The literature documenting the value of drug-like molecules found in natural products is vast. Although many dietary and herbal remedies have been found to be effective for treating intestinal inflammation, the identification of their active components has lagged behind. In this study, we find that a major ginger component, furanodienone (FDN), is a selective pregnane X receptor (PXR) ligand with agonistic transcriptional outcomes. We show that FDN binds within a sub-pocket of the PXR ligand binding domain (LBD), with subsequent alterations in LBD structure. Using male mice, we show that orally provided FDN has potent PXR-dependant anti-inflammatory outcomes that are colon-specific. Increased affinity and target gene activation in the presence of synergistically acting agonists indicates further opportunities for augmenting FDN activity, efficacy and safety. Collectively, these results support the translational potential of FDN as a therapeutic agent for the treatment and prevention of colonic diseases.
- MeSH
- Anti-Inflammatory Agents pharmacology chemistry MeSH
- Furans pharmacology MeSH
- Colitis drug therapy chemically induced metabolism pathology MeSH
- Colon drug effects pathology metabolism MeSH
- Humans MeSH
- Ligands MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Pregnane X Receptor * metabolism genetics MeSH
- Inflammation drug therapy metabolism MeSH
- Zingiber officinale * chemistry MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
The Aurora protein kinases are well-established regulators of spindle building and chromosome segregation in mitotic and meiotic cells. In mouse oocytes, there is significant Aurora kinase A (AURKA) compensatory abilities when the other Aurora kinase homologs are deleted. Whether the other homologs, AURKB or AURKC can compensate for loss of AURKA is not known. Using a conditional mouse oocyte knockout model, we demonstrate that this compensation is not reciprocal because female oocyte-specific knockout mice are sterile, and their oocytes fail to complete meiosis I. In determining AURKA-specific functions, we demonstrate that its first meiotic requirement is to activate Polo-like kinase 1 at acentriolar microtubule organizing centers (aMTOCs; meiotic spindle poles). This activation induces fragmentation of the aMTOCs, a step essential for building a bipolar spindle. We also show that AURKA is required for regulating localization of TACC3, another protein required for spindle building. We conclude that AURKA has multiple functions essential to completing MI that are distinct from AURKB and AURKC.
- MeSH
- Spindle Apparatus genetics MeSH
- Aurora Kinase A genetics MeSH
- Aurora Kinase B genetics MeSH
- Aurora Kinase C genetics MeSH
- Cell Nucleus Division genetics MeSH
- Fetal Proteins genetics MeSH
- Humans MeSH
- Meiosis genetics MeSH
- Mice MeSH
- Oocytes growth & development metabolism MeSH
- Microtubule-Organizing Center metabolism MeSH
- Spindle Poles genetics MeSH
- Protein Serine-Threonine Kinases genetics MeSH
- Microtubule-Associated Proteins genetics MeSH
- Cell Cycle Proteins genetics MeSH
- Proto-Oncogene Proteins genetics MeSH
- Chromosome Segregation genetics MeSH
- Gene Expression Regulation, Developmental genetics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
