The tone of the enteric cannabinoids system is disturbed in STC, and the decreased enteric FAAH activity contributes to colonic inertia in STC.

Background: Aortic dissecting aneurysm (ADA) represents an aortic remodeling disease with a high mortality rate. Fat mass and obesity-associated protein (FTO) exerts RNA demethylation function to regulate gene expression related to stem cell differentiation, DNA damage repair, and tumorigenesis, but the role of FTO in ADA is still unclear.Methods: The expression and location of FTO in 43 ADA tissues and 11 normal tissues were determined by RT-qPCR, WB, immunohistochemistry, and immunofluorescence staining. Detecting proliferation and migration of VSMCs. M6A methylated RNA immuno-precipitation qRT-PCR and dual luciferase reporter assay were performed for determining m6A level and interaction between m6A modulation and Klf5 mRNA, respectively.Results: FTO are highly expressed in VSMCs. FTO was positively correlated with BMI, triglyceride, and D-dimer (all P < 0.05). Functionally, both AngII-induced FTO expression and over expression of FTO promote cell proliferation and migration, whereas knockdown of FTO inhibits these functions. Mechanically, we identified Krüppel-like factor 5 (Klf5) as a target of FTO mediating m6A modification. Overexpression of FTO reduced m6A modification on Klf5 mRNA and promoted Klf5 mRNA expression. Furthermore, the p-GSK3β and Klf5 levels increased after FTO overexpression. Finally, knockdown of FTO suppresses the p-GSK3β levels and Klf5 expression regardless of AngII treatment.Conclusions: Our study revealed that FTO expression significantly contributes to the phenotype conversion of VSMCs and the ADA by the demethylation function (m6A), thereby providing a novel therapeutic target.

Novel effective drugs are still urgently needed in the prevention and treatment of oral adenoid cystic carcinoma (ACC). In this study, we have assessed the antitumor potential and molecular mechanisms of flavokawain B (FKB) as a kava chalcone on the ACC-2 cell line in vitro. The results demonstrated that FKB could significantly inhibit the cell proliferation of ACC-2 in a dose-dependent manner that was associated with induced apoptosis and cell cycle G2-M arrest, and the half maximal inhibitory concentration (IC50) of flavokawain-B treatment for 48 h was estimated to be 4.69 ± 0.43 µmol/L. Mechanistically, FKB could induce the release of cytochrome c from mitochondria into the cytosol, and activate the cleavage of caspase-3 and, eventually, the poly(ADP-ribose) polymerase (PARP), in a dose-dependent manner, leading to marked apoptotic effect of ACC-2 cells. The apoptotic action of FKB was associated with the increased expression of proapoptotic proteins: Bim, Bax, Bak and a decreased expression of antiapoptotic Bcl-2. Among them, Bim expression was significantly induced by FKB, and knockdown of Bim expression by short-hairpin RNAs attenuated the inhibitory effect induced by FKB on ACC-2 cells. These results suggest Bim may be one of the potential transcriptional targets, and suggests the potential usefulness of FKB for the prevention and treatment of ACC.Key words: flavokawain B (FKB), apoptosis, Bcl-2, Bim, ACC-2.Résumé : Il existe toujours un besoin urgent de nouveaux médicaments efficaces pour la prévention et le traitement du carcinome adénoïde kystique (CAK). Dans la présente étude, nous avons évalué le potentiel antitumoral et les mécanismes moléculaires du flavokawain B (FKB), une chalcone issue du kava, sur les cellules CAK-2 in vitro. Les résultats ont montré que FKB a pu inhiber considérablement la prolifération des cellules CAK-2 en fonction de la dose administrée, ce qui été associé à l'arrêt du cycle cellulaire en G2-M et à l'induction de l'apoptose, et que la valeur CI 50 après le traitement au flavokawain B pendant 48 heures a été de 4,69 ± 0,43 µmol/L. Du point de vue des mécanismes, FKB a pu induire la libération du cytochrome c des mitochondries dans le cytosol, et activer le clivage de la caspase-3 et de la poly(ADP-ribose) polymé-rase (PARP) de manière dose dépendante, ce qui a eu un effet apoptotique marqué sur les cellules CAK-2. L'action apoptotique de FKB a été associée à la surexpression des protéines pro-apoptotiques Bim, Bax, Bak et à la sous-expression de la Bcl-2 antiapoptotique. FKB a particulièrement augmenté l'expression de Bim, et l'inhibition de cette expression par les petits ARN en épingle à cheveux a atténué l'effet inhibiteur induit par FKB sur les cellules CAK-2. Ces résultats donnent à penser que Bim pourrait être une cible de transcription potentielle et que FKB pourrait être utile pour la prévention et le traitement du CAK.

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