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Background: Previous studies including our group have indicated the effects of ezetimibe on increased plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) concentration, while the rapid expression in different organs and the potential molecular mechanisms for this impact have not been carefully evaluated. Methods: Thirty rats were randomly divided into two groups (n = 15 for each), which were orally administrated with ezetimibe (10 mg/kg/day) or normal saline. Blood samples were obtained at day 3 after orally administration, and the PCSK9 levels were determined by ELISA. We further analyzed the mRNA expression of PCSK9, low-density lipoprotein receptor (LDLR), sterol regulator element-binding protein 2 (SREBP2), and hepatocyte nuclear factor 1 alpha (HNF-1α) by real-time PCR, as well as the protein expression by western blot, in liver, intestine and kidney respectively. Results: Ezetimibe significantly increased plasma PCSK9 levels compared with control group, while there was no significant difference between the two groups with regard to lipid profile at day 3. Moreover, ezetimibe remarkably increased the expression of PCSK9, LDLR, SREBP2 and HNF-1α in liver. Enhanced expression of PCSK9, LDLR and SREBP2 protein were found in intestine and kidney, while no changes in the expression of HNF-1α were observed in intestine and kidney of rats with ezetimibe treatment. Conclusions: The data demonstrated that ezetimibe increased PCSK9 expression through the SREBP2 and HNF-1α pathways in different organs, subsequently resulting in elevated plasma PCSK9 levels prior to the alterations of lipid profile in rats. [ABSTRACT FROM AUTHOR]

Background Recent studies have demonstrated that microRNA-22 (miR-22) was deregulated in many types of cancers and was involved in various cellular processes related to carcinogenesis. However, the clinical significance and prognostic value of miR-22 in epithelial ovarian cancer (EOC) haven't been investigated. Methods 109 pairs of fresh EOC tissue and matched adjacent normal tissue specimens were collected between May 2007 and March 2013. Real-time quantitative RT-PCR assay was performed to evaluate the expression levels of miR-22. The chi-square test was used to assess miR-22 expression with respect to clinicopathological parameters. The survival curves of the patients were determined using the Kaplan-Meier method and Cox regression, and the log-rank test was used for statistical evaluations. Results miR-22 expression in EOC tissues was significantly lower than that in matched normal adjacent tissues (mean ± SD: 1.944 ± 1.026 vs. 4.981 ± 1.507, P < 0.0001). Low miR-22 expression level was correlated with FIGO stage (P = 0.006), tumor grade (P = 0.03), and lymph node metastases (P = 0.01). Kaplan-Meier analysis with the log-rank test indicated that low miR-22 expression had a significant impact on overall survival (44.4% vs. 64.5%; P = 0.005) and progression-free survival (23.5% vs. 52.6%; P = 0.004). Conclusions Our data demonstrated that the expression of miR-22 was downregulated in EOC, and associated with overall survival as well as progression-free survival, suggesting that miR-22 could serve as an efficient prognostic factor for EOC patients. [ABSTRACT FROM AUTHOR]

Background: Metabolic syndrome (MetSyn) increases the incidence of cardiovascular disease. Information on changes in prevalence of MetSyn in developing countries is limited. This study aims to compare MetSyn prevalence and its associated vascular risk over the period between 2002 and 2010 in a population which has had the world’s fastest economic development over the past three decades. Methods: Two health surveys were conducted by using the multistage cluster random sampling method in a Chinese population of 85 million in southern China. The participants received a full medical check-up, including measurement of blood pressure (BP), obesity indices, fasting lipids and glucose levels. Data describing socio-economic status and lifestyle factors were also collected through interview. Metabolic syndrome was defined in accordance with the International Diabetes Federation criteria. Results: A total of 3,561 participants from Survey 2010 were included in the data analysis. Women had a significantly higher prevalence of MetSyn than men. Comparison between the two surveys shows that age-standardized prevalence of MetSyn increased fourfold (from 5.4% in 2002 to 21.3% in 2010) in those ≧ 20 years. Among the MetSyn components, prevalence of hyperglycaemia has increased most (from 9.1% to 53.1%). The age-standardized prevalence of central obesity, hypertension, hypertriglyceridaemia and low HDL-cholesterol increased from 13.5% to 25.4%, from 23.6% to 40.8%, from 12.1% to 17.4% and from 32.1% to 71.1%, respectively. Differences between rural and urban residents in the prevalence in MetSyn and its components narrowed in 2010. Conclusions: Cardiovascular risk escalated dramatically in this population between 2002 and 2010. The escalation may relate to the rapid economic development, which led to accelerating changes in nutrition, lifestyle, and socio-economic status. Our findings suggest that health transition in rapidly developing second- and third-world countries may be much faster than what has been observed in Western countries. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via the original article. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via the original article. [ABSTRACT FROM AUTHOR]

Background: Under physiological conditions, CXCL12 modulates cell proliferation, survival, angiogenesis, and migration mainly through CXCR4. Interestingly, the newly discovered receptor CXCR7 for CXCL12 is highly expressed in many tumor cells as well as tumor-associated blood vessels, although the level of CXCR7 in normal cells is low. Recently, many studies have suggested that CXCR7 promotes cell growth and metastasis in more than 20 human malignancies, among which lung cancer is the leading cause of cancer-associated deaths worldwide. Thus, the mechanism of CXCR7 in the progression of lung cancer is urgently needed.Methods: First, we explored CXCR4 and CXCR7 expression in human lung cancer specimens and cell lines by immunohistochemistry, western blot and flow cytometry. Then, we chose the human lung adenocarcinoma cell line A549 that stably overexpressed CXCR7 through the way of lentivirus-mediated transduction. Next, "wound healing" assay and transwell assay were applied to compare the cell migration and invasion ability, and stripe assay was used to evaluate the cell polarization. Last, our team established a mouse xenograft model of human lung cancer and monitored tumor proliferation and metastasis by firefly luciferase bioluminescence imaging in SCID/Beige mice.Results: In clinical lung cancer samples, CXCR7 expression was almost not detected in normal tissue but upregulated in lung tumor tissue, whereas, CXCR4 was highly expressed in both normal and tumor tissues. Furthermore, overexpression of CXCR7 enhanced A549 cell migration and polarization in vitro. Besides, mouse xenograft model of human lung cancer showed that CXCR7 promoted primary lung tumor's growth and metastasis to the second organ, such as liver or bone marrow in SCID/Beige mice in vivo.Conclusions: This study describes the multiple functions of CXCR7 in lung cancer. Thus, these results suggest that CXCR7 may be a malignancy marker and may provide a novel target for anticancer therapy. [ABSTRACT FROM AUTHOR]

Backgrounds: Knowledge discovery from breast cancer treatment records has promoted downstream clinical studies such as careflow mining and therapy analysis. However, the clinical treatment text from electronic health data might be recorded by different doctors under their hospital guidelines, making the final data rich in author- and domain-specific idiosyncrasies. Therefore, breast cancer treatment entity normalization becomes an essential task for the above downstream clinical studies. The latest studies have demonstrated the superiority of deep learning methods in named entity normalization tasks. Fundamentally, most existing approaches adopt pipeline implementations that treat it as an independent process after named entity recognition, which can propagate errors to later tasks. In addition, despite its importance in clinical and translational research, few studies directly deal with the normalization task in Chinese clinical text due to the complexity of composition forms.Methods: To address these issues, we propose PASCAL, an end-to-end and accurate framework for breast cancer treatment entity normalization (TEN). PASCAL leverages a gated convolutional neural network to obtain a representation vector that can capture contextual features and long-term dependencies. Additionally, it treats treatment entity recognition (TER) as an auxiliary task that can provide meaningful information to the primary TEN task and as a particular regularization to further optimize the shared parameters. Finally, by concatenating the context-aware vector and probabilistic distribution vector from TEN, we utilize the conditional random field layer (CRF) to model the normalization sequence and predict the TEN sequential results.Results: To evaluate the effectiveness of the proposed framework, we employ the three latest sequential models as baselines and build the model in single- and multitask on a real-world database. Experimental results show that our method achieves better accuracy and efficiency than state-of-the-art approaches.Conclusions: The effectiveness and efficiency of the presented pseudo cascade learning framework were validated for breast cancer treatment normalization in clinical text. We believe the predominant performance lies in its ability to extract valuable information from unstructured text data, which will significantly contribute to downstream tasks, such as treatment recommendations, breast cancer staging and careflow mining. [ABSTRACT FROM AUTHOR]

Background: HSV-1 is a common pathogen that infects 50–90% of the human population worldwide. HSV-1 causes numerous infection-related diseases, some of which are severely life-threatening. There are antiviral medications with activity against HSV-1. However, with the emergence of drug-resistant mutant strains of HSV-1, there is an urgent need to develop new effective anti-HSV-1 agents. Methods: Therefore, we screened a chemical library of approximately 1500 compounds to identify inhibitors of HSV-1-induced toxicity for further drug development. Moreover, we performed several experiments, including western blot analysis, Q-PCR analysis and luciferase activity assay, to explore the antiviral mechanism of the candidates. Results: Here, we identified a small molecule, mitoxantrone dihydrochloride, with potency against HSV-1-induced toxicity. Furthermore, the viral titers and expression levels of HSV-1 viral proteins were potently reduced by the presence of MD in many cell lines. Using Q-PCR analysis, we found that MD efficiently reduced the transcription of viral genes that are essential for DNA synthesis, namely, UL5, UL9, UL29, UL30, UL42 and UL52. Notably, MD also significantly inhibited the transcription of the immediate early genes ICP0, ICP22, ICP27 and ICP47, all of which are required for the expression of early and late viral gene products. Using immunofluorescence and western blot analysis, we found that the antiviral effect of MD was independent of the activation of the NF-κB and MAPK pathways. Furthermore, we found that the reduction in the transcription of viral immediate early genes was not related to the promoter activities of ICP0. Conclusions: Therefore, the identification of compound MD as an inhibitor of toxicity induced by HSV-1 highlights its potential use in the development of novel anti-HSV-1 drugs. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation and oxidative stress play important roles in early brain injury following subarachnoid hemorrhage (SAH). This study is the first to show that activation of apelin receptor (APJ) by apelin-13 could reduce endoplasmic reticulum (ER)-stress-associated inflammation and oxidative stress after SAH.Methods: Apelin-13, apelin siRNA, APJ siRNA, and adenosine monophosphate-activated protein kinase (AMPK) inhibitor-dorsomorphin were used to investigate if the activation of APJ could provide neuroprotective effects after SAH. Brain water content, neurological functions, blood-brain barrier (BBB) integrity, and inflammatory molecules were evaluated at 24 h after SAH. Western blotting and immunofluorescence staining were applied to assess the expression of target proteins.Results: The results showed that endogenous apelin, APJ, and p-AMPK levels were significantly increased and peaked in the brain 24 h after SAH. In addition, administration of exogenous apelin-13 significantly alleviated neurological functions, attenuated brain edema, preserved BBB integrity, and also improved long-term spatial learning and memory abilities after SAH. The underlying mechanism of the neuroprotective effects of apelin-13 is that it suppresses microglia activation, prevents ER stress from overactivation, and reduces the levels of thioredoxin-interacting protein (TXNIP), NOD-like receptor pyrin domain-containing 3 protein (NLRP3), Bip, cleaved caspase-1, IL-1β, TNFα, myeloperoxidase (MPO), and reactive oxygen species (ROS). Furthermore, the use of APJ siRNA and dorsomorphin abolished the neuroprotective effects of apelin-13 on neuroinflammation and oxidative stress.Conclusions: Exogenous apelin-13 binding to APJ attenuates early brain injury by reducing ER stress-mediated oxidative stress and neuroinflammation, which is at least partly mediated by the AMPK/TXNIP/NLRP3 signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever that was first described in China in 2011. We report a patient who died of Severe fever with thrombocytopenia syndrome virus (SFTSV) infection, with a rapidly progressive central nervous system (CNS) disturbance, in Dongyang, Zhejiang Province, China, in 2017. Case presentation: A 64-year-old man was admitted to hospital after 4 days of fever. SFTSV was detected 1 day after the patient was admitted to hospital. The patient presented with CNS disturbance and died 4 days after admission. Detailed clinical and epidemiological investigations and laboratory tests were conducted. Reduced platelet, white blood cell, lymphocyte, and neutrophil counts, elevated lactate dehydrogenase, creatine kinase, aspartate aminotransferaseand alanine aminotransferase concentrations, and an increased activated partial thromboplastin time were observed. In a phylogenetic analysis, the isolate clustered close to a strain derived from South Korea. Conclusions: This is the first case of SFTSV infection with CNS disturbance in Dongyang, Zhejiang Province, China. The surveillance of suspected cases of SFTS is important in SFTSV endemic regions. [ABSTRACT FROM AUTHOR]

Background: Identification of loci for grain yield (GY) and related traits, and dissection of the genetic architecture are important for yield improvement through marker-assisted selection (MAS). Two genome-wide association study (GWAS) methods were used on a diverse panel of 166 elite wheat varieties from the Yellow and Huai River Valleys Wheat Zone (YHRVWD) of China to detect stable loci and analyze relationships among GY and related traits. Results: A total of 326,570 single nucleotide polymorphism (SNP) markers from the wheat 90 K and 660 K SNP arrays were chosen for GWAS of GY and related traits, generating a physical distance of 14,064.8 Mb. One hundred and twenty common loci were detected using SNP-GWAS and Haplotype-GWAS, among which two were potentially functional genes underpinning kernel weight and plant height (PH), eight were at similar locations to the quantitative trait loci (QTL) identified in recombinant inbred line (RIL) populations in a previous study, and 78 were potentially new. Twelve pleiotropic loci were detected on eight chromosomes; among these the interval 714.4–725.8 Mb on chromosome 3A was significantly associated with GY, kernel number per spike (KNS), kernel width (KW), spike dry weight (SDW), PH, uppermost internode length (UIL), and flag leaf length (FLL). GY shared five loci with thousand kernel weight (TKW) and PH, indicating significantly affected by two traits. Compared with the total number of loci for each trait in the diverse panel, the average number of alleles for increasing phenotypic values of GY, TKW, kernel length (KL), KW, and flag leaf width (FLW) were higher, whereas the numbers for PH, UIL and FLL were lower. There were significant additive effects for each trait when favorable alleles were combined. UIL and FLL can be directly used for selecting high-yielding varieties, whereas FLW can be used to select spike number per unit area (SN) and KNS. Conclusions: The loci and significant SNP markers identified in the present study can be used for pyramiding favorable alleles in developing high-yielding varieties. Our study proved that both GWAS methods and high-density genetic markers are reliable means of identifying loci for GY and related traits, and provided new insight to the genetic architecture of GY. [ABSTRACT FROM AUTHOR]

Background: Controlled turnover of proteins as mediated by the ubiquitin proteasome system (UPS) is an important element in plant defense against environmental and pathogen stresses. E3 ligases play a central role in subjecting proteins to hydrolysis by the UPS. Recently, it has been demonstrated that a specific class of E3 ligases termed the U-box ligases are directly associated with the defense mechanisms against abiotic and biotic stresses in several plants. However, no studies on U-box E3 ligases have been performed in one of the important staple crops, barley. Results: In this study, we identified 67 putative U-box E3 ligases from the barley genome and expressed sequence tags (ESTs). Similar to Arabidopsis and rice U-box E3 ligases, most of barley U-box E3 ligases possess evolutionary well-conserved domain organizations. Based on the domain compositions and arrangements, the barley U-box proteins were classified into eight different classes. Along with this new classification, we refined the previously reported classifications of U-box E3 ligase genes in Arabidopsis and rice. Furthermore, we investigated the expression profile of 67 U-box E3 ligase genes in response to drought stress and pathogen infection. We observed that many U-box E3 ligase genes were specifically up-and-down regulated by drought stress or by fungal infection, implying their possible roles of some U-box E3 ligase genes in the stress responses. Conclusion: This study reports the classification of U-box E3 ligases in barley and their expression profiles against drought stress and pathogen infection. Therefore, the classification and expression profiling of barley U-box genes can be used as a platform to functionally define the stress-related E3 ligases in barley. [ABSTRACT FROM AUTHOR]

Background: Chinese word segmentation (CWS) and part-of-speech (POS) tagging are two fundamental tasks of Chinese text processing. They are usually preliminary steps for lots of Chinese natural language processing (NLP) tasks. There have been a large number of studies on CWS and POS tagging in various domains, however, few studies have been proposed for CWS and POS tagging in the clinical domain as it is not easy to determine granularity of words.Methods: In this paper, we investigated CWS and POS tagging for Chinese clinical text at a fine-granularity level, and manually annotated a corpus. On the corpus, we compared two state-of-the-art methods, i.e., conditional random fields (CRF) and bidirectional long short-term memory (BiLSTM) with a CRF layer. In order to validate the plausibility of the fine-grained annotation, we further investigated the effect of CWS and POS tagging on Chinese clinical named entity recognition (NER) on another independent corpus.Results: When only CWS was considered, CRF achieved higher precision, recall and F-measure than BiLSTM-CRF. When both CWS and POS tagging were considered, CRF also gained an advantage over BiLSTM. CRF outperformed BiLSTM-CRF by 0.14% in F-measure on CWS and by 0.34% in F-measure on POS tagging. The CWS information brought a greatest improvement of 0.34% in F-measure, while the CWS&POS information brought a greatest improvement of 0.74% in F-measure.Conclusions: Our proposed fine-grained CWS and POS tagging corpus is reliable and meaningful as the output of the CWS and POS tagging systems developed on this corpus improved the performance of a Chinese clinical NER system on another independent corpus. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the most common cancer among women worldwide, and approximately 70% of breast cancers are hormone receptor-positive and express estrogen receptor-α (ERα) or/and progesterone receptor. Therapies targeting ERα have been successfully used in patients with ERα+ breast cancer. However, intrinsic or acquired resistance to anti-estrogen therapy presents a major challenge. The Wnt/β-catenin signaling pathway regulates various processes that are important for cancer progression, and emerging evidences have shown a close interaction between Wnt/β-catenin and ERα signaling. miR-190 is also involved in ER signaling and our previous study indicated that miR-190 suppresses breast cancer metastasis. Methods: The effect of miR-190 on breast cancer anti-estrogen sensitivity was investigated both in vitro and in vivo. The protein expression levels and localization were analyzed by western blotting and immunofluorescence, respectively. Chromatin immunoprecipitation and dual-luciferase reporter assays were used to validate the regulation of the zinc-finger E-box binding homeobox 1/ ERα-miR-190-SRY-related high mobility group box 9 (ZEB1/ERα-miR-190-SOX9) axis. Results: miR-190 increased the anti-estrogen sensitivity of breast cancer cells both in vitro and in vivo. miR-190 inhibited Wnt/β-catenin signaling by targeting SOX9, and its expression inversely correlated with that of SOX9 in breast cancer samples. Furthermore, ERα and ZEB1 competitively regulated miR-190 expression. Conclusions: Our data uncover the ZEB1/ERα-miR-190-SOX9 axis and suggest a mechanism by which the Wnt/β-catenin signaling pathway is involved in breast cancer anti-estrogen therapy. [ABSTRACT FROM AUTHOR]

Background: The application of artificial intelligence techniques for processing electronic health records data plays increasingly significant role in advancing clinical decision support. This study conducts a quantitative comparison on the research of utilizing artificial intelligence on electronic health records between the USA and China to discovery their research similarities and differences.Methods: Publications from both Web of Science and PubMed are retrieved to explore the research status and academic performances of the two countries quantitatively. Bibliometrics, geographic visualization, collaboration degree calculation, social network analysis, latent dirichlet allocation, and affinity propagation clustering are applied to analyze research quantity, collaboration relations, and hot research topics.Results: There are 1031 publications from the USA and 173 publications from China during 2008-2017 period. The annual numbers of publications from the USA and China increase polynomially. JAMIA with 135 publications and JBI with 13 publications are the top prolific journals for the USA and China, respectively. Harvard University with 101 publications and Zhejiang University with 12 publications are the top prolific affiliations for the USA and China, respectively. Massachusetts is the most prolific region with 211 publications for the USA, while for China, Taiwan is the top 1 with 47 publications. China has relatively higher institutional and international collaborations. Nine main research areas for the USA are identified, differentiating 7 for China.Conclusions: There is a steadily growing presence and increasing visibility of utilizing artificial intelligence on electronic health records for the USA and China over the years. The results of the study demonstrate the research similarities and differences, as well as strengths and weaknesses of the two countries. [ABSTRACT FROM AUTHOR]

Background: Circadian rhythms are oscillating physiological and behavioral changes governed by an internal molecular clock, and dysfunctions in circadian rhythms have been associated with ageing and various neurodegenerative diseases. However, the evidence directly connecting the neurodegeneration-associated proteins to circadian control at the molecular level remains sparse. Methods: Using meta-analysis, synchronized animals and cell lines, cells and tissues from FUS R521C knock-in rats, we examined the role of FUS in circadian gene expression regulation. Results: We found that FUS, an oscillating expressed nuclear protein implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), exerted a novel feedback route to regulate circadian gene expression. Nr1d1-encoded core circadian protein REV-ERBα bound the Fus promoter and regulated the expression of Fus. Meanwhile, FUS was in the same complex as PER/CRY, and repressed the expression of E box-containing core circadian genes, such as Per2, by mediating the promoter occupancy of PSF-HDAC1. Remarkably, a common pathogenic mutant FUS (R521C) showed increased binding to PSF, and caused decreased expression of Per2. Conclusions: Therefore, we have demonstrated FUS as a modulator of circadian gene expression, and provided novel mechanistic insights into the mutual influence between circadian control and neurodegeneration-associated proteins. [ABSTRACT FROM AUTHOR]

Background: Extracting relationships between chemicals and diseases from unstructured literature have attracted plenty of attention since the relationships are very useful for a large number of biomedical applications such as drug repositioning and pharmacovigilance. A number of machine learning methods have been proposed for chemical-induced disease (CID) extraction due to some publicly available annotated corpora. Most of them suffer from time-consuming feature engineering except deep learning methods. In this paper, we propose a novel document-level deep learning method, called recurrent piecewise convolutional neural networks (RPCNN), for CID extraction.Results: Experimental results on a benchmark dataset, the CDR (Chemical-induced Disease Relation) dataset of the BioCreative V challenge for CID extraction show that the highest precision, recall and F-score of our RPCNN-based CID extraction system are 65.24, 77.21 and 70.77%, which is competitive with other state-of-the-art systems.Conclusions: A novel deep learning method is proposed for document-level CID extraction, where domain knowledge, piecewise strategy, attention mechanism, and multi-instance learning are combined together. The effectiveness of the method is proved by experiments conducted on a benchmark dataset. [ABSTRACT FROM AUTHOR]

Background: Great progress has been achieved in the study of the aerobic glycolysis or the so-called Warburg effect in a variety of cancers; however, the regulation of the Warburg effect in Nasopharyngeal carcinoma (NPC) has not been completely defined. Methods: Gene expression pattern of NPC cells were used to test associations between Chibby and β-catenin expression. Chibby siRNAs and over-expression vector were transfected into NPC cells to down-regulate or up-regulate Chibby expression. Loss- and gain-of function assays were performed to investigate the role of Chibby in NPC cells. Western blot, cell proliferation, Glucose uptake, Lactate release, ATP level, and O2 consumption assays were used to determine the mechanism of Chibby regulation of underlying targets. Finally, immunohistochemistry assay of fresh NPC and nasopharyngeal normal tissue sample were used to detect the expression of Chibby, β-Catenin, and PDK1 by immunostaining. Results: We observed that Chibby, a β-catenin-associated antagonist, is down-regulated in nasopharyngeal carcinoma cell lines and inhibits Wnt/β-Catenin signaling induced Warburg effect. Mechanism study revealed that Chibby regulates aerobic glycolysis in NPC cells through pyruvate dehydrogenase kinase 1(PDK1), an important enzyme involved in glucose metabolism. Moreover, Chibby suppresses aerobic glycolysis of NPC via Wnt/β-Catenin-Lin28/let7-PDK1 cascade. Chibby and PDK1 are critical for Wnt/β-Catenin signaling induced NPC cell proliferation both in vitro and in vivo. Finally, immunostaining assay of tissue samples provides an important clinical relevance among Chibby, Wnt/β-Catenin signaling and PDK1. Conclusions: Our study reveals an association between Chibby expression and cancer aerobic glycolysis, which highlights the importance of Wnt/β-catenin pathway in regulation of energy metabolism of NPC. These results indicate that Chibby and PDK1 are the potential target for NPC treatment. [ABSTRACT FROM AUTHOR]

Background: Previous studies including our group have indicated the effects of ezetimibe on increased plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) concentration, while the rapid expression in different organs and the potential molecular mechanisms for this impact have not been carefully evaluated. Methods: Thirty rats were randomly divided into two groups (n = 15 for each), which were orally administrated with ezetimibe (10 mg/kg/day) or normal saline. Blood samples were obtained at day 3 after orally administration, and the PCSK9 levels were determined by ELISA. We further analyzed the mRNA expression of PCSK9, low-density lipoprotein receptor (LDLR), sterol regulator element-binding protein 2 (SREBP2), and hepatocyte nuclear factor 1 alpha (HNF-1α) by real-time PCR, as well as the protein expression by western blot, in liver, intestine and kidney respectively. Results: Ezetimibe significantly increased plasma PCSK9 levels compared with control group, while there was no significant difference between the two groups with regard to lipid profile at day 3. Moreover, ezetimibe remarkably increased the expression of PCSK9, LDLR, SREBP2 and HNF-1α in liver. Enhanced expression of PCSK9, LDLR and SREBP2 protein were found in intestine and kidney, while no changes in the expression of HNF-1α were observed in intestine and kidney of rats with ezetimibe treatment. Conclusions: The data demonstrated that ezetimibe increased PCSK9 expression through the SREBP2 and HNF-1α pathways in different organs, subsequently resulting in elevated plasma PCSK9 levels prior to the alterations of lipid profile in rats. [ABSTRACT FROM AUTHOR]