Edible plant extracellular vesicles: An emerging tool for bioactives delivery.

The extracellular vesicles (EVs) in edible food have a typical saucer-like structure and are nanoparticles released by numerous cells. They have different components and interact with other biological samples in diverse ways. Therefore, these nanoparticles could be used to develop bioactives delivery nanoplatforms and anti-inflammatory treatments to meet the stringent demands of current clinical challenges. This review aims to summarize current researches into EVs from edible plants, particularly those that can protect siRNAs or facilitate drug transportation. We will discuss their isolation, characterization and functions, their regulatory effects under various physiological and pathological conditions, and their immune regulation, anti-tumor, regeneration, and anti-inflammatory effects. We also review advances in their potential application as bioactives carriers, and medicinal and edible plants that change their EVs compositions during disease to achieve a therapy propose. It is expected that future research on plant-derived EVs will considerably expand their application.

Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis.

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease that is increasingly prevalent worldwide. Liver inflammation is an important contributor to disease progression from nonalcoholic fatty liver (NAFL) to NASH, but there is a lack of efficient therapies. In the current study we evaluated the therapeutic potential of givinostat, a histone deacetylase (HDAC) inhibitor, in the treatment of NASH in vivo and in vitro. Liver inflammation was induced in mice by feeding a methionine- and choline-deficient diet (MCD) or a fructose, palmitate, cholesterol diet (FPC). The mice were treated with givoinostat (10 mg·kg-1·d-1, ip) for 8 or 10 weeks. At the end of the experiment, the livers were harvested for analysis. We showed that givoinostat administration significantly alleviated inflammation and attenuated hepatic fibrosis in MCD-induced NASH mice. RNA-seq analysis of liver tissues form MCD-fed mice revealed that givinostat potently blocked expression of inflammation-related genes and regulated a broad set of lipid metabolism-related genes. In human hepatocellular carcinoma cell line HepG2 and human derived fetal hepatocyte cell line L02, givinostat significantly decreased palmitic acid-induced intracellular lipid accumulation. The benefit of givinostat was further confirmed in FPC-induced NASH mice. Givinostat administration significantly attenuated hepatic steatosis, inflammation as well as liver injury in this mouse model. In conclusion, givinostat is efficacious in reversing diet-induced NASH, and may serve as a therapeutic agent for the treatment of human NASH.

P300/CBP inhibition sensitizes mantle cell lymphoma to PI3Kδ inhibitor idelalisib.

Mantle cell lymphoma (MCL) is a lymphoproliferative disorder lacking reliable therapies. PI3K pathway contributes to the pathogenesis of MCL, serving as a potential target. However, idelalisib, an FDA-approved drug targeting PI3Kδ, has shown intrinsic resistance in MCL treatment. Here we report that a p300/CBP inhibitor, A-485, could overcome resistance to idelalisib in MCL cells in vitro and in vivo. A-485 was discovered in a combinational drug screening from an epigenetic compound library containing 45 small molecule modulators. We found that A-485, the highly selective catalytic inhibitor of p300 and CBP, was the most potent compound that enhanced the sensitivity of MCL cell line Z-138 to idelalisib. Combination of A-485 and idelalisib remarkably decreased the viability of three MCL cell lines tested. Co-treatment with A-485 and idelalisib in Maver-1 and Z-138 MCL cell xenograft mice for 3 weeks dramatically suppressed the tumor growth by reversing the unsustained inhibition in PI3K downstream signaling. We further demonstrated that p300/CBP inhibition decreased histone acetylation at RTKs gene promoters and reduced transcriptional upregulation of RTKs, thereby inhibiting the downstream persistent activation of MAPK/ERK signaling, which also contributed to the pathogenesis of MCL. Therefore, additional inhibition of p300/CBP blocked MAPK/ERK signaling, which rendered maintaining activation to PI3K-mTOR downstream signals p-S6 and p-4E-BP1, thus leading to suppression of cell growth and tumor progression and eliminating the intrinsic resistance to idelalisib ultimately. Our results provide a promising combination therapy for MCL and highlight the potential use of epigenetic inhibitors targeting p300/CBP to reverse drug resistance in tumor.