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Background and Aim: Silybin is the major biologically active compound of silymarin, the standardized extract of the milk thistle (Silybum marianum). Increasing numbers of studies have shown that silybin can improve nonalcoholic steatohepatitis (NASH) in animal models and patients; however, the mechanisms underlying silybin's actions remain unclear.Methods: Male C57BL/6 mice were fed a methionine-choline deficient (MCD) diet for 8 weeks to induce the NASH model, and silybin was orally administered to the NASH mice. The effects of silybin on lipid accumulation, hepatic fibrosis, oxidative stress, inflammation-related gene expression and nuclear factor kappa B (NF-κB) activities were evaluated by biochemical analysis, immunohistochemistry, immunofluorescence, quantitative real-time PCR and western blot.Results: Silybin treatment significantly alleviated hepatic steatosis, fibrosis and inflammation in MCD-induced NASH mice. Moreover, silybin inhibited HSC activation and hepatic apoptosis and prevented the formation of MDBs in the NASH liver. Additionally, silybin partly reversed the abnormal expression of lipid metabolism-related genes in NASH. Further study showed that the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway played important roles in the silybin-derived antioxidant effect, as evidenced by the upregulation of Nrf2 target genes in the silybin treatment group. In addition, silybin significantly downregulated the expression of inflammation-related genes and suppressed the activity of NF-κB signaling.Conclusions: Silybin was effective in preventing the MCD-induced increases in hepatic steatosis, fibrosis and inflammation. The effect was related to alteration of lipid metabolism-related gene expression, activation of the Nrf2 pathway and inhibition of the NF-κB signaling pathway in the NASH liver. [ABSTRACT FROM AUTHOR]

Abstract: Cancer cells undergo comprehensive metabolic reprogramming to meet the increased requirements of energy and building blocks for proliferation. Lipin‐1, a phosphatidic acid phosphatase converting phosphatidic acid (PA) to diacylglycerol (DAG), is upregulated in lung adenocarcinoma (LUAD) cell lines and tumor tissues. In this study, we reveal high lipin‐1 expression is correlated with poor prognosis of patients with LUAD. Knockdown of lipin‐1 decreases cell viability and proliferation in LUAD cells, whereas it has less effect on nontumorigenic lung cells. Autophagy and ER stress play important roles in tumor initiation and progression. Lipin‐1 knockdown induces the initiation of autophagy while disrupts formation of autolysosome. Lipin‐1 silencing induces the activation of ER stress through the IRE1α pathway. Furthermore, we demonstrate disrupted ER homeostasis contributes to the cell phenotype, and the elevated autophagy initiation is due to the ER stress in part. For the first time, we show lack of lipin‐1 enhances the sensitivity of LUAD cells to cisplatin treatment. Our results suggest that lipin‐1 is a potential target, alone or combined with other treatment, for lung cancer therapy. [ABSTRACT FROM AUTHOR]

The Notch2 is a critical membrane receptor for B-cell functions, and also displays various biological roles in lymphoma pathogenesis. In this article, we reported that 3 of 69 (4.3%) diffuse large B-cell lymphomas (DLBCLs) exhibited a truncate NOTCH2 mutation at the nucleotide 7605 (G/A) in the cDNA sequence, which led to partial deletion of the C-terminal of PEST (proline-, glutamic acid-, serine- and threonine-rich) domain. The truncate Notch2 activated both the Notch2 and the NF-κB signals and promoted the proliferation of B-cell lymphoma cell lines, including DLBCL and Burkitt's lymphoma cell lines. Moreover, the ectopic proliferation was completely inhibited by ammonium pyrrolidinedithiocarbamate (PDTC), an NF-κB inhibitor. Simultaneously, PDTC also reduced the expression level of Notch2. Based on these results, we conclude that the Notch2 receptor with PEST domain truncation enhances cell proliferation which may be associated with the activation of the Notch2 and the NF-κB signaling. Our results are expected to provide a possible target for new DLBCL therapies by suppressing the Notch2 and the NF-κB signaling. [ABSTRACT FROM AUTHOR]

Using air quality monitoring data of 2018, 2020 and 2021 from national monitoring stations in Hangzhou, the disaster cycles, with levels of ozone (O3), fine particulate matter (PM2.5), and coarse particulate matter (PM10) were determined. The damage to human health from pollutants, which represents the loss of open space functionality, was determined by a review of the literature. Using the theory of resilience evaluation, a correlation was established between pollutant concentrations and system functions, and resilience performance curves of different types of open spaces were constructed for the urban open space pollutant disaster cycle to evaluate the resilience and related properties for open space responses to O3, PM2.5, and PM10 pollution disasters. The results indicate that open spaces in scenic and cultural areas are more resilient to pollution than residential areas and commercial transportation residential mixed zones. All open spaces were the most robust to PM10 and had the highest redundancy for O3 and PM10, while had the lowest redundancy for PM2.5. All open spaces responded most rapidly to PM2.5, partly because of larger scale meteorological changes in cities. All open spaces had the strongest resilience to PM10 disasters, followed by O3 disasters, with the worst resilience to PM2.5 disasters, with a resilience index range of [0.5, 1]. The results and methods can help enhance urban resilience by bringing new ideas and broadening urban resilience theory and research. The strategy of enhancing greenery in urban open spaces was found to significantly reduce the impact of air pollution disasters, thereby reducing human health damage to users of open spaces. This is significant for enhancing urban resilience and building urban health infrastructure. [ABSTRACT FROM AUTHOR]

Abstract: The aims of this study are to investigate the effects of gravitational environment produced by a superconducting magnet on osteoblast morphology, proliferation and adhesion. A superconducting magnet which can produce large gradient high magnetic field (LGHMF) and provide three apparent gravity levels was employed to simulate space gravity environment. The effects of LGHMF on osteoblast morphology, proliferation, adhesion and the gene expression of fibronectin and collagen I were detected by scanning electron microscopy, immunocytochemistry, adhesion assays and real time PCR, respectively, after exposure of osteoblasts to LGHMF for 24h. Osteoblast morphology was affected by LGHMF and the most evident morphology alteration was observed at condition. Proliferative abilities of MC3T3 and MG-63 cell were affected under LGHMF conditions compared to control condition. The adhesive abilities of MC3T3 and MG-63 cells to extracellular matrix (ECM) proteins (fibronectin, laminin, collagen IV) were also affected by LGHMF , moreover, the effects of LGHMF on osteoblast adhesion to different ECM proteins were different. Fibronectin gene expression in MG63 cells under zero gravity condition was increased significantly compared to other conditions. Collagen I gene expression in MG-63 and MC3T3 cells was altered by both magnetic field and alerted gravity. The study indicates that the superconducting magnet which can produce LGHMF may be a novel ground-based space gravity simulator and can be used for biological experiment at cellular level. [Copyright &y& Elsevier]

Background: Cinobufacini, the sterilized hot water extraction of dried toad skin, has been widely used in the treatment of inflammation and cancers. Recently we found cinobufacini could ameliorate dextran sulfate sodium (DSS)-induced colitis in mice, but the underlying mechanism was not fully understood. In current study, we explored the effect of cinobufacini on gut microbiota in DSS-induced acute colitic mouse model by pyrosequencing of colonic contents. Methods: C57BL/6 mice were supplied with normal or 3.0% DSS containing drinking water. DSS-treat mice were gavaged daily either with vehicle (water) or cinobufacini (10.0 or 30.0 mg/kg) for 7 days. The composition of the gut microbiota was assessed by analyzing 16S rRNA gene sequences. Results: Our data indicated that cinobufacini reversed DSS-induced gut dysbiosis and enhanced intestinal barrier integrity. Moreover, changing of some specific microbial groups such as Proteobacteria and Bacteroides was closely correlated with the re-establishment of intestinal equilibrium and the recovery of intestinal function. Conclusion: Cinobufacini prevents colitis in mice by modifying the composition and function of gut microbiota. The current study provides additional mechanistic insight in the therapeutic effect of cinobufacini treatment and may pave the way for clinical application of cinobufacini in colitis therapy. [ABSTRACT FROM AUTHOR]

The present research, comprised of two studies, examines the features and factor structure of the Teacher Caring Questionnaire, a measure of teacher caring developed in the Zhejiang province of China. In the first study, features of teacher caring were derived from open-ended teacher and student descriptions of caring teacher behaviour. A second sample of teachers then rated the necessity of each of the features as an aspect of teacher caring. In the second study, the development of a self-report questionnaire based on these eight features is described, and its factor structure examined through exploratory and confirmatory factor analyses. This process resulted in six initial factors, which were subsequently combined into three higher order factors, which appear to best capture the instrument’s structure. Internal consistency estimates for the three resulting subscales were calculated for five samples, and test–retest reliability calculated for Sample 5. Support for the convergent, discriminant and predictive validity of the measure were examined through correlations with conceptually similar measures, andt-tests comparing subscale scores for participants who indicated willingness to provide help (or not) under different conditions. Our analyses suggest that the Teacher Caring Questionnaire holds promise as a measure of teacher caring in the Zhejiang province. Furthermore, our method might inform similar efforts to develop context-grounded measures, as well as efforts to examine the cultural relevance of existing measures. [ABSTRACT FROM AUTHOR]

miRNA (miR) 34a has been shown to modulate critical gene transcripts involved in tumorigenesis, but its role in tumor-mediated immunosuppression is largely unknown. PD-L1 plays an important role in immune responses, however, presently its transcriptional regulatory mechanisms are not well understood. In the present study, we analyzed the expression of PD-L1 and miR-34a in 44 acute myeloid leukemia (AML) samples, and observed an inverse correlation between PD-L1 and miR-34a expression. Overexpression of miR-34a in HL-60 and Kasumi-1 cells blocked PD-L1 expression, and reduced PD-L1 surface expression. Using luciferase reporter assay and mutagenesis, we identified miR-34a as a putative binder of the PD-L1-3′UTR. Surface expression of PD-L1 induced by chemotherapeutic agents could also be reversed by miR-34a; furthermore, PD-L1 specific T cell apoptosis was reduced as well following miR-34a transfection. We also found that there is a positive feedback between PD-L1 expression and AKT activation. Our data suggest that miR-34a can regulate PD-L1 expression by targeting PD-L1 mRNA, and our present findings shed new light on the complex regulation of PD-L1 in human tumors, and on miR-34a in cancer immuno-based therapy. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study is to investigate the effects of the clinostat-simulated microgravity on MCF-7 cells (a breast cancer cell line) biological characteristics. MCF-7 cells were incubated for 24h in an incubator and then rotated in a clinostat as a model of simulated microgravity for 24, 48 and 72h, respectively. The effects of the clinostat-simulated microgravity on MCF-7 cells proliferation, invasion, migration, gelatinase production, adhesion, cell cycle, apoptosis and vinculin expression were detected. The results showed that the clinostat-simulated microgravity affected breast cancer cell invasion, migration, adhesion, cell cycle, cell apoptosis and vinculin expression. These results may explore a new field of vision to study tumor metastasis in future. [Copyright &y& Elsevier]

Summary Little is known about the cellular events promoting metastasis. We show that knockout of phospholipase D 2 (PLD2), which generates the signaling lipid phosphatidic acid (PA), inhibits lung metastases in the mammary tumor virus (MMTV) -Neu transgenic mouse breast cancer model. PLD2 promotes local invasion through the regulation of the plasma membrane targeting of MT1-MMP and its associated invadopodia. A liposome pull-down screen identifies KIF5B, the heavy chain of the motor protein kinesin-1, as a new PA-binding protein. In vitro assays reveal that PA specifically and directly binds to the C terminus of KIF5B. The binding between PLD2-generated PA and KIF5B is required for the vesicular association of KIF5B, surface localization of MT1-MMP, invadopodia, and invasion in cancer cells. Taken together, these results identify a role of PLD2-generated PA in the regulation of kinesin-1 motor functions and breast cancer metastasis and suggest PLD2 as a potential therapeutic target for metastatic breast cancer. [ABSTRACT FROM AUTHOR]