E17110 promotes reverse cholesterol transport with liver X receptor β agonist activity in vitro

AbstractLiver X receptor (LXR) plays an important role in reverse cholesterol transport (RCT), and activation of LXR could reduce atherosclerosis. In the present study we used a cell-based screening method to identify new potential LXRβ agonists. A novel benzofuran-2-carboxylate derivative was identified with LXRβ agonist activity: E17110 showed a significant activation effect on LXRβ with an EC50 value of 0.72μmol/L. E17110 also increased the expression of ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) in RAW264.7 macrophages. Moreover, E17110 significantly reduced cellular lipid accumulation and promoted cholesterol efflux in RAW264.7 macrophages. Interestingly, we found that the key amino acids in the LXRβ ligand-binding domain had distinct interactions with E17110 as compared to TO901317. These results suggest that E17110 was identified as a novel compound with LXRβ agonist activity in vitro via screening, and could be developed as a potential anti-atherosclerotic lead compound

Small molecules targeting Pin1 as potent anticancer drugs

Background: Pin1 is a member of the evolutionarily conserved peptidyl-prolyl isomerase (PPIase) family of proteins. Following phosphorylation, Pin1-catalyzed prolyl-isomerization induces conformational changes, which serve to regulate the function of many phosphorylated proteins that play important roles during oncogenesis. Thus, the inhibition of Pin1 provides a unique means of disrupting oncogenic pathways and therefore represents an appealing target for novel anticancer therapies.Methods: As Pin1 is conserved between yeast and humans, we employed budding yeast to establish a high-throughput screening method for the primary screening of Pin1 inhibitors. This effort culminated in the identification of the compounds HWH8-33 and HWH8-36. Multifaceted approaches were taken to determine the inhibition profiles of these compounds against Pin1 activity in vitro and in vivo, including an isomerization assay, surface plasmon resonance (SPR) technology, virtual docking, MTT proliferation assay, western blotting, cell cycle analysis, apoptosis analysis, immunofluorescence analysis, wound healing, migration assay, and nude mouse assay.Results:In vitro, HWH8-33 and HWH8-36 could bind to purified Pin1 and inhibited its enzyme activity; showed inhibitory effects on cancer cell proliferation; led to G2/M phase arrest, dysregulated downstream protein expression, and apoptosis; and suppressed cancer cell migration. In vivo, HWH8-33 suppressed tumor growth in the xenograft mice after oral administration for 4 weeks, with no noticeable toxicity. Together, these results show the anticancer activity of HWH8-33 and HWH8-36 against Pin1 for the first time.Conclusion: In summary, we identified two hit compounds HWH8-33 and HWH8-36, which after further structure optimization have the potential to be developed as antitumor drugs

A Novel Small Molecule Which Increases Osteoprotegerin Expression and Protects Against Ovariectomy-Related Bone Loss in Rats

The ratio of osteoprotegerin (OPG) to the receptor activator of NF-κB ligand (RANKL) is a key determinant in the regulation of bone metabolism. The study was performed to screen novel anti-osteoporotic drugs regulating OPG/RANKL ratio and evaluate their effect on bone metabolism. According to the screening results and in vitro results, we found a small molecule, E09241, significantly increased the ratio of OPG/RANKL by mainly increasing OPG expression. Our in vitro studies showed that E09241 increased the alkaline phosphatase (ALP) activity of mouse osteoblasts, promoted mineralization, and increased the expression of osteogenic differentiation-related genes. In addition, we observed that E09241 inhibited RANKL-induced osteoclast differentiation and reduced the expression of osteoclast differentiation-related proteins nuclear factor of activated T cells c1 (NFATc1) and matrix metalloproteinase 9 (MMP-9). More importantly, E09241 exerted therapeutic protection against bone loss in ovariectomized rats in vivo. This protective effect was confirmed to be achieved by inhibiting bone resorption and promoting bone formation in vivo. Mechanistically, E09241 regulates OPG expression through canonical Wnt/β-catenin signaling. Our findings suggest that E09241 is a promising small-molecule compound for treating osteoporosis with a dual effect on osteoblasts and osteoclasts

Identification of Dehydroxytrichostatin A as a Novel Up-Regulator of the ATP-Binding Cassette Transporter A1 (ABCA1)

molecule

Identification of New Antifungal Agents Targeting Chitin Synthesis by a Chemical-Genetic Method

Fungal infection is a leading cause of mortality in immunocompromised population; thus, it is urgent to develop new and safe antifungal agents. Different from human cells, fungi have a cell wall, which is composed mainly of polysaccharide glucan and chitin. The unique cell wall structure is an ideal target for antifungal drugs. In this research, a chemical-genetic method was used to isolate antifungal agents that target chitin synthesis in yeast cells. From a compound library, we isolated two benzothiazole compounds that showed greater toxicity to yeast mutants lacking glucan synthase Fks1 compared to wild-type yeast cells and mutants lacking chitin synthase Chs3. Both of them inhibited the activity of chitin synthase in vitro and reduced chitin level in yeast cells. Besides, these compounds showed clear synergistic antifungal effect with a glucan synthase inhibitors caspofungin. Furthermore, these compounds inhibited the growth of Saccharomyces cerevisiae and opportunistic pathogen Candida albicans. Surprisingly, the genome-wide mass-spectrometry analysis showed decreased protein level of chitin synthases in cells treated with one of these drugs, and this decrease was not a result of downregulation of gene transcription. Therefore, we successfully identified two new antifungal agents that inhibit chitin synthesis using a chemical-genetic method

Identification of anti-Gram-negative bacteria agents targeting the interaction between ribosomal proteins L12 and L10

Gram-negative bacteria have become the main pathogens and cause serious clinical problems with increased morbidity and mortality. However, the slow discovery of new antimicrobial agents is unable to meet the need for the treatment of bacterial infections caused by drug-resistant strains. The interaction of L12 and L10 is essential for ribosomal function and protein synthesis. In this study, a yeast two-hybrid system was established to successfully detect the interaction between L12 and L10 proteins from gram-negative bacteria Escherichia coli, which allows us to screen compounds that specifically disrupt this interaction. With this system, we identified two compounds IMB-84 and IMB-87 that block L12−L10 interaction and show bactericidal activity against E. coli. We used glutathione-S-transferase (GST) pull-down and surface plasmon resonance (SPR) assays to demonstrate that these compounds disrupt L12−L10 interaction in vitro and the target of compounds was further confirmed by the overexpression of target proteins. Moreover, protein synthesis and elongation factor G-dependent GTPase activities are inhibited by two compounds. Therefore, we have identified two antibacterial agents that disrupt L12−L10 interaction by using yeast two-hybrid system. KEY WORDS: Yeast two-hybrid, Escherichia coli, Ribosome, L12/L10, Antimicrobial agent

Social Value of Urban Green Space Based on Visitors’ Perceptions: The Case of the Summer Palace, Beijing, China

Urban green spaces play a key role in constructing an ecological civilization in China. In this context, the realization and assessment of the social value of urban green spaces have received increasing attention. Taking the visitors of the Summer Palace in Beijing as the research object, this study used the public participation geographic information system (PPGIS) to collect research data, assess the social value of ecosystem services in the Summer Palace, and determine its spatial distribution. By examining the social value of urban green spaces, this study explored the relationship between the spatial distribution of ecosystem social value and environmental landscape features. The influence of different environmental values on the spatial distribution of the visitors’ perceived social value was also investigated to provide a decision-making basis for the planning and management of urban ecological spaces and the supply and protection of urban ecological products. This study found that cultural, historical, and aesthetic values were preferred by an increasing number of visitors. The hotspots of social value in the Summer Palace of Beijing have three cores and multiple centers. By analyzing the relationship between the three value types with higher preference and the environmental landscape features of the Summer Palace, this study found that the distribution of social values is closely related to the architectural complexes and waters. Anthropocentrists have smaller sample sizes and generally lower social value indices within the sample group, and ecocentrists have higher perceptions of overall social values

Socio-Economic Inequalities in Tobacco Consumption of the Older Adults in China: A Decomposition Method

Background: In China, tobacco consumption is a leading risk factor for non-communicable diseases, and understanding the pattern of socio-economic inequalities of tobacco consumption will, thus, help to develop targeted policies of public health control. Methods: Data came from the China Health and Retirement Longitudinal Study in 2013, involving 17,663 respondents aged 45 and above. Tobacco use prevalence and tobacco use quantities were defined for further analysis. Using the concentration index (CI) and its decomposition, socio-economic inequalities of tobacco consumption grouped by gender were estimated. Results: The concentration index of tobacco use prevalence was 0.044 (men 0.041; women −0.039). The concentration index of tobacco use quantities among smokers was 0.039 (men 0.033; women 0.038). The majority of the inequality could be explained by educational attainment, age, area, and economic quantiles. Conclusions: Tobacco consumption was more common among richer compared to poorer people in China. Gender, educational attainments, age, areas, and economic quantiles were strong predictors of tobacco consumption in China. Public health policies need to be targeted towards men in higher economic quantiles with lower educational attainment, and divorced or widowed women, especially in urban areas of China