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Synthesis and physicochemical characterization of novel phenotypic probes targeting the nuclear factor-kappa B signaling pathway.

ABSTRACT: Activation of nuclear factor-kappa B (NF-?B) and related upstream signal transduction pathways have long been associated with the pathogenesis of a variety of inflammatory diseases and has recently been implicated in the onset of cancer. This report provides a synthetic and compound-based property summary of five pathway-related small-molecule chemical probes identified and optimized within the National Institutes of Health-Molecular Libraries Probe Center Network (NIH-MLPCN) initiative. The chemical probes discussed herein represent first-in-class, non-kinase-based modulators of the NF-?B signaling pathway, which were identified and optimized through either cellular phenotypic or specific protein-target-based screening strategies. Accordingly, the resulting new chemical probes may allow for better fundamental understanding of this highly complex biochemical signaling network and could advance future therapeutic translation toward the clinical setting.

SUBMITTER: Hershberger PM

PROVIDER: S-EPMC3678512 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Synthesis and physicochemical characterization of novel phenotypic probes targeting the nuclear factor-kappa B signaling pathway.

Hershberger Paul M PM Peddibhotla Satyamaheshwar S Sessions E Hampton EH Divlianska Daniela B DB Correa Ricardo G RG Pinkerton Anthony B AB Reed John C JC Roth Gregory P GP

Beilstein journal of organic chemistry 20130508

Activation of nuclear factor-kappa B (NF-κB) and related upstream signal transduction pathways have long been associated with the pathogenesis of a variety of inflammatory diseases and has recently been implicated in the onset of cancer. This report provides a synthetic and compound-based property summary of five pathway-related small-molecule chemical probes identified and optimized within the National Institutes of Health-Molecular Libraries Probe Center Network (NIH-MLPCN) initiative. The che ...[more]

PMID: 23766805

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Project description:Progranulin is closely related to neuronal survival in a neuroinflammatory mouse model and attenuates inflammatory reactions. Atsttrin is an engineered protein composed of three progranulin fragments and has been shown to have an effect similar to that of progranulin. Atsttrin has anti-inflammatory actions in multiple arthritis mouse models, and it protects against further arthritis development. However, whether Atsttrin has a role in neuroinflammation remains to be elucidated. In this study, we produced a neuroinflammatory mouse model by intracerebroventricular injection of 1 μL lipopolysaccharide (10 μg/μL). Atsttrin (2.5 mg/kg) was administered via intraperitoneal injection every 3 days over a period of 7 days before intracerebroventricular injection of 1 μL lipopolysaccharide (10 μg/μL). In addition, astrocyte cultures were treated with 0, 100 or 300 ng/mL lipopolysaccharide, with 200 ng/mL Atsttrin simultaneously. Immunohistochemistry, enzyme-linked immunosorbent assay and real-time reverse transcription-polymerase chain reaction were performed to examine the protein and mRNA levels of inflammatory mediators and to assess activation of the nuclear factor kappa B signaling pathway. Progranulin expression in the brain of wild-type mice and in astrocyte cultures was increased after lipopolysaccharide administration. The protein and mRNA expression levels of tumor necrosis factor-α, interleukin-1β and inducible nitric oxide synthase were increased in the brain of progranulin knockout mice after lipopolysaccharide administration. Atsttrin treatment reduced the lipopolysaccharide-induced increase in the protein and mRNA levels of tumor necrosis factor-α, interleukin-1β, matrix metalloproteinase-3 and inducible nitric oxide synthase in the brain of progranulin knockout mice. Atsttrin also reduced the expression of cyclooxygenase-2, inducible nitric oxide synthase and matrix metalloproteinase 3 mRNA in lipopolysaccharide-treated astrocytes in vitro, and decreased the concentration of tumor necrosis factor a and interleukin-1β in the supernatant. Furthermore, Atsttrin significantly reduced the levels of phospho-nuclear factor kappa B inhibitor a in the brain of lipopolysaccharide-treated progranulin knockout mice and astrocytes, and it decreased the expression of nuclear factor kappa B2 in astrocytes. Collectively, our findings show that the anti-neuroinflammatory effect of Atsttrin involves inhibiton of the nuclear factor kappa B signaling pathway, and they suggest that Atsttrin may have clinical potential in neuroinflammatory therapy. The study was approved by the Animal Ethics Committee of Qilu Hospital of Shandong University, China (approval No. KYLL-2015(KS)-088) on February 10, 2015.

Dataset Information

Synthesis and physicochemical characterization of novel phenotypic probes targeting the nuclear factor-kappa B signaling pathway.

Publications

Synthesis and physicochemical characterization of novel phenotypic probes targeting the nuclear factor-kappa B signaling pathway.

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