Vicious Cycle-Breaking Lipid Nanoparticles Remodeling Multicellular Crosstalk to Reverse Liver Fibrosis.

During liver fibrogenesis, the reciprocal crosstalk among capillarized liver sinusoidal endothelial cells (LSECs), activated hepatic stellate cells (HSCs), and dysfunctional hepatocytes constructs a self-amplifying vicious cycle, greatly exacerbating the disease condition and weakening therapeutic effect. Limited by the malignant cellular interactions, the previous single-cell centric treatment approaches show unsatisfactory efficacy and fail to meet clinical demand. Herein, a vicious cycle-breaking strategy is proposed to target and repair pathological cells separately to terminate the malignant progression of liver fibrosis. Chondroitin sulfate-modified and vismodegib-loaded nanoparticles (CS-NPs/VDG) are designed to efficiently normalize the fenestrae phenotype of LSECs and restore HSCs to quiescent state by inhibiting Hedgehog signaling pathway. In addition, glycyrrhetinic acid-modified and silybin-loaded nanoparticles (GA-NPs/SIB) are prepared to restore hepatocytes function by relieving oxidative stress. The results show successful interruption of vicious cycle as well as distinct fibrosis resolution in two animal models through multiregulation of the pathological cells. This work not only highlights the significance of modulating cellular crosstalk but also provides a promising avenue for developing antifibrotic regimens.

An Autologous Macrophage-Based Phenotypic Transformation-Collagen Degradation System Treating Advanced Liver Fibrosis.

In advanced liver fibrosis (LF), macrophages maintain the inflammatory environment in the liver and accelerate LF deterioration by secreting proinflammatory cytokines. However, there is still no effective strategy to regulate macrophages because of the difficulty and complexity of macrophage inflammatory phenotypic modulation and the insufficient therapeutic efficacy caused by the extracellular matrix (ECM) barrier. Here, AC73 and siUSP1 dual drug-loaded lipid nanoparticle is designed to carry milk fat globule epidermal growth factor 8 (MFG-E8) (named MUA/Y) to effectively inhibit macrophage proinflammatory signals and degrade the ECM barrier. MFG-E8 is released in response to the high reactive oxygen species (ROS) environment in LF, transforming macrophages from a proinflammatory (M1) to an anti-inflammatory (M2) phenotype and inducing macrophages to phagocytose collagen. Collagen ablation increases AC73 and siUSP1 accumulation in hepatic stellate cells (HSCs) and inhibits HSCs overactivation. Interestingly, complete resolution of liver inflammation, significant collagen degradation, and HSCs deactivation are observed in methionine choline deficiency (MCD) and CCl4 models after tail vein injection of MUA/Y. Overall, this work reveals a macrophage-focused regulatory treatment strategy to eliminate LF progression at the source, providing a new perspective for the clinical treatment of advanced LF.

Progress on the pathological tissue microenvironment barrier-modulated nanomedicine.

Imbalance in the tissue microenvironment is the main obstacle to drug delivery and distribution in the human body. Before penetrating the pathological tissue microenvironment to the target site, therapeutic agents are usually accompanied by three consumption steps: the first step is tissue physical barriers for prevention of their penetration, the second step is inactivation of them by biological molecules, and the third step is a cytoprotective mechanism for preventing them from functioning on specific subcellular organelles. However, recent studies in drug-hindering mainly focus on normal physiological rather than pathological microenvironment, and the repair of damaged physiological barriers is also rarely discussed. Actually, both the modulation of pathological barriers and the repair of damaged physiological barriers are essential in the disease treatment and the homeostasis maintenance. In this review, we present an overview describing the latest advances in the generality of these pathological barriers and barrier-modulated nanomedicine. Overall, this review holds considerable significance for guiding the design of nanomedicine to increase drug efficacy in the future.

Sequential Nano-Penetrators of Capillarized Liver Sinusoids and Extracellular Matrix Barriers for Liver Fibrosis Therapy.

During liver fibrogenesis, liver sinusoidal capillarization and extracellular matrix (ECM) deposition construct dual pathological barriers to drug delivery. Upon capillarization, the vanished fenestrae in liver sinusoidal endothelial cells (LSECs) significantly hinder substance exchange between blood and liver cells, while excessive ECM further hinders the delivery of nanocarriers to activated hepatic stellate cells (HSCs). Herein, an efficient nanodrug delivery system was constructed to sequentially break through the capillarized LSEC barrier and the deposited ECM barrier. For the first barrier, LSEC-targeting and fenestrae-repairing nanoparticles (named HA-NPs/SMV) were designed on the basis of the modification with hyaluronic acid and the loading of simvastatin (SMV). For the second barrier, collagenase I and vitamin A codecorated nanoparticles with collagen-ablating and HSC-targeting functions (named CV-NPs/siCol1α1) were prepared to deliver siCol1α1 with the goal of inhibiting collagen generation and HSC activation. Our in vivo results showed that upon encountering the capillarized LSEC barrier, HA-NPs/SMV rapidly released SMV and exerted a fenestrae-repairing function, which allowed more CV-NPs/siCol1α1 to enter the space of Disse to degrade deposited collagen and finally to achieve higher accumulation in activated HSCs. Scanning electronic microscopy images showed the recovery of liver sinusoids, and analysis of liver tissue sections demonstrated that HA-NPs/SMV and CV-NPs/siCol1α1 had a synergetic effect. Our pathological barrier-normalization strategy provides an antifibrotic therapeutic regimen.

Efficacy and safety of sodium oligomannate in the treatment of Alzheimer's disease.

To evaluate the efficacy and safety of sodium oligomannate in the treatment of Alzheimer's disease. Patients with mild-to-moderate AD were randomly divided into three groups, the scores of ADAS-Cog, ADL, CIBIC-plus, NPI and CSDD were evaluated at the 0th, 12th, 24th, 36th and 48th weeks of medication. Comparing the mean scores of each scale in each cycle of each group. Using SPSS21.0 software for measurement data using t test, Chi-square test was used for counting data. A total of 72 patients with AD were included. The difference of CIBIC-plus score at week 12(P=0.007) and 24(P=0.005), ADAS-Cog scores (P=0.01) at week 24 in GV-971 group was statistically significant compared with that in the control group. The CIBIC-plus score at week 24(P=0.01) and week 48 (P=0.04), CSDD scores at week 48(P=0.02) of GV-971 group was statistically significant compared with that of donepezil group. There were 2 cases of adverse reaction of increased stool frequency in GV-971 (5.67%), and 2 cases of adverse reaction of nausea in donepezil group (8.33%), the difference was statistically significant. GV-971 is as effective as donepezil in the treatment of Alzheimer's disease, and may even be better. It has good safety.

A bibliometric analysis of Wnt signaling pathway: from the top-100 cited articles to emerging trends.

BACKGROUND: Wnt signaling pathway plays a vital role in the regulation of development. An increasing number of articles about Wnt pathway components have been published. By analyzing these studies' characteristics and qualities, we aim to reveal the current research focus and emerging trends in Wnt signaling. METHODS: The databases of Web of Science Core Collection, BIOSIS Citation Index, MEDLINE, etc. were utilized to identify articles on May 23rd, 2020. Wnt signaling pathway-related articles were identified, the 100 most cited articles and articles in the last decade were selected and calculated for citations without self-citation. The subsequent analysis included citation density (citations/article age), time-related flux, authorship, institution, journal, geographic distribution, and theme. RESULTS: These articles were published mainly from 2000 to 2009 (62%). Citations per article ranged from 599 to 3,780 with a median number of 880 times. Most studies (66%) came from the United States. Nusse Roel and Clevers Hans (15 and 13 papers) have contributed significantly to the field. The most highlighted study themes were cancer (15%), embryo development (14%), and cytoplasm signal transduction (11%). From 2011 to 2020, interest in emerging subtopics, including osteogenesis, immune, apoptosis, autophagy, microRNA, and cancer stem cell, are rising. CONCLUSIONS: Cancer, embryo development, stem cell, and signal transduction process still play a major role in the field. With multiple emerging subtopics and investigation on an integrated view of the Wnt signal network, the association of Wnt with diseases was further revealed.

[Effects of tree age and basal area on boreal forest tree mortality in Canada].

Taking the poplar (Populus spp.), jack pine (Pinus banksiana), and black spruce (Picea mariana) in northern Canada as test objects, a repeated investigation was conducted on the living and dead trees at 134 fixed sampling plots, and linear regression models were applied to study the effects of tree age, basal area, and stand type on the mortality of the three tree species. Generally, the tree mortality increased with increasing tree age and basal area. Poplar had a higher mortality in jack pine stand but a lower mortality in black spruce stand. In black spruce stand, tree age was the major factor affecting the mortality of jack pine, while in poplar stand, tree basal area was the important factor. In the three stands, tree age had significant effects on the mortality of black spruce. Species composition had significant effects on the mortality of the tree species, and the interactions between tree age, basal area, and stand type all had significant effects on the mortality of each tree species. The mortality of the same tree species in different stands differed significantly.