (IRF8) activation. We found that splenic DC precursors express beta-catenin, and DCs from mice with CD11c-specific constitutive beta-catenin activation upregulated IRF8 through targeting of the Irf8 promoter, leading to in vivo expansion of IRF8-dependent CD8a+, plasmacytoid, and CD103+ CD11b2 DCs. beta-catenin–stabilized CD8a+ DCs secreted elevated IL-12 upon in vitro microbial stimulation, and pharmacological beta-catenin inhibition blocked this response in wild-type cells. Upon infections with Toxoplasma gondii and vaccinia virus, mice with stabilized DC beta-catenin displayed abnormally high Th1 and CD8+ T lymphocyte responses, respectively. Collectively, these results reveal a novel and unexpected function for beta-catenin in programming DC differentiation toward subsets that orchestrate proinflammatory immunity to infection.

Topics: Animals; Antigens, CD; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; CD11c Antigen; CD8 Antigens; CD8-Positive T-Lymphocytes; Cell Differentiation; Dendritic Cells; Enzyme Activation; Female; Inflammation; Integrin alpha Chains; Interferon Regulatory Factors; Interleukin-12; Mice; Mice, Inbred C57BL; Mice, Knockout; Parasite Load; Promoter Regions, Genetic; Pyrimidinones; Receptors, Cell Surface; Signal Transduction; Spleen; Th1 Cells; Toxoplasma; Toxoplasmosis; Vaccinia; Vaccinia virus