👤 Heyang Sun

Although papillary thyroid carcinoma (PTC) is associated with a generally favorable prognosis, about 15% of patients present recurrence and distant metastasis in the next decade leading to death. Angiopoietin-like 4 (ANGPTL4) is secreted to circulation and belongs to the angiopoietin-like proteins. The expression of ANGPTL4 was increased in several solid tumor tissues compared to corresponding paracancerous tissues. ANGPTL4 was identified as pro-tumorigenic protein, including stimulating tumor cell growth, promoting tumor metastasis. However, the clinical significance and biological function of ANGPTL4 in PTC is still unclear. Hence, the purpose of this study was to evaluate the role of ANGPTL4 in PTC, investigating the possibility of whether ANGPTL4 could become a novel target for PTC therapy. We investigated the expression level of ANGPTL4 and pAKT in PTC and paracancerous tissue by immunohistochemistry. We determined the effect of ANGPTL4 in PTC cell proliferation through cell counting kit-8 (CCK-8) and cell cycle by flow cytometry analysis. Furthermore, the correlation between ANGPTL4 expression levels and PTC cell proliferation from the TCGA data set was analyzed by GSEA. We explored the role of ANGPTL4 on the phosphorylation of AKT and proliferation in PTC cells via overexpression or knockdown assays and AKT inhibitor assay. In the present study, we found that ANGPTL4 was highly expressed in both protein and mRNA level in PTC compared with adjacent noncancerous tissues or benign nodule. ANGPTL4 expression increased according to thyroid tumor progression. ANGPTL4 level was positively correlated with the size of PTC. ANGPTL4 increased cell proliferation and decreased cell cycle arrest of PTC. Knockdown of ANGPTL4 inhibited the phosphorylation of AKT. ANGPTL4 regulated PTC cell proliferation through AKT signaling pathway. Our findings suggested that ANGPTL4 was increased in PTC compared with adjacent noncancerous tissues, and ANGPTL4 increased cell proliferation and inhibited cell cycle arrest in PTC cells via promoting AKT phosphorylation. The study may provide fundamental information to suggest its suitability as a target for the treatment of PTC. Show less

Variation in genes implicated in homocysteine and lipid metabolism systems may influence antidepressant response for patients with major depressive disorder (MDD). This study aimed to investigate whether association of polymorphisms on the MTHFR, ApoE and ApoA4 genes with the treatment response in MDD subjects. A total of 281 Han Chinese MDD patients received a single antidepressant drug (SSRI or SNRI) for at least 6 weeks, among whom 275 were followed up for 8 weeks. Their response to 6 weeks' treatment and remission to 8 weeks' treatment with antidepressant drugs was determined by changes in the 17-item Hamilton Depression Rating Scale (HARS-17) score. Single SNP and haplotype associations with treatment response were analyzed by UNPHASED 3.0.13. Logistic regression analysis was used to explore the interactions between genotypes and gender or drug type on treatment outcome, only those SNPs that had interactional association with gender or drug type were subjected to further stratified analysis. In total group, the haplotype (C-A) in MTHFR (rsl801133 and rs1801131) and the ApoE rs405509 AA genotype were significantly associated with better efficacy of antidepressants; In gender subgroups, only haplotype (C-A) in MTHFR (rsl801133 and rs1801131) was significantly associated with better efficacy of antidepressants in male subgroup; In drug type subgroup, the haplotype (C-A) in MTHFR (rsl801133 and rs1801131) and haplotype (G-C) in ApoE (rs7412 and rs405509) were associated with better efficacy of antidepressants in SNRI treated subgroup; The ApoA4 rs5092 G allele and GG genotype were associated with worse efficacy of antidepressants in SNRI treated subgroup. Genetic polymorphisms in homocysteine and lipid metabolism systems are associated with antidepressant response, particularly for the interactions of the certain genetic with gender or drug type. Show less

Fish intestine is an important constituent of the mucosal immune system. The gut and gut-associated lymphoid tissue construct a local immune environment. A Shewanella algae strain was previously reported to be a pathogen causing ascitic disease accompanied with intestinal inflammation in Cynoglossus semilaevis. This study aimed to investigate the intestine immune response in C. semilaevis to S. algae infection at the protein level. Two-dimensional electrophoresis coupled with mass spectrometry proteomics was utilized to compare protein expression in the intestines from normal and S. algae-infected C. semilaevis. A total of 70 differentially expressed proteins (DEPs), consisting of 16 upregulated and 54 downregulated proteins, were identified in the intestine tissue of C. Semilaevis. These protein expression changes were further validated using western blot analysis and quantitative real-time PCR. Gene ontology enrichment analysis showed that these 70 DEPs could be assigned across three categories: "cellular components", "molecular function", and "biological process". Forty-one DEPs (six up-regulated and 35 down-regulated proteins) related to metabolic processes were identified. In addition, 20 DEPs (eight up-regulated and 12 down-regulated proteins) related to stress and immune responses were identified. A protein-protein interaction network generated by the STRING (Search Tool for the Retrieval of Interacting Genes/protein) revealed that 30 DEPs interacted with one another to form an integrated network. Among them, 29 DEPs were related to stress, immune, and metabolism processes. In the network, some of the immune related proteins (C9, FGB, KNG1, apolipoprotein A-IV-like, and PDIA3) were up-regulated and most DEPs involved in metabolism processes were down-regulated. These results indicate that the immune defense response of the intestine was activated and the intestinal function associated with metabolism processes was disturbed. This study provides valuable information for further research into the functions of these DEPs in fish. Show less

The fabrication of electrochemical biosensors to directly, rapidly and ultrasensitively detect disease markers in urine or blood samples has become a new and competitive challenge in the field of sensor research. In this paper, a novel electrochemical immunosensor with high selectivity and sensitivity for the detection of the depression marker human apolipoprotein A4 (Apo-A4) was successfully constructed using zeolite imidazole ester metal organic skeleton-nitrogen doped graphene composites (ZIF-8@N-Gr). To this end, because of the higher surface area and biocompatibility, ZIF-8 with abundant biomolecular binding sites provided a good microenvironment for effectively immobilizing antigens. ZIF-8@N-Gr presented a flake structure, as the electrode displayed excellent electrical conductivity, which enhanced the electron transfer and significantly amplified the current signal of the immunosensor. More importantly, these immunosensors are capable of assaying human apolipoprotein A4 (Apo-A4) in 100% serum without suffering from any significant biological interference. Under optimized experimental conditions, the sensor was used for the analysis of whole serum samples and presented a wide linear range from 1.47 × 10 Show less

Long noncoding RNAs (lncRNAs) are currently considered to have a vital and wide range of biological functions, but the molecular mechanism underlying triglycerides metabolism remains poorly understood. This study aims to identify novel lncRNAs differentially expressed in rat livers with hypertriglyceridemia and elucidated the function role in TG metabolism. Differentially expressions of lncRNAs in rat livers with hypertriglyceridemia were identified by transcriptome sequencing and validated by real-time PCR. The role of lnc19959.2 in triglyceride metabolism was assessed both in vitro and in vivo. RNA pulldown and RIP assays were conducted to evaluate the interactions between lnc19959.2 and its target proteins. ChIP and Dual report assays were performed to detect the interactions between transcription factors and promoters of its target genes. We identified a novel lncRNA, and lnc19959.2 was upregulated in rat livers with hypertriglyceridemia. The knockdown of lnc19959.2 has profound TG lowering effects in vitro and in vivo. Subsequently, the genome-wide analysis identified that the knockdown of lnc19959.2 caused the deregulation of many genes during TG homeostasis. Further mechanism studies revealed that lnc19959.2 upregulated ApoA4 expression via ubiquitinated transcription inhibitor factor Purb, while it specifically interacted with hnRNPA2B1 to downregulate the expression of Cpt1a, Tm7sf2, and Gpam, respectively. In the upstream pathway, palmitate acid upregulated CCAAT/Enhancer-Binding Protein Beta (Cebpb) and facilitated its binding to the promoter of lnc19959.2, which resulted in significant promotion of lnc19959.2 transcriptional activity. Our findings provide novel insights into a new layer regulatory complexity of an lncRNA modulating triglyceride homeostasis by a novel lncRNA lnc19959.2. Show less

The ε4 allele of the apolipoprotein E (APOE) gene and lower apolipoprotein E (apoE) protein levels in plasma are risk factors for Alzheimer disease, but the underlying biological mechanisms are not fully understood. Half of plasma apoE circulates on high-density lipoproteins (HDLs). Higher apoE levels in plasma HDL were previously found to be associated with lower coronary heart disease risk, but the coexistence of another apolipoprotein, apoC3, modified this lower risk. To investigate associations between the presence of apoE in different lipoproteins with cognitive function, particularly the risk of dementia. This prospective case-cohort study embedded in the Ginkgo Evaluation of Memory Study (2000-2008) analyzed data from 1351 community-dwelling participants 74 years and older. Of this group, 995 participants were free of dementia at baseline (recruited from September 2000 to June 2002) and 521 participants were diagnosed with incident dementia during follow-up until 2008. Data analysis was performed from January 2018 to December 2019. Enzyme-linked immunosorbent assay-measured concentration of apoE in whole plasma, HDL-depleted plasma (non-HDL), HDL, and HDL subspecies that contain or lack apoC3 or apoJ. Adjusted hazard ratios for risk of dementia and Alzheimer disease during follow-up and adjusted differences (β coefficients) in Alzheimer Disease Assessment-Cognitive Subscale (ADAS-cog) and Modified Mini-Mental State Examination scores at baseline. Among 1351 participants, the median (interquartile range) age was 78 (76-81) years; 639 (47.3%) were women. The median (interquartile range) follow-up time was 5.9 (3.7-6.5) years. Higher whole plasma apoE levels and higher apoE levels in HDL were associated with better cognitive function assessed by ADAS-cog (whole plasma, β coefficient, -0.15; 95% CI, -0.24 to -0.06; HDL, β coefficient, -0.20; 95% CI, -0.30 to -0.10) but were unassociated with dementia or Alzheimer disease risk. When separated by apoC3, a higher apoE level in HDL that lacks apoC3 was associated with better cognitive function (ADAS-cog per SD: β coefficient, 0.17; 95% CI, -0.27 to -0.07; Modified Mini-Mental State Examination score per SD: β coefficient, 0.25; 95% CI, 0.07 to 0.42) and lower risk of dementia (hazard ratio per SD, 0.86; 95% CI, 0.76 to 0.99). In contrast, apoE levels in HDL that contains apoC3 were unassociated with any of these outcomes. In a prospective cohort of older adults with rigorous follow-up of dementia, the apoE level in HDL that lacked apoC3 was associated with better cognitive function and lower dementia risk. This finding suggests that the cardioprotective associations of this novel lipoprotein extend to dementia. Show less

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic diseases in the world. Nowadays, the percentage of non-obese or lean patients with NAFLD is increasing. NAFLD in non-obese populations, especially the lean subgroup with a normal waist circumference (WC), might lead to more problems than obese individuals, as these individuals may not visit clinics for NAFLD diagnosis or ignore the diagnosis of NAFLD. If the precise characteristics of these populations, especially the lean subgroup, are identified, the clinicians would be able to provide more appropriate advice and treatment to these populations. To investigate the prevalence, clinical characteristics, risk factors, and possible indicators for NAFLD in lean Chinese adults with a normal WC. People without diabetes mellitus or significant alcohol consumption who underwent routine health examinations were included. Their fatty liver index (FLI), abdominal ultrasonography results, and controlled attenuation parameter were all assessed. Genotyping for single-nucleotide polymorphisms associated with NAFLD was performed in another small group consisting of biopsy-proven NAFLD subjects and healthy controls. A total of 2715 subjects who underwent routine health examinations were included in the study. Among 810 lean participants with a normal WC, 142 (17.5%) fulfilled the diagnostic criteria for NAFLD. Waist-height ratio, hemoglobin, platelets, and triglycerides were significant factors associated with the presence of NAFLD in these participants. The appropriate cut-off value of the FLI score in screening for NAFLD in the lean subjects with a normal WC was 25.15, which had a 77.8% sensitivity and 75.9% specificity. There was no significant difference in the single-nucleotide polymorphisms in the NAFLD is not uncommon in lean Chinese adults even with a normal WC. Metabolic factors, rather than genetic factors, may play important roles in the development of NAFLD in this population. A lower cut-off value of the FLI score in screening for NAFLD should be used for lean Chinese adults with a normal WC. Show less

Whether HDL is associated with dementia risk is unclear. In addition to apoA1, other apolipoproteins are found in HDL, creating subspecies of HDL that may have distinct metabolic properties. We measured apoA1, apoC3, and apoJ levels in plasma and apoA1 levels in HDL that contains or lacks apoE, apoJ, or apoC3 using a modified sandwich ELISA in a case-cohort study nested within the Ginkgo Evaluation of Memory Study. We included 995 randomly selected participants and 521 participants who developed dementia during a mean of 5.1 years of follow-up. The level of total apoA1 was not significantly related to dementia risk, regardless of the coexistence of apoC3, apoJ, or apoE. Higher levels of total plasma apoC3 were associated with better cognitive function at baseline (difference in Modified Mini-Mental State Examination scores tertile 3 vs. tertile 1: 0.60; 95% CI: 0.23, 0.98) and a lower dementia risk (adjusted hazard ratio tertile 3 vs. tertile 1: 0.73; 95% CI: 0.55, 0.96). Plasma concentrations of apoA1 in HDL and its apolipoprotein-defined subspecies were not associated with cognitive function at baseline or with the risk of dementia during follow-up. Similar studies in other populations are required to better understand the association between apoC3 and Alzheimer's disease pathology. Show less

As the important components in polycomb repressive complexes 1 (PRC1) and heterochromatin protein 1 (HP1), Chromobox (CBX) family members are involved in epigenetic regulatory function, transcriptional repression, and other cellular metabolisms. Increasing studies have indicated significant associations between CBX and tumorigenesis, which is a progression in different types of cancers. However, the information about the roles of each CBX in gastric cancer is extremely limited. We explored CBX mRNA expression, corrections with clinicopathological parameters, protein expression, prognostic values, enrichment analysis with several databases including Oncomine, Human Protein Atlas, UALCAN, Kaplan-Meier plotter, cBioPortal, GeneMANIA, and Enrichr. In our study, comparing to the normal tissues, higher mRNA expression of CBX1/2/3/4/5/8 and lower mRNA expression of CBX7 were found in GC tissues while upregulations of CBX1/2/3/4/5/8 and downregulations of CBX7 were indicated to be significantly correlated to the nodal metastasis status and individual cancer stages in GC patients. As for protein level, the expression of CBX2/3/4/5/6 was higher and the expression of CBX7 was lower in the GC tissues than those in the normal. What is more, higher mRNA expression of CBX1/5/6/8 and lower mRNA expression of CBX7 were markedly correlated to poor outcomes of OS and FP in GC patients. Besides, high mutation rate of CBXs (42%) was observed in GC patients. We suggest that CBX5/7 may serve as potential therapeutic targets for GC while CBX1/8 may serve as potential prognostic indicators for GC. Show less

Cholesteryl ester transfer protein (CETP) is an attractive therapeutic target for the prevention and treatment of cardiovascular diseases by lowering low-density lipoprotein cholesterol levels as well as raising high-density lipoprotein cholesterol levels in human plasma. Herein, a series of ursolic acid 3β-ester derivatives were designed, synthesized and evaluated for the CETP inhibiting activities. Among these compounds, the most active compound is U12 with an IC Show less

Juvenile neuronal ceroid lipofuscinosis (JNCL, aka. juvenile Batten disease or CLN3 disease) is a lysosomal storage disease characterized by progressive blindness, seizures, cognitive and motor failures, and premature death. JNCL is caused by mutations in the Ceroid Lipofuscinosis, Neuronal 3 (CLN3) gene, whose function is unclear. Although traditionally considered a neurodegenerative disease, CLN3 disease displays eye-specific effects: Vision loss not only is often one of the earliest symptoms of JNCL, but also has been reported in non-syndromic CLN3 disease. Here we described the roles of CLN3 protein in maintaining healthy retinal pigment epithelium (RPE) and normal vision. Using electroretinogram, fundoscopy and microscopy, we showed impaired visual function, retinal autofluorescent lesions, and RPE disintegration and metaplasia/hyperplasia in a Cln3 ~ 1 kb-deletion mouse model [1] on C57BL/6J background. Utilizing a combination of biochemical analyses, RNA-Seq, Seahorse XF bioenergetic analysis, and Stable Isotope Resolved Metabolomics (SIRM), we further demonstrated that loss of CLN3 increased autophagic flux, suppressed mTORC1 and Akt activities, enhanced AMPK activity, and up-regulated gene expression of the autophagy-lysosomal system in RPE-1 cells, suggesting autophagy induction. This CLN3 deficiency induced autophagy induction coincided with decreased mitochondrial oxygen consumption, glycolysis, the tricarboxylic acid (TCA) cycle, and ATP production. We also reported for the first time that loss of CLN3 led to glycogen accumulation despite of impaired glycogen synthesis. Our comprehensive analyses shed light on how loss of CLN3 affect autophagy and metabolism. This work suggests possible links among metabolic impairment, autophagy induction and lysosomal storage, as well as between RPE atrophy/degeneration and vision loss in JNCL. Show less

RNA G-quadruplexes (RG4s) appear to be important in post-transcriptional gene regulation, but their pathophysiological functions remain unknown. MicroRNA-26a (miR-26a) is emerging as a therapeutic target for various human diseases, however the mechanisms underlying endogenous miR-26a regulation are poorly understood. Herein, we study the role of RG4 in miR-26a expression and function in vitro and in vivo. Putative RG4s within liver-enriched miRNAs were predicted by bioinformatic analysis, and the presence of an RG4 structure in the miR-26a-1 precursor (pre-miR-26a-1) was further analyzed by biophysical and biochemical methods. RG4 stabilizers, pre-miR-26a-1 overexpression plasmids, and luciferase reporter assays were used to assess the effect of RG4 on pre-miR-26a-1 maturation. Both miR-26a knock-in and knockout mouse models were employed to investigate the influence of this RG4 on miR-26a expression and function. Moreover, the interaction between RG4 in pre-miR-26a-1 and DEAH-box helicase 36 (DHX36) was determined by biophysical and molecular methods. Finally, miR-26a processing and DHX36 expression were quantified in the livers of obese mice. We identify a guanine-rich sequence in pre-miR-26a-1 that can fold into an RG4 structure. This RG4 impairs pre-miR-26a-1 maturation, resulting in a decrease in miR-26a expression and subsequently an increase in miR-26a cognate targets. In line with known miR-26a functions, this RG4 can regulate hepatic insulin sensitivity and lipid metabolism in vitro and in vivo. Furthermore, we reveal that DHX36 can bind and unwind this RG4 structure, thereby enhancing miR-26a maturation. Intriguingly, there is a concordant decrease of miR-26a maturation and DHX36 expression in obese mouse livers. Our findings define a dynamic DHX36/RG4/miR-26a regulatory axis during obesity, highlighting an important role of RG4 in physiology and pathology. Specific RNA sequences called G-quadruplexes (or RG4) appear to be important in post-transcriptional gene regulation. Obesity leads to the formation of these RG4 structures in pre-miR-26a-1 molecules, impairing the maturation and function of miR-26a, which has emerged as a therapeutic target in several diseases. This contributes to hepatic insulin resistance and the dysregulation of liver metabolism. Show less

MicroRNAs (miRNAs) are involved in many biological activities including immune defense against pathogens. In this study, we applied high-throughput sequencing technology to examine miRNAs in Japanese flounder (Paralichthys olivaceus) infected with Streptococcus iniae at different times. A total of 1038 miRNAs were identified, of which, 249 were novel miRNAs, and 81 showed differential expression (named DEmiRNAs) after S. iniae infection. Of the 81 DEmiRNAs identified, 34 and 58 occurred at 6 h and 24 h post-infection, respectively; most DEmiRNAs were strongly time-specific, and only 13.6% of the DEmiRNAs were shared between the two time points. A total of 9582 target genes were predicted for the 81 DEmiRNAs. The putative target genes were enriched in various GO and KEGG pathways of biological processes and molecular/cellular functions, in particular endocytosis, regulation of transcription, lysososme, and the signaling pathways of MAPK, ErbB, and AMPK. One of the DEmiRNAs, pol-3p-10740₁₇₅, was found to target dual specificity phosphatase 6 (Dusp6) and repress the expression of the latter. Transfection of flounder FG cells with pol-3p-10740₁₇₅ caused a significant inhibition on S. iniae invasion. The results of this study provided the first S. iniae-induced miRNA profile in Japanese flounder and indicated that flounder miRNAs play an important role in antibacterial immunity. Show less

Hypercholesterolemia- and atherosclerosis-caused vasomotor property dysfunction may be involved in many clinic manifestations of atherosclerosis, including angina, acute myocardial infarction, and sudden cardiac death. However, its underlying mechanism is not clear. The endothelial glycocalyx is a protective surface layer on the endothelial cells, serving as a molecular sieve, cell adhesion modulator, and mechanosensor for blood flow. In the present study, we demonstrated by confocal microscopy in Sprague-Dawley (SD) male rats fed a 12-wk high-cholesterol diet (HC) compared with the normal diet (NC) that the dimension of the endothelial glycocalyx reduced significantly in both the common carotid artery (2.89 ± 0.41 µm and 3.25 ± 0.44 μm, respectively) and the internal sinus region (2.35 ± 0.07 µm and 3.46 ± 0.86 μm, respectively). Furthermore, we showed by real-time PCR that this dimension modification of endothelial glycocalyx may be attributed to a significant downregulation of heparan sulfate proteoglycan (HSPG)-related genes, including syndecan-3, glypican-1, and EXT1, not resulting from an enhanced shedding of sulfated glycosaminoglycans (sGAGs) from the vessel wall to the plasma. Meanwhile, the mean contraction and relaxation forces of the common carotid artery with responses to norepinephrine (NE) and acetylcholine (ACh) decreased ~0.34- and 0.13-fold, respectively, accompanied by a lower level of nitric oxide (NO) release. These findings suggest that the atherogenic high cholesterol diet diminished endothelial glycocalyx and disturbed the local NO release, thus contributing to the impaired vasomotor properties of the vessel. Show less

Skeletal fluorosis causes growth plate impairment and growth retardation during bone development. Longitudinal bone development is accomplished by endochondral ossification in growth plate. However, the mechanism of fluoride impairs growth plate is unclear. To explore the effect of fluoride on various glycosaminoglycans (GAGs) and related signaling pathways in growth plate during endochondral ossification, SD rats and ATDC5 cells were treated with fluoride and carried out a series of experiments. We found that the expression of heparan sulfate (HS), a kind of GAGs in extracellular matrix, was significantly increased in the growth plate of fluoride-treated rats compared with control rats. Furthermore, the expression of HS synthetic enzyme exostosin 1 (EXT1) and glypican 6 (GPC6), a core protein of HS proteoglycan (HSPG), were significantly increased in fluoride-treated ATDC5 cells compared with control cells (P < 0.05). The expression of related molecules including fibroblast growth factor receptor-3 (FGFR3), signal transducer and activator of transcription 1 (STAT1) and parathyroid hormone-related protein (PTHrP) were significantly increased in the fluoride-treated groups compared with control groups (P < 0.05), and there was significantly decreased in the expression of Indian hedgehog (Ihh) in fluoride-treated groups compared with control groups (P < 0.05). Our data suggested that fluoride increased the content of HSPG in extracellular matrix by promoting the expression of EXT1 and GPC6. Fluoride also activated FGFR3 signaling pathway, inhibited Ihh/PTHrP feedback loop and inhibited endochondral ossification. Nevertheless, the regulation of fluoride on HSPG and related pathways FGFR3 and Ihh/PTHrP feedback loop during endochondral ossification needs to be further studied. Show less

Aim of this study was to identify biomarkers between different grades of bladder cancer (BLCA) and its prognostic value. mRNA expression data from GSE32549 and GSE71576 were extracted for further analysis. Differentially expressed genes (DEGs) were identified using GEO2R web tool. Gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and protein-protein interaction (PPI) network were conducted to explore the function and relationship of DEGs. The Cancer Genome Atlas (TCGA) database was used for external validation and Gene set enrichment analysis (GSEA) analysis was used to further identify FADS1 pathways. Bladder cancer cells and patient specimens were used to further demonstrate the function of FADS1. Datasets from GEO identified a panel of DEGs. Functional enrichment analysis highlighted that DEGs were associated with nuclear division, spindle, cell cycle and p53 signaling pathway. External validation from TCGA demonstrated that FADS1 was an independent prognostic marker in BLCA patients. In cell lines and tumor specimen analysis, FADS1 was overexpressed in the tumor specimen, compared with adjacent tissues, and positively correlated with tumor grade of BLCA. Moreover, FADS1 could enhance the proliferation ability and influence cell cycle of bladder cancer cells. FADS1 was an independent prognostic biomarker for BLCA and could confer the bladder cancer cells increased proliferation ability. Show less

Metabolic abnormality is the major feature of laryngeal squamous cell carcinoma (LSCC), however, the underlying mechanism remain largely elusive. Fatty acid desaturase 1 (FADS1), as the key rate-limiting enzyme of polyunsaturated fatty acids (PUFAs), catalyzes dihomo-gamma-linolenic acid (DGLA) to arachidonic acid (AA). In this study, we reported that the expression of FADS1 was upregulated in LSCC, high FADS1 expression was closely associated with the advanced clinical features and poor prognosis of the recurrent LSCC patients after chemotherapy. Liquid chromatograph-mass spectrometry (LC-MS) analysis revealed that FADS1 overexpression induced greater conversion of DGLA to AA, suggesting an increased activity of FADS1. Similarly, the level of prostaglandin E2 (PGE Show less

Lung adenocarcinoma (LUAD) is the most common and lethal cancer worldwide. Radiotherapy (RT) is widely used at all stages of LUAD, and the development of immunotherapy substantially enhances the survival of LUAD patients. Although the emerging treatments for LUAD have improved prognosis, only a small fraction of patients can benefit from clinical therapies. Thereby, approaches assessing responses to RT and immunotherapy in LUAD patients are essential. After integrating the analysis of RT, immunization, mRNA, and clinical information, we constructed a signature based on 308 tumor-infiltrating B lymphocyte-specific genes (TILBSig) using a machine learning method. TILBSig was composed of 6 B cell-specific genes (PARP15, BIRC3, RUBCNL, SP110, TLE1, and FADS3), which were highly associated with the overall survival as independent factors. TILBSig was able to differentiate better survival compared with worse survival among different patients, and served as an independent factor for clinical characteristics. The low-risk TILBSig group was correlated with more immune cell infiltration (especially B lineages) and lower cancer stem cell characteristics than the high-risk group. The patients with lower risk scores were more likely to respond to RT and immunotherapy. TILBSig served as an excellent predicator for prognosis and response to immunotherapy and RT in LUAD patients. 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

Teleost zebrafish and neonatal mammalian hearts exhibit the remarkable capacity to regenerate through dedifferentiation and proliferation of pre-existing cardiomyocytes (CMs). Although many mitogenic signals that stimulate zebrafish heart regeneration have been identified, transcriptional programs that restrain injury-induced CM renewal are incompletely understood. Here, we report that mutations in Show less

Aging-related cognitive ability impairments are one of the main threats to public health, and impaired hippocampal neurogenesis is a major cause of cognitive decline during aging. However, the regulation of adult neurogenesis in the hippocampus requires further study. Here, we investigated the role of microRNA-153 (miR-153), a highly conserved microRNA in mice and humans, in adult neurogenesis. During the passaging of neural stem cells (NSCs) in vitro, endogenous miR-153 expression was downregulated, with a decrease in neuronal differentiation ability. In addition, miR-153 overexpression increased the neurogenesis of NSCs. Further studies showed that miR-153 regulated neurogenesis by precisely targeting the Notch signaling pathway through inhibition of Jagged1 and Hey2 translation. In vivo analysis demonstrated that miR-153 expression was decreased in the hippocampi of aged mice with impaired cognitive ability, and that miR-153 overexpression in the hippocampus promoted neurogenesis and markedly increased the cognitive abilities of the aged mice. Overall, our findings revealed that miR-153 affected neurogenesis by regulating the Notch signaling pathway and elucidated the function of miR-153 in aging-related, hippocampus-dependent cognitive ability impairments, and neurodegenerative diseases. Show less

Interleukin 17D (IL‑17D) plays an important role in host defense against inflammation and infection. In the present study, the role of nuclear factor erythroid 2‑related factor 2 (Nrf2) in regulating the production of IL‑17D was investigated under hyperoxia. For this purpose, neonatal rats were randomized into two groups; the model group was exposed to hyperoxia (80‑85% O2), while the control group was maintained under normoxic conditions (21% O2). Small intestine tissue was collected on postnatal days 3, 7, 10 and 14. IL‑17D expression was detected by immunofluorescence, immunohistochemistry and western blotting. The levels of Nrf2 and kelch‑like ECH‑associated protein 1 (keap1) were detected by immunohistochemistry and western blotting. Results showed that IL‑17D expression in intestine epithelial cells increased steadily, reaching a peak on day 7, and decreased gradually on days 10 and 14 under hyperoxia. Nrf2 expression was consistent with IL‑17D, and it was positively correlated with IL‑17D. However, on postnatal days 10 and 14, the number of CD4+ T cells and CD19+ B cells expressing IL‑17D was increased, and positive cells of the model group were significantly more than that of the control group. Keap1 levels were lower at the early stage. In conclusion, the expression levels of intestinal IL‑17D and Nrf2 were altered simultaneously following neonatal rat development in hyperoxia, indicating that Nrf2 may be involved in regulating the expression of IL‑17D in intestinal epithelial cells. Moreover, IL‑17D in intestinal epithelial cells may play a unique immunological role during hyperoxia. Show less

Type 2 cytokine‑associated immunity may be involved in the pathogenesis of allergic asthma. Although interleukin 27 (IL‑27) has been reported as an initiator and suppressor of T‑helper 1 (Th1) and T‑helper 2 (Th2) responses, respectively, its effects on the development of asthma remain unclear. In the present study, mice were induced and challenged with ovalbumin and received subsequent intranasal administration of IL‑27. Total and differential cell counts were determined from Wright‑Giemsa‑stained cytospins, whereas the cytokine levels were detected using ELISA. In addition, the expression levels of signal transducer and activator of transcription (STAT) 1, STAT3, GATA‑binding protein‑3 (GATA3) and T‑bet (T‑box transcription factor) were analyzed in T cells by western blot analysis. Their corresponding mRNA expression levels were determined by quantitative PCR. Airway remodeling was assessed by conventional pathological techniques. The results indicated that intranasal administration of IL‑27 ameliorated airway inflammation and hyperresponsiveness in an acute model of asthma. Furthermore, IL‑27 prevented airway remodeling in a chronic model of asthma. Following administration of IL‑27, the mRNA expression levels of STAT1 and T‑bet were upregulated, while those of GATA3 were downregulated. Moreover, the phosphorylation levels of STAT1 and STAT3 were increased. Taken together, these findings demonstrated that intranasal administration of IL‑27 ameliorated Th2‑related allergic lung inflammation and remodeling in mouse models of asthma by repairing both the STAT1 and STAT3 pathways. Show less

Density of tumor infiltrating lymphocytes (TIL) and expressions of certain immune-related genes have prognostic and predictive values in hepatocellular carcinoma (HCC); however, factors determining the immunophenotype of HCC patients are still unclear. In the current study, the transcript sequencing data of liver cancer were systematically analyzed to determine an immune gene marker for the prediction of clinical outcome of HCC. RNASeq data and clinical follow-up information were downloaded from The Cancer Genome Atlas (TCGA), and the samples were assigned into high-stage and low-stage groups. Immune pathway-related genes were screened from the Molecular Signatures Database v4.0 (MsigDB) database. LASSO regression analysis was performed to identify robust immune-related biomarkers in predicting HCC clinical outcomes. Moreover, an immune gene-related prognostic model was established and validated by test sets and Gene Expression Omnibus (GEO) external validation sets. We obtained 319 immune genes from MsigDB, and the genes have different expression profiles in high-stage and low-stage of HCC. Univariate survival analysis found that 17 genes had a significant effect on HCC prognosis, among them, 13 (76.5%) genes were prognostically protective factors. Further lasso regression analysis identified seven potential prognostic markers (IL27, CD1D, NCOA6, CTSE, FCGRT, CFHR1, and APOA2) of robustness, most of which are related to tumor development. Cox regression analysis was further performed to establish a seven immune gene signature, which could stratify the risk of samples in training set, test set and external verification set ( This study constructed a 7-immunogenic marker as novel prognostic markers for predicting survival of HCC patients. Show less

The interleukin-17 (IL-17) family is a relatively new family of cytokines consisting of 6 related factors (IL-17A-IL-17F), while the receptor family consists of 5 members: IL-17RA-IL-17RE. IL-17A is the prototype member of this family, which is also the signature cytokine of T helper 17 (Th17) cells. Th17 cells are involved in the development of autoimmune disease, inflammation, and tumors. Although IL-17D is similar to IL-17A in its ability to induce inflammatory cytokine production, there are fewer studies on IL-17D. Recently, the role of IL-17D in tumors and infections has attracted our attention. Some knowledge of function of IL-17D has been gained by studies using nonmammalian species. In this review, we introduce the structural characteristics, expression patterns, and biological characteristics of IL-17D along with its potential function in the pathogenesis of disease. Show less

Asthma-COPD overlap (ACO; previously referred to as asthma-COPD overlap syndrome) is characterized by persistent airflow limitation consistent with COPD, together with several distinguishing features of asthma. Asthma-COPD overlap syndrome is a condition of mixing symptoms of asthma and COPD, because of its complexity, it is difficult to find effective diagnostic markers in clinic. Our aims were to detect the expression of serum cytokines in patients with asthma, explore the diagnostic potential of differential serum cytokines in ACOS. Ninety asthmatic patients were divided into ACOS group and non-ACOS group according to the major and minor criteria of ACOS, 15 kinds of cytokines including IL-3, IL-4, IL-8, IL-9, IL-13, IL-17A, VEGFA, VEGFC, VEGFD, bFGF, Fit-1 PIGF, Tie-2 were detected by MSD, and IL-27 and TGF-beta were determined by ELISA assay. The serum levels of IL-9, VEGFA and PIGF in patients with ACOS were significantly higher than those in non-ACOS group ( The results suggested that IL-8 was highly sensitive and VEGFA was highly specificity, both of which could be used as biomarkers for the diagnosis of ACOS. Show less

Fuzhong buffalo, a native breed of Guangxi Zhuang Autonomous Region, is traditionally used as a draft animal to provide farm power in the rice cultivation. In addition, the Fuzhong buffalo also prepared for the bullfighting festival organized by the locals. The detection of the selective signatures in its genome can help in elucidating the selection mechanisms in its stamina and muscle development of a draft animal. In this study, we analyzed 27 whole genomes of buffalo (including 15 Fuzhong buffalo genomes and 12 published buffalo genomes from Upper Yangtze region). The ZHp, ZFst, π-Ratio, and XP-EHH statistics were used to identify the candidate signatures of positive selection in Fuzhong buffalo. Our results detected a set of candidate genes involving in the pathways and GO terms associated with the response to exercise (e.g., ALDOA, STAT3, AKT2, EIF4E2, CACNA2D2, TCF4, CDH2), immunity (e.g., PTPN22, NKX2-3, PIK3R1, ITK, TMEM173), nervous system (e.g., PTPN21, ROBO1, HOMER1, MAGI2, SLC1A3, NRG3, SNAP47, CTNNA2, ADGRL3). In addition, we also identified several genes related to production and growth traits (e.g., PHLPP1, PRKN, MACF1, UCN3, RALGAPA1, PHKB, PKD1L). Our results depicted several pathways, GO terms, and candidate genes to be associated with response to exercise, immunity, nervous system, and growth traits. The selective sweep analysis of the Fuzhong buffalo demonstrated positive selection pressure on potential target genes involved in behavior, immunity, and growth traits, etc. Our findings provided a valuable resource for future research on buffalo breeding and an insight into the mechanisms of artificial selection. Show less

The phenotype via conventional cardiac MRI analysis of MYH7 (β-myosin heavy chain)- and MYBPC3 (β-myosin-binding protein C)-associated hypertrophic cardiomyopathy (HCM) groups is similar. Few studies exist on the genotypic-phenotypic association as assessed by machine learning in HCM patients. To explore the phenotypic differences based on radiomics analysis of T Prospective observational study. In all, 102 HCM patients with pathogenic, or likely pathogenic mutation, in MYH7 (n = 68) or MYBPC3 (n = 34) genes. Cardiac MRI was performed at 3.0T with balanced steady-state free precession (bSSFP), phase-sensitive inversion recovery (PSIR) late gadolinium enhancement (LGE), and modified Look-Locker inversion recovery (MOLLI) T All patients underwent next-generation sequencing and Sanger genetic sequencing. Left ventricular native T Mann-Whitney U-tests and Student's t-tests were performed to assess differences between subgroups. A receiver operating characteristic (ROC) curve was used to assess the model's ability to stratify patients based on radiomic features. There were no significant differences between MYH7- and MYBPC3-associated HCM subgroups based on traditional native T Radiomic analysis of native T 3 TECHNICAL EFFICACY STAGE: 2 J. MAGN. RESON. IMAGING 2020;52:1714-1721. Show less