👤 Deyu Fang

Leucine rich repeat and immunoglobulin-like domain-containing protein 1 (Lingo-1) has gained considerable interest as a potential therapy for demyelinating diseases since it inhibits axonal regeneration and myelin production. However, the results of clinical trials targeted at Lingo-1 have been unsatisfactory. Amphoterin-induced gene and open reading frame-3 (AMIGO3), which is an analog of Lingo-1, might be an alternative therapeutic target for brain damage. In the present study, we investigated the effects of AMIGO3 on neural circuits in immature mice after status convulsion (SC) induced by kainic acid. The expression of both AMIGO3 and Lingo-1 was significantly increased after SC, with levels maintained to 20 days after SC. Following SC, transmission electron microscopy revealed the impaired microstructure of myelin sheaths and Western blot analysis showed a decrease in myelin basic protein expression, and this damage was alleviated by downregulation of AMIGO3 expression. The ROCK/RhoA signaling pathway was inhibited at 20 days after SC by downregulating AMIGO3 expression. These results indicate that AMIGO3 plays important roles in seizure-induced damage of myelin sheaths as well as axon growth and synaptic plasticity via the ROCK/RhoA signaling pathway. Show less

Orf virus (ORFV) is a member of the genus Parapoxvirus and family Poxviridae. The virus has a worldwide distribution and infects sheep, goats, humans, and wild animals. However, due to the complex structure of the poxvirus, the underlying mechanism of the entry and infection by ORFV remains largely unknown. ORFV ORF047 encodes a protein named L1R. Poxviral L1R serves as the receptor-binding protein and blocks virus binding and entry independently of glycosaminoglycans (GAGs). The study aimed to identify the host interaction partners of ORFV ORF047. Yeast two-hybrid cDNA library of sheep testicular cells was applied to screen the host targets with ORF047 as the bait. ORF047 was cloned into a pBT3-N vector and expressed in the NMY51 yeast strain. Then, the expression of bait proteins was validated by Western blot analysis. Sheep SERP1and PABPC4 were identified as host target proteins of ORFV ORF047, and a Co-IP assay further verified their interaction. New host cell proteins SERP1and PABPC4 were found to interact with ORFV ORF047 and might involve viral mRNA translation and replication. Show less

Severe negative energy balance around parturition is an important contributor to ketosis, a metabolic disorder that occurs most frequently in the peripartal period. Autophagy and mitophagy are important processes responsible for breaking down useless or toxic cellular material, and in particular damaged mitochondria. However, the role of autophagy and mitophagy during the occurrence and development of ketosis is unclear. The objective of this study was to investigate autophagy and mitophagy in the livers of cows with subclinical ketosis (SCK) and clinical ketosis (CK). We assessed autophagy by measuring the protein abundance of microtubule-associated protein 1 light chain 3-II (LC3-II; encoded by MAP1LC3) and sequestosome-1 (p62, encoded by SQSTM1), as well as the mRNA abundance of autophagy-related genes 5 (ATG5), 7 (ATG7), and 12 (ATG12), beclin1 (BECN1), and phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3). Mitophagy was evaluated by measuring the protein abundance of the mitophagy upstream regulators PTEN-induced putative kinase 1 (PINK1) and Parkin. Liver and blood samples were collected from healthy cows [n = 15; blood β-hydroxybutyrate (BHB) concentration <1.2 mM], cows with SCK (n = 15; blood BHB concentration 1.2 to 3.0 mM) and cows with CK (n = 15; blood BHB concentration >3.0 mM with clinical signs) with similar lactation numbers (median = 3, range = 2 to 4) and days in milk (median = 6, range = 3 to 9). The serum activity of aspartate aminotransferase and alanine aminotransferase was greater in cows with CK than in healthy cows. Levels of oxidative stress biomarkers malondialdehyde and hydrogen peroxide were also higher in liver tissue from ketotic cows (SCK and CK) than from healthy cows. Compared with cows with CK and healthy cows, the hepatic mRNA abundance of MAP1LC3, SQSTM1, ATG5, ATG7, ATG12, and PIK3C3 was upregulated in cows with SCK. Compared with healthy cows, cows with SCK had a lower abundance of p62 and a greater abundance of LC3-II, but levels of both were higher in cows with CK. The mRNA abundance of ATG12 was lower in cows with CK than in healthy cows. Furthermore, the hepatic protein abundance of PINK1 and Parkin was greater in cows with SCK and slightly lower in cows with CK than in healthy cows. These data demonstrated differences in the hepatic activities of autophagy and mitophagy in cows with SCK compared with cows with CK. Although the precise mechanisms for these differences could not be discerned, autophagy and mitophagy seem to be involved in ketosis. Show less

Age-related macular degeneration (AMD) is a common cause of vision loss. The epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells, accompanied by oxidative damage, plays a crucial role in AMD. It is well known that manganese superoxide dismutase (MnSOD) encoded by SOD2 is a critical molecule in fighting against oxidative stress, and Snail encoded by SNAI1 is the essential transcription factor for EMT. However, the effect of MnSOD on EMT and the underlying mechanism in RPE cells remains unknown. In this study, we found that MnSOD knockdown triggered the EMT by upregulating Snail, while MnSOD overexpression reversed EMT even with TGFβ treatment in RPE cells, and the anti-oxidative stress activity of MnSOD mediated this observation. In addition, Snail depletion increased both expression and activity of MnSOD while Snail overexpression decreased MnSOD expression and activity, and Dual-luciferase reporter and ChIP assays showed that Snail directly bound to E-box (CACCTG) in the SOD2 promoter. Moreover, MnSOD over-expression and Snail interference co-treatment strengthened the anti-oxidation and EMT reversing. Therefore, our findings demonstrate that MnSOD prevents EMT of RPE cells in AMD through inhibiting oxidative injury to RPE. Moreover, a critical EMT transcription factor, Snail, functions as a new negative transcriptional factor of SOD2. Herein, the Snail-MnSOD axis forms a mutual loop in the development of AMD, which may be a novel systemic treatment target for preventing AMD. Show less

Digestive system carcinoma is one of the most devastating diseases worldwide. Lack of valid clinicopathological parameters as prognostic factors needs more accurate and effective biomarkers for high-confidence prognosis that guide decision-making for optimal treatment of digestive system carcinoma. The aim of the present study was to establish a novel model to improve prognosis prediction of digestive system carcinoma, with a particular interest in transcription factors (TFs). A TF-related prognosis model of digestive system carcinoma with data from TCGA database successively were processed by univariate and multivariate Cox regression analyses. Then, for evaluating the prognostic prediction value of the model, ROC curve and survival analysis were performed by external data from GEO database. Furthermore, we verified the expression of TFs expression by qPCR in digestive system carcinoma tissue. Finally, we constructed a TF clinical characteristics nomogram to furtherly predict digestive system carcinoma patient survival probability with TCGA database. By Cox regression analysis, a panel of 17 TFs (NFIC, YBX2, ZBTB47, ZNF367, CREB3L3, HEYL, FOXD1, TIGD1, SNAI1, HSF4, CENPA, ETS2, FOXM1, ETV4, MYBL2, FOXQ1, ZNF589) was identified to present with powerful predictive performance for overall survival of digestive system carcinoma patients based on TCGA database. A nomogram that integrates TFs was established, allowing efficient prediction of survival probabilities and displaying higher clinical utility. The 17-TF panel is an independent prognostic factor for digestive system carcinoma, and 17 TFs based nomogram might provide implication an effective approach for digestive system carcinoma patient management and treatment. Show less

Epithelial-mesenchymal transition (EMT) mediated by fluid shear stress (FSS) in the tumor microenvironment plays an important role in driving metastasis of the malignant tumor. As a mechanotransducer, Yes-associated protein (YAP) is known to translocate into the nucleus to initiate transcription of genes involved in cell proliferation upon extracellular biophysical stimuli. Here, we showed that FSS facilitated cytoskeleton rearrangement in hepatocellular carcinoma cells, which led to the release of YAP from its binding partner, integrin β subunit, in the cytomembrane. Moreover, we found that upregulation of guanine nucleotide exchange factor (GEF)-H1, a microtubule-associated Rho GEF, is a critical step in the FSS-induced translocation of YAP. Nuclear YAP activated the expression of the EMT-regulating transcription factor SNAI1, but suppressed the expression of N6-methyladenosine (m Show less

To explore FGF1 and miR-143-3p expression in hepatocellular carcinoma (HCC) cells and its related mechanisms. Eighty-two HCC patients treated at our hospital from January 2018 to January 2019 were enrolled as Group A, while further 80 healthy people undergoing physical examinations during the same time period were enrolled as Group B. HCC cells and normal human liver cells were purchased, with HepG2 and SMMC-7721 cells transfected with pcDNA3.1-FGF1, si-FGF1, NC, miR-143-3p-inhibitor and miR-143-3p-mimics. FGF1 and miR-143-3p expression was detected by qRT-PCR. The expression of N-cadherin, vimentin, Snail, Slug, E-cadherin and γ-catenin was detected by Western Blotting (WB). Cell proliferation was detected by MTT assay. Cell invasion was detected by Transwell. Cell apoptosis was detected by flow cytometry (FCM). FGF1 was highly expressed but miR-143-3p was poorly expressed in HCC cells. Areas under the curves (AUCs) of the two indicators were > 0.8. The indicators were correlated with the age, gender, tumor invasion, degree of differentiation, tumor location and TNM staging of the patients. Silencing FGF1 and overexpressing miR-143-3p could promote cell apoptosis, inhibit cell growth, cell epithelial-mesenchymal transition (EMT) and the expression of N-cadherin, vimentin, Snail and Slug, and increase the expression of E-cadherin and γ-catenin. Dual luciferase reporter gene assay (DLRGA) confirmed that FGF1 and miR-143-3p had a targeted relationship. The rescue experiment showed that the proliferation, invasion and apoptosis of HepG2 and SMMC-7721 cells in the miR-143-3p-mimics+pcDNA3.1-FGF1 and miR-143-3p-inhibitor+Si-FGF1 groups were not different from those in the miR-NC group. Inhibiting FGF1 can upregulate miR-143-3p-mediated Hedgehog signaling pathway, and affect cells' EMT, proliferation and invasion, so FGF1 is expected to become a potential therapeutic target for HCC. Show less

Parkinson's disease (PD) is a complex neurodegenerative disorder with a strong genetic component. A growing number of variants and genes have been reported to be associated with PD; however, there is no database that integrate different type of genetic data, and support analyzing of PD-associated genes (PAGs). By systematic review and curation of multiple lines of public studies, we integrate multiple layers of genetic data (rare variants and copy-number variants identified from patients with PD, associated variants identified from genome-wide association studies, differentially expressed genes, and differential DNA methylation genes) and age at onset in PD. We integrated five layers of genetic data (8302 terms) with different levels of evidences from more than 3,000 studies and prioritized 124 PAGs with strong or suggestive evidences. These PAGs were identified to be significantly interacted with each other and formed an interconnected functional network enriched in several functional pathways involved in PD, suggesting these genes may contribute to the pathogenesis of PD. Furthermore, we identified 10 genes were associated with a juvenile-onset (age ≤ 30 years), 11 genes were associated with an early-onset (age of 30-50 years), whereas another 10 genes were associated with a late-onset (age > 50 years). Notably, the AAOs of patients with loss of function variants in five genes were significantly lower than that of patients with deleterious missense variants, while patients with Show less

Glioblastoma (GBM), a lethal primary brain tumor, contains glioma stem cells (GSCs) that promote malignant progression and therapeutic resistance. SOX2 is a core transcription factor that maintains the properties of stem cells, including GSCs, but mechanisms associated with posttranslational SOX2 regulation in GSCs remain elusive. Here, we report that DNA-dependent protein kinase (DNA-PK) governs SOX2 stability through phosphorylation, resulting in GSC maintenance. Mass spectrometric analyses of SOX2-binding proteins showed that DNA-PK interacted with SOX2 in GSCs. The DNA-PK catalytic subunit (DNA-PKcs) was preferentially expressed in GSCs compared to matched non-stem cell tumor cells (NSTCs) isolated from patient-derived GBM xenografts. DNA-PKcs phosphorylated human SOX2 at S251, which stabilized SOX2 by preventing WWP2-mediated ubiquitination, thus promoting GSC maintenance. We then demonstrated that when the nuclear DNA of GSCs either in vitro or in GBM xenografts in mice was damaged by irradiation or treatment with etoposide, the DNA-PK complex dissociated from SOX2, which then interacted with WWP2, leading to SOX2 degradation and GSC differentiation. These results suggest that DNA-PKcs-mediated phosphorylation of S251 was critical for SOX2 stabilization and GSC maintenance. Pharmacological inhibition of DNA-PKcs with the DNA-PKcs inhibitor NU7441 reduced GSC tumorsphere formation in vitro and impaired growth of intracranial human GBM xenografts in mice as well as sensitized the GBM xenografts to radiotherapy. Our findings suggest that DNA-PK maintains GSCs in a stem cell state and that DNA damage triggers GSC differentiation through precise regulation of SOX2 stability, highlighting that DNA-PKcs has potential as a therapeutic target in glioblastoma. Show less

In humans and mice, melanocortin receptor 4 (MC4R) and melanocortin receptor accessory protein 2 (MRAP2) can form a complex and control energy balance, thus regulating body weight and obesity. In pigs, a missense variant (p.Asp298Asn) of MC4R has been suggested to be associated with growth and fatness; however, the effect of Asp298Asn substitution on MC4R function is controversial, limiting its application in animal breeding. Here we examined the effect of this polymorphism on MC4R constitutive activity, cell surface expression and signaling, and its interaction with MRAP2 in pigs. We found that: (i) both pig MC4R Show less

Introduction: Obesity is considered a serious public health problem. Efforts have been directed to search for candidate genes such as LEP, LEPR, and MC4R involved in the leptin-melanocortin system. The neuroendocrine regulation of these genes on energy intake and balance influences the pathogenesis of this disease. Contradictory results regarding the association of these genes with obesity raise the need for new research. Objective: To analyze the association between obesity and LEP rs2167270, LEPR rs1137101, and MC4R rs17782313 polymorphisms and the clinical and biochemical variables in obese adults from Barranquilla, Colombia. Materials and methods: We analyzed 111 obese adults and 155 non-obese individuals as controls. The polymorphisms were determined by real-time PCR. Besides, anthropometric measures, blood pressure, and biochemical tests were evaluated. Results: No statistical differences were found in allele and genotype frequencies of gene polymorphisms between groups. The CC genotype of MC4R rs17782313 polymorphism was associated with increased systolic blood pressure and T allele and TT genotype, with decreased HDL cholesterol in obese adults. The effect of the other polymorphisms on these variables was not evidenced. Conclusions: LEP rs2167270, LEPR rs1137101, and MC4R rs17782313 polymorphisms were not associated with obesity in the population under study. MC4R rs17782313 polymorphisms were associated with an increase in systolic blood pressure and a decrease in HDL cholesterol. Show less

Epigenetic regulation of gene expression has been reported in the pathogenesis of metabolic disorders such as diabetes and liver steatosis in humans. However, the molecular mechanisms of fatty liver hemorrhagic syndrome (FLHS) in chickens have been rarely studied. H3K27ac chromatin immunoprecipitation coupled with high-throughput sequencing and high-throughput RNA sequencing was performed to compare genome-wide H3K27ac profiles and transcriptomes of liver tissue between healthy and FLHS chickens. In total, 1,321 differential H3K27ac regions and 443 differentially expressed genes were identified (| log2Fold change| ≥ 1 and Show less

Pancreatitis is the inflammation of the pancreas. However, little is known about the genes associated with pancreatitis severity. Our microarray analysis of pancreatic tissues from mild and severe acute pancreatitis mice models identified angiopoietin-like 4 (ANGPTL4) as one of the most significantly upregulated genes. Clinically, ANGPTL4 expression was also increased in the serum and pancreatic tissues of pancreatitis patients. The deficiency in ANGPTL4 in mice, either by gene deletion or neutralizing antibody, mitigated pancreatitis-associated pathological outcomes. Conversely, exogenous ANGPTL4 exacerbated pancreatic injury with elevated cytokine levels and apoptotic cell death. High ANGPTL4 enhanced macrophage activation and infiltration into the pancreas, which increased complement component 5a (C5a) level through PI3K/AKT signaling. The activation of the C5a receptor led to hypercytokinemia that accelerated acinar cell damage and furthered pancreatitis. Indeed, C5a neutralizing antibody decreased inflammatory response in LPS-activated macrophages and alleviated pancreatitis severity. In agreement, there was a significant positive correlation between C5a and ANGPTL4 levels in pancreatitis patients. Taken together, our study suggests that targeting ANGPTL4 is a potential strategy for the treatment of pancreatitis. Show less

FABP4 is a candidate gene for carcass and meat quality traits in livestock and poultry. However, the effects of FABP4 have not been examined in the Yanbian yellow cattle, an economically important local cattle breed in China. In this study, we characterized single nucleotide polymorphisms (SNPs) in FABP4 in this cattle breed and their associations with meat quality traits. Six SNPs (referred to as SNP1-6) were identified in FABP4 by direct sequencing and polymerase chain reaction-restriction fragment length polymorphism. The six SNPs were significantly correlated with meat quality traits. In particular, the GG and GA genotypes of SNP1 were significantly associated with water and fat contents and GG and AA genotypes of SNP1 were significantly associated with protein contents (P < 0.05). The fat content and marbling in heterozygous individuals at SNP2-6 were significantly higher than those in wild-type or mutant individuals (P < 0.05), while protein content was significantly higher in wild-type and mutant individuals than in heterozygous individuals (P < 0.05). A gene expression analysis indicated that the lipid metabolism-related genes FABP4, PPARγ, ANGPTL4, and LPL show similar expression patterns with respect to FABP4 genotypes, with the highest levels in wild-type individuals and the lowest levels in mutants. In conclusion, FABP4 SNPs can be used for marker-assisted selection in Yanbian yellow cattle breeding. Show less

Selective intrauterine growth restriction (sIUGR) is a severe complication in monochorionic (MC) twin pregnancies, and it carries increased risks of poor prognosis. Current data suggest that vascular anastomoses and unequal placental sharing may be the key contributor to discordant foetal growth. While MC twins derive from a single zygote and have almost identical genetic information, the precise mechanisms remain unknown. DNA hydroxymethylation is a newly discovered epigenetic feature associated with gene regulation and modification. Here, we investigate discordant hydroxymethylation patterns between two placental shares of sIUGR and analyse the potential role of aberrant hydroxymethylation of angiopoietin-like 4 ( Show less

Hypoxia induces a vast array of long noncoding RNAs (lncRNA) in breast cancer cells, but their biological functions remain largely unknown. Here, we identified a hitherto uncharacterized hypoxia-induced lncRNA RAB11B-AS1 in breast cancer cells. RAB11B-AS1 is a natural lncRNA upregulated in human breast cancer and its expression is induced by hypoxia-inducible factor 2 (HIF2), but not HIF1, in response to hypoxia. RAB11B-AS1 enhanced the expression of angiogenic factors including VEGFA and ANGPTL4 in hypoxic breast cancer cells by increasing recruitment of RNA polymerase II. In line with increased angiogenic factors, conditioned media from RAB11B-AS1-overexpressing breast cancer cells promoted tube formation of human umbilical vein endothelial cells Show less

The application of tetracycline (TET) is very common in medical treatment, fisheries, and animal husbandry, resulting in its frequent detection with abundant concentrations in the aquatic environment. Though the effects of TET on zebrafish (Danio rerio) at embryonic and larval stages have been reported, there is very limited information on the possible long-term effect on aquatic fishes at the juvenile stage, especially at environmentally relevant levels. In this study, we have exposed juvenile zebrafish to two levels of TET at 1 and 100 µg/L for one month until their adulthood. The result showed that both levels of TET can significantly increase the body weight of the zebrafish, while there is no change in the body length. TET exposure also affected the liver microstructure by lipid vacuoles generation and global lipidomics analysis revealed a significant upregulation in hepatic triglyceride (TAG) levels. The metabolomics analysis showed great dysregulations in hepatic metabolic pathways including linoleic acid metabolism, tyrosine metabolism, and methionine metabolism, which are known to be linked with increased body weight gain through hepatic lipid accumulation. The hepatic gene expression involved in lipid transport (e.g., apoa4 and fabp11) and lipogenic factors (e.g., ppar) have been significantly upregulated in the livers of TET exposed zebrafish. Interestingly, the 16 rRNA gene sequence-based zebrafish gut microbial community analysis revealed an enhanced community diversity and altered microbial community composition upon TET exposure. To our knowledge, this is the first study showing that TET exposure can increase the body weight in juvenile zebrafish and the study on the ecotoxicity of antibiotic occurrences in the aquatic system can be further warranted. Show less

Primary cilia are lost during cancer development, but the mechanism regulating cilia degeneration is not determined. While transcription factor nuclear factor-erythroid 2-like 2 (NRF2) protects cells from oxidative, proteotoxic, and metabolic stress in normal cells, hyperactivation of NRF2 is oncogenic, although the detailed molecular mechanisms by which uncontrolled NRF2 activation promotes cancer progression remain unclear. Here, we report that NRF2 suppresses hedgehog (Hh) signaling through Patched 1 (PTCH1) and primary ciliogenesis via p62/sequestosome 1 (SQSTM1). PTCH1, a negative regulator of Hh signaling, is an NRF2 target gene, and as such, hyperactivation of NRF2 impairs Hh signaling. NRF2 also suppresses primary cilia formation through p62-dependent inclusion body formation and blockage of Bardet-Biedl syndrome 4 (BBS4) entrance into cilia. Simultaneous ablation of PTCH1 and p62 completely abolishes NRF2-mediated inhibition of both primary ciliogenesis and Hh signaling. Our findings reveal a previously unidentified role of NRF2 in controlling a cellular organelle, the primary cilium, and its associated Hh signaling pathway and also uncover a mechanism by which NRF2 hyperactivation promotes tumor progression via primary cilia degeneration and aberrant Hh signaling. A better understanding of the crosstalk between NRF2 and primary cilia/Hh signaling could not only open new avenues for cancer therapeutic discovery but could also have significant implications regarding pathologies other than cancer, including developmental disorders, in which improper primary ciliogenesis and Hh signaling play a major role. Show less

Plant height is a vital agronomic trait that greatly determines crop yields because of the close relationship between plant height and lodging resistance. Legumes play a unique role in the worldwide agriculture; however, little attention has been given to the molecular basis of their height. Here, we characterized the first dwarf mutant Show less

Luffa cylindrica is a nutrient-dense vegetable with medical properties and can alleviate metabolic diseases. Numerous evidences demonstrated gut microbiota impacted the progress of nonalcoholic fatty liver disease (NAFLD). This study was to investigate the underlying mechanism of L. cylindrica supplementation against NALFD via gut microbiota from hepatic transcriptional and metabolic analysis. In diet-induced obese mice, we observed L. cylindrica supplementation (2 g/kg body weight) effectively alleviated high-fat diet-induced obese symptoms such as body weight, fat deposition, and insulin resistance. Notably, L. cylindrica supplementation significantly relieved hepatic steatosis and inflammation infiltration to decrease hepatic toxicity. RNA-sequencing analysis showed that 130 hepatic genes in total significantly altered responding to L. cylindrica supplementation. And signaling pathway analysis revealed that L. cylindrica supplementation down-regulated the transcriptional expressions of CD36 and Rxrg to inhibit hepatic lipid synthesis. Moreover, L. cylindrica supplementation increased the transcriptional expressions of Ass1, Cps1, Cth, Got1, Tat, and Gls2 to enhance amino acid levels (Gly, Ala, Pro, Val, Ile, Asn, Met, and Phe) and improve hepatic abnormal gluconeogenesis. Furthermore, in antibiotic-treated obese mice, L. cylindrica supplementation did not change these gene expressions along with the hepatic levels of lipid and amino acids. Taken together, L. cylindrica supplementation could effectively suppress hepatic steatosis in diet-induced obese mice through inhibiting lipid synthesis and enhancing amino acid levels in liver, which depended on gut microbiota. Thus, L. cylindrica might be one promising dietary supplementation targeting at gut microbiota to reduce NAFLD risk. Show less

Clinical reports suggest a potential link between excess retinoids and development of depression. Although it has been shown that all-trans retinoic acid (ATRA) administration induces behavioral changes, further insight into how ATRA is involved is lacking. The hippocampus seems to be a major target of retinoids, and abnormal synaptic plasticity of the hippocampus is involved in depression. We examined two genes associated with synaptic function, discs large homolog 2 ( Show less

Aberrant activation of ERK signaling is a hallmark of lung cancer. Although constitutively activating mutations of EGFR and KRAS contribute to the hyperactivation of ERK1/2, other mechanisms remain elusive. In this study, the zinc finger protein ZNF251 was found to be upregulated in clinical lung cancer samples, and it promoted the growth of lung cancer cells and the growth of primary lung KPC cells from mouse models (Ad-Cre, Kras Show less

Numerous evidences have shown that circular RNAs (circRNAs) play a key role in regulating the pathogenesis of cancer. However, the mechanism of circRNAs in urothelial carcinoma of bladder (UCB) remains largely unclear. In this study, we found circFAM114A2 was significantly downregulated both in UCB tissue specimens and cell lines, and the expression level was highly correlated with pathological TNM stage and grade. Functionally, overexpression of circFAM114A2 dramatically inhibited the migration, invasion and proliferation of UCB cells in vitro, and suppressed tumor growth in vivo. Mechanistically, we confirmed miR-762 was copiously pulled down by circFAM114A2 in 5637 and T24 cells. Fluorescence in situ hybridization (FISH) further indicated the cytoplasmic interactions between circFAM114A2 and miR-762. By using luciferase reporter assay, we found that miR-762 could directly target TP63. Subsequently, we found that circFAM114A2 might increase the expression of ∆NP63 (main isoform of TP63 in UCB) by sponging miR-762. Taken together, our results demonstrated that circFAM114A2 might serve as a competing endogenous RNA (ceRNA) of miR-762 in regulating the expression of ∆NP63, thus suppressed UCB progression through circFAM114A2/miR-762/∆NP63 axis. Show less

IL-27 attenuates allergic inflammation and improves lung function in mouse models of allergic asthma. However, plasma IL-27 levels of asthma patients and the association with clinical features remain poorly understood. This study examined plasma IL-27 protein expression in untreated asthma patients and controls, analyzed its correlation with Th2 inflammation and lung function, and evaluated the effect of corticosteroids on IL-27 expression. Plasma IL-27 levels were lower in untreated asthma patients compared to controls. Plasma IL-27 levels were inversely correlated with sputum IL-5 mRNA expression in Th2 The results indicate that low levels of IL-27 in peripheral blood are closely related to Th2 inflammation and lung function of asthma patients. Low IL-27 levels in combination with high Th2 inflammation identify an asthma phenotype with high AHR and substantial response to corticosteroids. Understanding of this interaction could help to elucidate the inherent inflammation heterogeneity of asthma. Show less

The authors informed the journal that an error occurred in their manuscript.Figure 3C was mistakenly merged by the authors.The new version of the Figure 3C is as below.Reference:1. Meng Zhang, Xiuxiu Tan, Junjie Huang, Zekai Ke, Yukun Ge, Hu Xiong, Wei Lu, Lu Fang, Zhiming Cai, Song Wu: Association of 3 Common Polymorphisms of IL-27 Gene with Susceptibility to Cancer in Chinese: Evidence From an Updated Meta-Analysis of 27 Studies. Med Sci Monit 2015; 21: 2505-2513. DOI: 10.12659/MSM.895032. Show less

The aim of this study was to investigate potential genetic overlap between essential tremor and Parkinson's disease in a cohort of 825 subjects from an Eastern Chinese population. A total of 441 Parkinson's disease patients and 384 healthy controls were recruited. The MassARRAY System was used to detect three essential tremor-related single nucleotide polymorphisms. Odds ratio (OR) and 95% confidential interval (CI) were calculated to assess the relationship between polymorphisms and Parkinson's disease susceptibility. Our results demonstrated that the odds ratios of rs3794087 of SLC1A2, rs9652490 of LINGO1, and rs17590046 of PPARGC1A were 0.71 (95% CI = 0.55-0.91), 0.99 (95% CI = 0.78-1.26), and 0.88 (95% CI = 0.62-1.25), respectively. An essential tremor SNP (rs3794087 of SLC1A2) is associated with a decreased risk of PD in the Eastern Han Chinese population, while rs9652490 (LINGO1) and rs17590046 (PPARGC1A) do not show an association. Show less

Genome-wide association studies (GWAS) have identified common variants for quantitative traits (insulin resistance and impaired insulin release) of type 2 diabetes (T2D) across different ethnics including China, but results were inconsistent. The study included 1654 subjects who were selected from the 2010-2012 China National Nutrition and Health Surveillance (CNNHS). Insulin resistance and impaired insulin release were assessed by homeostasis model assessment (HOMA). The study included 64 diabetes-related single nucleotide polymorphisms (SNPs), which were done using Mass ARRAY. A logistic regression model was employed to explore the associations of SNPs with insulin resistance and impaired insulin release by correcting for the confounders. The 5q11.2-rs4432842, RASGRP1-rs7403531, and SEC16B-rs574367 increased the risk of insulin resistance with OR = 1.23 (95% CI: 1.04-1.45, OR = 1.35 (95% CI: 1.13-1.62), OR = 1.34 (95% CI: 1.07-1.67), respectively, while MAEA-rs6815464 decreased the risk of insulin resistance (OR = 0.84, 95% CI: 0.71-1.00). CENTD2-rs1552224, TSPAN8-rs7961581 and ANK1-rs516946 was associated with increased risk of impaired insulin release with OR = 1.47 (95% CI: 1.09-1.99), OR = 1.25 (95% CI: 1.03-1.51), OR = 1.39 (95% CI: 1.07-1.81), respectively. Our findings would provide insight into the pathogenesis of individual SNPs and T2D. Show less

Epithelial-mesenchymal transition (EMT)-related genes play an important role in immunosuppression. However, the correlations of EMT-related genes to prognosis and tumor-infiltrating lymphocytes in different cancers remain unclear. TCGA, GEO databases were used to analyze the expression, prognosis, and immune infiltration of EMT markers in cancer. RT-qPCR, immunohistochemistry, and western blot were used to analysis the expression and prognosis of SNAI1 in gastrointestinal cancers. High SNAI1 expression was closely related with poorer overall survival in gastrointestinal cancers in TCGA cohort. High SNAI1 expression was closely related with poorer overall survival in gastrointestinal cancers, and was validated in GEO database. Simultaneously, high expression of SNAI1 correlates with clinical relevance of gastric cancer. Moreover, SNAI1 expression was associated with tumor-infiltrating immune cells in gastrointestinal cancers. In addition, RT-qPCR, immunohistochemistry, and western blot showed SNAI1 expression was higher in gastrointestinal cancers compared to the normal tissues. Finally, high SNAI1 expression was closely related with poorer overall survival and correlates with clinical relevance of gastrointestinal cancers in an independent validation cohort. In summary, the results approaches to suggest that SNAI1 can be used as a prognostic biomarker for determining prognosis and immune infiltration in gastrointestinal cancers. Show less

Ovarian cancer is a highly invasive type of cancer. A previous study demonstrated that E-cadherin expression was upregulated in a human ovarian cancer cell line with a high expression of WW domain-containing oxidoreductase (WWOX), which is a tumor suppressor. Also, the migration and invasion ability of these cells was reduced. Snail family members are involved in the epithelial-to-mesenchymal transition (EMT) of ovarian cancer cells, and the expression of Snail family members is regulated by the transcription factor Elf5. The aim of the present research was to elucidate the role of WWOX in EMT of ovarian carcinoma cells through the Elf5/Snail pathway by gain and loss of function approaches in in vitro experiments. First, a WWOX gene expressing plasmid was transfected into CD133+CD117+ HO8910 ovarian carcinoma cells, and an Elf5 shRNA plasmid was transfected into these cells to assess the changes in EMT-related factors, including Snail1, and the invasive ability of tumor cells ability. Second, the human ovarian carcinoma cell lines HO8910 and SKOV3 were divided into six groups to detect the same indicators. The results demonstrated that the high expression of WWOX resulted in an increased E-cadherin expression, decreased Snail1 activity, and decreased invasion ability in CD133+CD117+ HO8910 cells. Elf5 shRNA transfection did not affect the WWOX expression; however, it decreased the expression of E-cadherin and Elf5 activity, while increasing Snail1 activity and invasion ability in CD133+CD117+ HO8910 cells. It was also observed that WWOX overexpression in HO8910 and SKOV3 cells inhibited the expression of EMT-related proteins and inhibited cell migration and invasion. Taken together, the results of the present report suggest that WWOX can decrease Snail1 activity by enhancing the activity of Elf5, thus upregulating E-cadherin expression and eventually inhibiting EMT of ovarian carcinoma. Show less