Gentiana lutea is a bitter herb that is traditionally used to improve gastric disorders. Recently, we have shown that Gentiana lutea extract (GE) also modulates the lipid metabolism of human keratinocytes in vitro and in vivo. In the present study, we investigated the role of GE on ceramide synthesis in human primary keratinocytes (HPKs) and psoriasis-like keratinocytes. We could demonstrate that GE increased the concentrations of glucosylceramides and the ceramide AS/AdS subclass without affecting the overall ceramide content in HPKs. The expression of ceramide synthase 3 (CERS3) and elongases (ELOVL1 and 4) was reduced in psoriasis lesions compared to healthy skin. Psoriasis-like HPKs, generated by stimulating HPKs with cytokines that are involved in the pathogenesis of psoriasis (IL-17, TNF-α, IL-22 and IFN-γ) showed increased levels of IL-6, IL-8 and increased expression of DEFB4A, as well as decreased expression of ELOVL4. The treatment with GE partly rescued the reduced expression of ELOVL4 in psoriasis-like HPKs and augmented CERS3 expression. This study has shown that GE modulates ceramide synthesis in keratinocytes. Therefore, GE might be a novel topical treatment for skin diseases with an altered lipid composition such as psoriasis.
- MeSH
- ceramidy metabolismus MeSH
- elongasy mastných kyselin genetika metabolismus MeSH
- Gentiana chemie MeSH
- keratinocyty cytologie účinky léků metabolismus MeSH
- kultivované buňky MeSH
- lidé MeSH
- membránové proteiny genetika metabolismus MeSH
- metabolismus lipidů účinky léků MeSH
- oční proteiny genetika metabolismus MeSH
- primární buněčná kultura MeSH
- psoriáza genetika metabolismus MeSH
- regulace genové exprese účinky léků MeSH
- rostlinné extrakty chemie farmakologie MeSH
- sfingosin-N-acyltransferasa genetika metabolismus MeSH
- studie případů a kontrol MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The development and progression of colorectal cancer (CRC), a major cause of cancer-related death in the western world, is accompanied with alterations of sphingolipid (SL) composition in colon tumors. A number of enzymes involved in the SL metabolism have been found to be deregulated in human colon tumors, in experimental rodent studies, and in human colon cancer cells in vitro. Therefore, the enzymatic pathways that modulate SL levels have received a significant attention, due to their possible contribution to CRC development, or as potential therapeutic targets. Many of these enzymes are associated with an increased sphingosine-1-phosphate/ceramide ratio, which is in turn linked with increased colon cancer cell survival, proliferation and cancer progression. Nevertheless, more attention should also be paid to the more complex SLs, including specific glycosphingolipids, such as lactosylceramides, which can be also deregulated during CRC development. In this review, we focus on the potential roles of individual SLs/SL metabolism enzymes in colon cancer, as well as on the pros and cons of employing the current in vitro models of colon cancer cells for lipidomic studies investigating the SL metabolism in CRC.
- MeSH
- alkalická ceramidasa genetika metabolismus MeSH
- ceramidy metabolismus MeSH
- fosfotransferasy s alkoholovou skupinou jako akceptorem genetika metabolismus MeSH
- kyselá ceramidasa genetika metabolismus MeSH
- laktosylceramidy metabolismus MeSH
- lidé MeSH
- lysofosfolipidy metabolismus MeSH
- metabolismus lipidů genetika MeSH
- modely nemocí na zvířatech MeSH
- nádorové buňky kultivované MeSH
- nádory tračníku enzymologie genetika patologie MeSH
- neutrální ceramidasa genetika metabolismus MeSH
- protoonkogenní proteiny c-akt genetika metabolismus MeSH
- regulace genové exprese u nádorů * MeSH
- sfingolipidy metabolismus MeSH
- sfingosin-N-acyltransferasa genetika metabolismus MeSH
- sfingosin analogy a deriváty metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Cystic fibrosis is the most common genetic disease, in which symptoms may be alleviated but not fully eliminated. Ceramides have long been implicated in the inflammatory etiology of cystic fibrosis, with contradicting reports with regards to their role. Recently, significant biological and biophysical differences have been observed between long- and very long-chain ceramides. This work reveals that long-chain ceramides are upregulated whereas very long-chain ceramides are downregulated in cell lines, mouse animal model, and patients with cystic fibrosis, compared with their controls. Treatment with fenretinide decreases the levels of long-chain ceramides and increases the levels of very long-chain ceramides. Our results show that restoration of cystic fibrosis conductance regulator (CFTR) expression is associated with normalization of aberrant levels of specific ceramides. This demonstrates for the first time a correlation between CFTR protein expression and regulation of specific ceramide levels. Furthermore, using cystic fibrosis lung epithelial cell lines, we demonstrate that this effect can be attributed to the transcriptional downregulation of ceramide synthase 5 (Cers5) enzyme. We also discovered a partial synergism between fenretinide and zinc (Zn2+), which deficiency has been reported in patients with cystic fibrosis. Overall, in addition to having direct translational application, we believe that our findings contribute to the understanding of ceramide metabolism in cystic fibrosis, as well as other inflammatory diseases where imbalances of ceramides have also been observed. KEY MESSAGES: Long- and very long-chain ceramides (LCCs and VLCCs) are biochemically distinct. LCCs are upregulated whereas VLCCs are downregulated in cystic fibrosis. Fenretinide downregulates the levels of LCCs and upregulates the levels of VLCCs. Fenretinide changes the balance of LCCs and VLCCs by downregulating Cers5 enzyme. Fenretinide and zinc ions cooperate in the modulation of ceramide levels.
- MeSH
- aktivace transkripce účinky léků MeSH
- buněčné linie MeSH
- ceramidy analýza krev metabolismus MeSH
- cystická fibróza krev farmakoterapie metabolismus MeSH
- dospělí MeSH
- down regulace účinky léků MeSH
- fenretinid terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- PPAR gama agonisté MeSH
- sfingosin-N-acyltransferasa antagonisté a inhibitory genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH