To investigate the effects of small molecule compound bicyclol on type 2 diabetes mellitus (T2DM) and its mechanism of action, KKAy mice were treated with various doses of bicyclol (100, 200, and 400 mg·kg^-1·d^-1) with metformin (200 mg·kg^-1·d^-1) as a positive control, respectively. Age-matched C57BL/6J mice were used as the non-diabetic control (Con). The effect on hyperglycemia was evaluated by the levels of no-fasting blood glucose, fasting blood glucose (FPG), and glucose tolerance. Whole body insulin sensitivity was evaluated by fasting plasma insulin (FPI) and homeostasis model assessment-insulin resistance (HOMA-IR). The hepatic response to insulin was evaluated by insulin-induced activation of insulin signaling pathway. Western blot was performed to detect hepatic protein expressions. All animal experimental procedures were approved by the Animal Ethics Committee of Chinese Academy of Medical Sciences. KKAy mice showed T2DM characteristics such as hyperglycemia and insulin resistance, including attenuated response to insulin in the liver. A 28-day treatment of bicyclol suppressed both FPG and no-fasting blood glucose, in a dose-and time-dependent manner. Moreover, FPI and HOMA-IR values were both significantly decreased, and hepatic insulin-induced-phosphorylation of IRβ and Akt were up-regulated in KKAy mice after bicyclol treatment. Phosphorylation of FoxO1, the key transcription factor for regulating gluconeogenesis, was also significantly elevated by bicyclol treatment. These results suggested that bicyclol has some therapeutic effects on hyperglycemia in a time-and dose-dependent manner in KKAy mice. Its mechanism might be attributed to improving insulin resistance, enhancing hepatic insulin signaling pathway, and inhibiting gluconeogenesis. No significant interference on the hypoglycemic effect of metformin by bicyclol was observed in this study.

The incidence of thrombotic diseases has increased in the past decade, a factor endangering human health. Currently, antithrombotic drugs used in the clinic have side effects such as inducing bleeding. Data from clinical observation indicate that congenital deficiency of factor XI (FXI) gene decreases the incidence of stroke and deep venous thrombosis, without causing spontaneous bleeding. This unique property of FXI makes it a potential new target for antithrombotic drugs development. Many studies have focused on the discovery of novel inhibitors targeting FXI. This review summarizes the research progress in searching for the inhibitors against FXI.

To provide a basis for the establishment of the commodity grade of Astragali Radix (AR), we compared the chemical components and the anti-fatigue effect of different grades of AR. The components of primary metabolites were analyzed by ¹H NMR and the contents of five flavonoids were determined by HPLC-UV with different grades of AR. Fatigue efficacy of different grades of AR was compared. All the procedures were approved by the Laboratory Animal Ethics Committee of the Shanxi University. The results showed that the content of water soluble extracts (WSE) of the Grade Ⅱ AR was the lowest, and 21 compounds were identified through ¹H NMR spectrum. There are 3 components showing a higher content in the Grade-top AR, and 7 components were higher in the Grade-Ⅳ, and 7 other components were higher in the Grade-Ⅱ AR. Total flavonoid content was the highest in Grade-Ⅱ but it was the lowest in the Grade-Ⅳ. Pharmacodynamic results showed that AR could significantly enhance the exhaustion time of rats and improve the biochemical indexes of serum and gastrocnemius muscle, and the best anti-fatigue effect was observed with Grade -Ⅱ AR. Therefore, chemical composition and efficacy index were used to evaluate the quality of different grades of AR, and the quality evaluation approach was established based on chemical and pharmacological effects to provide a scientific basis for the development of AR. The study may provide useful information for construction of the quality grade standard of AR.

Mutation and amplification of epidermal growth factor receptor (EGFR), one of the most important driver gene, are both reported to participate in the regulation of lung cancer development and progression. Here we investigated the effect and molecular mechanism of tripartite motif 25 (TRIM25) in the regulation of development of lung cancer. CCK-8 and Transwell assays were used to explore the tumor-promoting effect of TRIM25. Results showed that knockdown of TRIM25 significantly inhibited cell proliferation (34% inhibition rate) and invasion (42% inhibition rate). Gene set enrichment analysis (GSEA), Western blot and immunohistochemistry were adopted to detect the effect of TRIM25 on EGFR expression and its downstream signal activity. The results explained that TRIM25 not only up-regulated the expression level of EGFR, but also promoted EGFR signal activation. Co-immunoprecipitation, real-time PCR and cycloheximide (CHX) inhibit protein degradation assays were employed to explore the molecular mechanism of TRIM25 in regulating EGFR stability. Preliminary exploration results indicate that TRIM25 increases the expression level of EGFR and activates its downstream signaling activity through promoting K63-linked ubiquitination of EGFR. Restoration of EGFR expression rescues the phenotype of TRIM25 depletion. In A549 cells, overexpression of EGFR increased cell proliferation rate 1.5-fold and invasion rate 1.6-fold compared with knockdown of TRIM25 cells. Similarly, in H1975 cells, cell proliferation rate was enhanced 2-fold and invasion rate was improved 1.7-fold. These data suggest that TRIM25 promotes lung cancer development via maintaining EGFR stability and continuous EGFR signaling activation. The human lung cancer tissues were obtained from lung cancer patients at Cancer Hospital Chinese Academy of Medical Sciences. Informed consent was obtained from all participants in accordance with the Declaration of Helsinki. The study was approved by the Ethics Committee of the Cancer Hospital Chinese Academy of Medical Sciences.

Enzymes play crucial functional roles in all biological processes. Enzymatic inhibitors can regulate enzyme activity and may become the starting point for drug discovery. Mass spectrometry (MS) has the advantage for rapid qualitative and quantitative analyses of compounds and enzyme reactions, emerging as an important analytical tool in enzyme inhibitor screening assay for drug discovery. This review will highlight recent advances in the inhibitor screening assay using MS and related techniques, including frontier affinity chromatography, immobilized enzyme beads, ultrafiltration, surface plasmon resonance, capillary electrophoresis and microfluidic chips. The existing MS methods for screening enzyme inhibitor were divided into two types:affinity screening and activity screening.

Akkermansia muciniphila (A. muciniphila) is an intestinal bacterium that was isolated from human feces in 2004. Its specialization in mucin degradation makes it a key organism that maintains the intestinal mucosal barrier function. A. muciniphila, which is the only representative of the Verrucomicrobia that can be cultured, is relatively easy to be detected in metagenomic analysis. For the past few years, A. muciniphila has quickly attracted the attention of researchers and become a medical and biological hotspot due to the close correlation between its intestinal colonization and the development and progression of various metabolic diseases. This review introduces the biological characteristics and colonization environment of A. muciniphila, and reviews its relationship with host health and disease, especially focusing on the metabolic disease and related mechanism, as well as the factors affecting its colonization in the host, expecting to provide evidence and clues for drug development targeting A. muciniphila.

The 16S rDNA sequencing method was adopted to study the effects of mulberry leaf flavonoids, polysaccharides and alkaloids on intestinal microflora in db/db diabetic mice. The animal experiment was examined by the Ethics Committee of Nanjing University of Chinese Medicine. Ten db/m mice were control group and forty db/db mice were randomly divided into model group, metformin group, mulberry flavonoid (MF) group, mulberry polysaccharide (MP) group and mulberry alkaloid (MA) group. After intragastric administration for six weeks, fresh feces were collected for detection of intestinal microflora. There were Firmicutes, Bacteroidetes, Proteobacteria, Saccharibacteria, Tenericutes, Deferribacteres, Verrucomicrobia, Cyanobacteria in each group. The results showed that the intestinal microflora of db/db mice changed significantly from phylum level to genus level. The proportion of Firmicutes and Proteobacteria in model group decreased significantly, and the proportion of Bacteroidetes increased. The difference in species abundance distribution between model group and other groups was significant, which indicated that the community distribution was disordered in model group. After administration, the Bacteroidetes, Lachnospiraceae, Roseburia and Desulfovibrio were effectively regulated, especially in the alkaloid group. The difference in species abundance distribution between drug-treated group and blank group also became smaller. It is suggested that the active components of mulberry leaf have the effect of improving the intestinal microflora imbalance in db/db mice.

Diabetes is a metabolic disease with an extremely high incidence in China. In parallel with an increased incidence yearly, the population of diabetes is showing a trend towards younger age. Therefore, it is urgent to carry out research on diabetes in order to develop strategy for prevention. In recent years, metabolomics has made significant progress in the study of biomarkers, pathogenesis, early diagnosis and prognosis, and evalua tion of drug efficacy in diabetes. However, limited by metabolomics technology and the complexity of diabetes research, metabolomics in the diabetes research remains challenging. We summarize the progress and prospect the future development of metabolomics in the diabetes research.

Amyotrophic lateral sclerosis (ALS) is among the most common type of motor neuron diseases, and its pathogenesis remains unclear. In recent years, our understanding of the genetic basis of ALS has led to the development of various ALS disease models, which allow for screening of ALS-related drugs and treatment methods. This review focuses on the research progress of ALS, summarizes the systems of commonly used experi mental animal models, including transgenic animals, gene knockout approaches and autonomous animal models, points to the problems needing attention in standardized ALS non-clinical research, and proposes the criteria for selection of standardized R&D model.

Protein acetylation is a process of adding an acetyl group to a protein lysine residue with the help of acetyltransferase, which is a pivotal protein post-translational modification linking acetyl-CoA metabolism and cell signal transduction. Recently, the development of mass spectrometry has deepened our understanding of lysine acetylation. Lysine acetylation is involved in many processes such as gene transcription, protein degradation, cellular metabolism, and stress response, which affects biological processes by regulating protein interactions, activity, stability and localization. Protein acetylation is widely happened and plays important regulatory roles in a diversity of human diseases such as metabolic diseases, tumors and cardiovascular diseases. Besides, deacetylase inhibitors have displayed a great potential in the treatment of various diseases especially tumors and metabolic associated diseases. In this review, we summarized the advances and application of acetylation, and discussed the remaining problems in this area.