Polycomb repressive complex 2 (PRC2) consists of three core subunits, EZH2, EED and SUZ12, and plays pivotal roles in transcriptional regulation. The catalytic subunit EZH2 methylates histone H3 ...lysine 27 (H3K27), and its activity is further enhanced by the binding of EED to trimethylated H3K27 (H3K27me3). Small-molecule inhibitors that compete with the cofactor S-adenosylmethionine (SAM) have been reported. Here we report the discovery of EED226, a potent and selective PRC2 inhibitor that directly binds to the H3K27me3 binding pocket of EED. EED226 induces a conformational change upon binding EED, leading to loss of PRC2 activity. EED226 shows similar activity to SAM-competitive inhibitors in blocking H3K27 methylation of PRC2 target genes and inducing regression of human lymphoma xenograft tumors. Interestingly, EED226 also effectively inhibits PRC2 containing a mutant EZH2 protein resistant to SAM-competitive inhibitors. Together, we show that EED226 inhibits PRC2 activity via an allosteric mechanism and offers an opportunity for treatment of PRC2-dependent cancers.
Current research suggests that chronic high-fat dietary intake can lead to bone loss in adults; however, the mechanism by which high-fat diets affect the development of osteoporosis in individuals is ...unclear. As high-fat diets are strongly associated with ferroptosis, whether ferroptosis mediates high-fat diet-induced bone loss was the focus of our current study. By dividing the mice into a high-fat diet group, a high-fat diet + ferroptosis inhibitor group and a normal chow group, mice in the high-fat group were given a high-fat diet for 12 weeks. The mice in the high-fat diet + ferroptosis inhibitor group were given 1 mg/kg Fer-1 per day intraperitoneally at the start of the high-fat diet. Microscopic CT scans, histological tests, and biochemical indicators of ferroptosis were performed on bone tissue from all three groups at the end of the modelling period. Mc3t3-E1 cells were also used in vitro and divided into three groups: high-fat medium group, high-fat medium+ferroptosis inhibitor group, and control group. After 24 hours of incubation in high-fat medium, Mc3t3-E1 cells were assayed for ferroptosis marker proteins and biochemical parameters, and osteogenesis induction was performed simultaneously. Cellular alkaline phosphatase content and expression of osteogenesis-related proteins were measured at day 7 of osteogenesis induction. The results showed that a high-fat diet led to the development of femoral bone loss in mice and that this process could be inhibited by ferroptosis inhibitors. The high-fat diet mainly affected the number of osteoblasts produced in the bone marrow cavity. The high-fat environment in vitro inhibited osteoblast proliferation and osteogenic differentiation, and significant changes in ferroptosis-related biochemical parameters were observed. These findings have implications for the future clinical treatment of bone loss caused by high-fat diets.
Histone lysine methyltransferase NSD2 (WHSC1/MMSET) is overexpressed frequently in multiple myeloma due to the t(4;14) translocation associated with 15% to 20% of cases of this disease. NSD2 has been ...found to be involved in myelomagenesis, suggesting it may offer a novel therapeutic target. Here we show that NSD2 methyltransferase activity is crucial for clonogenicity, adherence, and proliferation of multiple myeloma cells on bone marrow stroma in vitro and that NSD2 is required for tumorigenesis of t(4;14)+ but not t(4;14)- multiple myeloma cells in vivo. The PHD domains in NSD2 were important for its cellular activity and biological function through recruiting NSD2 to its oncogenic target genes and driving their transcriptional activation. By strengthening its disease linkage and deepening insights into its mechanism of action, this study provides a strategy to therapeutically target NSD2 in multiple myeloma patients with a t(4;14) translocation.
There is very limited evidence in the NHANES database linking serum apolipoprotein B and lumbar bone mineral density (BMD) in adults aged 20-59 years. There are few studies associating apolipoprotein ...B concentrations with BMD, and there is some debate about the association between obesity and BMD. Therefore, the purpose of this study was to determine the association between serum apolipoprotein B concentrations and lumbar spine BMD in adults aged 20-59 years and to predict its association with risk of osteopenia or osteoporosis.
A cross-sectional study of the entire US ambulatory population was conducted using data from the National Health and Nutrition Examination Survey (NHANES) database. Weighted multiple regression equation models were used to assess the association between serum apolipoprotein B and lumbar BMD. A logistic weighted regression model was used to assess the association between serum apolipoprotein B concentrations and risk of osteopenia or osteoporosis. Subsequent stratified analyses were performed to refine the primary population of association.
Our study showed a significant negative association between serum apolipoprotein B concentration and lumbar BMD and a significant positive association with the risk of osteoporosis or osteopenia in the total population. After stratifying by sex, age and race, we concluded differently. The association of serum apolipoprotein B concentration with lumbar spine BMD and risk of osteopenia or osteoporosis was significant in male, but not in female. After stratification by age, the negative association between serum apolipoprotein B concentrations and lumbar BMD and the positive association with risk of osteopenia or osteoporosis was more significant in the 30-39 and 50-59 years age groups. When stratified by race, serum apolipoprotein B concentrations were significantly negatively associated with lumbar BMD and positively associated with risk of osteopenia or osteoporosis in Mexican American and non-Hispanic black populations. Thus, these findings suggest that these associations are influenced by sex, age, and race, respectively.
Our results suggest that the association between serum apolipoprotein B levels and the risk of lumbar BMD and osteopenia or osteoporosis varies by sex, age, and race. In men, elevated serum apolipoprotein B levels were negative for bone quality. Elevated serum apolipoprotein B levels in the age groups 30-39 and 50-59 years also had a negative effect on bone quality. In the Mexican American and Non-Hispanic Black populations, elevated serum apolipoprotein B levels also had a significant negative effect on bone quality.
•TC is preferable than RC due to the elevated heat absorption temperature.•OEU is better than FGC to extract moderate temperature flue gas energy.•FGC cannot thoroughly extract moderate temperature ...flue gas energy in TC.•Double-channel-tail-flue enjoys higher thermal efficiency and boiler efficiency.
Supercritical carbon dioxide (sCO2) cycle is suitable for high temperature heat source, but introduces challenging in absorbing moderate/low temperature flue gas energy for coal fired power plant. Here, we explore the effect of flue gas cooler (FGC) and overlap energy utilization (OEU) on sCO2 cycle. FGC and OEU extract moderate temperature flue gas energy by a splitting CO2 flow rate from the cycle and a combined cycle, respectively. Recompression cycle plus reheating (RC + RH) and tri-compression cycle plus reheating (TC + RH) are two basic cycle types for coal fired power plant. A thermodynamics model coupling with thermal–hydraulic characteristic is developed. The analysis is performed for a 100 MW rated power capacity. For RC + RH, we show that OEU yields an electric power efficiency increment of 0.13% compared to FGC, which is caused by smaller pressure drops in boiler components when using OEU. Even though TC + RH introduces difficulty in absorbing moderate/low temperature flue gas energy, OEU still can decrease outlet flue gas temperature (Tfg,ex) to 126 °C, which is acceptable. However, FGC achieves a higher Tfg,ex of 172.6 °C by a pinch temperature difference limit of 30 °C, which deteriorates boiler efficiency thus it is not acceptable. We conclude that OEU is better than FGC, no matter for RC + RH or TC + RH. The double-channel-tail-flue concept is proposed to not only increase thermal efficiency of the system, but also elevate boiler efficiency. This paper presents an important clue to design thermodynamics cycle for small capacity coal fired power plant, which is expected to have fast response with respect to load variations.
For the supercritical carbon dioxide (S-CO2) cycle, the split method is limited to analyzing cycle performance by splitting the working fluid flow rate and components. In this study, we propose a new ...optimization method based on the split method, which can simply and efficiently improve the efficiency of complex cycles. The application of the split method is expanded and used to guide cycle optimization. Then, an optimization roadmap for generalized cycles is proposed. The numerical model of the recompression cycle with reheating (RC + RH) was implemented, which was split into two single regenerative cycles with reheating (SCRs), one exhibiting an efficiency below 100% (SCR1) and the other an efficiency of 100% (SCR2). Subsequently, a generalized optimization roadmap was proposed: (1) enhancing the energy efficiency of the cycle with an efficiency below 100% and (2) enhancing the mass flow rate ratio of the cycle with an efficiency of 100%. Based on the optimization roadmap, the air heat recovery was proposed for coal-fired plant, the net power efficiency increased from 45.61% to 46.40%. Our work provides a new roadmap for cycle optimization, and can serve as an important reference for optimizing the efficiency of a complex process in research.
In this study, electrospray ionization mass spectrometry (ESI-MS) was used to investigate the binding interactions of ten flavonoid aglycones and ten flavonoid glycosides with DNA duplexes. Relative ...binding affinities of the flavonoids toward DNA duplexes were estimated based on the fraction of bound DNA. The results revealed that the 4′-OH group of flavonoid aglycones was essential for their DNA-binding properties. Flavonoid glycosides with sugar chain linked on ring A or ring B showed enhanced binding toward the duplexes over their aglycone counterparts, whereas glycosylation of the flavonol quercetin on ring C exhibited a less pronounced effect. The aglycone skeletons and other hydroxyl substitutions on the aglycone also have an effect on the fractions of bound DNA. Upon collision-induced dissociation, the complexes containing flavonoid aglycones underwent the predominant ejection of a neutral ligand molecule, suggesting an intercalative DNA-binding mode. However, for complexes containing flavonoid glycosides, the loss of nucleobase increased to different extents, indicating a stronger binding or different binding mode. The results may provide not only a deeper insight into the DNA-binding properties of flavonoids but also a useful guideline for the design of efficient DNA-binding agents for chemotherapy.
The introduction of highly thermally conductive expanded graphite in polymers can functionally improve the thermal conductivity of epoxy resins. In this study, expanded graphite particles were thus ...introduced into an epoxy polymer matrix via solution blending method with ultrasonic procedure in order to improve the thermal conductivity of the epoxy matrix. The thermal conductivity of epoxy composites was analyzed by laser flash method. The dispersive status of the fillers was characterized by scanning electron microscope (SEM). The thermal stability of the composites was investigated through Thermo-gravimetric analysis (TGA). The results show that the thermal conductivity of epoxy resins increases significantly due to the addition of EG(expanded graphite) particles. As a matter of fact, the thermal conductivity of epoxy composites increases with the increase of EG particles loading from 0wt% to 4.5wt%. The distribution of EG particles in the matrix greatly affects the thermal conductivities of epoxy composites. The thermal conductivity of (KH550@EG)/epoxy composites is greatly improved compared with untreated EG/epoxy composites. The thermal conductivity value of the composites at 4.5wt% loading obtained by experiment is 1.0W/(mK) with a thermal decomposition temperature improved to 348°C from 318°C of pure epoxy.
The epidermal growth factor receptor (EGFR) C797S mutation is the most common on-target resistance mechanism to osimertinib in patients with advanced non-small-cell lung cancer (NSCLC). Currently ...there are no effective treatment options for NSCLC patients harboring EGFR C797S triple mutants (Del19/T790M/C797S and L858R/T790M/C797S). Herein, we report an orally bioavailable EGFR PROTAC, HJM-561, which selectively degrades the EGFR C797S-containing triple mutants. HJM-561 potently inhibits the proliferation of Del19/T790M/C797S and L858R/T790M/C797S Ba/F3 cells while sparing cells expressing wild type EGFR. Oral administration of HJM-561 shows robust anti-tumor activity in EGFR Del19/T790M/C797S-driven Ba/F3 CDX and PDX models that were resistant to osimertinib treatment. Taken together, our results suggest that HJM-561 is a promising therapeutic option for overcoming EGFR triple mutation-mediated drug resistance in NSCLC.
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