bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Potential Binding Sites for Selective Inhibitor Design of Human Soluble Epoxide Hydrolase
Authors: Bzówka Maria , Mitusińska Karolina , Góra Artur 
Published: May 2020

Abstract
Human soluble epoxide hydrolase (hsEH) has been known to be involved in the hydrolysis of epoxyeicosatrienoic acids (EETs), which are anti-inflammatory and cardioprotective signalling molecules. Since the conversion of EETs into the corresponding diols generates non-bioactive molecules, the enzyme’s inhibition would be beneficial. hsEH quickly became the molecular target, however, the proposed inhibitors directed toward this enzyme have not undergone clinical trials, mostly due to their low solubility in water. Our goal is to indicate new regions, distinct from those already investigated, that could be considered during the development of novel and perhaps more soluble inhibitors of hsEH. To fulfil this goal, we used a combination of classical and mixed-solvent molecular dynamics (cMD and MixMD) simulations and a ligand tracking approach. Such a strategy, considers conformational changes in the interior of the enzyme, extends conformational space of binding cavities, and provides insight into different sets of potential binding modes. By analysis of the local distribution of different molecular probes (water and organic cosolvent molecules), we were able to identify potential binding sites (hot-spots), which can indicate the location of the most important functional groups for the binding of designed inhibitors. The uniqueness of the binding spots was examined by superpositioning the indicated hot-spots with a map of chemical interactions between the known inhibitors and hsEH. We analysed all available crystal structures of hsEHs with inhibitors deposited in the PDB database to gain insight into the binding modes of the known inhibitors and to find similarities and dissimilarities between them. By comparing the results obtained based on the map of chemical interactions, with the regions identified by using cMD and MixMD, we were able to identify regions that have not been targeted by ligands until now and which are promising possible binding sites for polar groups that would be beneficial for inhibitors solubility.
Children with oligoarticular Juvenile Idiopathic Arthritis have skewed synovial monocyte polarization pattern with functional impairment – a distinct inflammatory pattern for oligoarticular juvenile arthritis
Authors: Schmidt Tobias , Berthold Elisabet , Arve-Butler Sabine , Gullstrand Birgitta , Mossberg Anki , Kahn Fredrik , Bengtsson Anders A , Månsson Bengt , Kahn Robin 
Published: May 2020

Abstract
Background
Juvenile idiopathic arthritis (JIA) is an umbrella term of inflammatory joint diseases in children. Oligoarthritis is the most common form in the Western world, representing roughly 60% of all patients. Monocytes and macrophages play an important role in adult arthritides, but their role in oligoarticular JIA is less studied. Polarization highly influences monocytes’ and macrophages’ effector functions, broadly separated into pro-inflammatory M1 or anti-inflammatory M2 phenotypes. Here, we set out to investigate the polarization pattern and functional aspects of synovial monocytes in oligoarticular juvenile idiopathic arthritis (JIA).
Methods
Paired synovial fluid, blood samples (n = 13) and synovial biopsies (n = 3) were collected from patients with untreated oligoarticular JIA. Monocytes were analyzed for polarization markers by flow cytometry and qPCR. Effector function was analyzed by a phagocytosis assay. Polarization of healthy monocytes was investigated by stimulation with synovial fluid in vitro. Monocyte/macrophage distribution, polarization and mRNA expression were investigated in biopsies by immunohistochemistry, immunofluorescence and in situ hybridization.
Results
Children with oligoarticular JIA have polarized synovial fluid monocytes of a specific M1(IFNg)/M2(IL-4)-like pattern. This was evidenced by increased surface expression of CD40 (p < 0.001), CD86 (p < 0.001) and CD206 (p < 0.001), but not CD163, as compared to paired circulating monocytes, and extensively explored at the mRNA level were synovial fluid monocytes differentially expressed classical markers of M1(IFNg)/M2(IL-4) polarization. Synovial fluid monocytes were functionally affected, as assessed by reduced capacity to phagocytose (p < 0.01). Synovial fluid induced M2 (CD16 and CD206), but not M1 (CD40 and CD86) markers in healthy monocytes and did not induce cytokine production. Single and co-expression of surface CD40 and CD206, as well as mRNA expression of IL-10 and TNF, was observed in monocytes/macrophages in synovial biopsies.
Conclusion
Children with untreated oligoarticular JIA have similar and distinct synovial fluid monocyte polarization pattern of mixed pro- and anti-inflammatory features. This pattern was not exclusively a result of the synovial fluid milieu as monocytes/macrophages in the synovial membrane show similar patterns. Our study highlights a distinct polarization pattern in oligoarticular JIA, which could be utilized for future treatment strategies.
Human Recombinant Fibroblast Growth Factor-18 (Sprifermin), Enhances Cartilage Healing in a Cartilage Injury Model
Authors: Hendesi Honey , Stewart Suzanne , Gibison Michelle L , Guehring Hans , Richardson Dean W. , Dodge George R 
Published: May 2020

Abstract
Background: Post traumatic osteoarthritis is a disabling condition impacting mostly young and active population. In the present study we investigated the impact of intra-articular sprifermin, a recombinant truncated fibroblast growth factor 18, on the outcome of microfracture treatment, a widely used surgical technique to enhance cartilage healing at the site of injury. Methods: For the purpose if this study, we created a cartilage defect and performed microfracture treatment in fetlock joints of 18 horses, treated joints with one of three doses of sprifermin (10, 30, or 100 mg) or with saline, hyaluronan (HA), and evaluated animals functional and structural outcomes over 24 weeks. For primary outcome measures we performed histological evaluations and performed gene expression analysis of aggrecan, collagen types I and II, and cartilage oligomeric matrix protein (COMP) in three regions of interest. As secondary outcome measures we examined animal’s lameness, performed arthroscopic, radiographic, and CT scan imaging, and gross morphology assessment. Results: We detected the highest treatment benefit following 100 mg sprifermin treatment. Overall histological assessment showed an improvement in the kissing region and expression of constitutive genes showed a concentration dependent enhancement, especially in the peri-lesion area. We detected a significant improvement in lameness scores, arthroscopic evaluations, radiography, and CT scans following sprifermin treatment when results from three dose-treatment groups were combined. Conclusion: Our results demonstrated for the first time, an enhancement in outcomes of the microfracture treatment following sprifermin treatment, suggesting a cartilage regenerative role and a potential benefit of sprifermin treatment in early cartilage injuries.
Downregulation of ceramide synthase 1 promotes oral cancer through endoplasmic reticulum stress
Authors: CHEN WEN , LIU ZHE , WU CHENZHOU , CHEN YAFEI , QIU LING , ZHANG ZHUOYUAN , SUN HAIBIN , CHEN SIYU , AN ZIJIAN , LI YI , LI LONGJIANG 
Published: May 2020

Abstract
Background
C18 ceramide (CER) plays an important role in the occurrence and development of oral squamous cell carcinoma (OSCC). However, the function of ceramide synthase 1 (CERS1), a key enzyme in C18 CER synthesis, in OSCC is still unclear. The aim of our study was to investigate the relationship between CERS1 and oral cancer.
Methods
The expression of CERS1 on 48 pairs of matching OSCC patients’ cancer and normal tissues was determined by quantitative real-time PCR (RT-PCR). A mouse OSCC model induced by 4-nitroquinolin-1-oxide (4NQO) was established on CERS1+/+ and CERS1-/- C57BL/N6 mice. The functions of CERS1 downregulated were accessed by cell counting kit-8 method, colony formation assay, EdU DNA Proliferation in vitro Detection, wound healing test and Annexin V/PI double staining. RT-PCR, Western blot and luciferase assay were performed to explore the molecular mechanisms of CERS1.
Results
In this study, we found that the expression of CERS1 was downregulated in oral cancer tissues and cell lines. In the mouse OSCC model, CERS1 knockout was associated with the severity of oral malignant transformation. Immunohistochemical studies showed significant upregulation of PCNA, MMP2, MMP9, and BCL2 expression and downregulation of BAX expression in the pathological hyperplastic area. In addition, CERS1 knockdown promoted cell proliferation, migration and invasion in vitro. CERS1 knockdown caused endoplasmic reticulum stress (ER stress) and induced the activating transcription factor 4 (ATF4) pathway. ATF4 upregulated VEGFA transcription to promote tumor growth and metastasis. In addition, mild ER stress caused by CERS1 knockdown could induce cisplatin resistance.
Conclusions
Our study suggests that CERS1 is downregulated in oral cancer. The downregulation of CERS1 promotes the aggressiveness of OSCC and chemotherapeutic drug resistance by inducing mild ER stress.
The clinical value of the changes of peripheral lymphocyte subsets absolute counts in patients with non-small cell lung cancer
Authors: Xia Ying , Li Wentao , Li Yongmin , Liu Yunhe , Ye Songshan , Liu Aqing , Yu Jianchun , Jia Yingjie , Liu Xu , Chen Huayu , Guo Yongtie 
Published: May 2020

Abstract
Background: Immune function strongly influences the outcome of patients with non-small cell lung cancer(NSCLC). It’s vital to understand the immune state of patients through detecting the level of lymphocyte subsets including percentage and number timely and accurately, and helpful to evaluate conditions of prognosis and adjust the treatment program for patients.Methods: Blood sample was obtained from 172 patients with NSCLC and 55 normal controls(NCs).The absolute count and percentages of CD3+,CD3+CD4+,CD3+CD8+, B and NK cells were determined by flow cytometry simultaneously with single platform technologies. Then 172 patients were followed up for the study of effects of the lymphocyte on disease progression and disease free survival(DFS). The factors affecting disease progression were analyzed by Binary Logistic regression.Calculating survivals were with the method of Kaplan-Meier. The log-rank test and proportional hazard regression model (enter method) were used for univariable and multivariable analyses respectively. Results: The absolute counts of CD3+, CD3+CD4+, CD3+CD8+, B and NK cells were significantly decreased in patients contrasted with NCs(P<0.05), no difference in percentages(P>0.05) except NK cells between patients and NCs. Relative to NCs, patients with NSCLC at stage Ⅰ and Ⅱ had lower absolute count of lymphocyte subsets(P<0.01), patients at stage Ⅲ~Ⅳ were also significantly lower compared with those in control group (P<0.01), no significant differences were observed in the percentages between patients and NCs. Compared the absolute counts of CD3+, CD3+CD4+, CD3+CD8+, B and NK cells among patients at different stages, only CD3+CD4+ was associated with clinical stages obviously. Patients with treatment of chemotherapy after surgery or only surgery showed different effects on absolute counts of CD3+CD4+,CD3+CD8+, NK and B cells . Binary Logistic regression showed CD3+CD4+ and CD3+CD8+ could contribute to favorable prognosis. Multivariate analysis of prognostic factors of DFS showed CD3+CD4+ cell was independent factor for predicting DFS .Conclusions:Compared to NCs, patients with NSCLC at different stages showed decreased absolute lymphocyte count obviously, rather than lymphocyte percentage, which persists for months or years after chemotherapy. The high level of baseline absolute CD3+CD4+ cells count(>502 cells/ul) contributed to longer disease free survival.Chinese Clinic Trial Registry number:ChiCTR-IOR-17014139; Registry date:2017/12/25
WITHDRAWN: EGFL6 Modulates WNT Signaling to Drive Esophageal Cancer Metastasis and Proliferation
Authors: Wang Yanhong , Kang Jing , Tian Jihua , Jia Hongyan , Wang Juanjuan , Shi Ruyi , Chang Sijia , Ji He , Yang Jia , Gao Yuan , Wang Guiqin , Ren Xiaojun 
Published: May 2020

Abstract
Background
Esophageal cancer (EC) is the sixth deadliest cancer in the world. There has been no breakthrough in the research on EC in the past few decades. Epidermal growth factor-like protein 6 (EGFL6), as a member of the epidermal growth factor superfamily, plays an important role in the occurrence and development of some tumors. However, the role of EGFL6 in the EC has never explored.
Methods
Immunohistochemical staining was used to evaluate the expression level of EGEC6 protein in human EC and its adjacent non-tumor tissues, and analyzed the correlation between the expression level of EGFL6 protein and clinical pathological indexes and survival rate. In vitro, by constructing EGFL6 silence and overexpressed EC cells,used CCK-8, clone formation, wound healing assays, transwell experiment and flow cytometry to explore the effects of EGFL6 on the proliferation, invasion, migration and apoptosis of EC. By using real-time PCR or western blot to detect the related marker genes of epithelial-mesenchymal transformation (EMT), tumor stem cells (TSCs) and Wnt/β-catenin. In vivo, established a nude mouse EC transplantation tumor model.
Results
The results showed that the expression level of EGFL6 in EC is significantly higher than that in adjacent non-tumor tissues, and is related to poor prognosis of patients. In vitro, CCK-8, clone formation, wound healing assays, transwell experiment and flow cytometry results show that EGFL6 overexpression can promotes proliferation, invasion and migration of EC cells and inhibits apoptosis. EGFL6 silencing inhibits proliferation, invasion and migration of EC cells and promotes apoptosis. Real-time PCR and Western-blot detection of EMT-related markers found that EGFL6 can induce EC cells EMT. Real-time PCR detection of esophageal cancer stem cell-related genes showed that EGFL6 may maintain the expression of esophageal cancer stem cell-like cell population. Western-blot detection of Wnt/β-catenin signaling marker genes showed that EGFL6 participated in the expression of Wnt/β-catenin signaling pathway. In vivo experiments found that knockout of EGFL6 could inhibit the formation of subcutaneous tumors in nude mice.
Conclusion
Taken together, our study identified a novel role and mechanism of EGFL6 in EC and provided epigenetic therapeutic strategies for the treatment of EC.
EZH2-mediated epigenetic silencing of ZIC4 in hepatocellular carcinoma
Authors: Wang Jinghui , Yang Zhu , Long Fengxi , Luo Li , Li Gao , Chen Changpei , Sun Dongxue , Tang Dongxin 
Published: May 2020

Abstract
Background: The present study aimed to explore the role of ZIC4 in human liver cancer.Methods: Illumina450 genome-wide methylation data was downloaded from The Cancer Genome Atlas for 50 available liver tumor/surrounding pairs. Wound healing test, colony formation and flow cytometry assay were utilized to analyze cell migration, survival and apoptosis. The effects of EZH2 and ZIC4 on tumor growth were also investigated through in vivo xenograft and orthotopic implantation experiments. Results: ZIC4 was hypermethylated in liver cancer tissues and cell lines. EZH2 knockdown and DZNep mediated H3K27me3 contributes to ZIC4 expression. The antitumor effect of EZH2 knockdown on hepatocellular carcinoma growth, metastasis and epithelial-mesenchymal transition progression in vitro were rescued by sh-ZIC4. Downregulation of ZIC4 also rescued the antitumor effect of DZNep in vivo.Conclusions: Epigenetic silencing of ZIC4 by EZH2 mediated H3K27me3 is an important mechanism in human liver cancer and provide a new therapeutic target for the treatment of hepatocellular carcinoma disease.
MiR-103a-3p promotes tumour glycolysis in colorectal cancer via Hippo/YAP1/HIF1A axis
Authors: Sun Zhenqiang , Zhang Qiuge , Yuan Weitang , Li Xiaoli , Chen Chen , Guo Yaxin , Shao Bo , Dang Qin , Zhou Quanbo , Wang Qisan , Wang Guixian , Liu Jinbo , Kan Quancheng 
Published: May 2020

Abstract
Background
Glycolysis plays an essential role in the growth and metastasis of solid cancer and has received increasing attention in recent years. However, the complex regulatory mechanisms of tumour glycolysis remain elusive. This study aimed to explore the molecular effect and mechanism of the noncoding RNA miR-103a-3p on glycolysis in colorectal cancer (CRC).
Methods
We explored the effects of miR-103a-3p on glycolysis and the biological functions of CRC cells in vitro and in vivo. Furthermore, we investigated whether miR-103a-3p regulates HIF1A expression through the Hippo/YAP1 pathway, and evaluated the role of the miR-103a-3p-LATS2/SAV1-YAP1-HIF1A axis in promoting glycolysis and angiogenesis in CRC cells and contributing to invasion and metastasis of CRC cells.
Results
We found that miR-103a-3p is highly expressed in CRC tissues and cell lines compared with matched controls and the high expression of miR-103a-3p is associated with poor patient prognosis. Under hypoxic conditions, a high level of miR-103a-3p can promote the proliferation, invasion, migration, angiogenesis and glycolysis of CRC cells. Moreover, miR-103a-3p knockdown inhibits the growth, proliferation, and glycolysis of CRC cells and promotes the Hippo-YAP signalling pathway in nude mice in a xenograft model. Here, we demonstrated that miR-103a-3p could directly target LATS2 and SAV1. Subsequently, we verified that TEAD1, a transcriptional coactivator of Yes-associated protein 1 (YAP1), directly binds to the HIF1A promoter region and the YAP1 and TEAD1 proteins could co-regulate the expression of HIF1A, thus promoting tumour glycolysis.
Conclusions
MiR-103a-3p, which is highly expressed in CRC cells, promotes HIF1A expression by targeting the core molecules LATS2 and SAV1 of the Hippo/YAP1 pathway, contributing to enhanced proliferation, invasion, migration, glycolysis and angiogenesis in CRC. Our study revealed the functional mechanisms of miR-103a-3p/YAP1/HIF1A axis in CRC glycolysis, which would provide potential intervention targets for molecular targeted therapy of CRC.
Ferroptosis induction induced by ginkgetin enhances therapeutic effect of cisplatin in EGFR wild type non-small cell lung cancer
Authors: Lou Jian-Shu , Zhao Li-Ping , Huang Zhi-Hui , Chen Xia-Yin , Xu Jing-Ting , TAI William Chi-Shing , Tsim Karl W.K. , Chen Yi-Tao , Xie Tian 
Published: May 2020

Abstract
Background Cisplatin (DDP) is the first-in-class drug for advanced and non-targetable non-small cell lung cancer (NSCLC). Recent study indicates that DDP could slightly induce non apoptotic cell death ferroptosis, and the cytotoxicity was promoted by ferroptosis inducer. The agents enhancing ferroptosis level therefore may increase anticancer effect of DDP. Several lines of evidence support the usage of phytochemicals in therapy of NSCLC. Ginkgetin, a bioflavonoid derived from Ginkgo biloba leaves, showed anti-cancer effect on NSCLC both in vitro and in vivo, which could strongly trigger autophagy. Ferroptosis can be triggered by autophagy, and which regulates redox homeostasis. Thus, we aim to elucidate the possible role of ferroptosis induction in accounting for synergy of ginkgetin with DDP in cancer therapy.Methods Ginkgetin promoted DDP-induced anticancer effect was observed via cytotoxicity assay and western blot. Ferroptosis triggered by ginkgetin in DDP treated NSCLC was observed via lipid peroxidation assay, labile iron pool assay, western blot, and QPCR. With ferroptosis blocking, the contribution of ferroptosis on ginkgetin + DDP induced cytotoxicity, Nrf2/HO-1 axis and apoptosis were determined via luciferase assay, immunostaining, chromatin immunoprecipitation (CHIP), and flow cytometry. The role of ferroptosis in ginkgetin + DDP treated NSCLC cells was illustrated by the application of ferroptosis inhibitor, which was further demonstrated in xenograft nude mice model.Results Ginkgetin synergized cisplatin in cytotoxicity in NSCLC cells, which concomitant with increased labile iron pool and lipid peroxidation: both these processes were the key characteristics of ferroptosis. The induction of ferroptosis, mediated by ginkgetin, was further confirmed by decline expressions of SLC7A11, GPX4 and GSH/GSSG ratio. In parallel, ginkgetin disrupted redox hemeostasis in DDP-treated cells, demonstrated by the enhanced ROS formation and inactivation on Nrf2/HO-1 axis. Ginkgetin also enhanced DDP-induced mitochondrial membrane potential (MMP) loss and apoptosis in cultured NSCLC cells. Furthermore, blocking ferroptosis reversed the gingketin-induced inactivation on Nrf2/HO-1, as well as the elevation on ROS formation, MMP loss and apoptosis in DDP-treated NSCLC cells.Conclusion This study firstly reported that ginkgetin promoted DDP-induced anticancer effect, which could be accounted by induction of ferroptosis.
Protective effects of N-acetylcysteine on myocardial injury induced by acute fluctuations in blood glucose
Authors: Zhang Wei , Peng Guanjing , Zhao Sheng , Li Yan , Han Ping , Li Yongzhi 
Published: May 2020

Abstract
Background: To investigate the effect of N -acetylcysteine (NAC) on oxidative stress and inflammation induced by acute fluctuations in blood glucose and the potential mechanism. Methods : Cannulated Wistar rats (n=6/group) were infused intravenously for 48 h with (1) saline (control), (2) 50% glucose intermittently (IHG), (3) 50% glucose continuously (PHG), (4) IHG plus NAC, or (5) PHG plus NAC. Levels of superoxide dismutase (SOD), nitric oxide (NO), nuclear factor-κB (NF-κB), inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF) in cardiac tissues were analyzed. We also evaluated apoptosis in the myocardium using a terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. Results : The IHG group had higher levels of oxidative and inflammatory markers in the myocardium than the PHG and control groups. Co-infusion with NAC prevented the elevation in inflammatory markers and NF-κB activity in the IHG + NAC and PHG + NAC groups. Apoptosis of myocardial cells was observed in the IHG group but was abolished by co-administration of NAC. Conclusions : Acute fluctuations in blood glucose levels induced more severe oxidative stress, inflammation and apoptosis in the myocardium than persistently high blood glucose levels. The antioxidant NAC may prevent apoptosis of myocardial cells caused by fluctuations in blood glucose levels in vivo , most likely because of its antioxidative and anti-inflammatory properties.