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

Analysis of occupational identity among family doctor teams and its influencing factors in Chengdu

BackgroundThe contracted family doctor services are the embodiment of the implementation of the new medical reform policy, and the transformation of the grass-roots health service mode. Studies have proved that the occupational stress in medical staff was at a high level. The enhancement of professional identity will contribute to strengthen team building，alleviate job burnout, and reduce turnover intention of family doctors. ObjectiveTo investigate the current situation of occupational identity among family doctor teams in Chengdu, to examine potential influencing factors of occupational identity, and to provide a reference for promoting career development and team building of family doctor teams. MethodsMulti-stage random cluster sampling was adopted to enroll study participants form 46 primary healthcare centers where family doctor contract services were implemented among 23 districts and counties in Chengdu between March 4 and 26, 2021. A total of 2 681 family doctors participated in this survey. A self-reported survey was conducted to collect participants' demographic and occupational data. The Effort-Reward Imbalance (ERI）questionnaire was implemented to assess occupational stress. The Professional Identity Scale was used to appraise occupational identity. ResultsA total of 2 327 valid questionnaires were collected, with a valid recovery rate of 86.80%, involving 1 715 females (73.7%) and 612 males (26.3%), with dominant age groups of 26−35 years (43.3%) and 36−45 years (30.4%), a high proportion of being married (82.8%), having college (36.0%) and undergraduate (47.3%) education, a high proportion of primary titles (66.0%) and informal work contract (66.1%). About 88.7% of family doctor team workers reported occupational stress. The average score of occupational identity was (3.68±0.62) points. There were significant differences in occupational identity scores among different professional title, work contract, working years in medical institutions, income, and effort/reward ratio (EER) groups (P < 0.05). ERR was negatively correlated with occupational identity (rs=−0.495, P<0.05）. The multiple regression model showed that occupational identity score in the non-staffed participants was lower than the score in the staffed ones (OR=0.429, 95%CI: 0.299−0.825). The occupational identity score in the participants having associate senior title or above was higher than in without professional title (OR=1.424, 95%CI: 1.194−2.328). The longer the working years, the higher the occupational identity score among the participants. The score of the more than 20 working years group was 1.820 times that of the less than 5 working years group (95%CI: 1.342−2.543). The higher the income, the higher the occupational identity score. The score of the 9001−12000 yuan per month group was 1.977 times that of the 1000−3000 yuan per month group (95%CI: 0.811−9.696) , and the score of the more than 12000 yuan per month group was 2.283 times that of the 1000−3000 yuan per month group (95%CI: 1.199−10.267）. ConclusionThe family doctor team workers generally report occupational stress, and their occupational identity is at a medium level in Chengdu. Relevant managers should implement intervention measures against the main influencing factors to reduce their work tension and improve their occupational identity

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

Research on vacuum brazing of W-coated diamond with Ni-based filler alloy

In order to alleviate the thermal damage and residual stresses of brazed diamond joints with Ni-based filler, W-coated diamond grains were used instead of conventional diamond grains and brazed onto 1045 steel substrates. The bonding interface properties, thermal damage and residual stresses of brazed W-coated diamond joints were investigated and studied. The results showed that the Ni-based filler exhibited good wettability to the W-coated diamond grains, and that the number and size of cracks at the bond interface of brazed W-coated diamond joints were significantly reduced compared with those of brazed conventional diamond joints. A dense and orderly Cr3C2 layer was generated on the surface of conventional diamond, while the disordered granular Cr3C2 growing into the filler alloy was formed on the surface of W-coated diamonds. With the isolation and protection of the coating, the brazed W-coated diamond grain surface has lower graphitization and better mechanical properties. At the same time, the thinner and more reasonable morphology of Cr3C2 layer on the surface of W-coated diamond effectively relieves the residual stress, and its maximum residual compressive stress is reduced by 9.43% compared with that of conventional diamond

In vivo nano contrast-enhanced photoacoustic imaging for dynamically lightening the molecular changes of rheumatoid arthritis

Rheumatoid arthritis (RA) is one of the most prevalent inflammatory joint disorders. Early diagnosis, accurate staging, and imaging guided treatment response of RA remain crucial clinical significances for improving treatment outcomes. In this study, we introduced endogenous melanin nanoparticles (MNPs) conjugated with Cyclic Arg-Gly-Asp (RGD) peptide (MNP-PEG-RGD) as a contrast agent for accurate photoacoustic imaging (PAI) of RA diagnosis. It was observed that the prepared nanoprobes had favorable PA sensitivity, photostability and biocompatibility. In vivo studies using RA mouse model revealed that this nanoprobe could target αvβ3 actively at 1 h post-injection, while the signal was remarkably increased in the arthritic joint which could earlier diagnose RA than conventional imaging system. It was of crucial importance to staging RA by PAI with significant difference in nanoprobes accumulation. Furthermore, we tracked the therapeutic efficacy of etanercept in RA treatment by PAI. The observed advancement of arthritis on the PAI was confirmed by histological and immunohistochemical analysis. In conclusion, this study shed light on the development of innovative multifunctional theranostic nanoplatform for both RA monitoring and treatment with a promising future in clinical translation