A lipidomic study: Nobiletin ameliorates hepatic steatosis through regulation of lipid alternation.

Hepatic lipidome has been given emphasis for years since hepatic steatosis is the most remarkable character of nonalcoholic fatty liver diseases, an increasingly serious health issue worldwide. Nobiletin (NOB), one of the citrus flavonoids, exerted outstanding effect on lipid metabolism disorder. However, the underlying mechanism of NOB exerting effect on hepatic lipid alternation remains unclear. In this study, the animal model was built by feeding APOE-/- mice with high fat diet (HFD). The results of Oil Red O-stained liver section and the biochemical assay of lipid parameters confirmed the protective effect of NOB on hepatic steatosis and global lipid metabolism disorder in APOE-/- mice. The hepatic lipidomic study revealed a total of 958 lipids significantly altered by HFD and a total of 86, 116, 212 lipid metabolites changed by L-NOB (50 mg/kg/d NOB), M-NOB (100 mg/kg/d NOB) and H-NOB (200 mg/kg/d NOB) respectively. In the further screening analysis, an amount of 60 lipids were identified as the potential lipid markers of NOB treatment, most of which belonged to glycerophospholipids lipid categories and exhibited obvious correlation with each other and the lipid parameters related to hepatic steatosis. Taken together, our data demonstrated that glycerophospholipids metabolism played an indispensable role in the progression of hepatic steatosis and the protective effect of NOB. Besides, the modulation towards genes involved in lipid synthesis was observed after NOB administration in this study. These finding illustrated the antihepatic steatosis effect of NOB based on altering hepatic lipidome, particularly the glycerophospholipids metabolism, and provided a new insight in the pathogenesis of hepatic steatosis.

Nobiletin mitigates NAFLD via lipophagy and inflammation.

Nonalcoholic fatty liver disease (NAFLD), an increasingly serious health issue around the world, is characterized as a lipid metabolic disorder without any satisfactory treatment. Nobiletin (NOB), a citrus flavonoid, is considered a promising candidate for NAFLD prevention although there is limited research towards its exact mechanism. In this study, the preventative effect of NOB on NAFLD was investigated using high fat diet-fed ApoE-/- mice and free fatty acid-treated HepG2 cells. The results of hematoxylin and eosin staining of liver sections revealed that L-NOB (50 mg kg-1 d-1 NOB), M-NOB (100 mg kg-1 d-1 NOB) and H-NOB (200 mg kg-1 d-1 NOB) could significantly ameliorate NAFLD. Further exploration illustrated that NOB alleviated hepatic steatosis mainly via TFEB-mediated lysosomal biogenesis and lipophagy. Besides, NOB could mitigate NLRP3 inflammasome assembly and modulate M1/M2 macrophage polarization in vivo and in vitro. The mechanisms above allowed NOB to attenuate NAFLD, but their close association needed further investigation. Our research not only illustrated NOB as a potential candidate for NAFLD prevention, but also provided new insight into the pathogenic mechanisms of NAFLD development.

Subacute toxicity of mesoporous silica nanoparticles to the intestinal tract and the underlying mechanism.

The biological safety of mesoporous silica nanoparticles (MSNs) has gradually attracted attention. However, few studies of their toxicity to the intestine and mechanism are available. In this study, their primary structures were characterized, and their subacute toxicity to mice was investigated. After 2 weeks of intragastric administration of MSNs, they significantly enhanced serum ALP, ALT, AST and TNF-α levels and caused infiltration of inflammatory cells in the spleen and intestines. MSNs induced intestinal oxidative stress and colonic epithelial cell apoptosis in mice. Intestinal epithelial cells exhibited mitochondrial ridge rupture and membrane potential decrease after MSN treatment. Additionally, MSNs increased ROS and NLRP3 levels and inhibited expression of the autophagy proteins LC3-II and Beclin1. MSNs significantly changed the intestinal flora diversity in mice, especially for harmful bacteria, leading to intestinal microecology imbalance. Meanwhile, MSNs influenced the expression of metabolites, which were involved in a range of metabolic pathways, including pyrimidine metabolism, central carbon metabolism in cancer, protein digestion and absorption, mineral absorption, ABC transport and purine metabolism. These results indicated that the subacute toxicity of mesoporous silicon was mainly caused by intestinal damage. Thus, our research provides additional evidence about the safe dosage of MSNs in the clinical and food industries.

Novel fenugreek gum-cellulose composite hydrogel with wound healing synergism: Facile preparation, characterization and wound healing activity evaluation.

Hydrogels can be used as bioactive dressings, which outperform traditional dressings and are widely used in wound hemostasis and healing. However, it is still a challenge to develop a hydrogel with good stability and strong mechanical properties for wound hemostasis and healing. Herein, we developed a novel composite polysaccharide hydrogel from fenugreek gum and cellulose. Fenugreek gum was combined with cellulose through hydrogen bonding to form a hydrogel to improve the mechanical properties of the composite hydrogel. The composite hydrogel had a porous structure, thermal stability, good water absorption and a sustained release effect. Furthermore, the composite hydrogel demonstrated good biocompatibility in vitro and in vivo. Notably, the superior performance of wound hemostasis and healing has been confirmed. Our results indicated that the composite hydrogel was a promising medical dressing and had the potential to promote wound healing.

Injectable Hydrogel-Based Nanocomposites for Cardiovascular Diseases.

Cardiovascular diseases (CVDs), including a series of pathological disorders, severely affect millions of people all over the world. To address this issue, several potential therapies have been developed for treating CVDs, including injectable hydrogels as a minimally invasive method. However, the utilization of injectable hydrogel is a bit restricted recently owing to some limitations, such as transporting the therapeutic agent more accurately to the target site and prolonging their retention locally. This review focuses on the advances in injectable hydrogels for CVD, detailing the types of injectable hydrogels (natural or synthetic), especially that complexed with stem cells, cytokines, nano-chemical particles, exosomes, genetic material including DNA or RNA, etc. Moreover, we summarized the mainly prominent mechanism, based on which injectable hydrogel present excellent treating effect of cardiovascular repair. All in all, it is hopefully that injectable hydrogel-based nanocomposites would be a potential candidate through cardiac repair in CVDs treatment.

[Role of lipophagy in the regulation of lipid metabolism and the molecular mechanism].

Recent studies have discovered a selective autophagy-lipophagy, which can selectively identify and degrade lipids and plays an important role in regulating cellular lipid metabolism and maintaining intracellular lipid homeostasis. The process of lipophagy can be directly or indirectly regulated by genes, enzymes, transcriptional regulators and other factors. This review examines the role of lipophagy in reducing liver lipid content, regulating pancreatic lipid metabolism, and regulating adipose tissue differentiation, and summarizes the findings of the molecules (Rab GTPase, enzymes, ion channels, transcription factors, small molecular substances) involved in the regulation of lipophagy, which points to new directions for the treatment of diseases caused by lipid accumulation.

Bclaf1 promotes angiogenesis by regulating HIF-1α transcription in hepatocellular carcinoma.

The development of hepatocellular carcinomas (HCC) depends on their local microenvironment and the induction of neovascularization is a decisive step in tumor progression, since the growth of solid tumors is limited by nutrient and oxygen supply. Hypoxia is the critical factor that induces transcription of the hypoxia inducible factor-1α (HIF-1α) encoding gene HIF1A and HIF-1α protein accumulation to promote angiogenesis. However, the basis for the transcriptional regulation of HIF1A expression in HCC is still unclear. Here, we show that Bclaf1 levels are highly correlated with HIF-1α levels in HCC tissues, and that knockdown of Bclaf1 in HCC cell lines significantly reduces hypoxia-induced HIF1A expression. Furthermore, we found that Bclaf1 promotes HIF1A transcription via its bZIP domain, leading subsequently to increased transcription of the HIF-1α downstream targets VEGFA, TGFB, and EPO that in turn promote HCC-associated angiogenesis and thus survival and thriving of HCC cells. Moreover, we demonstrate that HIF-1α levels and microvessel density decrease after the shRNA-mediated Bclaf1 knockdown in xenograft tumors. Finally, we found that Bclaf1 levels increase in hypoxia in a HIF-1α dependent manner. Therefore, our study identifies Bclaf1 as a novel positive regulator of HIF-1α in the hypoxic microenvironment, providing new incentives for promoting Bcalf1 as a potential therapeutic target for an anti-HCC strategy.