Cystic fibrosis (CF) is the most common autosomal-recessive disease in Caucasians caused by mutations in the CF transmembrane regulator (CFTR) gene. Patients are usually diagnosed in infancy and are burdened with extensive medical treatments throughout their lives. One of the first documented biochemical defects in CF, which predates the cloning of CFTR gene for almost three decades, is an imbalance in the levels of polyunsaturated fatty acids (PUFAs). The principal hallmarks of this imbalance are increased levels of arachidonic acid and decreased levels of docosahexaenoic acids (DHA) in CF. This pro-inflammatory profile of PUFAs is an important component of sterile inflammation in CF, which is known to be detrimental, rather than protective for the patients. Despite decades of intensive research, the mechanistic basis of this phenomenon remains unclear. In this review we summarized the current knowledge on the biochemistry of PUFAs, with a focus on the metabolism of AA and DHA in CF. Finally, a synthetic retinoid called fenretinide (N-(4-hydroxy-phenyl) retinamide) was shown to be able to correct the pro-inflammatory imbalance of PUFAs in CF. Therefore, its pharmacological actions and clinical potential are briefly discussed as well.
- MeSH
- antiflogistika farmakologie terapeutické užití MeSH
- cystická fibróza farmakoterapie metabolismus MeSH
- esenciální mastné kyseliny metabolismus MeSH
- fenretinid farmakologie terapeutické užití MeSH
- lidé MeSH
- nenasycené mastné kyseliny metabolismus MeSH
- zánět farmakoterapie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Zona pellucida binding protein 2 (Zpbp2) and ORMDL sphingolipid biosynthesis regulator 3 (Ormdl3), mapped downstream of Zpbp2, were identified as two genes associated with airway hyper-responsiveness (AHR). Ormdl3 gene product has been shown to regulate the biosynthesis of ceramides. Allergic asthma was shown to be associated with an imbalance between very-long-chain ceramides (VLCCs) and long-chain ceramides (LCCs). We hypothesized that Fenretinide can prevent the allergic asthma-induced augmentation of Ormdl3 gene expression, normalize aberrant levels of VLCCs and LCCs, and treat allergic asthma symptoms. We induced allergic asthma by house dust mite (HDM) in A/J WT mice and Zpbp2 KO mice expressing lower levels of Ormdl3 mRNA than WT. We investigated the effect of a novel formulation of Fenretinide, LAU-7b, on the AHR, inflammatory cell infiltration, mucus production, IgE levels, and ceramide levels. Although lower Ormdl3 expression, which was observed in Zpbp2 KO mice, was associated with lower AHR, allergic Zpbp2 KO mice were not protected from inflammatory cell infiltration, mucus accumulation, or aberrant levels of VLCCs and LCCs induced by HDM. LAU-7b treatment protects both the Zpbp2 KO and WT mice. The treatment significantly lowers the gene expression of Ormdl3, normalizes the VLCCs and LCCs, and corrects all the other phenotypes associated with allergic asthma after HDM challenge, except the elevated levels of IgE. LAU-7b treatment prevents the augmentation of Ormdl3 expression and ceramide imbalance induced by HDM challenge and protects both WT and Zpbp2 KO mice against allergic asthma symptoms. SIGNIFICANCE STATEMENT: Compared with A/J WT mice, KO mice with Zpbp2 gene deletion have lower AHR and lower levels of Ormdl3 expression. The novel oral clinical formulation of Fenretinide (LAU-7b) effectively lowers the AHR and protects against inflammatory cell infiltration and mucus accumulation induced by house dust mite in both Zpbp2 KO and WT A/J mice. LAU-7b prevents Ormdl3 overexpression in WT allergic mice and corrects the aberrant levels of very-long-chain and long-chain ceramides in both WT and Zpbp2 KO allergic mice.
- MeSH
- bronchiální astma farmakoterapie metabolismus MeSH
- ceramidy metabolismus MeSH
- down regulace účinky léků MeSH
- exprese genu účinky léků MeSH
- fenretinid farmakologie MeSH
- membránové proteiny metabolismus MeSH
- modely nemocí na zvířatech MeSH
- myši knockoutované MeSH
- myši MeSH
- respirační alergie farmakoterapie metabolismus MeSH
- zánět metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Although the administration of retinoids represents an important part of treatment for children suffering from high-risk neuroblastomas, approximately 50% of these patients do not respond to this therapy or develop resistance to retinoids during treatment. Our study focused on the comparative analysis of the expression of five genes and corresponding proteins (DDX39A, HMGA1, HMGA2, HOXC9 and PBX1) that have recently been discussed as possible predictive biomarkers of clinical response to retinoid differentiation therapy. Expression of these five candidate biomarkers was evaluated at both the mRNA and protein level in the same subset of 8 neuroblastoma cell lines after treatment with natural or synthetic retinoids. We found that the cell lines that were HMGA2-positive and/or HOXC9-negative have a reduced sensitivity to retinoids. Furthermore, the experiments revealed that the retinoid-sensitive cell lines showed a uniform pattern of change after treatment with both natural and sensitive retinoids: increased DDX39A and decreased PBX1 protein levels. Our results showed that in NBL cells, these putative protein biomarkers are associated with sensitivity or resistance to retinoids, and their endogenous or induced expression can distinguish between these two phenotypes.
- MeSH
- antitumorózní látky farmakologie MeSH
- bexaroten farmakologie MeSH
- biomarkery farmakologické metabolismus MeSH
- chemorezistence účinky léků genetika MeSH
- DEAD-box RNA-helikasy genetika metabolismus MeSH
- dítě MeSH
- fenretinid farmakologie MeSH
- fixace tkání MeSH
- homeodoménové proteiny genetika metabolismus MeSH
- isotretinoin farmakologie MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- nádorové buněčné linie MeSH
- nádory nervového systému genetika metabolismus patologie chirurgie MeSH
- neuroblastom genetika metabolismus patologie chirurgie MeSH
- novorozenec MeSH
- pre-B-buněčný leukemický transkripční faktor 1 genetika metabolismus MeSH
- předškolní dítě MeSH
- proliferace buněk účinky léků MeSH
- protein HMGA1A genetika metabolismus MeSH
- protein HMGA2 genetika metabolismus MeSH
- tretinoin analogy a deriváty farmakologie MeSH
- zalévání tkání do parafínu MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- antirevmatika aplikace a dávkování farmakologie MeSH
- fenretinid aplikace a dávkování farmakologie MeSH
- geny BRCA1 MeSH
- geny BRCA2 MeSH
- karcinom diagnóza prevence a kontrola MeSH
- kontraceptiva orální hormonální aplikace a dávkování farmakologie MeSH
- lidé MeSH
- nádorové biomarkery krev MeSH
- nádory vaječníků farmakoterapie chirurgie prevence a kontrola MeSH
- plošný screening metody MeSH
- vitamin D MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- MeSH
- antitumorózní látky farmakokinetika farmakologie toxicita MeSH
- ceramidy farmakokinetika farmakologie toxicita MeSH
- deferoxamin farmakokinetika farmakologie toxicita MeSH
- fenretinid farmakokinetika farmakologie toxicita MeSH
- hodnocení léčiv metody využití MeSH
- hydroxymočovina farmakokinetika farmakologie MeSH
- hypoxie buňky účinky léků MeSH
- lékařská onkologie metody trendy MeSH
- modely u zvířat MeSH
- paclitaxel farmakokinetika farmakologie MeSH
- sfingosin farmakokinetika farmakologie MeSH
- způsoby aplikace léků MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- MeSH
- analýza kolonii tvořících jednotek využití MeSH
- antitumorózní látky farmakokinetika farmakologie toxicita MeSH
- deferoxamin farmakokinetika farmakologie toxicita MeSH
- fenretinid farmakokinetika farmakologie toxicita MeSH
- fluorescenční mikroskopie metody přístrojové vybavení využití MeSH
- lékařská onkologie metody trendy MeSH
- leukemie farmakoterapie imunologie MeSH
- lidé MeSH
- melfalan farmakokinetika farmakologie toxicita MeSH
- neuroblastom farmakoterapie imunologie MeSH
- nežádoucí účinky léčiv MeSH
- průtoková cytometrie využití MeSH
- sfingosin farmakokinetika farmakologie toxicita MeSH
- techniky tkáňových kultur využití MeSH
- testy toxicity metody přístrojové vybavení využití MeSH
- Check Tag
- lidé MeSH
