Abnormal metabolism of cholesterol may be a contributing factor in nonalcoholic steatohepatitis (NASH) pathogenesis. Accumulating evidence has shown that liver X receptor (LXR) is closely related to ...intrahepatic inflammation and fibrosis. In this study, we evaluated the effects of a novel liver-specific LXR inverse agonist, SR9243, on antifibrosis in NASH mice. A high-cholesterol diet was employed to induce NASH in BALB/c mice by either carbon tetrachloride (CCL4) administration or bile-duct ligation (BDL). Once NASH was induced, mice were treated with SR9243 for one month by intraperitoneal (i.p.) injection. Liver tissues were collected to determine the degree of fibrosis and intrahepatic inflammation via pathological examination and QPCR; serum was collected to analyze the plasma lipid levels and liver function by clinical biochemistry. The mice developed hepatic steatosis, severe hepatic inflammation, and fibrosis by BDL or CCL4. Treatment with SR9243 significantly reduced the severity of hepatic inflammation and ameliorated hepatic fibrosis; simultaneously, body weight, serum glucose, and plasma lipid levels were controlled effectively. Our data demonstrate that SR9243 exerts an antifibrotic and anti-inflammatory effect in NASH mice; hence these findings highly suggest that LXR inverse agonist could be therapeutically important in NASH treatment.
The retinoblastoma binding protein RBP2 (KDM5A) is a histone demethylase that promotes gastric cancer cell growth and is enriched in drug-resistant lung cancer cells. In tumor-prone mice lacking the ...tumor suppressor gene RB or MEN1, genetic ablation of RBP2 can suppress tumor initiation, but the pathogenic breadth and mechanistic aspects of this effect relative to human tumors have not been defined. Here, we approached this question in the context of lung cancer. RBP2 was overexpressed in human lung cancer tissues where its depletion impaired cell proliferation, motility, migration, invasion, and metastasis. RBP2 oncogenicity relied on its demethylase and DNA-binding activities. RBP2 upregulated expression of cyclins D1 and E1 while suppressing the expression of cyclin-dependent kinase inhibitor p27 (CDKN1B), each contributing to RBP2-mediated cell proliferation. Expression microarray analyses revealed that RBP2 promoted expression of integrin-β1 (ITGB1), which is implicated in lung cancer metastasis. Mechanistic investigations established that RBP2 bound directly to the p27, cyclin D1, and ITGB1 promoters and that exogenous expression of cyclin D1, cyclin E1, or ITGB1 was sufficient to rescue proliferation or migration/invasion, respectively. Taken together, our results establish an oncogenic role for RBP2 in lung tumorigenesis and progression and uncover novel RBP2 targets mediating this role.
Abstract
Layered MoS
2
is considered as one of the most promising two-dimensional photocatalytic materials for hydrogen evolution and water splitting; however, the electronic structure at the MoS
2
...-liquid interface is so far insufficiently resolved. Measuring and understanding the band offset at the surfaces of MoS
2
are crucial for understanding catalytic reactions and to achieve further improvements in performance. Herein, the heterogeneous charge transfer behavior of MoS
2
flakes of various layer numbers and sizes is addressed with high spatial resolution in organic solutions using the ferrocene/ferrocenium (Fc/Fc
+
) redox pair as a probe in near-field scanning electrochemical microscopy, i.e. in close nm probe-sample proximity. Redox mapping reveals an area and layer dependent reactivity for MoS
2
with a detailed insight into the local processes as band offset and confinement of the faradaic current obtained. In combination with additional characterization methods, we deduce a band alignment occurring at the liquid-solid interface.
The diagnostic performance of indocyanine green (ICG) fluorescence-guided sentinel lymph node biopsy (SLNB) for the presence of metastases in breast cancer remains unclear.
We performed a ...meta-analysis to investigate the diagnostic performance of ICG-guided SLNB.
Eligible studies were identified from searches of the databases PubMed and EMBASE up to September 2015. Studies that reported the detection rate of ICG fluorescence-guided SLNB with full axillary lymph node dissection and histological or immunohistochemical examinations were included. A meta-analysis was performed to generate pooled detection rate, sensitivity, specificity, false negative rate, diagnostic odds ratio (DOR) and a summary receiver operator characteristic curve (SROC).
Nineteen published studies were included to generate a pooled detection rate, comprising 2594 patients. The pooled detection rate was 0.98 (95% confidence interval CI, 0.96-0.99). Six studies finally met the criteria for meta-analysis, which yielded a pooled sensitivity of 0.92 (95% CI, 0.85-0.96), specificity 1 (95% CI, 0.97-1), and DOR 311.47 (95% CI, 84.11-1153.39). The area under the SROC was 0.9758. No publication bias was found.
ICG fluorescence-guided SLNB is viable for detection of lymph node metastases in breast cancer. Large-scale randomized multi-center trials are necessary to confirm our results.
Tetracentron sinense is an endemic and endangered deciduous tree. It belongs to the Trochodendrales, one of four early diverging lineages of eudicots known for having vesselless secondary wood. ...Sequencing and resequencing of the T. sinense genome will help us understand eudicot evolution, the genetic basis of tracheary element development, and the genetic diversity of this relict species.
Here, we report a chromosome-scale assembly of the T. sinense genome. We assemble the 1.07 Gb genome sequence into 24 chromosomes and annotate 32,690 protein-coding genes. Phylogenomic analyses verify that the Trochodendrales and core eudicots are sister lineages and showed that two whole-genome duplications occurred in the Trochodendrales approximately 82 and 59 million years ago. Synteny analyses suggest that the γ event, resulting in paleohexaploidy, may have only happened in core eudicots. Interestingly, we find that vessel elements are present in T. sinense, which has two orthologs of AtVND7, the master regulator of vessel formation. T. sinense also has several key genes regulated by or regulating TsVND7.2 and their regulatory relationship resembles that in Arabidopsis thaliana. Resequencing and population genomics reveals high levels of genetic diversity of T. sinense and identifies four refugia in China.
The T. sinense genome provides a unique reference for inferring the early evolution of eudicots and the mechanisms underlying vessel element formation. Population genomics analysis of T. sinense reveals its genetic diversity and geographic structure with implications for conservation.
BACKGROUND:Metabolic disorders such as obesity and diabetes mellitus can cause dysfunction of endothelial cells (ECs) and vascular rarefaction in adipose tissues. However, the modulatory role of ECs ...in adipose tissue function is not fully understood. Other than vascular endothelial growth factor–vascular endothelial growth factor receptor-mediated angiogenic signaling, little is known about the EC-derived signals in adipose tissue regulation. We previously identified Argonaute 1 (AGO1; a key component of microRNA-induced silencing complex) as a crucial regulator in hypoxia-induced angiogenesis. In this study, we intend to determine the AGO1-mediated EC transcriptome, the functional importance of AGO1-regulated endothelial function in vivo, and the relevance to adipose tissue function and obesity.
METHODS:We generated and subjected mice with EC-AGO1 deletion (EC-AGO1-knockout KO) and their wild-type littermates to a fast food–mimicking, high-fat high-sucrose diet and profiled the metabolic phenotypes. We used crosslinking immunoprecipitation- and RNA-sequencing to identify the AGO1-mediated mechanisms underlying the observed metabolic phenotype of EC-AGO1-KO. We further leveraged cell cultures and mouse models to validate the functional importance of the identified molecular pathway, for which the translational relevance was explored using human endothelium isolated from healthy donors and donors with obesity/type 2 diabetes mellitus.
RESULTS:We identified an antiobesity phenotype of EC-AGO1-KO, evident by lower body weight and body fat, improved insulin sensitivity, and enhanced energy expenditure. At the organ level, we observed the most significant phenotype in the subcutaneous and brown adipose tissues of KO mice, with greater vascularity and enhanced browning and thermogenesis. Mechanistically, EC-AGO1 suppression results in inhibition of thrombospondin-1 (THBS1/TSP1), an antiangiogenic and proinflammatory cytokine that promotes insulin resistance. In EC-AGO1-KO mice, overexpression of TSP1 substantially attenuated the beneficial phenotype. In human endothelium isolated from donors with obesity or type 2 diabetes mellitus, AGO1 and THBS1 are expressed at higher levels than the healthy controls, supporting a pathological role of this pathway.
CONCLUSIONS:Our study suggests a novel mechanism by which ECs, through the AGO1-TSP1 pathway, control vascularization and function of adipose tissues, insulin sensitivity, and whole-body metabolic state.
Endemic species are important components of regional biodiversity and hold the key to understanding local adaptation and evolutionary processes that shape species distributions. This study ...investigated the biogeographic history of a relict conifer Pinus bungeana Zucc. ex Endl. confined to central China. We examined genetic diversity in P. bungeana using genotyping‐by‐sequencing and chloroplast and mitochondrial DNA markers. We performed spatial and temporal inference of recent genetic and demographic changes, and dissected the impacts of geography and environmental gradients on population differentiation. We then projected P. bungeana's risk of decline under future climates. We found extremely low nucleotide diversity (average π 0.0014), and strong population structure (global FST 0.234) even at regional scales, reflecting long‐term isolation in small populations. The species experienced severe bottlenecks in the early Pliocene and continued to decline in the Pleistocene in the western distribution, whereas the east expanded recently. Local adaptation played a small (8%) but significant role in population diversity. Low genetic diversity in fragmented populations makes the species highly vulnerable to climate change, particularly in marginal and relict populations. We suggest that conservation efforts should focus on enhancing gene pool and population growth through assisted migration within each genetic cluster to reduce the risk of further genetic drift and extinction.
Increasing variability of future climate imposes challenges for the persistence of endangered relict species. This study infers the evolutionary history and the impacts of demography and landscape factors on population structure and diversity of the red list pine Pinus bungeana. We show that drastic bottlenecks during the Pliocene and Pleistocene and long‐term isolation in fragmented habitats resulted in extremely low genetic diversity in P. bungeana, which exposes the species to high risk of decline under future climate, particularly in marginal and relict populations.
The increase in drug-resistant strains poses a severe challenge for Helicobacter pylori (Hp) treatment, and the failure of traditional triple or bismuth quadruple therapy makes it difficult to ...eradicate Hp. Tailored therapies should be expanded, and traditional Chinese medicine (TCM) may provide the potential regimen. The aim of the present study is to systematically compare TCM-based therapy (TCM combined with Western medicine) and Western medicine as a rescue therapy for Hp re-eradication. Studies through June 12, 2021, with keywords “Helicobacter pylori,” “medicine, Chinese traditional,” or “rescue treatment” and their related expressions were retrieved from PubMed, SinoMed, China National Knowledge Infrastructure, and Wanfang databases. Randomized clinical trials based on PICOS (population, intervention, comparators, outcomes, and study design) eligibility criteria that evaluated the efficacy and safety of integrated therapy on Hp re-eradication were included. The extracted contents included the demographic data of the participants, specific treatment measures, and the results of outcome indicators and safety indicators. Review Manager 5.3 software was used to perform this meta-analysis. Outcome measures including the HP re-eradication rate, symptom remission rate, and adverse effects were seriously analyzed. Under the guide of PRISMA, 18 studies were finally included. Pooled results showed significant differences in eradication rate between integrated and Western medicine therapy in intention-to-treat (ITT) analysis (OR = 2.21, 95% CI: (1.74, 2.81), P<0.01). Symptom remission is higher in the administration of integrated therapy than in the administration of Western medicine therapy (OR = 2.45, 95% CI: (1.78, 3.37), P<0.01). It is also indicated that integrated therapy showed significantly less adverse effects (OR = 0.60, 95% CI: (0.42, 0.84), P<0.01. In conclusion, compared with Western medicine therapy, integrated therapy yields a higher eradication rate and acceptable safety profiles.
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