Paraquat, as one of the most widely used herbicides globally, is highly toxic to humans, and chronic exposure and acute ingestion leads to high morbidity and mortality rates. Here, we report user-friendly, photo-responsive paraquat-loaded supramolecular vesicles, prepared via one-pot self-assembly of amphiphilic, ternary host-guest complexes between cucurbit[8]uril, paraquat, and an azobenzene derivative. In this vesicle formulation, paraquat is only released upon UV or sunlight irradiation that converts the azobenzene derivative from its trans- to its cis- form, which in turn dissociates the ternary host-guest complexations and the vesicles. The cytotoxicity evaluation of this vesicle formulation of paraquat on in vitro cell models, in vivo zebrafish models, and mouse models demonstrates an enhanced safety profile. Additionally, the PQ-loaded vesicles’ herbicidal activity against a model of invasive weed is nearly identical to that of free paraquat under natural sunlight. This study provides a safe yet effective herbicide formulation.

In parallel with the prevalence metabolic syndrome, nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in most countries. It features a constellation of simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and even hepatocellular carcinoma. There are no approved drugs for effective management of NAFLD and NASH. Jianpi Huoxue formula (JPHX) mainly consists of Atractylodes macrocephal (Baizhu), Salvia miltiorrhiza (Danshen), Rasux Paeonia Alba (Baishao), Rhizoma Alismatis (Zexie), and Fructus Schisandrae Chinensis (Wuweizi), which may have beneficial effects on NAFLD. The aim of the study was to identify the effect of JPHX on NAFLD. A NAFLD model was induced by methionine-choline-deficient food (MCD) in Wistar rats and orally administered with simultaneous JPHX, once a day for 8 weeks. Hepatocellular injury, lipid profile, inflammation, fibrosis, and apoptosis were evaluated. The results showed that JPHX significantly decreased the abnormal serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels compared with the MCD model (P<0.05). Furthermore, JPHX protected MCD diet-fed rats from accumulation of hepatic triglycerides (TG) and total cholesterol (TC). Histological examination demonstrated that JPHX noticeably normalized the NAFLD activity score (NAS). Moreover, JPHX ameliorated liver inflammation by decreasing TNF-α levels and reduced collagen and matrix metalloproteinases in MCD diet-fed rats. In addition, JPHX prevented rats from MCD-induced cellular apoptosis, as suggested by TUNEL staining, and suppressed the activation of caspase 3 and 7 proteins. JPHX also inhibited the phosphorylation of JNK. In conclusion, JPHX exhibited a hepatoprotective effect against NAFLD in an MCD experimental model.

Existing knowledge of the role of epigenetic modifiers in pancreas development has exponentially increased. However, the function of TET dioxygenases in pancreatic endocrine specification remains obscure. We set out to tackle this issue using a human embryonic stem cell (hESC) differentiation system, in which TET1/TET2/TET3 triple knockout cells display severe defects in pancreatic β-cell specification. The integrative whole-genome analysis identifies unique cell-type-specific hypermethylated regions (hyper-DMRs) displaying reduced chromatin activity and remarkable enrichment of FOXA2, a pioneer transcription factor essential for pancreatic endoderm specification. Intriguingly, TET depletion leads to significant changes in FOXA2 binding at the pancreatic progenitor stage, in which gene loci with decreased FOXA2 binding feature low levels of active chromatin modifications and enriches for bHLH motifs. Transduction of full-length TET1 but not the TET1-catalytic-domain in TET-deficient cells effectively rescues β-cell differentiation accompanied by restoring PAX4 hypomethylation. Taking these findings together with the defective generation of functional β-cells upon TET1-inactivation, our study unveils an essential role of TET1-dependent demethylation in establishing β-cell identity. Moreover, we discover a physical interaction between TET1 and FOXA2 in endodermal lineage intermediates, which provides a mechanistic clue regarding the complex crosstalk between TET dioxygenases and pioneer transcription factors in epigenetic regulation during pancreas specification.

Objective: To evaluate the effect LMHFV on body weight gain, NAFLD and muscle strength and explore effect in mitochondrial biogenesis, AMPKα and p38 pathways. Methods: Vibration platform used in this study provides specific whole-body cyclic mechanical stimulation at low magnitude (0.3 g) and high frequency (50 Hz). Diabetic mice (8-9 mice per group) (C57BL/KsJ-m+/+Lepr db) were randomly divided into untreated group (no vibration) and two vibration groups. Lean mice (8 mice) were used as non-diabetic control for both groups. Two diabetic vibration groups received LMHFV every day for 20 min/day and 40 min/day separately. Results: After 8 weeks of treatment, results showed that body weight, liver weight, fat pad weight, glucose level and insulin level were lower in vibration group when compared with the untreated group. The ratio of fat in liver was significantly decreased after vibration treatment. Muscle strength was significantly increased after vibration. Mitochondrial biogenesis-related gene expression was increased in soleus, gastrocnemius and liver. AMPKα mRNA expression level was increased in soleus and gastrocnemius after vibration treatment. p38 and AMPKα mRNA expression level and protein expression level in liver were enhanced with vibration treatment. Moreover, phosphorylation of p38 and AMPKα was enhanced in liver. Conclusion: LMHFV applied in our study decreases body weight gain and improves muscle strength and NAFLD in diabetic mice which were partly through improving mitochondrial biogenesis by enhancing p38 and AMPKα pathway.