Background and Aims
Trimethylation of Lys36 on histone 3 (H3K36me3) catalyzed by histone methyltransferase SET domain‐containing 2 (SETD2) is one of the most conserved epigenetic marks from yeast to ...mammals. SETD2 is frequently mutated in multiple cancers and acts as a tumor suppressor.
Approach and Results
Here, using a liver‐specific Setd2 depletion model, we found that Setd2 deficiency is sufficient to trigger spontaneous HCC. Meanwhile, Setd2 depletion significantly increased tumor and tumor size of a diethylnitrosamine‐induced HCC model. The mechanistic study showed that Setd2 suppresses HCC not only through modulating DNA damage response, but also by regulating lipid metabolism in the liver. Setd2 deficiency down‐regulated H3K36me3 enrichment and expression of cholesterol efflux genes and caused lipid accumulation. High‐fat diet enhanced lipid accumulation and promoted the development of HCC in Setd2‐deficient mice. Chromatin immunoprecipitation sequencing analysis further revealed that Setd2 depletion induced c‐Jun/activator protein 1 (AP‐1) activation in the liver, which was trigged by accumulated lipid. c‐Jun acts as an oncogene in HCC and functions through inhibiting p53 in Setd2‐deficient cells.
Conclusions
We revealed the roles of Setd2 in HCC and the underlying mechanisms in regulating cholesterol homeostasis and c‐Jun/AP‐1 signaling.
A simple and practical method for the synthesis of 2-aminobenzothiazoles through visible-light-initiated malic acid-promoted cascade coupling/cyclization of aromatic amines and KSCN with ambient air ...as an oxidant in eco-friendly bis(methoxypropy) ether at ambient temperature was developed.
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By using ambient air as the oxidant and malic acid as the promoter, a practical method for the preparation of 2-aminobenzothiazoles through visible-light-initiated cascade reaction of aromatic amines and KSCN in eco-friendly bis(methoxypropy)ether under metal-, hazardous additive-, photocatalyst-free conditions was established.
A dynamic cross-linked supramolecular network of poly(glycidyl methacrylate)s derivative chains was constructed on mesoporous silica nanoparticles via disulfide bond and ion–dipole interactions ...between cucurbit7urils and protonated diamines in the polymer chains. This kind of multifunctional organic–inorganic hybrid material with pH- and glutathione- (GSH-) stimuli responsiveness can be applied to anticancer drug delivery and controlled release. Good release performance toward doxorubicin hydrochloride (DOX) was achieved under the simulative tumor intracellular environment (pH = 5.0, C GSH = 2–10 mM). Significantly, the release amount of DOX increased upon lowering the solution pH value and increasing the concentration of GSH, as demonstrated by a series of controlled release experiments. Furthermore, the DOX-loaded hybrid nanomaterials displayed apparent cell-growth inhibition effects to cancer cell lines, as evidenced by MTT assay and confocal laser scanning microscopy.
Activation of transcription enhancers, especially super-enhancers, is one of the critical epigenetic features of tumorigenesis. However, very few studies have systematically identified the enhancers ...specific in cancer tissues.
Here, we studied the change of histone modifications in MMTV-PyVT breast cancer model, combining mass spectrometry-based proteomics and ChIP-seq-based epigenomics approaches. Some of the proteomic results were confirmed with western blotting and IHC staining. An inhibitor of H3K27ac was applied to study its effect on cancer development.
H3K27ac and H4K8ac are elevated in cancer, which was confirmed in patient tissue chips. ChIP-seq revealed that H4K8ac is co-localized with H3K27ac on chromatin, especially on distal enhancers. Epigenomic studies further identified a subgroup of super-enhancers marked by H3K4me3 peaks in the intergenic regions. The H3K4me3-enriched regions enhancers are associated with higher level of H3K27ac and H4K8ac compared with the average level of conventional super-enhancers and are associated with higher transcription level of their adjacent genes. We identified 148 H3K4me3-enriched super-enhancers with higher gene expression in tumor, which may be critical for breast cancer. One inhibitor for p300 and H3K27ac, C646, repressed tumor formation probably through inhibiting Vegfa and other genes.
Taken together, our work identifies novel regulators and provides important resource to the genome-wide enhancer studies in breast cancer and raises the possibility of cancer treatment through modulating enhancer activity.
Mesoporous silica nanoparticles (MSNs) are promising solid supports for controlled anticancer drug delivery. Herein, we report biocompatible layer-by-layer (LbL) coated MSNs (LbL-MSNs) that are ...designed and crafted to release encapsulated anticancer drugs, e.g., doxorubicin hydrochloride (DOX), by changing the pH or by adding competitive agents. The LbL coating process comprises bis-aminated poly(glycerol methacrylate)s (BA-PGOHMAs) and cucurbit7uril (CB7), where CB7 serves as a molecular bridge holding two different bis-aminated polymeric layers together by means of host–guest interactions. This integrated nanosystem is tuned to respond under specific acidic conditions or by adding adamantaneamine hydrochloride (AH), attributed to the competitive binding of hydronium ions or AH to CB7 with BA-PGOHMAs. These LbL-MSN hybrids possess excellent biostability, negligible premature drug leakage at pH 7.4, and exceptional stimuli-responsive drug release performance. The pore sizes of the MSNs and bis-aminated compounds (different carbon numbers) of BA-PGOHMAs have been optimized to provide effective integrated nanosystems for the loading and release of DOX. Significantly, the operating pH for the controlled release of DOX matches the acidifying endosomal compartments of HeLa cancer cells, suggesting that these hybrid nanosystems are good candidates for autonomous anticancer drug nanocarriers actuated by intracellular pH changes without any invasive external stimuli. The successful cellular uptake and release of cargo, e.g., propidium iodide (PI), in human breast cancer cell line MDA-231 from PI-loaded LbL-MSNs have been confirmed by confocal laser scanning microscopy (CLSM), while the cytotoxicities of DOX-loaded LbL-MSNs have been quantified by the Cell Counting Kit-8 (CCK-8) viability assay against HeLa cell lines and fibroblast L929 cell lines. The uptake of DOX-loaded LbL-MSNs by macrophages can be efficiently reduced by adding biocompatible hydrophilic poly(ethylene glycol) or CB7 without destroying the capping. In vivo tumor-growth inhibition experiments with BALB/c nude mice demonstrated a highly efficient tumor-growth inhibition rate of DOX-loaded LbL-MSNs, suggesting that the novel type of LbL-MSN materials hold great potentials in anticancer drug delivery.
Chronic neuropathic pain is a frequent sequel to peripheral nerve injury and maladaptive nervous system function. Divanillyl sulfone (DS), a novel structural derivative of 4,4'-dihydroxydibenzyl ...sulfoxide from a traditional Chinese medicine Gastrodia elata with anti-nociceptive effects, significantly alleviated neuropathic pain following intrathecal injection. Here, we aimed to investigate the underlying mechanisms of DS against neuropathic pain.
A chronic constrictive injury (CCI) mouse model of neuropathic pain induced by sciatic nerve ligation was performed to evaluate the effect of DS by measuring the limb withdrawal using Von Frey filament test. Immunofluorescence staining was used to assess the cell localizations and expressions of Iba-1, ASC, NLRP3, and ROS, the formation of autolysosome. The levels of NLRP3-related proteins (caspase-1, NLRP3, and IL-1β), mitophagy-related proteins (LC3, Beclin-1, and p62), and apoptosis-related proteins (Bcl-XL and Bax) were detected by Western blotting. The apoptosis of BV-2 cell and caspase activity were evaluated by flow cytometry.
DS significantly alleviated the neuropathic pain by increasing the mechanical withdrawal threshold and inhibiting the activation of NLRP3 in CCI-induced model mice. Our findings indicated that DS promoted the mitophagy by increasing the LC3II and Beclin 1 and decreasing the levels of p62 protein in BV-2 cell. This is accompanied by the inhibition of NLRP3 activation, which was shown as inhibited the expression of NLRP3 in lysates as well as the secretion of mature caspase-1 p10 and IL-1β p17 in supernatants in cultured BV-2 microglia. In addition, DS could promote mitophagy-induced improvement of dysfunctional mitochondria by clearing intracellular ROS and restoring mitochondrial membrane potential.
Together, our findings demonstrated that DS ameliorate chronic neuropathic pain in mice by suppressing NLRP3 inflammasome activation induced by mitophagy in microglia. DS may be a promising therapeutic agent for chronic neuropathic pain.
Although antibiotics have been widely used in clinical applications to treat pathogenic infections at present, the problem of drug-resistance associated with abuse of antibiotics is becoming a ...potential threat to human beings. We report a biohybrid nanomaterial consisting of antibiotics, enzyme, polymers, hyaluronic acid (HA), and mesoporous silica nanoparticles (MSNs), which exhibits efficient in vitro and in vivo antibacterial activity with good biocompatibility and negligible hemolytic side effect. Herein, biocompatible layer-by-layer (LBL) coated MSNs are designed and crafted to release encapsulated antibiotics, e.g., amoxicillin (AMO), upon triggering with hyaluronidase, produced by various pathogenic Staphylococcus aureus (S. aureus). The LBL coating process comprises lysozyme (Lys), HA, and 1,2-ethanediamine (EDA)-modified polyglycerol methacrylate (PGMA). The Lys and cationic polymers provided multivalent interactions between MSN-Lys-HA-PGMA and bacterial membrane and accordingly immobilized the nanoparticles to facilitate the synergistic effect of these antibacterial agents. Loading process was characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), thermogravimetric analysis (TGA), and X-ray diffraction spectroscopy (XRD). The minimal inhibition concentration (MIC) of MSN-Lys-HA-PGMA treated to antibiotic resistant bacteria is much lower than that of isodose Lys and AMO. Especially, MSN-Lys-HA-PGMA exhibited good inhibition for pathogens in bacteria-infected wounds in vivo. Therefore, this type of new biohybrid nanomaterials showed great potential as novel antibacterial agents.
This study was conducted to investigate the expression of the spindle assembly checkpoint kinase tyrosine/threonine kinase (TTK) in triple positive breast cancer (TPBC) and its effect on TPBC cells. ...We analyzed the status of TTK in 69 TPBC samples using immunohistochemistry. The correlation between TTK and clinicopathological parameters was analyzed using a chi-squared test. The prognostic value of TTK was evaluated using Kaplan-Meier survival curves. We analyzed the role of TTK in the invasion and proliferation of TPBC cells in vitro and in vivo. The mean age of the 69 patients with TPBC enrolled in this study was 53 years (range: 29-86 years). TTK expression was positively correlated with tumor size (p=0.034), p53 status (p=0.023), TNM stage (p=0.023), and Ki-67 index (p<0.001). The Kaplan-Meier curves revealed that TTK expression was correlated with poor disease-free survival (p=0.001) and overall survival (p=0.050). Multivariate proportional hazard regression analyses showed that TTK and TNM staging were significant independent predictors of disease-free survival (p=0.007 and p=0.034, respectively). Additionally, TTK knockdown inhibited the invasion and proliferation of the BT474 TPBC cell line. The findings of this study indicate that TTK overexpression is associated with cancer progression and prognosis in patients with TPBC, whereas TTK knockdown inhibits the invasion and proliferation of TPBC cells. Thus, TTK might serve as a prognostic marker for TPBC.
The obesity-lung cancer association remains controversial. Concerns over confounding by smoking and reverse causation persist. The influence of obesity type and effect modifications by race/ethnicity ...and tumor histology are largely unexplored.
We examined associations of body mass index (BMI), waist circumference (WC), and waist-hip ratio (WHR) with lung cancer risk among 1.6 million Americans, Europeans, and Asians. Cox proportional hazard regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for potential confounders. Analyses for WC/WHR were further adjusted for BMI. The joint effect of BMI and WC/WHR was also evaluated.
During an average 12-year follow-up, 23 732 incident lung cancer cases were identified. While BMI was generally associated with a decreased risk, WC and WHR were associated with increased risk after controlling for BMI. These associations were seen 10 years before diagnosis in smokers and never smokers, were strongest among blacks, and varied by histological type. After excluding the first five years of follow-up, hazard ratios per 5 kg/m2 increase in BMI were 0.95 (95% CI = 0.90 to 1.00), 0.92 (95% CI = 0.89 to 0.95), and 0.89 (95% CI = 0.86 to 0.91) in never, former, and current smokers, and 0.86 (95% CI = 0.84 to 0.89), 0.94 (95% CI = 0.90 to 0.99), and 1.09 (95% CI = 1.03 to 1.15) for adenocarcinoma, squamous cell, and small cell carcinoma, respectively. Hazard ratios per 10 cm increase in WC were 1.09 (95% CI = 1.00 to 1.18), 1.12 (95% CI = 1.07 to 1.17), and 1.11 (95% CI = 1.07 to 1.16) in never, former, and current smokers, and 1.06 (95% CI = 1.01 to 1.12), 1.20 (95% CI = 1.12 to 1.29), and 1.13 (95% CI = 1.04 to 1.23) for adenocarcinoma, squamous cell, and small cell carcinoma, respectively. Participants with BMIs of less than 25 kg/m2 but high WC had a 40% higher risk (HR = 1.40, 95% CI = 1.26 to 1.56) than those with BMIs of 25 kg/m2 or greater but normal/moderate WC.
The inverse BMI-lung cancer association is not entirely due to smoking and reverse causation. Central obesity, particularly concurrent with low BMI, may help identify high-risk populations for lung cancer.
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•The Sb mineralization in the Banxi deposit primarily occurred during 130–120 Ma.•Zircon (U-Th)/He system in altered host rocks can be completely reset by hydrothermal Sb ...mineralization and record its age.•This study proves zircon (U-Th)/He dating can be viable for constraining the timing of low-temperature hydrothermal mineralization.
The Banxi Sb deposit is one of world-class Sb deposits located in the Xiangzhong Sb-Au metallogenic province in southern China. However, the mineralization age of this deposit is still not well constrained due to a lack of suitable minerals for reliable radiometric dating. Since the fluid-inclusion data suggest that the temperature of ore-forming fluids in the Banxi deposit is up to 330 °C, zircon (U-Th)/He thermochronometry with the closure temperature of 160–200 °C was chosen here to elucidate the timing of Sb mineralization of this deposit. Detrital zircons within three samples of altered host rocks in the Banxi deposit yielded (U-Th)/He dates of 132–113 Ma (weighted mean = 121 ± 12 Ma), 132–124 Ma (weighted mean = 129 ± 3 Ma) and 142–113 Ma (weighted mean = 125 ± 10 Ma), respectively, which are broadly consistent with the Rb-Sr and Sm-Nd isochron ages of hydrothermal sulfide minerals (~130 Ma). Combining with the reported ages of adjacent Sb deposits, we propose that Sb mineralization in the Banxi deposit may have primarily taken place during 130–120 Ma.
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