Neuroprotective effect of formononetin in ameliorating learning and memory impairment in mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia among elderly population. Deranged ß-amyloid (Aß) trafficking across the blood-brain barrier is known to be a critical element in the pathogenesis of AD. In the vascular endothelial cells of hippocampus, Aß transport is mainly mediated by low-density lipoprotein-associated protein 1 (LRP1) and the receptor for advanced glycation end (RAGE) products; therefore, LRP1 and RAGE endothelial cells are potential therapeutic targets for AD. In this study, we explored the effects of Formononetin (FMN) on learning and memory improvement in APP/PS1 mice and the related mechanisms. We found that FMN significantly improved learning and memory ability by suppressing Aß production from APP processing, RAGE-dependent inflammatory signaling and promoted LRP1-dependent cerebral Aß clearance pathway. Moreover, FMN treatment alleviated ultrastructural changes in hippocampal vascular endothelial cells. In conclusion, we believe that FMN may be an efficacious and promising treatment for AD.

Modeling Methodology for Site Selection Evaluation of Underground Coal Gasification Based on Combination Weighting Method with Game Theory.

The lack of systematic geological work is an essential reason why underground coal gasification (UCG) has not been industrialized for a long time. Building a scientific index system and favorable area evaluation technology for the UCG site selection is the key to breaking through the geological bottleneck. Aiming at the problems of the single index weight determination method, intense subjectivity, and poor reliability of current evaluation models, we put forward an evaluation modeling methodology for the UCG site selection using the combination weighting method with the game theory. The factors of coal resource conditions associated with the potential risk of UCG are systematically analyzed. From the six dimensions of the geological structure, hydrogeology, seam occurrence, coal properties, reserves, and roof lithology, 23 key factors were selected as evaluation indexes to construct a hierarchical model composed of the target layer, category index layer, and index layer. The influence of each index on UCG and its reasonable value range were systematically analyzed. The evaluation index system for UCG site selection was formed. The improved analytic hierarchy process (AHP) was adopted to sequence indices and determine their subjective weight. And the variability, conflict, and information amount of the index data were analyzed by the CRiteria Importance Through Intercriteria Correlation (CRITIC) method to calculate the objective weight. Then, the subjective and objective weights were combined through game theory. On this basis, fuzzy theory was employed to calculate the membership of indices and construct the fuzzy comprehensive judgment matrix. The evaluation model of the UCG site selection was applied to the suitability evaluation of resource conditions of UCG pilot projects at Zhongliangshan (ZLS), Huating (HT), and Shanjiaoshu (SJS) mines in China. The result shows that the resource conditions of HT are the best, followed by ZLS and, finally, SJS, which are consistent with the actual running effects of the three UCG pilot projects. It indicates that the evaluation model can provide a scientific theoretical basis and reliable technical support for the UCG site selection.

Dauricine suppresses the growth of pancreatic cancer in vivo by modulating the Hedgehog signaling pathway.

Pancreatic cancer is a highly malignant cancer associated with high expression levels of sonic hedgehog signaling molecule (Shh), patched 1 (Ptch1), smoothened frizzled class receptor (Smo) and glioma-associated oncogene family zinc finger 1 (Gli1) in the hedgehog (Hh) signaling pathway. Inhibition of the Hh signaling pathway is a potential therapeutic target for pancreatic cancer. The aim of the present study was to investigate the effects of dauricine in a pancreatic cancer BxPC-3 ×enograft animal model and examine the underlying molecular mechanisms through Hh signaling pathway. High-and low-dose dauricine treatment significantly suppressed tumor growth with no concomitant effect on the spleen index. In addition, dauricine induced apoptosis and cell cycle arrest in pancreatic cancer BxPC-3 cells. The inhibitory effects of dauricine on pancreatic cancer may be mediated by the suppression of the Hh signaling pathway, as indicated by the decreases in the gene and protein expression levels of Shh, Ptch1, Smo and Gli1. The effects of dauricine were similar to those of 5-fluorouracil. Dauricine, a naturally occurring alkaloid, may be a potential anticancer agent for the treatment of pancreatic cancer.

Microgravity potentiates stem cell proliferation while sustaining the capability of differentiation.

A three-dimensional (3D) clinostat is a device for generating multidirectional G force, resulting in an environment with an average of 10(3) G. Here we report that human mesenchymal stem cells (hMSCs) cultured in a 3D-clinostat (group CL) showed marked proliferation (13-fold in a week) compared with cells cultured under normal conditions of 1 G (group C) (4-fold in a week). Flow cytometry revealed a 6-fold increase in the number of hMSCs double-positive for CD44/CD29 or CD90/CD29 in group CL after 7 days in culture, compared with group C. Telomere length remained the same in cells from both groups during culturing. Group C cells showed increasing expression levels of type II collagen and aggrecan over the culture period, whereas group CL cells showed a decrease to undetectable levels. Pellets of hMSCs from each group were explanted into cartilagedefective mice. The transplants from group CL formed hyaline cartilage after 7 days, whereas the transplants from group C formed only noncartilage tissue containing a small number of cells. These results show that hMSCs cultured in a 3D-clinostat possess the strong proliferative characteristic of stem cells and retain their ability to differentiate into hyaline cartilage after transplantation. On the contrary, cells cultured in a 1-G environment do not maintain these features. Simulated microgravity may thus provide an environment to successfully expand stem cell populations in vitro without culture supplements that can adversely affect stem cell-derived transplantations. This method has significant potential for regenerative medicine and developmental biology.

Simulated microgravity maintains the undifferentiated state and enhances the neural repair potential of bone marrow stromal cells.

Recently, regenerative medicine with bone marrow stromal cells (BMSCs) has gained significant attention for the treatment of central nervous system diseases. Here, we investigated the activity of BMSCs under simulated microgravity conditions. Mouse BMSCs (mBMSCs) were isolated from C57BL/6 mice and harvested in 1G condition. Subjects were divided into 4 groups: cultured under simulated microgravity and 1G condition in growth medium and neural differentiation medium. After 7 days of culture, the mBMSCs were used for morphological analysis, reverse transcription (RT)-polymerase chain reaction, immunostaining analysis, and grafting. Neural-induced mBMSCs cultured under 1G conditions exhibited neural differentiation, whereas those cultured under simulated microgravity did not. Moreover, under simulated microgravity conditions, mBMSCs could be cultured in an undifferentiated state. Next, we intravenously injected cells into a mouse model of cerebral contusion. Graft mBMSCs cultured under simulated microgravity exhibited greater survival in the damaged region, and the motor function of the grafted mice improved significantly. mBMSCs cultured under simulated microgravity expressed CXCR4 on their cell membrane. Our study indicates that culturing cells under simulated microgravity enhances their survival rate by maintaining an undifferentiated state of cells, making this a potentially attractive method for culturing donor cells to be used in grafting.