Search

Lysine benzoylation (Kbz) is a recently discovered histone modification. Here, the authors characterize writers, erasers and readers of histone Kbz in S. cerevisiae and identify non-histone proteins bearing Kbz, laying foundations to dissect the roles of Kbz in diverse cellular processes.

Abstract p62/SQSTM1 is frequently up-regulated in many cancers including hepatocellular carcinoma. Highly expressed p62 promotes hepato-carcinogenesis by activating many signaling pathways including Nrf2, mTORC1, and NFκB signaling. However, the underlying mechanism for p62 up-regulation in hepatocellular carcinoma remains largely unclear. Herein, we confirmed that p62 was up-regulated in hepatocellular carcinoma and its higher expression was associated with shorter overall survival in patients. The knockdown of p62 in hepatocellular carcinoma cells decreased cell growth in vitro and in vivo. Intriguingly, p62 protein stability could be reduced by its acetylation at lysine 295, which was regulated by deacetylase Sirt1 and acetyltransferase GCN5. Acetylated p62 increased its association with the E3 ligase Keap1, which facilitated its poly-ubiquitination-dependent proteasomal degradation. Moreover, Sirt1 was up-regulated to deacetylate and stabilize p62 in hepatocellular carcinoma. Additionally, Hepatocyte Sirt1 conditional knockout mice developed much fewer liver tumors after Diethynitrosamine treatment, which could be reversed by the re-introduction of exogenous p62. Taken together, Sirt1 deacetylates p62 at lysine 295 to disturb Keap1-mediated p62 poly-ubiquitination, thus up-regulating p62 expression to promote hepato-carcinogenesis. Therefore, targeting Sirt1 or p62 is a reasonable strategy for the treatment of hepatocellular carcinoma.

Tumor necrosis factor (TNF) receptor type II (TNFR2) is expressed in various tumor cells and some immune cells, such as regulatory T cells and myeloid-derived suppressing cells. TNFR2 contributes a lot to the tumor microenvironment. For example, it directly promotes the occurrence and growth of some tumor cells, activates immunosuppressive cells, and supports immune escape. Existing studies have proved the importance of TNFR2 in cancer treatment. Here, we reviewed the activation mechanism of TNFR2 and its role in signal transduction in the tumor microenvironment. We summarized the expression and function of TNFR2 within different immune cells and the potential opportunities and challenges of targeting TNFR2 in immunotherapy. Finally, the advantages and limitations of TNFR2 to treat tumor-related diseases are discussed, and the problems that may be encountered in the clinical development and application of targeted anti-TNFR2 agonists and inhibitors are analyzed.

Backgrounds In advanced pancreatic ductal adenocarcinoma (PDAC), immune therapy, including immune checkpoint inhibitors, has limited efficacy, encouraging the study of combination therapy.Methods Tumor necrosis factor receptor 2 (TNFR2) was analyzed via immunohistochemistry, immunofluorescence, western blotting, and ELISAs. The in vitro mechanism that TNFR2 regulates programmed cell death 1 ligand 1 (PD-L1) was investigated using immunofluorescence, immunohistochemistry, flow cytometry, western blotting, and chromatin immunoprecipitation (ChIP). In vivo efficacy and mechanistic studies, using C57BL/6 mice and nude mice with KPC cell-derived subcutaneous and orthotopic tumors, employed antibodies against TNFR2 and PD-L1. Survival curves were constructed for the orthotopic model and a genetically engineered PDAC model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre). Mass cytometry, immunohistochemistry, and flow cytometry analyzed local and systemic alterations in the immunophenotype.Results TNFR2 showed high expression and is a prognostic factor in CD8+ T cell-enriched pancreatic cancer. TNFR2 promotes tumorigenesis and progression of pancreatic cancer via dual effect: suppressing cancer immunogenicity and partially accelerating tumor growth. TNFR2 positivity correlated with PD-L1, and in vitro and in vivo, it could regulate the expression of PDL1 at the transcription level via the p65 NF-κB pathway. Combining anti-TNFR2 and PD-L1 antibodies eradicated tumors, prolonged overall survival in pancreatic cancer, and induced strong antitumor immune memory and secondary prevention by reducing the infiltration of Tregs and tumor-associated macrophages and inducing CD8+ T cell activation in the PDAC microenvironment. Finally, the antitumor immune response derived from combination therapy is mainly dependent on CD8+ T cells, partially dependent on CD4+ T cells, and independent of natural killer cells.Conclusions Anti-TNFR2 and anti-PD-L1 combination therapy eradicated tumors by inhibiting their growth, relieving tumor immunosuppression, and generating robust memory recall.

Abstract Chemoresistance remains a major obstacle to successful cancer therapy, especially for advanced cancers. It used to be recognised as a stable outcome resulting from genetic changes. However, recent studies showed that chemoresistance can also be unstable and reversible with the involvement of non‐genetic alterations. In the present study, we found that activating transcription factor 4 (ATF4) is downregulated in chemoresistant gastric cancer cells. The over‐expression of ATF4 reversed chemoresistance by activating CHOP transcription to enhance drug‐induced apoptosis, and vice versa. Moreover, casein kinase 1 delta (CK1δ) was identified as the kinase responsible for ATF4‐S219 phosphorylation, which triggered βTrCP‐mediated ATF4 polyubiquitination to promote its proteasomal degradation subsequently. Interestingly, drug withdrawal gradually restored chemosensitivity as well as ATF4 expression in chemoresistant cells, highlighting the dependence of dynamic drug resistance on ATF4 protein expression. In line with these findings, the inhibition of ATF4 protein degradation by CK1δ or proteasome inhibitors overcame chemoresistance both in vitro and in vivo. Taken together, these results indicate that CK1δ stimulates βTrCP‐dependent ATF4 polyubiquitination and subsequent proteasomal degradation to promote chemoresistance in gastric cancer. Stabilisation of the ATF4 protein with bortezomib (BTZ), an anticancer drug that inhibits proteasomal degradation, might be a rational strategy to improve chemotherapeutic efficacy in gastric cancer.

The purpose of this study is to explore the occupants’ subjective evaluation of the indoor environmental quality (IEQ) of hotels with the same physical environment and different decoration styles, and to reveal the influence of different decoration styles on the subjective evaluation of the indoor environmental quality. The study found a hotel with three mainstream styles of modern simple style, British pastoral style, and modern Japanese style, and adopted standard rooms with the same area, pattern, lighting, orientation, and decoration cost. The only variable controlled was the decoration style, and the subjective feelings of customers on the physical environment were investigated. Based on the literature and 604 online comments, the researchers designed a questionnaire and collected 710 effective questionnaires for empirical analysis. The analysis results of KH coder and SPSS software (Chicago, IL, USA) show that ➀ the light environment in the indoor environment (including indoor natural lighting, lighting and other influencing factors) and non-light visual factors (including indoor color matching, plant layout, closeness to nature, decoration texture, space materials, decoration atmosphere and other factors) has the greatest impact on the subjective evaluation of decoration style, especially on the subjective evaluation of modern simple indoor environment. ➁ Light environment, air quality and non-light visual factors play a key role in the subjective evaluation of the indoor environment of the British pastoral-style hotels. ➂ The light environment, thermal environment and non-light visual factors are the most sensitive to the subjective evaluation of the indoor environment of modern Japanese-style hotels. ➃ Thermal environment, light environment, acoustic environment, air quality environment and non-light visual factors have the greatest impact on the subjective evaluation of the hotel indoor environment. Based on the findings, this study puts forward some suggestions to improve the interior environment of the hotel with different decoration styles to improve the quality and attractiveness of the hotel.

As an important part of a hotel’s internal environment, color design affects not only customers’ hotel stay experiences, but also their check-in experiences. However, how hotel guests’ emotional experiences are affected by interior color design is understudied in China. Drawing on the theory of color psychology, we designed a Virtual Reality (VR) experiment and a questionnaire to explore how hotel guests’ emotional experience can be influenced by the color scheme of hotel interior color design. The results show that hotel rooms decorated in yellow have a pleasurable effect, those decorated in gray a calming effect, and those decorated in blue a relatively neutral effect. Young participants have more negative emotional responses to rooms decorated in dark yellow. The emotional impact of both gray and yellow with higher grayscale values shifts from positive to negative with the improvement of customers’ educational background. Low grayscale color schemes are preferred over high grayscale ones, and indoor environments with synergistic colors are preferred over contrasting colors. It is also found that male subjects tend to have more positive emotional reactions to all color schemes than females. For most subjects, age and education have no effect on their emotional reactions to different color schemes. These findings have important implications for hotel interior environment color design.

The chromatographic fingerprint of 14 batches of Artemisia rupestris L. samples were established in this study. The constituents of ten components in Artemisia rupestris L. were determined using quantitative analysis of multi-components by single marker (QAMS) and the external standard method (ESM). Due to their stability and accessibility, chlorogenic acid and linarin were used as references to calculate the relative correction factors (RCFs) of apigenin-C-6,8-pentoside-hexoside, apigenin-C-6,8-di-pentoside, luteolin, 3,4-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid, 4,5-dicaffeoylquinic acid, chrysosplenetin B, and sbsinthin, based on high-performance liquid chromatography (HPLC). The value calculated by QAMS was consistent with that of the ESM, and the reproducibility of RCFs was found to be reliable. In conclusion, simultaneous determination of the ten components by the QAMS method and chromatographic fingerprint analysis were feasible and accurate in evaluating the quality of Artemisia rupestris L. and can be used as reference in traditional Chinese medicine quality control.

In this paper, we introduce a new graph operation called subdivision vertex-edge join (denoted by G 1 S ▹ ( G 2 V ∪ G 3 E ) for short), and then the adjacency spectrum, the Laplacian spectrum and the signless Laplacian spectrum of G 1 S ▹ ( G 2 V ∪ G 3 E ) are respectively determined in terms of the corresponding spectra for a regular graph G 1 and two arbitrary graphs G 2 and G 3 . All the above can be viewed as the generalizations of the main results in [X. Liu, Z. Zhang, Bull. Malays. Math. Sci. Soc., 2017:1⁻17]. Furthermore, we also determine the normalized Laplacian spectrum of G 1 S ▹ ( G 2 V ∪ G 3 E ) whenever G i are regular graphs for each index i = 1 , 2 , 3 . As applications, we construct infinitely many pairs of A-cospectral mates, L-cospectral mates, Q-cospectral mates and L -cospectral mates. Finally, we give the number of spanning trees, the (degree-)Kirchhoff index and the Kemeny’s constant of G 1 S ▹ ( G 2 V ∪ G 3 E ) , respectively.

The gut microbiota and liver cancer have a complex interaction. However, the role of gut microbiome in liver tumor initiation remains unknown. Herein, liver cancer was induced using hydrodynamic transfection of oncogenes to explore liver tumorigenesis in mice. Gut microbiota depletion promoted liver tumorigenesis but not progression. Elevated sterol regulatory element-binding protein 2 (SREBP2) was observed in mice with gut flora disequilibrium. Pharmacological inhibition of SREBP2 or Srebf2 RNA interference attenuated mouse liver cancer initiation under gut flora disequilibrium. Furthermore, gut microbiota depletion impaired gut tryptophan metabolism to activate aryl hydrocarbon receptor (AhR). AhR agonist Ficz inhibited SREBP2 posttranslationally and reversed the tumorigenesis in mice. And, AhR knockout mice recapitulated the accelerated liver tumorigenesis. Supplementation with Lactobacillus reuteri, which produces tryptophan metabolites, inhibited SREBP2 expression and tumorigenesis in mice with gut flora disequilibrium. Thus, gut flora disequilibrium promotes liver cancer initiation by modulating tryptophan metabolism and up-regulating SREBP2. [ABSTRACT FROM AUTHOR]