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
- antiflogistika farmakologie chemie MeSH
- furany farmakologie MeSH
- kolitida farmakoterapie chemicky indukované metabolismus patologie MeSH
- kolon účinky léků patologie metabolismus MeSH
- lidé MeSH
- ligandy MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- pregnanový X receptor * metabolismus genetika MeSH
- zánět farmakoterapie metabolismus MeSH
- zázvor lékařský * chemie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články 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
- aparát dělícího vřeténka genetika MeSH
- aurora kinasa A genetika MeSH
- aurora kinasa B genetika MeSH
- aurora kinasa C genetika MeSH
- dělení bunečného jádra genetika MeSH
- fetální proteiny genetika MeSH
- lidé MeSH
- meióza genetika MeSH
- myši MeSH
- oocyty růst a vývoj metabolismus MeSH
- organizační centrum mikrotubulů metabolismus MeSH
- póly dělícího vřeténka genetika MeSH
- protein-serin-threoninkinasy genetika MeSH
- proteiny asociované s mikrotubuly genetika MeSH
- proteiny buněčného cyklu genetika MeSH
- protoonkogenní proteiny genetika MeSH
- segregace chromozomů genetika MeSH
- vývojová regulace genové exprese genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
