Bakuchiol and ethyl (linoleate/oleate) synergistically modulate endocannabinoid tone in keratinocytes and repress inflammatory pathway mRNAs
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ABSTRACT:
PROVIDER: PRJNA894510 | ENA |
REPOSITORIES: ENA
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Project description:The endocannabinoid (eCB) system plays an active role in epidermal homeostasis. Phytocannabinoids such as CBD modulate this system but also act through eCB-independent mechanisms. This study evaluated effects of CBD, bakuchiol (BAK) and ethyl (linoleate/oleate) (ELN) in keratinocytes (KCs) and reconstituted human epidermis (RHE). Molecular docking simulations showed that each compound binds the active site of the eCB carrier fatty-acid-binding protein 5 (FABP5). However, BAK and ethyl linoleate bound this site with highest affinity when combined 1:1 (w/w) and in vitro assays showed that BAK+ELN most effectively inhibited FABP5 and fatty acid amide hydrolase (FAAH). In TNF-stimulated KCs, BAK+ELN reversed TNF-induced expression shifts and uniquely down-regulated type I interferon genes and PTGS2 (COX-2). BAK+ELN also repressed expression of genes linked to KC differentiation but up-regulated those associated with proliferation. Finally, BAK+ELN inhibited cortisol secretion in RHE skin (not observed with CBD). These results support a model in which BAK and ELN synergistically interact to inhibit eCB degradation, favoring eCB mobilization and inhibition of downstream inflammatory mediators (e.g., TNF, COX-2, type I interferon). Topical combination of these ingredients may thus enhance cutaneous eCB tone or potentiate other modulators, suggesting new ways to modulate the eCB system for innovative skincare product development.
2022-11-23 | GSE216614 | GEO
Project description:The endocannabinoid (eCB) system plays an active role in epidermal homeostasis. Phytocannabinoids such as cannabidiol modulate this system but also act through eCB-independent mechanisms. This study evaluated the effects of cannabidiol, bakuchiol (BAK), and ethyl (linoleate/oleate) (ELN) in keratinocytes and reconstituted human epidermis. Molecular docking simulations showed that each compound binds the active site of the eCB carrier FABP5. However, BAK and ethyl linoleate bound this site with the highest affinity when combined 1:1 (w/w), and in vitro assays showed that BAK + ELN most effectively inhibited FABP5 and fatty acid amide hydrolase. In TNF-stimulated keratinocytes, BAK + ELN reversed TNF-induced expression shifts and uniquely downregulated type I IFN genes and PTGS2 (COX2). BAK + ELN also repressed expression of genes linked to keratinocyte differentiation but upregulated those associated with proliferation. Finally, BAK + ELN inhibited cortisol secretion in reconstituted human epidermis skin (not observed with cannabidiol). These results support a model in which BAK and ELN synergistically interact to inhibit eCB degradation, favoring eCB mobilization and inhibition of downstream inflammatory mediators (e.g., TNF, COX-2, type I IFN). A topical combination of these ingredients may thus enhance cutaneous eCB tone or potentiate other modulators, suggesting novel ways to modulate the eCB system for innovative skincare product development.
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Project description:HepG2 cells are only treated with 60 μg/ml sodium oleate as group 1, and treated with 60 μg/ml sodium oleate and 50 ng/ml E2 as group 2, and treated with 60 μg/ml sodium oleate, 50 ng/ml E2 and ER-alpha as group 3. All the treatment last for 48 hours and each group have two replications.
2019-10-05 | E-MTAB-7318 | biostudies-arrayexpress
Project description:A global transcriptomic study enables investigating human skeletal muscle gene targets of palmitate versus oleate and the capacity of oleate to alter palmitate-effects.
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Project description:Ethyl carbamate is a common food contaminant prevalent in fermented food with probable carcinogenic effects in animals. To date, other toxicological properties of ethyl carbamate are not well characterized. Using the genetic model Caenorhabditis elegans, we found that chronic exposure to ethyl carbamate during larval development inhibits growth while exposure at adulthood inhibits reproduction, shortens lifespan, and promotes degeneration of dopaminergic neurons. Through whole-transcriptome RNA-sequencing, we found that ethyl carbamate invokes a widespread transcriptomic response inducing the differential expression of > 4,000 genes by at least 2-fold. Functional analysis of RNA-sequencing data revealed that genes up-regulated enrich to various neuron regulatory processes and xenobiotic defense. Gene expression analysis confirms that various genes functioning within phase 1 and 2 detoxification responses along with ABC transporters are highly up-regulated in response to ethyl carbamate exposure, suggesting the induction of oxidative stress. Overall, these findings demonstrates new toxicological properties of chronic ethyl carbamate exposure and provide new insights into the effects in has on transcriptome regulation in the C. elegans model.
2022-04-13 | GSE190099 | GEO
Project description:Methanogenic and non-methanogenic oleate-degrading enrichment cultures
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Project description:The breakdown of epidermal barrier and consequent loss of skin hydration is a feature of skin aging and eczematous dermatitis. Few treatments, however, resolve these underlying processes to provide full symptomatic relief. In this study, we generated a novel compound, isosorbide di-(linoleate/oleate) (IDL), by esterifying isosorbide with sunflower fatty acids. Topical effects of IDL in skin were compared to those of ethyl linoleate/oleate (EL), which has previously been shown to improve skin barrier function. Both IDL and EL down-regulated inflammatory gene expression, but IDL more effectively up-regulated the expression of genes associated with keratinocyte differentiation (e.g., KRT1, GRHL2, SPRR4). Consistent with this, IDL increased abundance of epidermal barrier proteins (filaggrin and involucrin) and prevented cytokine-mediated stratum corneum degradation. IDL also down-regulated expression of “unhealthy skin signature” genes linked to loss of epidermal homeostasis and uniquely repressed an interferon-inducible co-expression module activated in multiple skin diseases including psoriasis. In a double-blind placebo-controlled trial enrolling females with dry skin, 2% IDL lotion applied over 2 weeks significantly improved skin hydration and decreased transepidermal water loss (NCT04253704). These results demonstrate mechanisms by which IDL improves skin hydration and epidermal barrier function, supporting IDL as an effective intervention for treatment of xerotic pruritic skin.
2020-11-16 | GSE157932 | GEO
Project description:Potent chemotherapeutic agents are required to counteract the aggressive behavior of cancer cells and patients often experience severe side effects, due to tissue toxicity. This study addresses if a better balance between efficacy and toxicity can be attained using the tumoricidal complex alpha1-oleate, formed by a synthetic, alpha-helical peptide comprising the N-terminal 39 amino acids of alpha-lactalbumin and the fatty acid oleic acid. Bladder cancer was established, by intra-vesical instillation of MB49 cells on day 0 and the treatment group received five instillations of alpha1-oleate (1.7-17mM) on days 3-11. A dose-dependent reduction in tumor size, bladder size and bladder weight was recorded in the alpha1-oleate treated group, compared to sham-treated mice. Tumor markers Ki-67, Cyclin D1 and VEGF were inhibited in a dose-dependent manner, as was the expression of cancer-related genes. Remarkably, toxicity for healthy tissue was not detected in alpha1-oleate-treated, tumor bearing mice or in healthy mice or rabbits, challenged with increasing doses of the active complex. The results define a dose-dependent therapeutic effect of alpha1-oleate in a murine bladder cancer model.
2020-04-09 | GSE148308 | GEO
Project description:The goal of the study was to determine the direct targets of four oleate-responsive transcription factors (Oaf1p, Pip2p, Oaf3p, Adr1p) in the presence and absence of the fatty acid oleate. This data is part of a larger study outlined below: A novel network topology-based clustering approach was used to characterize a dynamic transcriptional regulatory network responsive to the fatty acid oleate. Condition-specific large-scale chromatin localization data were generated for four fatty-acid related regulators, and used to construct physical interaction networks. Data integration and simple statistical analysis of dynamic network architecture led to the identification of a regulatory role for a previously uncharacterized protein, and unique mechanism for coordination and regulation of multiple biological responses through the formation of related parallel combinatorial control motifs. Temporal coordination and specificity are achieved through the ability of a regulator (Oaf1p) to have multiple context-specific activities under the same condition. The analysis suggests that active paths for a transcriptional response can be highly interconnected in parallel and involve multiple functions for individual regulators through combinatorial control. Keywords: ChIP-chip, growth condition
2007-04-19 | GSE5863 | GEO
Project description:Bladder cancer is common and one of the most costly cancer forms, due to a lack of curative therapies. Recently, clinical safety and efficacy of the alpha1-oleate complex was demonstrated in a placebo-controlled study of non-muscle invasive bladder cancer. This study investigated if long-term therapeutic efficacy is improved by repeated treatment cycles and by combining alpha1-oleate with low-dose chemotherapy. Rapidly growing bladder tumors were treated by intravesical instillation of alpha1-oleate, Epirubicin or Mitomycin C alone or in combination. One treatment cycle arrested tumor growth, with a protective effect lasting at least four weeks in mice receiving 8.5 mM of alpha1-oleate alone or 1.7 mM of alpha-oleate combined with Epirubicin or Mitomycin C. Repeated treatment cycles extended protection, defined by a lack of bladder pathology and a virtual absence of bladder cancer-specific gene expression. Synergy with Epirubicin was detected at the lower alpha1-oleate concentration and alpha1-oleate was shown to enhance the uptake and nuclear translocation of Epirubicin, by tumor cells. Effects at the chromatin level affecting cell proliferation were further suggested by reduced BrdU incorporation. In addition, alpha1-oleate triggered DNA fragmentation, defined by the TUNEL assay. The results suggest that bladder cancer development may be prevented long-term in the murine model, by alpha1-oleate alone or in combination with low-dose Epirubicin. In addition, the combination of alpha1-oleate and Epirubicin reduced the size of established tumors. Exploring these potent preventive and therapeutic effects will be of immediate interest in patients with bladder cancer.
2023-02-25 | GSE209881 | GEO