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.

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.

Pancreatic ductal adenocarcinoma (PDAC) is associated with metaplastic changes in the pancreas but the transcriptional program underlying these changes is incompletely understood. The zinc finger transcription factor, PRDM3, is lowly expressed in normal pancreatic acini and its expression increases during tumorigenesis. Although PRDM3 promotes proliferation and migration of PDAC cell lines, the role of PRDM3 during tumor initiation from pancreatic acinar cells in vivo is unclear. In this study, we showed that high levels of PRDM3 expression in human pancreas was associated with pancreatitis, and well-differentiated but not poorly differentiated carcinoma. We examined PRDM3 function in pancreatic acinar cells during tumor formation and pancreatitis by inactivating Prdm3 using a conditional allele (Ptf1a CreER ;Prdm3 flox/flox mice) in the context of oncogenic Kras expression and supraphysiological cerulein injections, respectively. In Prdm3-deficient mice, Kras G12D-driven preneoplastic lesions were more abundant and progressed to high-grade precancerous lesions more rapidly. This is consistent with our observations that low levels of PRDM3 in human PDAC was correlated significantly with poorer survival in patient. Moreover, loss of Prdm3 in acinar cells elevated exocrine injury, enhanced immune cell activation and infiltration, and greatly increased acinar-to-ductal cell reprogramming upon cerulein-induced pancreatitis. Whole transcriptome analyses of Prdm3 knockout acini revealed that pathways involved in inflammatory response and Hif-1 signaling were significantly upregulated in Prdm3-depleted acinar cells. Taken together, our results suggest that Prdm3 favors the maintenance of acinar cell homeostasis through modulation of their response to inflammation and oncogenic Kras activation, and thus plays a previously unexpected suppressive role during PDAC initiation.

2Pancreatic ductal adenocarcinoma (PDAC) is associated with metaplastic changes in the 3 pancreas but the transcriptional program underlying these changes is incompletely understood. 4The zinc finger transcription factor, PRDM3, is lowly expressed in normal pancreatic acini and 5 its expression increases during tumorigenesis. Although PRDM3 promotes proliferation and 6 migration of PDAC cell lines, the role of PRDM3 during tumor initiation from pancreatic acinar 7 cells in vivo is unclear. In this study, we showed that high levels of PRDM3 expression in human 8 pancreas was associated with pancreatitis, and well-differentiated but not poorly differentiated 9 carcinoma. We examined PRDM3 function in pancreatic acinar cells during tumor formation and 10 pancreatitis by inactivating Prdm3 using a conditional allele (Ptf1a CreER ;Prdm3 flox/flox mice) in the 11 context of oncogenic Kras expression and supraphysiological cerulein injections, respectively. In 12Prdm3-deficient mice, Kras G12D -driven preneoplastic lesions were more abundant and progressed 13 to high-grade precancerous lesions more rapidly. This is consistent with our observations that 14 low levels of PRDM3 in human PDAC was correlated significantly with poorer survival in patient. 15Moreover, loss of Prdm3 in acinar cells elevated exocrine injury, enhanced immune cell 16 activation and infiltration, and greatly increased acinar-to-ductal cell reprogramming upon 17 cerulein-induced pancreatitis. Whole transcriptome analyses of Prdm3 knockout acini revealed 18 that pathways involved in inflammatory response and Hif-1 signaling were significantly 19 upregulated in Prdm3-depleted acinar cells. Taken together, our results suggest that Prdm3 20 favors the maintenance of acinar cell homeostasis through modulation of their response to 21 inflammation and oncogenic Kras activation, and thus plays a previously unexpected suppressive 22 role during PDAC initiation. 23

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.

Background Non-alcoholic steatohepatitis (NASH) is an advanced form of non-alcoholic fatty liver disease (NAFLD) for which there is yet any standard pharmacotherapy. Traditional Chinese medicine formula such as Qushihuayu (QSHY) composing of multiple bioactive compounds has been used to treat NAFLD and NASH and shows beneficial effects over single compound treatment. This study aimed to investigate the mechanism of hepatoprotective effect of QSHY formula using a rat model. Methods Six-weeks old male Wistar rats were given methionine/choline supplemented (MCS) diet for 8 weeks and used as the blank control. Another 7 rats, which received methionine/choline deficient (MCD) diet in the first 6 weeks and a MCS&MCD (1:1) mixture diet in the last 2 weeks, were used as the model group. The groups of QSHY pre-treatment, low dosage, medium dosage and high dosage were given the same diet as the model group. Except for pre-treatment group (1 week in advanced of other groups), all QSHY treatment groups received QSHY formula by gavage every day since the MCD diet started. Results In the MCD diet group, the QSHY formula decreased the serum ALT and AST levels, lipid droplets, inflammation foci, FAS and α-SMA protein expression than MCD diet group. MAPK pathways phospharylation were markedly depressed by the QSHY formula. Moreover, QSHY formula enhanced PPAR-γ and p-p65 translocating into nucleus. The administration of QSHY increased hepatic mRNA levels of Transcription Factor 1 alpha (HNF1A), Hepatocyte Nuclear Factor 4 alpha (HNF4A) and Forkhead box protein A3 (FOXA3) which play a pivotal role in Hepatic stellate cell (HSCs) reprogramming. Conclusion These findings suggest that QSHY formula exerts a hepatoprotective effect against steatosis and fibrosis presumably via depressed MAPK pathways phosphorylation, reinforcement of PPAR-γ and p-p65 translocating into nucleus and enhanced HSCs reprogramming.

Existing knowledge of the role of epigenetic modifiers in pancreas development has 15 exponentially increased. However, the function of TET dioxygenases in pancreatic endocrine 16 specification remains obscure. We set out to tackle this issue using a human embryonic stem cell 17 (hESC) differentiation system, in which TET1/TET2/TET3 triple knock-out cells displayed severe 18 defects in pancreatic β-cell specification. Integrative whole-genome analysis identified unique cell-19 type-specific hypermethylated regions (hyper-DMRs) displaying reduced chromatin activity and 20 remarkable enrichment for the binding of FOXA2, a pioneer transcription factor essential for 21 pancreatic endoderm specification. Intriguingly, hundreds of hyper-DMRs recently identified in type-22 2 diabetes pathogenesis overlapped with the hyper-DMRs we found in TET-deficient cells. 23Furthermore, transduction of TET1 in TET-deficient cells effectively rescued β-cell differentiation 24 and reversed hypermethylation and suppression of the β-cell determinant PAX4. Genome-wide 25 mapping of TET1 showed that TET1 co-localized at a subset of FOXA2 targets featuring high levels 26of active chromatin modifications in pancreatic progenitors. Taking these findings together with the 27 defective generation of functional β-cells upon TET1-inactivation, our study not only unveils an 28 essential role of TET1-dependent epigenetic regulation in establishing β-cell identity but also 29 provides a new mechanistic clue regarding the complex crosstalk between TET dioxygenases and 30 pioneer transcription factors in lineage specification. 31