An artificial "closed-loop" system that mimics the glucose-responsive insulin secretion of pancreas β-cells can potentially improve the treatment efficacy for diabetes. Herein, a lipid bilayer-coated polymeric nanoparticle (NP) with "core-shell" structure is designed. As far as it is known, it is the first and only intravenous nanoplatform utilizing enzymatic-oxidation scheme to achieve glucose-responsive insulin delivery so far. Ethoxy acetal-derivatized dextran nanoparticles (Ace-DEX NPs) are constructed as "inner core" loaded with insulin, and coloading glucose oxidase (GOx) and catalase (CAT) endow the "inner core" excellent glucose-sensitive ability. Red blood cell membrane (RBCm)-derived coating is adopted as "outer shell." It collectively provides a closed microenvironment for GOx-based enzymatic-oxidation scheme and camouflages it from elimination. Above all, the anchored glucose transporters (GLUTs) on the "outer shell" are able to sense blood glucose levels and facilitate the transport of outer blood glucose getting inside. Under a hyperglycemic condition, the internalized glucose is catalytically converted into gluconic acid with the aid of the GOx and subsequently triggers acid degradation of the "inner core" to secrete insulin. By governing the blood glucose levels on an automatic and continuous basis, the RBCm-Ace-DEX NPs can effectively respond to hyperglycemia and turn to resting conditions under normoglycemia.

In this study, we investigate the relationship between γ-PGA productivity and biocontrol capacity of Bacillus subtilis BsE1; one bacterial isolate displayed 62.14% biocontrol efficacy against Fusarium root rot. The γ-PGA yield assay, motility assay, wheat root colonization assay, and biological control assay were analysed in different γ-PGA yield mutants of BsE1. The pgsB (PGA-synthase-CapB gene) deleted mutant of BsE1 reduced γ-PGA yield and exhibited apparent decline of in vitro motile ability. Deletion of pgsB impaired colonizing capacity of BsE1 on wheat root in 30 days, also lowered biocontrol efficacies from 62.08% (wild type BsE1) to 14.22% in greenhouse experiment against Fusarium root rot. The knockout of pgdS and ggt (genes relate to two γ-PGA degrading enzymes) on BsE1, leads to a considerable improvement in polymer yield and biocontrol efficacy, which attains higher level compared with wild type BsE1. Compared with ΔpgsB mutant, defense genes related to reactive oxygen species (ROS) and phytoalexin expressed changes by notable levels on wheat roots treated with BsE1, demonstrating the functional role γ-PGA plays in biocontrol against Fusarium root rot. γ-PGA is not only important to the motile and plant root colonization ability of BsE1, but also essential to the biological control performed by BsE1 against Fusarium root rot. Our goal in this study is to reveals a new perspective of BCAs screening on bacterial isolates, without good performance during pre-assays of antagonism ability.

Summary Hepatic stellate cells (HSCs) play a central role in the progression of liver fibrosis by producing extracellular matrices. The development of drugs to suppress liver fibrosis has been hampered by the lack of human quiescent HSCs (qHSCs) and an appropriate in vitro model that faithfully recapitulates HSC activation. In the present study, we developed a culture system to generate qHSC-like cells from human-induced pluripotent stem cells (hiPSCs) that can be converted into activated HSCs in culture. To monitor the activation process, a red fluorescent protein ( RFP ) gene was inserted in hiPSCs downstream of the activation marker gene actin alpha 2 smooth muscle ( ACTA2 ). Using qHSC-like cells derived from RFP reporter iPSCs, we screened a repurposing chemical library and identified therapeutic candidates that prevent liver fibrosis. Hence, hiPSC-derived qHSC-like cells will be a useful tool to study the mechanism of HSC activation and to identify therapeutic agents.

No abstract

Problem Rupture of fetal membranes is a crucial event at parturition, which is preceded by extensive extracellular matrix (ECM) remodeling. Our recent studies have demonstrated that the human fetal membranes are capable of de novo synthesis of serum amyloid A1 (SAA1), an acute phase protein, and the abundance of SAA1 in the amnion was increased at parturition. However, the exact role of SAA1 in human parturition remains to be established. Method of study The effects of SAA1 on the abundance of collagenases and lysyl oxidase, the enzyme that cross‐links collagens, were investigated in culture primary human amnion fibroblasts and tissue explants with an aim to examine the involvement of SAA1 in the ECM remodeling in the amnion. Results Serum amyloid A1 (SAA1) time‐ and dose‐dependently increased the abundance of collagenases MMP‐1, MMP‐8, and MMP‐13, while decreased the abundance of lysyl oxidase‐like 1 (LOXL1). These effects of SAA1 were attenuated by siRNA‐mediated knockdown of the Toll‐like receptor (TLR) 4 and its antagonist CLI‐095, but not by siRNA‐mediated knockdown of TLR2. Furthermore, the inhibitors for NF‐κB (JSH‐23) and mitogen‐activated protein kinases (MAPKs) p38 (SB203580) and JNK (SP600125) could also attenuate the effects of SAA1, while the inhibitor for MAPK ERK1/2 (PD 98059) could block the effects of SAA1 only on MMP‐1, MMP‐8, and LOXL1 but not on MMP‐13. Conclusion These data highlight a possible role for SAA1 in ECM remodeling preceding membrane rupture by regulating the expression of collagenases MMP‐1, MMP‐8, MMP‐13, and LOXL1 through TLR4‐mediated activation of the NF‐κB and MAPK pathways in amnion fibroblasts.

Rice-flavor baijiu is one of the four basic flavor types of Chinese baijiu. Microbial composition plays a key role in the classification of baijiu flavor types and the formation of flavor substances. In this study, we used high-throughput sequencing technology to study the changes of microbial community in the production of rice-flavor baijiu, and compared the microbial community characteristics during production of rice-, light-, and strong-flavor baijiu. The results showed that the species diversity of bacteria was much higher than that of fungi during the brewing of rice-flavor baijiu. The bacterial diversity index first increased and then decreased, while the diversity of fungi showed an increasing trend. A variety of major microorganisms came from the environment and raw rice materials; the core bacteria were Lactobacillus, Weissella, Pediococcus, Lactococcus, Acetobacter, etc., among which Lactobacillus was dominant (62.88–99.23%). The core fungi were Saccharomyces (7.06–83.50%) and Rhizopus (15.21–90.89%). Temperature and total acid content were the main physicochemical factors affecting the microbial composition. Non-metric multidimensional scaling analysis showed that during the fermentation of rice-, light-, and strong-flavor baijiu, their microbial communities formed their own distinct systems, with considerable differences among different flavor types. Compared with the other two flavor types of baijiu, in the brewing process of rice-flavor baijiu, microbial species were fewer and dominant microorganisms were prominent, which may be the main reason for the small variety of flavor substances in rice-flavor baijiu. This study provides a theoretical basis for the production of rice-flavor baijiu, and lays a foundation for studying the link between baijiu flavor formation and microorganisms.

Hepatitis B, one of the most common contagious viral hepatitis with high infection rate, is challenging to treat. Although the treatment for hepatitis B has been improved over the years, many therapeutic drugs still have either severe adverse effects or insufficient effectiveness via systemic administration. In this study, we confirmed that glycyrrhetinic acid can enhance the accumulation of entecavir in HepaRG cell and liver. Then we constructed a novel albumin nanoparticle co-loading entecavir and glycyrrhetinic acid (ETV-GA-AN) to improve liver accumulation of entecavir and investigated its ability to deliver both drugs to liver. In vitro cellular uptake study and in vivo tissue distribution experiment showed that these negatively charged ETV-GA-AN (112 ± 2 nm in diameter) can increase the accumulation of entecavir in hepatic HepaRG cells and improve entecavir distribution in liver. We also revealed the mechanism that glycyrrhetinic acid enhances intracellular accumulation of entecavir by inhibiting the activity of specific efflux transporters. Our delivery system is the first liver-targeted albumin nanoparticle that utilizes the site-specific co-delivery strategy to delivery entecavir and glycyrrhetinic acid. As it combines high efficiency and low toxicity, it possess great potential for treating hepatitis B.

No abstract