RESUMEN
Urolithin A (UroA), a dietary phytochemical, is produced by gut bacteria from fruits rich in natural polyphenols ellagitannins (ETs). The efficiency of ETs metabolism to UroA in humans depends on gut microbiota. UroA has shown a variety of pharmacological activities. In this study we investigated the effects of UroA on atherosclerotic lesion development and stability. Apolipoprotein E-deficient (ApoE-/-) mice were fed a high-fat and high-cholesterol diet for 3 months to establish atherosclerosis model. Meanwhile the mice were administered UroA (50 mg·kg-1·d-1, i.g.). We showed that UroA administration significantly decreased diet-induced atherosclerotic lesions in brachiocephalic arteries, macrophage content in plaques, expression of endothelial adhesion molecules, intraplaque hemorrhage and size of necrotic core, while increased the expression of smooth muscle actin and the thickness of fibrous cap, implying features of plaque stabilization. The underlying mechanisms were elucidated using TNF-α-stimulated human endothelial cells. Pretreatment with UroA (10, 25, 50 µM) dose-dependently inhibited TNF-α-induced endothelial cell activation and monocyte adhesion. However, the anti-inflammatory effects of UroA in TNF-α-stimulated human umbilical vein endothelial cells (HUVECs) were independent of NF-κB p65 pathway. We conducted RNA-sequencing profiling analysis to identify the differential expression of genes (DEGs) associated with vascular function, inflammatory responses, cell adhesion and thrombosis in UroA-pretreated HUVECs. Human disease enrichment analysis revealed that the DEGs were significantly correlated with cardiovascular diseases. We demonstrated that UroA pretreatment mitigated endothelial inflammation by promoting NO production and decreasing YAP/TAZ protein expression and TEAD transcriptional activity in TNF-α-stimulated HUVECs. On the other hand, we found that UroA administration modulated the transcription and cleavage of lipogenic transcription factors SREBP1/2 in the liver to ameliorate cholesterol metabolism in ApoE-/- mice. This study provides an experimental basis for new dietary therapeutic option to prevent atherosclerosis.
RESUMEN
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) pose a significant threat to human health and cause a tremendous socioeconomic burden. Currently, the molecular mechanisms of NAFLD and NASH remain incompletely understood, and no effective pharmacotherapies have been approved. In the past five years, significant advances have been achieved in our understanding of the pathomechanisms and potential pharmacotherapies of NAFLD and NASH. Research advances include the investigation of the effects of the fibroblast growth factor 21 (FGF21) analog pegozafermin and the thyroid hormone receptor-ß (THRß) agonist resmetriom on hepatic fat content, NASH resolution and/or fibrosis regression. Future directions of NAFLD and NASH research (including combination therapy, organoids and humanized mouse models) are also discussed in this state-of-the-art review.
Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Animales , Ratones , Humanos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Hígado/metabolismo , Fibrosis , Terapia Combinada , Modelos Animales de EnfermedadRESUMEN
In the area of surgical applications, understanding the interaction between medical device materials and tissue is important since this interaction may cause complications. The interaction often consists of a cell monolayer touching the medical device that can be mimicked in vitro. Prominent examples of this are contact lenses, where epithelial cells interact with the contact lens, or stents and catheters, which are in contact with endothelial cells. To investigate those interactions, in previous studies, expensive microtribometers were used to avoid pressures in the contact area far beyond physiologically relevant levels. Here, we aim to present a new methodology that is cost- and time-efficient, more accessible than those used previously and allows for the application of more realistic pressures, while permitting a quantification of the damage caused to the monolayer. For this, a soft polydimethylsiloxane is employed that better mimics the mechanical properties of blood vessels than materials used in other studies. Furthermore, a technique to account for misalignments within the experiment set-up is presented. This is carried out using the raw spatial and force data recorded by the tribometer and adjusting for misalignments. The methodology is demonstrated using an endothelial cell (human umbilical vein endothelial cells) monolayer.