Aflatoxin B1 (AFB1) is a potent hepatocarcinogen in humans and exposure to AFB1 is known to cause both acute and chronic hepatocellular injury. As the liver is known to be the main target organ of aflatoxin, it is important to identify the key molecules that participate in AFB1-induced hepatotoxicity and to investigate their underlying mechanisms. In this study, the critical role of caveolin-1 in AFB1-induced hepatic cell apoptosis was examined. We found a decrease in cell viability and an increase in oxidation and apoptosis in human hepatocyte L02 cells after AFB1 exposure. In addition, the intracellular expression of caveolin-1 was increased in response to AFB1 treatment. Downregulation of caveolin-1 significantly alleviated AFB1-induced apoptosis and decreased cell viability, whereas overexpression of caveolin-1 reversed these effects. Further functional analysis showed that caveolin-1 participates in AFB1-induced oxidative stress through its interaction with Nrf2, leading to the downregulation of cellular antioxidant enzymes and the promotion of oxidative stress-induced apoptosis. In addition, caveolin-1 was found to regulate AFB1-induced autophagy. This finding was supported by the effect that caveolin-1 deficiency promoted autophagy after AFB1 treatment, leading to the inhibition of apoptosis, whereas overexpression of caveolin-1 inhibited autophagy and accelerated apoptosis. Interestingly, further investigation showed that caveolin-1 participates in AFB1-induced autophagy by regulating the EGFR/PI3K-AKT/mTOR signaling pathway. Taken together, our data reveal that caveolin-1 plays a crucial role in AFB1-induced hepatic cell apoptosis via the regulation of oxidation and autophagy, which provides a potential target for the development of novel treatments to combat AFB1 hepatotoxicity.

The cytotoxic effects of thirteen triterpene glycosides from Holothuria scabra Jaeger and Cucumaria frondosa Gunnerus (Holothuroidea) against four human cell lines were detected and their cytotoxicity-structure relationships were established. The apoptosis-inducing activity of a more potent glycoside echinoside A (1) in HepG2 cells was further investigated by determining its effect on the morphology, mitochondrial transmembrane potential (Δψ_m) and mRNA expression levels of the apoptosis-related genes. The results showed that the number of glycosyl residues in sugar chains and the side chain of aglycone could affect their cytotoxicity towards tumor cells and selective cytotoxicity. 1 significantly inhibited cell viability and induced apoptosis in HepG2 cells. 1 also markedly decreased the Δψ_m and Bcl-2/Bax mRNA express ratio, and up-regulated the mRNA expression levels of Caspase-3, Caspase-8 and Caspase-9 in HepG2 cells. Therefore, 1 induced apoptosis in HepG2 cells through both intrinsic and extrinsic pathway. These findings could potentially promote the usage of these glycosides as leading compounds for developing new antitumor drugs.

Background: Sulfur mustard (SM) is a highly toxic chemical warfare agent that has caused numerous casualties during wars and conflicts in the past century. Specific antidotes or therapeutic strategies are rare due to the complicated mechanism of toxicity, which still awaits elucidation. Clinical data show that acute lung injury (ALI) is responsible for most mortality and morbidity after SM exposure. Extracellular vesicles are natural materials that participate in intercellular communication by delivering various substances and can be modified. In this study, we aim to show that extracellular vesicles derived from human umbilical cord mesenchymal stromal cells (hucMSC-EVs) could exert therapeutic effects on SM-induced ALI, and to explain the underlying mechanism of effects. Methods: MiR-146a-5p contained in hucMSC-EVs may be involved in the process of hucMSC-EVs modulating the inflammatory response to SM-induced ALI. We utilized miR-146a-5p delivered by extracellular vesicles and further modified hucMSCs with a miR-146a-5p mimic or inhibitor to collect miR-146a-5p-overexpressing extracellular vesicles (miR-146a-5p⁺-EVs) or miR-146a-5p-underexpressing extracellular vesicles (miR-146a-5p⁻-EVs), respectively. Through in vivo and in vitro experiments, we investigated the mechanism. Results: The effect of miR-146a-5p⁺-EVs on improving the inflammatory reaction tied to SM injury was better than that of hucMSC-EVs. We demonstrated that miR-146a-5p delivered by hucMSC-EVs targeted TRAF6 to negatively regulate inflammation in SM-induced ALI models in vitro and in vivo. Conclusion: In summary, miR-146a-5p delivered by hucMSC-EVs targeted TRAF6, causing hucMSC-EVs to exert anti-inflammatory effects in SM-induced ALI; thus, hucMSC-EVs treatment may be a promising clinical therapeutic after SM exposure. Graphical

Four new triterpene glycosides, variegatusides C–F (1–4), together with three structurally known triterpene glycosides, variegatusides A and B (5, 6), and holothurin B (7), were isolated from the sea cucumber Stichopus variegates Semper (Holothuriidae), collected from the South China Sea. Their structures were elucidated on the basis of extensive spectral analysis (nuclear magnetic resonance (NMR) and electrospray ionization mass spectrometry (ESIMS)) and chemical evidence. Variegatusides C–F exhibit the same structural feature consisting of the presence of a 23-hydroxyl group at the holostane-type triterpene aglycone side chain. Variegatuside C (1) has a double bond (24, 25) in this same chain, while variegatuside D (2) exhibits a 8(9)-ene bond in the holostane-type triterpene aglycone, which has not been extracted from other sea cucumber species. Compound 4 is a native compound from the sea cucumber S. variegates Semper, which has been reported to be desacetylstichloroside B₁. Except for holothurin B, these glycosides have no sulfate group in their sugar chain and show potent antifungal activities in vitro biotests.

In animals, growth and development are strongly correlated with the gut microbiota and metabolic profiles. In this study, gut microbiome communities, metabolic profiles, and growth performance of Eriocheir sinensis under three dietary feed types based on waterweed plants only, freshwater snails only, and waterweed plants combined with freshwater snails were studied by using 16S rRNA gene sequencing and liquid chromatography-mass spectrometry. Results indicated that different feed types dramatically affected the growth performances of E. sinensis by altering the gut microbiota and metabolic profiles. Aquatic plants, such as waterweeds, played essential roles in shaping gut microbiome communities, and the optimal Bacteroides-to-Firmicutes ratio might strongly promote growth performance. Waterweed plants also helped decrease maleficent Proteobacteria caused by excess animal-type feedstuff, such as freshwater snails, and might have positive roles in antibacterial functions in gut. A diet based on waterweeds only resulted in lipid metabolism disorders, which significantly retarded the growth of E. sinensis. In summary, E. sinensis cultured with a diet of waterweeds and freshwater snails showed superior growth performance due to their healthy gut microbiota and metabolic homeostasis. Our findings unveiled the roles of aquatic plants and animal-type food such as freshwater snail in shaping the gut microbiota and metabolic processes and provided guidance for the aquaculture of E. sinensis in future.

Background: In routine clinical practice, non-standard doses of direct oral anticoagulants (DOACs) are commonly used in patients with atrial fibrillation (AF). However, data on the clinical outcomes of non-standard doses of DOACs are limited.Methods: The MEDLINE, Embase, and Cochrane Library databases were systematically searched from their inception until 30 June 2020 for studies that reported the effectiveness or safety outcomes of non-standard doses of DOACs compared with on-label doses of DOACs in patients with atrial fibrillation. Non-standard doses of DOACs were defined as under or over-dose of DOACs based on the recommended standard doses in drug labels. A random-effects meta-analysis was performed to calculate the pooled hazard ratio and associated 95% confidence interval (95% confidence interval). Subgroup analyses were conducted according to individual DOACs and different geographic regions.Results: Ten articles involving 148,909 patients with AF were included. There were no significant differences between under-dosing and on-label dosing with respect to stroke/systematic embolism (HR: 1.01, 95% CI: 0.93–1.09), major bleeding (HR: 0.98, 95% CI: 0.77–1.19), intracranial haemorrhage (HR: 1.07, 95% CI: 0.74–1.40), gastrointestinal bleeding (HR: 1.10, 95% CI: 0.82–1.39), and myocardial infarction (HR: 1.07, 95% CI: 0.89–1.25), except for an increased risk of death (HR: 1.37, 95% CI: 1.01–1.73). We observed a significant association between over-dosing of DOACs and increased risk of stroke/systematic embolism (HR: 1.18, 95% CI: 1.04–1.32), major bleeding (HR: 1.16, 95% CI: 1.03–1.29), and death (HR: 1.21, 95% CI: 1.03–1.38) compared with on-label dosing. Furthermore, over-dosing of DOACs increased the risk of stroke/systematic embolism (HR: 1.16; 95% CI: 1.00–1.33) and major bleeding events (HR: 1.18; 95% CI: 1.00–1.37) in Asian patients.Conclusion: A reduced dose of DOACs might be safely and effectively used in clinical practice, especially in Asian patients, whereas high-dose DOACs might not be well tolerated by Asian patients.