Hypoxia makes EZH2 inhibitor not easy-advances of crosstalk between HIF and EZH2.

Histone methylation plays a crucial role in tumorigenesis. Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that regulates chromatin structure and gene expression. EZH2 inhibitors (EZH2is) have been shown to be effective in treating hematologic malignancies, while their effectiveness in solid tumors remains limited. One of the major challenges in the treatment of solid tumors is their hypoxic tumor microenvironment. Hypoxia-inducible factor 1-alpha (HIF-1α) is a key hypoxia responder that interacts with EZH2 to promote tumor progression. Here we discuss the implications of the relationship between EZH2 and hypoxia for expanding the application of EZH2is in solid tumors.

EZH2 Inhibition Enhances PD-L1 Protein Stability Through USP22-Mediated Deubiquitination in Colorectal Cancer.

The regulation of PD-L1 is the key question, which largely determines the outcome of the immune checkpoint inhibitors (ICIs) based therapy. However, besides the transcription level, the protein stability of PD-L1 is closely correlated with its function and has drawn increasing attention. In this study, EZH2 inhibition enhances PD-L1 expression and protein stability, and the deubiquitinase ubiquitin-specific peptidase 22 (USP22) is identified as a key mediator in this process. EZH2 inhibition transcriptionally upregulates USP22 expression, and upregulated USP22 further stabilizes PD-L1. Importantly, a combination of EZH2 inhibitors with anti-PD-1 immune checkpoint blockade therapy improves the tumor microenvironment, enhances sensitivity to immunotherapy, and exerts synergistic anticancer effects. In addition, knocking down USP22 can potentially enhance the therapeutic efficacy of EZH2 inhibitors on colon cancer. These findings unveil the novel role of EZH2 inhibitors in tumor immune evasion by upregulating PD-L1, and this drawback can be compensated by combining ICI immunotherapy. Therefore, these findings provide valuable insights into the EZH2-USP22-PD-L1 regulatory axis, shedding light on the optimization of combining both immune checkpoint blockade and EZH2 inhibitor-based epigenetic therapies to achieve more efficacies and accuracy in cancer treatment.

Mechanism study of toluene removal using iron/nickel bimetallic catalysts supported on biochar.

The present study utilized rice husk biomass as a carrier to synthesize rice husk biochar loaded with iron and nickel. Mono-metallic and bimetallic catalysts were prepared for the removal of toluene as the tar model. The efficiency of the catalysts for the removal of toluene was investigated, and finally, the removal mechanisms of mono-metallic and bimetallic catalysts for toluene were revealed. The experimental results showed that the bimetallic-loaded biochar catalysts had excellent toluene removal performance, which was closely related to the ratio of loaded Fe and Ni. Among them, the catalyst DBC-Fe2.5 %-Ni2.5 % (2.5 wt% iron loading and 2.5 wt% nickel loading) obtained through secondary calcination at 700 °C achieved the highest toluene removal efficiency of 92.76 %. The elements of Fe and Ni in the catalyst were uniformly dispersed on the surface and in the pores of the biochar, and the catalyst had a layered structure with good adsorption. Under the interaction of Fe and Ni, the agglomeration and sintering of Ni were reduced, and the surface acidity of the catalyst was increased, the surface acidity was favorable for toluene removal. The iron­nickel catalyst did not form significant alloys when calcined at 400 °C, whereas strong metal interactions occurred at 700 °C, resulting in the formation of Fe0.64Ni0.36 alloy and NiFe2O4 alloy. This NiFe alloy had abundant active sites to enhance the catalytic cracking of toluene and provide lattice oxygen for the reaction. Furthermore, the functional groups on the catalyst surface also had an impact on toluene removal. The catalyst prepared in this paper reduces the cost of tar removal, can be applied to the removal of industrial pollutant tars, reduces the pollution of the environment, and provides theoretical guidance and technical reference for the efficient removal of tar.

Hydrogen-Rich and Clean Fuel Gas Production from Co-pyrolysis of Biomass and Plastic Blends with CaO Additive.

The treatment and disposal of waste biomass and plastics are of great importance to achieve both waste management and resource recycling. In this work, pyrolysis of biomass and plastic blends were investigated to identify the influence of temperature and in situ CaO addition on the production of hydrogen-rich, HCl-free, and low tar content fuel gases. The results show that the increase in temperature and the use of CaO significantly improved both the quantity and quality of the fuel gas and mitigated the formation of tar compounds and HCl. Moreover, H2 yield was significantly improved from 0.30 to 3.68 mmol/g with the increase in temperature from 550 to 850 °C. Also, the use of in situ CaO significantly increased the H2 yield by 28-88%. The H2/CO ratio was also enhanced from 0.35 to 1.50 with the temperature increase and CaO addition. Tar removal efficiency reached approximately 70.09% with the use of CaO at 850 °C. The produced HCl gas could be effectively absorbed by CaO through dechlorination reactions to form CaClOH at a highest mitigation efficiency of 92.37%. The results could be used to develop clean and efficient treatment technologies of waste biomass and plastics.

Geometric Constraints Regulate Energy Metabolism and Cellular Contractility in Vascular Smooth Muscle Cells by Coordinating Mitochondrial DNA Methylation.

Vascular smooth muscle cells (SMCs) can adapt to changes in cellular geometric cues; however, the underlying mechanisms remain elusive. Using 2D micropatterned substrates to engineer cell geometry, it is found that in comparison with an elongated geometry, a square-shaped geometry causes the nuclear-to-cytoplasmic redistribution of DNA methyltransferase 1 (DNMT1), hypermethylation of mitochondrial DNA (mtDNA), repression of mtDNA gene transcription, and impairment of mitochondrial function. Using irregularly arranged versus circumferentially aligned vascular grafts to control cell geometry in 3D growth, it is demonstrated that cell geometry, mtDNA methylation, and vessel contractility are closely related. DNMT1 redistribution is found to be dependent on the phosphoinositide 3-kinase and protein kinase B (AKT) signaling pathways. Cell elongation activates cytosolic phospholipase A2, a nuclear mechanosensor that, when inhibited, hinders AKT phosphorylation, DNMT1 nuclear accumulation, and energy production. The findings of this study provide insights into the effects of cell geometry on SMC function and its potential implications in the optimization of vascular grafts.

MFN2 Prevents Neointimal Hyperplasia in Vein Grafts via Destabilizing PFK1.

BACKGROUND: Mechanical forces play crucial roles in neointimal hyperplasia after vein grafting; yet, our understanding of their influences on vascular smooth muscle cell (VSMC) activation remains rudimentary. METHODS: A cuff mouse model was used to study vein graft hyperplasia. Fifteen percent to 1 Hz uniaxial cyclic stretch (arterial strain), 5% to 1 Hz uniaxial cyclic stretch or a static condition (venous strain) were applied to the cultured VSMCs. Metabolomics analysis, cell proliferation and migration assays, immunoblotting, co-immunoprecipitation, mutagenesis, pull-down and surface plasmon resonance assays were employed to elucidate the potential molecular mechanisms. RESULTS: RNA-sequencing in vein grafts and the controls identified changes in metabolic pathways and downregulation of mitochondrial protein MFN2 (mitofusin 2) in the vein grafts. Exposure of VSMCs to 15% stretch resulted in MFN2 downregulation, mitochondrial fragmentation, metabolic shift from mitochondrial oxidative phosphorylation to glycolysis, and cell proliferation and migration, as compared with that to a static condition or 5% stretch. Metabolomics analysis indicated an increased generation of fructose 1,6-bisphosphate, an intermediate in the glycolytic pathway converted by PFK1 (phosphofructokinase 1) from fructose-6-phosphate, in cells exposed to 15% stretch. Mechanistic study revealed that MFN2 physically interacts through its C-terminus with PFK1. MFN2 knockdown or exposure of cells to 15% stretch promoted stabilization of PFK1, likely through interfering the association between PFK1 and the E3 ubiquitin ligase TRIM21 (E3 ubiquitin ligase tripartite motif [TRIM]-containing protein 21), thus, decreasing the ubiquitin-protease-dependent PFK1 degradation. In addition, study of mechanotransduction utilizing pharmaceutical inhibition indicated that the MFN2 downregulation by 15% stretch was dependent on inactivation of the SP1 (specificity protein 1) and activation of the JNK (c-Jun N-terminal kinase) and ROCK (Rho-associated protein kinase). Adenovirus-mediated MFN2 overexpression or pharmaceutical inhibition of PFK1 suppressed the 15% stretch-induced VSMC proliferation and migration and alleviated neointimal hyperplasia in vein grafts. CONCLUSIONS: MFN2 is a mechanoresponsive protein that interacts with PFK1 to mediate PFK1 degradation and therefore suppresses glycolysis in VSMCs.

Shear stress regulates the SNAP23-mediated endothelial secretion of VWF through the GPR68/PKA/vimentin mechanotransduction pathway.

Von Willebrand Factor (VWF) can promote platelet adhesion to the post-atherosclerotic regions to initiate thrombosis. The synthesis and secretion of VWF are important functions of endothelial cells (ECs). However, the mechanism through which blood flow regulates endothelial secretion of VWF remains unclear. We utilized a parallel-plate flow apparatus to apply fluid shear stress to human umbilical vein endothelial cells (HUVECs). Compared with pulsatile shear stress that mimics laminar flow in the straight parts of arteries or upstream of atherosclerotic stenosis sites, short-term exposure to oscillatory shear stress (OS) that mimics disturbed flow increased VWF secretion independent of affecting synaptosomal-associated protein 23 (SNAP23) expression and promoted the translocation of SNAP23 to the cell membrane. Vimentin associated with SNAP23, and this association was enhanced by OS or histamine. Acrylamide, a reagent that disrupts vimentin intermediate filaments, prevented histamine/OS-induced SNAP23 translocation, as well as VWF secretion. Immunofluorescence analysis revealed that the polarity of the vimentin intermediate filament network decreased after stimulation with histamine or OS. In addition, inhibition of protein kinase A (PKA) or G protein coupled receptor 68 (GPR68) eliminated the histamine/OS-induced phosphorylation of vimentin at Ser38 and secretion of VWF. Furthermore, syntaxin 7 might assist with the translocation of SNAP23 to the cell membrane, thus playing a role in promoting VWF secretion. The GPR68/PKA/vimentin signaling pathway may represent a novel mechanism for the regulation of SNAP23-mediated VWF secretion by ECs under OS and provide strategies for the prevention of atherosclerosis-related thrombosis.

Concordance of chronic conditions among the household members in Shanghai: a cross-sectional study.

OBJECTIVES: Members living in the same household tend to share some similar behaviours and environment. We want to quantitatively assess the associations of chronic conditions to investigate the concordance of disease status among the household members. SETTING: Shanghai, China. PARTICIPANTS: Our data were from the fifth Health Service Survey in Shanghai in 2013. 12 002 households with 31 531 residents were selected in this survey by using a three-stage, stratified, random sampling method. OUTCOME MEASURES: Five highly prevalent chronic conditions, namely hypertension, diabetes, ischaemic heart disease (IHD), cerebrovascular disease (CVD) and obesity were chosen. The generalised estimating equations (GEE) model was used to estimate the associations adjusted for age, gender, education status, health insurance status, smoking and drinking. Using a subsample of adult children with parents' chronic conditions as the key risk factor and a subsample of wives with the chronic conditions of the husband as key risk factor, we reran our GEE models to explore chronic condition concordance within these relationships. RESULTS: A total of 10 198 households with 27 010 adult participants were included. Using all adult household members, we found positive statistically significant associations between one's chronic conditions and the same disease status of their household members (hypertension (OR=3.26, 95% CI 3.02 to 3.52); diabetes (OR=1.68, 95% CI 1.40 to 2.01); IHD (OR=5.31, 95% CI 3.56 to 7.92); CVD (OR=3.40, 95% CI 1.99 to 5.80); obesity (OR=3.41, 95% CI 2.34 to 4.96)). The results of analysing ad-child subsample and spouse subsample also showed similar associations. Moreover, the potential concordance of different chronic conditions was found between hypertension and diabetes. CONCLUSIONS: We found chronic condition concordance within households. This study provides evidence that the chronic conditions of other members of a household may be a significant risk factor for a household member's own health.