Search

Abstract Resistance to gemcitabine in pancreatic ductal adenocarcinoma (PDAC) leads to ineffective chemotherapy and, consequently, delayed treatment, thereby contributing to poor prognosis. Glycolysis is an important intrinsic reason for gemcitabine resistance as it competitively inhibits gemcitabine activity by promoting deoxycytidine triphosphate accumulation in PDAC. However, biomarkers are lacking to determine which patients can benefit significantly from glycolysis inhibition under the treatment of gemcitabine activity, and a comprehensive understanding of the molecular mechanisms that promote glycolysis in PDAC will contribute to the development of a strategy to sensitize gemcitabine chemotherapy. In this study, we aimed to identify a biomarker that can robustly indicate the intrinsic resistance of PDAC to gemcitabine and guide chemotherapy sensitization strategies. After establishing gemcitabine-resistant cell lines in our laboratory and collecting pancreatic cancer and adjacent normal tissues from gemcitabine-treated patients, we observed that circRNA hsa_circ_0008383 (namely cNEK6) was highly expressed in the peripheral blood and tumor tissues of patients and xenografts with gemcitabine-resistant PDAC. cNEK6 enhanced resistance to gemcitabine by promoting glycolysis in PDAC. Specifically, cNEK6 prevented K48 ubiquitination of small ribonucleoprotein peptide A from the BTRC, a ubiquitin E3 ligase; thus, the accumulated SNRPA stopped PP2Ac translation by binding to its G-quadruplexes in 5′ UTR of mRNA. mTORC1 pathway was aberrantly phosphorylated and activated owing to the absence of PP2Ac. The expression level of cNEK6 in the peripheral blood and tumor tissues correlated significantly and positively with the activation of the mTORC1 pathway and degree of glycolysis. Hence, the therapeutic effect of gemcitabine is limited in patients with high cNEK6 levels, and in combination with the mTORC1 inhibitor, rapamycin, can enhance sensitivity to gemcitabine chemotherapy.

Abstract Purpose Gestational diabetes mellitus (GDM) negatively affects the quality of life of pregnant women and is influenced by several factors. Research to date treats pregnant women with gestational diabetes as a homogeneous group based on their quality of life. We attempted to identify subgroups based on self-reported quality of life and explored variables associated with subgroups. Methods From September 1, 2020 to November 29, 2020, pregnant women with GDM from two hospitals in Guangdong Province were selected as subjects by convenience sampling method. Medical records provided sociodemographic data, duration of GDM, pregnancy status, and family history of diabetes. Participants completed validated questionnaires for quality of life, anxiety and depression. Latent profile analysis was used to identify profiles of quality of life in pregnant women with GDM, and then a mixed regression method was used to analyze the influencing factors of different profiles. Results A total of 279 valid questionnaires were collected. The results of the latent profile analysis showed that the quality of life of pregnant women with GDM could be divided into two profiles: C1 “high worry-high support” group (75.6%) and C2 “low worry-low support” group (24.4%). Daily exercise duration and depression degree are negative influencing factors, making it easier to enter the C1 group (p

Abstract Intrahepatic cholangiocarcinoma (ICC) is a rare but highly aggressive malignant tumor arising within the liver, with a 5-year survival rate of only 20–40% after surgery. The role of interleukin-8 (IL-8) in ICC progression remains elusive. A transcriptomic approach based on IL-8 stimulation first revealed significant upregulation of the prometastatic gene CD97 and key epithelial–mesenchymal transition (EMT) factors E-cadherin and vimentin. Immunohistochemistry of 125 ICC tissues confirmed the positive correlation between IL-8 and CD97. Multivariable Cox regression indicated that they are both independent predictors of ICC prognosis. Mechanistically, IL-8 treatment induced CD97 expression at 50 and 100 ng/ml in QBC-939 and QBE cells, respectively. Moreover, the induction of cell migration and invasion upon IL-8 treatment was attenuated by CD97 RNA interference, and the expression of EMT-associated genes was dramatically inhibited. To determine whether CXCR1 or CXCR2 are downstream effectors of IL-8, siCXCR2 was applied and shown to significantly attenuate the oncogenic effects of IL-8 by inhibiting the phosphorylation of PI3K/AKT. Finally, the induction of CD97 expression by the PI3K pathway was verified by treatment with the inhibitor LY294002. In vivo, the significant tumor growth and lung metastasis effects induced by intraperitoneal injection of IL-8 were greatly inhibited by silencing CD97 in nude mice. Collectively, the study presents a novel mechanism of the IL-8-CXCR2-PI3K/AKT axis in regulating CD97 expression, which leads to ICC metastasis mainly through EMT. The study may provide alternatives for targeting the tumor microenvironment in metastatic ICC.

BackgroundReduced brain volume, impaired cognition, and possibly a range of psychoneurological disorders have been reported in patients with non-alcoholic fatty liver disease (NAFLD); however, no underlying cause has been specified. Here, Mendelian randomization (MR) was employed to determine the causative NAFLD effects on cortical structure.MethodsWe used pooled-level data from FinnGen’s published genome-wide association study (GWAS) of NAFLD (1908 cases and 340,591 healthy controls), as well as published GWAS with NAFLD activity score (NAS) and fibrosis stage-associated SNPs as genetic tools, in addition to the Enigma Consortium data from 51,665 patients, were used to assess genetic susceptibility in relation to changes with cortical thickness (TH) and surface area (SA). A main estimate was made by means of inverse variance weighted (IVW), while heterogeneity and pleiotropy were detected using MR-Egger, weighted median, and MR Pleiotropy RESidual Sum and Outlier to perform a two-sample MR analysis.ResultsAt the global level, NAFLD reduced SA (beta = −586.72 mm2, se = 217.73, p = 0.007) and several changes in the cortical structure of the cerebral gyrus were found, with no detectable pleiotropy.ConclusionNAFLD causally affects cortical structures, which supports the presence of an intricate liver–brain axis.

Abstract With the increase in extremely low birth weight (ELBW) infants, their outcome attracted worldwide attention. However, in China, the related studies are rare. The hospitalized records of ELBW infants discharged from twenty-six neonatal intensive care units in Guangdong Province of China during 2008–2017 were analyzed. A total of 2575 ELBW infants were enrolled and the overall survival rate was 55.11%. From 2008 to 2017, the number of ELBW infants increased rapidly from 91 to 466, and the survival rate improved steadily from 41.76% to 62.02%. Increased survival is closely related to birth weight (BW), regional economic development, and specialized hospital. The incidence of complications was neonatal respiratory distress syndrome (85.2%), oxygen dependency at 28 days (63.7%), retinopathy of prematurity (39.3%), intraventricular hemorrhage (29.4%), necrotizing enterocolitis (12.0%), and periventricular leukomalacia (8.0%). Among the 1156 nonsurvivors, 90.0% of infants died during the neonatal period (≤ 28 days). A total of 768 ELBW infants died after treatment withdrawal, for reasons of economic and/or poor outcome. The number of ELBW infants is increasing in Guangdong Province of China, and the overall survival rate is improving steadily.

Abstract Background Acute myeloid leukemia (AML) is a myeloid neoplasm makes up 7.6% of hematopoietic malignancies. Super-enhancers (SEs) represent a special group of enhancers, which have been reported in multiple cell types. In this study, we explored super-enhancer profiling through ChIP-Seq analysis of AML samples and AML cell lines, followed by functional analysis. Methods ChIP-seq analysis for H3K27ac was performed in 11 AML samples, 7 T-ALL samples, 8 B-ALL samples, and in NB4 cell line. Genes and pathways affected by GNE-987 treatment were identified by gene expression analysis using RNA-seq. One of the genes associated with super-enhancer and affected by GNE-987 treatment was LYL1 basic helix-loop-helix family member (LYL1). shRNA mediated gene interference was used to down-regulate the expression of LYL1 in AML cell lines, and knockdown efficiency was detected by RT-qPCR and western blotting. The effect of knockdown on the growth of AML cell lines was evaluated by CCK-8. Western blotting was used to detect PARP cleavage, and flow cytometry were used to determine the effect of knockdown on apoptosis of AML cells. Results We identified a total of 200 genes which were commonly associated with super-enhancers in ≧10 AML samples, and were found enriched in regulation of transcription. Using the BRD4 inhibitor GNE-987, we assessed the dependence of AML cells on transcriptional activation for growth and found GNE-987 treatment predominantly inhibits cell growth in AML cells. Moreover, 20 candidate genes were selected by super-enhancer profile and gene expression profile and among which LYL1 was observed to promote cell growth and survival in human AML cells. Conclusions In summary, we identified 200 common super-enhancer-associated genes in AML samples, and a series of those genes are cancer genes. We also found GNE-987 treatment downregulates the expression of super-enhancer-associated genes in AML cells, including the expression of LYL1. Further functional analysis indicated that LYL1 is required for AML cell growth and survival. These findings promote understanding of AML pathophysiology and elucidated an important role of LYL1 in AML progression.

BackgroundTissue inhibitor of metalloproteinase 3 (TIMP3) was recently demonstrated capable to regulate some gene expression in a myocardial infarction model. Here we aim to explore the gene expression profile in TIMP3-treated cardiomyocytes and related potential cardiovascular functions.MethodsTotal RNA extracted from cultured neonatal rat ventricular myocytes (NRVMs) were used for RNA sequencing analysis and real-time PCR. KEGG pathway enrichment assay and Ingenuity Pathway Analysis (IPA) were performed to study the signaling pathways and downstream effects. Western blot was used to detect phosphorylation of protein kinase B (Akt). A Cell Counting Kit-8 assay was employed to evaluate the proliferation of human umbilical vein endothelial cells (HUVECs). Contraction rate of NRVMs was measured with microscopy.ResultsRNA sequencing data showed that expression of 2,526 genes were significantly modulated by recombinant TIMP3 (rTIMP3, 100 ng/ml) in NRVMs. Some differentially expressed genes (DEGs) were validated with real-time PCR. Several KEGG pathways including the phosphoinositide-3-kinase (PI3K)-Akt pathway were significantly regulated by rTIMP3. Phosphorylation of Akt was increased by rTIMP3 and a PI3K inhibitor LY294002 suppressed rTIMP3-induced up-regulation of some genes. Some DEGs were predicted by IPA to increase vascularization, and some to decrease heart rate. RTIMP3 could reduce the contraction rate of NRVMs and its conditioned media increased the proliferation of HUVECs.ConclusionTIMP3 can regulate expression of multiple genes partly through PI3K. Some DEGs were associated with activation of vascularization and some with heart rate reduction. This study suggests that TIMP3 can potentially modulate cardiovascular functions via DEGs.

Based on a long-term field investigation on chigger mites in southwest China from 2001 to 2019, the present study analyzed the infestation and distribution of chigger mites on the Chevrieri's field mouse (Apodemus chevrieri) in the region. A total of 12,516 individuals of chigger mites were collected from 1981 A. chevrieri mice, and 12,281 chiggers were identified as 107 species, 11 genera and 3 subfamilies in 2 families, which revealed a high species diversity of the mites on A. chevrieri mice. Of 1981 A. chevrieri mice, 633 ones were infested with chiggers with a relatively high overall prevalence (PM = 31.95%), mean abundance (MA = 6.32) and mean intensity (MI = 19.77). Of the 107 chigger species identified from A. chevrieri mice, three ones were the most dominant and they were Leptrombidium scutellare, L. densipunctatum and L. cricethrionis, which showed aggregated distribution among different individuals of the mice. A slightly positive association existed between every two dominant chigger species, which implied that the dominant chigger species tend to co-exist on A. chevrieri. The infestations of A. chevrieri with chiggers varied in different latitudes, altitudes and landscapes and they showed some heterogeneity along different environmental gradients. The logistic regression analysis showed that the risk factors for chigger infestations on A. chevrieri were landscapes, ages and altitudes, which implied that the environmental factors and host ages could influence the infestations of the mice with the mites. A theoretical curve of the species abundance distribution of chigger mites on A. chevrieri was successfully fitted by Preston's lognormal model, suggesting that the species abundance distribution conforms to the lognormal distribution pattern. The expected total species of chigger mites on A. chevrieri was roughly estimated to be 136 species and about 29 rare chigger species were probably missed in the sampling field investigation.

Abstract Background Neuroblastoma (NB) is a common extracranial malignancy with high mortality in children. Recently, super-enhancers (SEs) have been reported to play a critical role in the tumorigenesis and development of NB via regulating a wide range of oncogenes Thus, the synthesis and identification of chemical inhibitors specifically targeting SEs are of great urgency for the clinical therapy of NB. This study aimed to characterize the activity of the SEs inhibitor GNE987, which targets BRD4, in NB. Results In this study, we found that nanomolar concentrations of GNE987 markedly diminished NB cell proliferation and survival via degrading BRD4. Meanwhile, GNE987 significantly induced NB cell apoptosis and cell cycle arrest. Consistent with in vitro results, GNE987 administration (0.25 mg/kg) markedly decreased the tumor size in the xenograft model, with less toxicity, and induced similar BRD4 protein degradation to that observed in vitro. Mechanically, GNE987 led to significant downregulation of hallmark genes associated with MYC and the global disruption of the SEs landscape in NB cells. Moreover, a novel candidate oncogenic transcript, FAM163A, was identified through analysis of the RNA-seq and ChIP-seq data. FAM163A is abnormally transcribed by SEs, playing an important role in NB occurrence and development. Conclusion GNE987 destroyed the abnormal transcriptional regulation of oncogenes in NB by downregulating BRD4, which could be a potential therapeutic candidate for NB.

Abstract Recent studies uncovered the emerging roles of SAPCD2 (suppressor anaphase-promoting complex domain containing 2) in several types of human cancer. However, the functions and underlying mechanisms of SAPCD2 in the progression of neuroblastoma (NB) remain elusive. Herein, through integrative analysis of public datasets and regulatory network of GSK-J4, a small-molecule drug with anti-NB activity, we identified SAPCD2 as an appealing target with a high connection to poor prognosis in NB. SAPCD2 promoted NB progression in vitro and in vivo. Mechanistically, SAPCD2 could directly bind to cytoplasmic E2F7 but not E2F1, alter the subcellular distribution of E2F7 and regulate E2F activity. Among the E2F family members, the roles of E2F7 in NB are poorly understood. We found that an increasing level of nuclear E2F7 was induced by SAPCD2 knockdown, thereby affecting the expression of genes involved in the cell cycle and chromosome instability. In addition, Selinexor (KTP-330), a clinically available inhibitor of exportin 1 (XPO1), could induce nuclear accumulation of E2F7 and suppress the growth of NB. Overall, our studies suggested a previously unrecognized role of SAPCD2 in the E2F signaling pathway and a potential therapeutic approach for NB, as well as clues for understanding the differences in subcellular distribution of E2F1 and E2F7 during their nucleocytoplasmic shuttling.

Abstract Background Acute myeloid leukemia (AML) is a myeloid neoplasm accounts for 7.6% of hematopoietic malignancies. AML is a complex disease, and understanding its pathophysiology is contributing to the improvement in the treatment and prognosis of AML. In this study, we assessed the expression profile and molecular functions of CCAAT enhancer binding protein gamma (CEBPG), a gene implicated in myeloid differentiation and AML progression. Methods shRNA mediated gene interference was used to down-regulate the expression of CEBPG in AML cell lines, and knockdown efficiency was detected by RT-qPCR and western blotting. The effect of knockdown on the growth of AML cell lines was evaluated by CCK-8. Western blotting was used to detect PARP cleavage, and flow cytometry were used to determine the effect of knockdown on apoptosis of AML cells. Genes and pathways affected by knockdown of CEBPG were identified by gene expression analysis using RNA-seq. One of the genes affected by knockdown of CEBPG was Eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1), a known repressor of translation. Knockdown of EIF4EBP1 was used to assess its potential role in AML progression downstream of CEBPG. Results We explored the ChIP-Seq data of AML cell lines and non-AML hematopoietic cells, and found CEBPG was activated through its distal enhancer in AML cell lines. Using the public transcriptomic dataset, the Cancer Cell Line Encyclopedia (CCLE) and western blotting, we also found CEBPG was overexpressed in AML. Moreover, we observed that CEBPG promotes AML cell proliferation by activating EIF4EBP1, thus contributing to the progression of AML. These findings indicate that CEBPG could act as a potential therapeutic target for AML patients. Conclusion In summary, we systematically explored the molecular characteristics of CEBPG in AML and identified CEBPG as a potential therapeutic target for AML patients. Our findings provide novel insights into the pathophysiology of AML and indicate a key role for CEBPG in promoting AML progression.

Abstract Background Gallbladder carcinoma (GBC) was the most common malignancy of biliary tract. Patients with malignancies frequently present with activated coagulation pathways, which might potentially related to tumor progression and prognosis. The purpose of the study was to investigate the clinical significance of preoperative serum fibrinogen levels and platelet counts in GBC patients. Methods The preoperative fasting serum fibrinogen levels and platelet counts of 58 patients with GBC were measured by AUV2700 automatic biochemical analyzer, as well as 60 patients with cholesterol polyps and 60 healthy volunteers. Kaplan–Meier survival analysis was applied to show the correction between fibrinogen levels and outcome after surgery. Results The fibrinogen levels of patients with GBC were significantly higher than healthy gallbladder and cholesterol polyp of gallbladder (p 0.05) in multivariate analysis. Conclusions The preoperative serum fibrinogen levels and platelet counts might be reliable biomarkers for the occurance of disease, tumor depth, lymph node metastasis, distant metastasis and advanced TNM stage in patients with GBC. The serum fibrinogen levels might be a prognostic factor to predict outcome for GBC patients suffering from surgery treatment. Anticoagulation therapy might be considered to control cancer progression in future studies.

Objectives: To examine associations between maternal sulfur dioxide (SO2) exposure and congenital ear malformations risk in offspring.Methods: We surveyed 1676 cases with congenital ear malformations and 7950 controls from the Maternal and Child Health Certificate Registry of Liaoning Province between 2010 and 2015. SO2 concentrations were obtained from the Municipal Environment Protection Bureau of Liaoning Province. Multivariable logistic regression models and Restricted cubic splines (RCS) model were used to assess the aforementioned association.Results: There were significant associations between maternal SO2 exposure and congenital ear malformations risk during the 3 months before conception (OR Q4 vs. Q1 = 1.93, 95% CI = 1.43–2.59) and the 3 months after conception (OR Q4 vs. Q1 = 1.63, 95% CI = 1.22–2.18). Similar results were obtained in the analysis of single-month exposure windows, except for the third month before conception and the third month after conception. Moreover, these findings were broadly consistent across subgroups and robust in sensitivity analyses. There were non-linear dose-response associations between SO2 exposure and congenital ear malformations based on restricted cubic spline model analysis.Conclusion: Maternal SO2 exposure is associated with increased congenital ear malformations risk in offspring.

Abstract Background Mounting evidence shows that microRNA-34a (miR-34a) is involved in cancer prognosis. Therefore, we summarize the predictive role of miR-34a for survival in patients with gastrointestinal cancers (GICs). Methods All eligible studies were found by searching PubMed, Web of Science and EMBASE, and survival results were extracted. Then, the hazard ratio (HR) with the corresponding 95% confidence interval (CI) was calculated to evaluate the prognostic role of miR-34a in GICs. The association between miR-34a expression and clinicopathological characteristics was estimated by odds ratios (ORs) and 95% CIs. Results A total of 20 studies were included in this meta-analysis. For overall survival (OS), lower miR-34a expression could probably predict poorer outcome in GICs, with a pooled HR of 1.86 (95% CI: 1.52–2.28, P

BackgroundFirst-line surveillance on hepatitis B virus (HBV)-infected populations with B-mode ultrasound is relatively limited to identifying hepatocellular carcinoma (HCC) without elevated α-fetoprotein (AFP). To improve the present HCC surveillance strategy, the state of the art of artificial intelligence (AI), a deep learning (DL) approach, is proposed to assist in the diagnosis of a focal liver lesion (FLL) in HBV-infected liver background.MethodsOur proposed deep learning model was based on B-mode ultrasound images of surgery that proved 209 HCC and 198 focal nodular hyperplasia (FNH) cases with 413 lesions. The model cohort and test cohort were set at a ratio of 3:1, in which the test cohort was composed of AFP-negative HBV-infected cases. Four additional deep learning models (MobileNet, Resnet50, DenseNet121, and InceptionV3) were also constructed as comparative baselines. To evaluate the models in terms of diagnostic power, sensitivity, specificity, accuracy, confusion matrix, F1-score, and area under the receiver operating characteristic curve (AUC) were calculated in the test cohort.ResultsThe AUC of our model, Xception, achieved 93.68% in the test cohort, superior to other baselines (89.06%, 85.67%, 83.94%, and 78.13% respectively for MobileNet, Resnet50, DenseNet121, and InceptionV3). In terms of diagnostic power, our model showed sensitivity, specificity, accuracy, and F1-score of 96.08%, 76.92%, 86.41%, and 87.50%, respectively, and PPV, NPV, FPR, and FNR calculated from the confusion matrix were respectively 80.33%, 95.24%, 23.08%, and 3.92% in identifying AFP-negative HCC from HBV-infected FLL cases. Satisfactory robustness of our proposed model was shown based on 5-fold cross-validation performed among the models above.ConclusionsOur DL approach has great potential to assist B-mode ultrasound in identifying AFP-negative HCC from FLL found in surveillance of HBV-infected patients.

Evidence of the association between maternal sulfur dioxide (SO2) exposure and the risk of omphalocele is limited and equivocal. We aimed to assess the aforementioned topic during the first trimester of pregnancy. A population-based case-control study was carried out in infants consisting of 292 cases of omphalocele and 7,950 healthy infant controls. Exposure to SO2, particulate matter with aerodynamic diameters ≤ 10 μm, and nitrogen dioxide was assessed by averaging the concentration from all stations in the mother's residential city. SO2 exposure was categorized into three groups, with the lowest tertile defined as the reference category. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression models. Higher SO2 exposure during the first trimester was significantly associated with omphalocele risk [per standard deviation (42 ug/m3) increment: OR = 1.39, 95% CI = 1.22–1.65]. When focusing on shorter exposure windows, similar positive associations were observed for SO2 exposure in the first and third months of pregnancy. In addition, compared with the lowest tertile, high SO2 exposure in the second month of pregnancy increased the risk of omphalocele (OR = 2.80, 95% CI = 1.61–4.97). Maternal exposure to SO2 during the first trimester may increase the risk of omphalocele in offspring.

Abstract Background/Aims Pancreatic ductal adenocarcinoma (PDAC) is associated with high mortality, even after surgical resection. The existing predictive models for survival have limitations. This study aimed to develop better nomograms for predicting overall survival (OS) and cancer‐specific survival (CSS) in PDAC patients after surgery. Methods A total of 6323 PDAC patients were retrospectively recruited from the Surveillance, Epidemiology, and End Results (SEER) database and randomly allocated into training, validation, and test cohorts. Multivariate Cox regression analysis was conducted to identify significant independent factors for OS and CSS, which were used for construction of nomograms. The performance was evaluated, validated, and compared with that of the 8th edition AJCC staging system. Results Ten independent factors were significantly correlated with OS and CSS. The 1‐, 3‐, and 5‐year OS rates were 40%, 20%, and 15%, and 1‐, 3‐, and 5‐year CSS rates were 45%, 24%, and 19%, respectively. The nomograms were calibrated well, with c‐indexes of 0.640 for OS and 0.643 for CSS, respectively. Notably, relative to the 8th edition AJCC staging system, the nomograms were able to stratify each AJCC stage into three prognostic subgroups for more robust risk stratification. Furthermore, the nomograms achieved significant clinical validity, exhibiting wide threshold probabilities and high net benefit. Performance assessment also showed high predictive accuracy and reliability. Conclusions The predictive ability and reliability of the established nomograms have been validated, and therefore, these nomograms hold potential as novel approaches to predicting survival and assessing survival risks for PDAC patients after surgery.

Neuroblastoma (NB) is the most common solid tumor of the neural crest cell origin in children and has a poor prognosis in high-risk patients. The oncogene MYCN was found to be amplified at extremely high levels in approximately 20% of neuroblastoma cases. In recent years, research on the targeted hydrolysis of BRD4 to indirectly inhibit the transcription of the MYCN created by proteolysis targeting chimaera (PROTAC) technology has become very popular. dBET57 (S0137, Selleck, TX, USA) is a novel and potent heterobifunctional small molecule degrader based on PROTAC technology. The purpose of this study was to investigate the therapeutic effect of dBET57 in NB and its potential mechanism. In this study, we found that dBET57 can target BRD4 ubiquitination and disrupt the proliferation ability of NB cells. At the same time, dBET57 can also induce apoptosis, cell cycle arrest, and decrease migration. Furthermore, dBET57 also has a strong antiproliferation function in xenograft tumor models in vivo. In terms of mechanism, dBET57 targets the BET protein family and the MYCN protein family by associating with CRBN and destroys the SE landscape of NB cells. Combined with RNA-seq and ChIP-seq public database analysis, we identified the superenhancer-related genes TBX3 and ZMYND8 in NB as potential downstream targets of dBET57 and experimentally verified that they play an important role in the occurrence and development of NB. In conclusion, these results suggest that dBET57 may be an effective new therapeutic drug for the treatment of NB.

With the increasing application of medical imaging contrast materials, contrast-induced nephropathy (CIN) has become the third major cause of iatrogenic renal insufficiency. CIN is defined as an absolute increase in serum creatinine levels of at least 0.50 mg/dl or an increase >25% of serum creatinine from baseline after exposure to contrast. In this study, the protective effects of salvianolic acid B (Sal B) were detected in human renal tubular epithelial cells (HK-2) exposed to iopromide. The results showed that different concentrations of Sal B counteract the loss of cell viability induced by iopromide, and reduce cell apoptosis, the reactive oxygen species (ROS) levels, and the levels of endoplasmic reticulum stress (ERS)–related and apoptosis-related proteins such as p-IRE-1α, p-eIF-2α/eIF-2α, p-JNK, CHOP, Bax/Bcl-2, and cleaved caspase-3. In addition, Sal B at a concentration of 100 μmol/L inhibited ERS and reduced cell damage to a similar extent as the ERS inhibitor 4-PBA. Importantly, treatment with Sal B could abolish the injury induced by ERS agonist tunicamycin, increasing cell viability and the mitochondrial membrane potential, as well as significantly reducing ROS levels and the expression of Bax/Bcl-2, cleaved-caspase-3, GRP78, p-eIF2α, p-JNK, and CHOP. These results suggested that the protective effect of Sal B against HK-2 cell injury induced by iopromide may be related to the inhibition of ERS.

Limited studies have focused on the impact of ambient air pollution on spina bifida. A population-based case-control study was conducted in Liaoning Province, China to assess the associations between maternal PM10 exposures in various exposure windows and spina bifida risk. Data on spina bifida cases born between 2010 and 2015 were available from the Maternal and Child Health Certificate Registry of Liaoning Province. Controls were a random sample of healthy livebirths without any birth defects delivered in the selected five cities during 2010–2015. Ambient air monitoring data for PM10 were obtained from 75 monitoring stations in Liaoning Province. The multivariable logistic regression models were established to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI). We further performed sensitivity analyses by using three propensity score methods. A total of 749 spina bifida cases and 7,950 controls were included. After adjusting for potential confounders, spina bifida was associated with a 10 μg/m3 increment in PM10 during the first trimester of pregnancy (adjusted OR = 1.06, 95% CI: 1.00–1.12) and the 3 months before pregnancy (adjusted OR = 1.12, 95% CI: 1.06–1.19). The adjusted ORs in the final model for the highest vs. the lowest quartile were 1.51 (95% CI: 1.04–2.19) for PM10 during the first trimester of pregnancy and 2.01 (95% CI: 1.43–2.81) for PM10 during the 3 months before pregnancy. Positive associations were found between PM10 exposures during the single month exposure windows and spina bifida. Sensitivity analyses based on two propensity score methods largely reported similar positive associations. Our findings support the evidence that maternal PM10 exposure increases the risk of spina bifida in offspring. Further, validation with a prospective design and a more accurate exposure assessment is warranted.

Abstract We developed an in situ synthesis strategy for preparing well-dispersed CuO nanoparticles as aquathermolysis catalyst for viscosity reduction in Shengli heavy oil (China). A Cu(OH)2-contained microemulsion was employed as a carrier to disperse the precursor Cu(OH)2 to the heavy oil phase. Under aquathermolysis condition (240 °C, 2.5 MPa of N2), the Cu(OH)2 precursors would first be converted in situ to well-crystallized and size-homogeneous CuO nanoparticles naturally, catalyzed by which the viscosity of Shengli heavy oil could be reduced as much as 94.6%; simultaneously, 22.4% of asphaltenes were converted to light components. The agglomeration of the in situ prepared monoclinic CuO nanoparticles could be negligible throughout the catalytic reaction. Based on the characterization results of 1H NMR, elemental analysis and GC–MS of oil samples before and after catalytic aquathermolysis, the mechanism for viscosity reduction of heavy oil in the catalytic system was investigated.

Background/AimsPancreatic ductal adenocarcinoma (PDAC) can occur in different parts of the pancreas. This study aimed to identify clinicopathological characteristics independently correlated with the prognosis of PDAC of the pancreatic head/uncinate (PHC) or body-tail (PBTC), and to develop novel nomograms for predicting cancer-specific survival (CSS) according to different primary cancer locations.Methods1160 PDAC patients were retrospectively enrolled and assigned to training and test sets with each set divided into PHC and PBTC groups. Comparative analysis of clinicopathologic characteristics, survival analysis, and multivariate analysis were performed. Independent factors were identified and used for constructing nomograms. The performance of the nomograms was validated in the test set.ResultsPrimary tumor location was an independent risk factor for prognosis of PDAC after surgery. Specially, gender, fasting blood glucose, and preoperative cancer antigen 19-9 were significantly associated with prognosis of PHC, whereas age, body mass index, and lymph nodes were significantly correlated with the prognosis of PBTC. A significant difference in prognosis was found between PHC and PBTC in stage Ia and stage III. Three nomograms were established for predicting the prognosis for PDAC, PHC, and PBTC. Notably, these nomograms were calibrated modestly (c-indexes of 0.690 for PDAC, 0.669 for PHC, and 0.704 for PBTC), presented better accuracy and reliability than the 8th AJCC staging system, and achieved clinical validity.ConclusionsPHC and PBTC share the differential clinical-pathological characteristics and survival. The nomograms show good performance for predicting prognosis in PHC and PBTC. Therefore, these nomograms hold potential as novel approaches for predicting survival of PHC and PBTC patients after surgery.

Airway stenosis is a common problem in the neonatal intensive care unit (NICU) and pediatric intensive care unit (PICU). A tissue-engineered trachea is a new therapeutic method and a research hotspot. Successful vascularization is the key to the application of a tissue-engineered trachea. However, successful vascularization studies lack a complete description. In this study, it was assumed that rabbit bone marrow mesenchymal stem cells were obtained and induced by ascorbic acid to detect the tissue structure, ultrastructure, and gene expression of the extracellular matrix. A vascular endothelial cell culture medium was added in vitro to induce the vascularization of the stem cell sheet (SCS), and the immunohistochemistry and gene expression of vascular endothelial cell markers were detected. At the same time, vascular growth-related factors were added and detected during SCS construction. After the SCS and decellularized tracheal (DT) were constructed, a tetrandrine allograft was performed to observe its vascularization potential. We established the architecture and identified rabbit bone marrow mesenchymal stem cell membranes by 14 days of ascorbic acid, studied the role of a vascularized membrane in inducing bone marrow mesenchymal stem cells by in vitro ascorbic acid, and assessed the role of combining the stem cell membranes and noncellular tracheal scaffolds in vivo. Fourteen experiments confirmed that cell membranes promote angiogenesis at gene level. The results of 21-day in vitro experiments showed that the composite tissue-engineered trachea had strong angiogenesis. In vivo experiments show that a composite tissue-engineered trachea has strong potential for angiogenesis. It promotes the understanding of diseases of airway stenosis and tissue-engineered tracheal regeneration in newborns and small infants.

Chronic inflammatory arthritis (CIA) severely impacts quality of life in over 100 million people in China. In 2011, the European League Against Rheumatism (EULAR) developed recommendations for the role of nurses in the management of CIA. However, it remains unknown whether these recommendations could be fully implemented in China. Therefore, we aimed to solve the problem in this study. We conducted a nationwide cross-sectional study among 485 nurses in rheumatology and immunology departments based on an online questionnaire. The agreement of the recommendations by the subjects and the feasibility of the recommendations they believe were assessed by visual analogue scale (VAS). Our results showed that over 80% of the subjects agreed with each recommendation (VAS 5–10), and over 80% of the subjects considered the recommendations feasible (VAS 5–10). This study indicates that the EULAR recommendations can also be well implemented in China.

Abstract Background Cross-border malaria transmission in China is a major component of Chinese imported malaria cases. Such cases mostly are travellers returning from malaria endemic countries in Africa. By investigating malaria infectious status among Chinese worker in Africa, this study analysed the malaria risk factors, in order to establish infectious forecast model. Methods Chinese returnees data from Africa were collected at Guangzhou Baiyun International Airport, Guangzhou, China between August 2015 and March 2016 and were included in the cross-sectional and retrospective survey. Results A total of 1492 respondents were included in the study with the majority consisting of junior middle school educated male. Most of them are manual and technical workers hired by companies, with average of 37.04 years of age. Overall malaria incidence rate of the population was 8.98% (134/1492), and there were no significant differences regarding age, gender, occupation, or team. Forecast model was developed on the basis of malaria risk factors including working country, local ecological environment type, work duration and intensity of mosquito bite prevention. Conclusions The survey suggested that malaria incidence was high among Chinese travellers who had worked in Africa countries of heavy malaria burden. Further research on the frequency and severity of clinical episodes among Chinese travellers having worked in Africa is needed.

The incidence rate of intrahepatic cholangiocarcinoma is rising, and treatment options are limited. Therefore, new biological markers of intrahepatic cholangiocarcinoma are needed. Immunohistochemistry and enzyme-linked immunosorbent assay were applied to analyze the expressions of CD97, CD55, and soluble CD97 in 71 patients with intrahepatic cholangiocarcinoma and 10 patients with hepatolithiasis. CD97 and CD55 were not expressed in hepatolithiatic tissues, but positive expression was observed in 76.1% (54/71) and 70.4% (50/71) of intrahepatic cholangiocarcinoma patients. The univariate analyses indicated that the positive expressions of CD97 and CD55 were related to short intrahepatic cholangiocarcinoma survival of patients (both p = 0.001). Furthermore, CD97 and CD55 expressions and biliary soluble CD97 levels were significantly associated with histological grade (p = 0.004, 0.002, and 0.012, respectively), lymph node metastases (p = 0.020, 0.038, and 0.001, respectively), and venous invasion (p = 0.003, 0.002, and 0.001, respectively). The multivariate analyses indicated that lymph node metastases (hazard ratio: 2.407, p = 0.003), positive CD55 expression (hazard ratio: 4.096, p = 0.003), and biliary soluble CD97 levels (hazard ratio: 2.434, p = 0.002) were independent risk factors for the intrahepatic cholangiocarcinoma survival. The receiver operating characteristic (ROC) curve analysis indicated that when the cutoff values of biliary soluble CD97 were 1.15 U/mL, the diagnostic value for predicting lymph node metastasis had a sensitivity of 87.5% and a specificity of 51.3%. For intrahepatic cholangiocarcinoma patient death within 60 months at a cutoff value of 0.940 U/mL, the diagnostic value sensitivity was 89.3% and the specificity was 93.3%. Biliary soluble CD97 may be a new biological marker for early diagnosis, prediction of lymph node metastasis and poor prognosis, and discovery of a therapeutic target.

Objective To discuss the clinical significance of elevated serum citrulline levels in patients with epilepsy, and to provide new idea for improving the curative effect of antiepileptic drugs (AEDs). Methods Select 159 child and adolescent patients with cryptogenic epilepsy but without brain structural damage, screen serum concentration of citrulline in these patients by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and perform citrulline metabolism-related gene testing, including SLC25A13 gene and ASS1 gene, in part of those patients with a higher citrulline level, in order to identify the etiology of epilepsy. Results Among 159 patients, the citrulline levels of 18 cases were searched for 1.53-3.61 times higher than normal, and no causative mutation or novel mutation of SLC25A13 gene and ASS1 gene was found in 6 cases who were performed gene testing. AEDs were given to those 18 patients for at least one year. Seven cases (7/18) were free of clinical seizures, and 3 cases (3/18) had at least 75% reduction in seizure frequency, 3 cases (3/18) 50%-75% reduction in seizure frequency, 5 cases (5/18) seizure reduction below 50% . Compared with 30 cases with normal citrulline level (control group), the efficacy of AEDs in those 18 cases were significantly lower (Z = 1.759, P = 0.039). There was no significant difference between these 2 groups in basic features including sex, onset age, duration of seizure, seizure type, seizure frequency and kind of AEDs. Conclusions Higher citrulline level (1.53-3.61 times) may lead to a negative effect on the efficacy of AEDs of child and adolescent patients with cryptogenic epilepsy in this study. doi: 10.3969/j.issn.1672-6731.2014.11.013

BACKGROUND AND AIMS: EGFR activation and PKM2 expression are instrumental in tumorigenesis. EGFR activation regulates PKM2 functions in a subcellular compartment-dependent manner and promotes gene transcription and tumor growth. In addition, PKM2 is upregulated in EGFR-induced pathways in glioma malignancies. However, we found that PKM2 could also regulate the activity of the EGF/EGFR signaling pathway in gastric cancer cells. We aimed to define the biological mechanisms for PKM2 in regulating the cell motility and invasion. METHODS: We employed stable transfection with short hairpin RNA to stably silence the expression of PKM2 in the BGC823, SGC7901 and AGS gastric cancer cell lines. The effects of PKM2 in vitro were determined by assessing cell migration and invasion. Immunohistochemical analysis was used to explore the relationship among PKM2 and other proteins. RESULTS: Our results indicate that the knockdown of PKM2 decreased the activity of E-cadherin and enhanced the EGF/EGFR signaling pathway in the gastric cell lines BGC823 and SGC7901 that were positive for E-cadherin expression. However, in the undifferentiated gastric carcinoma cell line AGS, which lacks E-cadherin expression, PKM2 promoted cell migration and invasion. Immunohistochemical analyses showed that the levels of E-cadherin expression, ERK1/2 phosphorylation, and cytoplasmic PKM2 expression were correlated with each other. CONCLUSION: PKM2 may play different roles in differently differentiated gastric cancer cell types, and this finding would be consistent with the previous clinical research. The results of our study reveal an important link between PKM2 and E-cadherin during EGFR-stimulated gastric cancer cell motility and invasion.

Chigger mites are the vector of scrub typhus. This study estimates the infestation status and ecological characteristics of chiggers on the chestnut white-bellied rat Niviventer fulvescens in Southwest China between 2001 and 2019. Chiggers were identified under the microscope, and infestation indices were calculated. The Preston’s log-normal model was used to fit the curve of species abundance distribution. A total of 6,557 chiggers were collected in 136 of 342 N. fulvescens rats, showing high overall infestation indices (prevalence=39.8%, mean abundance=19.2, mean intensity=48.2) and high species diversity (S=100, H’=3.0). Leptotrombidium cangjiangense, Neotrombicula japonica, and Ascoschoengastia sifanga were the three dominant chigger species (constituent ratio=42.9%; 2,736/6,384) and exhibited an aggregated distribution among different rat individuals. We identified 100 chigger species, with 3 of them (Leptotrombidium scutellare, Leptotrombidium wenense, and Leptotrombidium deliense) as the main vectors of scrub typhus in China and nine species as potential vectors of this disease. Disease vector occurrence on N. fulvescens may increase the risk of spreading scrub typhus from rats to humans. Chigger infestation on N. fulvescens varied significantly in different environments. The species abundance distribution showed a log-normal distribution pattern. The estimated number of chigger species on N. fulvescens was 126 species. [ABSTRACT FROM AUTHOR]

Based on the field investigations in 91 investigation sites (counties) in southwest China between 2001 and 2019, the present paper reported the chigger mites on A. agrarius mice in southwest China for the first time by using a series of statistical methods. From 715 striped field mice captured in 28 of 91 investigated sites, only 255 chiggers were collected, and they were identified as 14 species, 6 genera in 3 subfamilies under 2 families. Of 715 A. agrarius mice, only 24 of them were infested with chigger mites with low overall prevalence (PM=3.4%), overall mean abundance (MA=0.36 mites/host) and overall mean intensity (MI=10.63 mites/host). The species diversity and infestation of chiggers on A. agrarius were much lower than those previously reported on some other rodents in southwest China. On a certain species of rodent, A. agrarius mouse in southwest China seems to have a very low susceptibility to chigger infestations than in other geographical regions. Of 14 chigger species, there were 3 dominant species, Leptotrombidium sialkotense, L. rupestre and Schoengastiella novoconfuciana, which were of aggregated distribution among different individuals of A. agrarius hosts. L. sialkotense, one of 6 main vectors of scrub typhus in China, was the first dominant on A. agrarius. The species similarity of chigger mites on male and female hosts was low with CSS=0.25, and this reflects the sex-bias of different genders of A. agrarius mice in harboring different chigger species. [ABSTRACT FROM AUTHOR]

Background: Current literature describes limited and controversial evidence on the associations between maternal preconception and first trimester exposure to particulate matter with a diameter ≤10 µm (PM10) and the risk of oral cleft (OC).Methods: We conducted a case-control study involving 3086 OC cases and 7950 controls, registered in the Maternal and Child Health Certificate Registry in Liaoning Province between 2010 and 2015. PM10 concentrations were obtained from the Environment Protection Bureau. The exposure windows included the 3 months before pregnancy, the first trimester and the individual months. Unconditional logistic regression model was performed to estimate the OR and 95% CI for the association between PM10 exposure and the risk of OC, cleft lip only (CLO), cleft palate only (CPO), and cleft lip and palate (CLP).Results: Maternal PM10 exposure was positively associated with an increased risk for OC during the 3 months preconception (per 10 µg/m3 increment: OR=1.04, 95% CI 1.01 to 1.07; highest vs lowest quartile: OR=1.23, 95% CI 1.04 to 1.45) and the first trimester (per 10 µg/m3 increment: OR=1.05, 95% CI 1.02 to 1.08; highest vs lowest quartile: OR=1.37, 95% CI 1.15 to 1.64). Analyses based on individual months presented similar positive associations, particularly in the second month of pregnancy (OR=1.77, 95% CI 1.51 to 2.09) for highest versus lowest quartile. In the subtype analysis, stronger associations were observed for CLO, whereas there was negligible evidence for CPO and CLP. Sensitivity analyses using propensity score matching generated similar findings.Conclusions: Our study provides evidence that PM10 exposure during the 3 months preconception and the first trimester increases the risk of OC. [ABSTRACT FROM AUTHOR]

Background: Enterovirus 71 (EV-A71) shows a potential of rapid death, but the natural history of the infection is poorly known. This study aimed to examine the natural history of EV-A71 infection.Methods: This was a prospective longitudinal observational study performed between January 1st and October 31st, 2012, at three hospitals in Guangdong, China. Subjects with positive EV-A71 RNA laboratory test results were included. Disease progression was documented with MRI, autopsies, and follow-up. Symptoms/signs with potential association with risk of death were analyzed.Results: Among the 288 patients, neurologic symptoms and signs were observed (emotional movement disorders, dyskinesia, involuntary movements, autonomic dysfunction, and disturbance of consciousness). Some of them occurred as initial symptoms. Myoclonic jerks/tremors were observed among >50% of the patients; nearly 40% of patients presented fatigue and 25% were with vomiting. Twenty-eight patients (9.7%) presented poor peripheral perfusion within 53.4 ± 26.1 h; 23 patients (8.0%) presented pulmonary edema and/or hemorrhage within 62.9 ± 28.6 h. Seventeen (5.9%) patients were in a coma. Seven (2.4%) patients died within 62.9 ± 28.6 h. Seventy-seven survivors underwent head and spinal cord MRI and 37.7% (29/77) showed abnormalities. Two fatal cases showed neuronal necrosis, softening, perivascular cuffing, colloid, and neuronophagia phenomenon in the brainstem.Conclusions: Patients with EV-A71 infection showed high complexity of symptoms and onset timing. Death risk may be indicated by autokinetic eyeball, eyeball ataxia, severe coma, respiratory rhythm abnormality, absent pharyngeal reflex, ultrahyperpyrexia, excessive tachycardia, pulmonary edema and/or hemorrhage, and refractory shock and ataxic respiration. Early assessment of these symptoms/signs is important for proper management. [ABSTRACT FROM AUTHOR]

Sini decoction is a well-known formula of traditional Chinese medicine, which has been used to treat cardiovascular disease for many years. Previously, we demonstrated that Sini decoction prevented doxorubicin-induced heart failure in vivo. However, its active components are still unclear. Thus, we investigated the active components of Sini decoction and their cardioprotective mechanisms in the in vitro neonatal rat cardiomyocytes and H9c2 cell line models of doxorubicin-induced cytotoxicity. Our results demonstrated that treatment with higenamine or [6]-gingerol increased viability of doxorubicine-injured cardiomyocytes. Moreover, combined use of higenamine and [6] -gingerol exerted more profound protective effects than either drug as a single agent, with effects similar to those of dexrazoxane, a clinically approved cardiac protective agent. In addition, we found that treatment with doxorubicin reduced SOD activity, increased ROS generation, enhanced MDA formation, induced release of LDH, and triggered the intrinsic mitochondria-dependent apoptotic pathway in cardiomyocytes, which was inhibited by cotreatment of higenamine and [6]-gingerol. Most importantly, the cytoprotection of higenamine plus [6]-gingerol could be abrogated by LY294002, a PI3K inhibitor. In conclusion, combination of higenamine and [6]-gingerol exerts cardioprotective effect against doxorubicin-induced cardiotoxicity through activating the PI3K/Akt signaling pathway. Higenamine and [6] -gingerol may be the active components of Sini decoction. [ABSTRACT FROM AUTHOR]

A nitrogen doped TiO2/Ni0.5Zn0.5Fe2O4 core–shell structure nanoparticles was prepared by low temperature sol–gel-hydrothermal process. The characterizations of the catalyst indicate that the Ni0.5Zn0.5Fe2O4 nanocrystals of about 25 nm are well-coated with crystalline N-doped titania. The absorption edges in the diffusion reflectance spectra of TiO0.98N1.02 and TiO1.37N0.63/Ni0.5Zn0.5Fe2O4 shift to visible light region. The core–shell nanocatalysts can effectively photodegrade organic pollutants in the dispersion system and can be recycled easily by an external magnetic field. [ABSTRACT FROM AUTHOR]

Abstract: Sinomenine (SIN) is an alkaloid isolated from the Chinese medicinal plant Sinomenium acutum. It is widely used as an immunosuppressive drug for treating autoimmune diseases. Due to its poor efficiency, the large-dose treatment presents some side effects and limits its further applications. In this study, we used chemical modification to improve the therapeutic effect of SIN in vitro and in vivo. A new derivative of sinomenine, named 1032, demonstrates significantly improved immunosuppressive activity over that of its parent natural compound (SIN). In an experimental autoimmune encephalomyelitis (EAE) model, 1032 significantly reduced encephalitogenic T cell responses and induced amelioration of EAE, which outcome was related to its selective inhibitory effect on the production of IL-17. By contrast, SIN treatment only led to a moderate alleviation of EAE severity and the expression level of IL-17 was not significantly reduced. Furthermore, 1032 exhibited suppression of Th17, but not Treg, cell differentiation, a result probably related to its inhibitory effect on IκB-α degradation as well as on IL-6 and TNF-α secretion in BMDCs. We speculate that 1032 as a novel anti-inflammatory agent may target DC to block IL-6 production, which in turn would terminate Th17 cell development. Thus, SIN derivative 1032 presents considerable potential in new drug development for treating autoimmune and inflammatory disease. [Copyright &y& Elsevier]

Prp43p is a RNA helicase required for pre-mRNA splicing and for the synthesis of large and small ribosomal subunits. The molecular functions and modes of regulation of Prp43p during ribosome biogenesis remain unknown. We demonstrate that the G-patch protein Pfa1p, a component of pre-40S pre-ribosomal particles, directly interacts with Prp43p. We also show that lack of Gno1p, another G-patch protein associated with Prp43p, specifically reduces Pfa1p accumulation, whereas it increases the levels of the pre-40S pre-ribosomal particle component Ltv1p. Moreover, cells lacking Pfa1p and depleted for Ltv1p show strong 20S pre-rRNA accumulation in the cytoplasm and reduced levels of 18S rRNA. Finally, we demonstrate that Pfa1p stimulates the ATPase and helicase activities of Prp43p. Truncated Pfa1p variants unable to fully stimulate the activity of Prp43p fail to complement the 20S pre-rRNA processing defect of Δpfa1 cells depleted for Ltv1p. Our results strongly suggest that stimulation of ATPase/helicase activities of Prp43p by Pfa1p is required for efficient 20S pre-rRNA-to-18S rRNA conversion. [ABSTRACT FROM AUTHOR]

Hypoxia-inducible factor-1 (HIF-1) plays a central role in tumor progression by regulating genes involved in proliferation, glycolysis, angiogenesis, and metastasis. To improve our understanding of HIF-1 regulation by kinome, we screened a kinasespecific small interference RNA library using a hypoxia-response element (HRE) luciferase reporter assay under hypoxic conditions. This screen determined that depletion of cellular SMG-1 kinase most significantly modified cellular HLF-1 activity in hypoxia. SMG-1 is the newest and least studied member of the phosphoinositide 3-kinase-related kinase family, which consists of ATM, ATR, DNA-PKcs, mTOR, and SMG-1. We individually depleted members of the phosphoinositide 3-kinase-related kinase family, and only SMG-1 deficiency significantly augmented HIF-1 activity in hypoxia. We subsequently discovered that SMG-1 kinase activity was activated by hypoxia, and depletion of SMG-1 up-regulated MAPK activity under low oxygen. Suppressing cellular MAPK by silencing ERK1/2 or by treatment with U0126, a MAPK inhibitor, partially blocked the escalation of HIF-1 activity resulting from SMG-1 deficiency in hypoxic cells. Increased expression of SMG-1 but not kinasedead SMG-1 effectively inhibited the activity of HIF1α. In addition, cellular SMG-1 deficiency increased secretion of the HIF1 α-regulated angiogenic factor, vascular epidermal growth factor, and survival factor, carbonic anhydrase IX (CA9), as well as promoted the hypoxic cell motility. Taken together, we discovered that SMG-1 negatively regulated HIF-1α activity in hypoxia, in part through blocking MAPK activation. [ABSTRACT FROM AUTHOR]

Abstract: Embedment of drug-like heterocyclic moieties was successfully employed in the novel modification of the readily available but poorly bioactive natural alkaloid sinomenine. Application of the newly proposed approach afforded a number of more potent sinomenine-like molecules with a significantly high hit rate. Among these new analogous, up to 500-fold increase of in vitro immunosuppressive activity was achieved. Further biological experiments of representative compound 4b indicated that it might inhibit NF-κB activation induced by TNF-α in a dose dependent way and showed remarkable in vivo treatment effects against the mouse experimental autoimmune uveoretinitis (EAU) disease models. [Copyright &y& Elsevier]