👤 Wenlu Jia

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant heart disease. An induced pluripotent stem cell line (EHTJUi003-A) was generated from umbilical cord blood mononuclear cells (UCBMCs) of a female neonate with heterozygous mutation of p.L460Wfs (c.1377delC) in the MYBPC3 gene. This iPSC model offers a very valuable resource to study the pathological mechanism of HCM in vitro. Show less

Dingxin Recipe (DXR) is a traditional Chinese medicine formula that has been reported to be effective and safe treatment for cardiovascular diseases, such as arrhythmias, coronary heart disease. Dingxin Recipe IV (DXR IV) was further improved from the DXR according to the traditional use. However, the mechanism of DXR IV in atherosclerosis is unclear. This study aimed to illustrate whether DXR IV improve atherosclerosis through modulating the lipid metabolism and gut microbiota in atherosclerosis mice. 40 male ApoE DXR IV exerted the anti-atherosclerosis effect by inhibiting the excessive cholesterol deposition in aorta and regulating the level of TG, TC, LDL-C and HDL-C. The composition of gut microbiota was changed. Interestingly, the relative abundance of Muribaculaceae and Ruminococcaceae increased after DXR IV administration, whereas the abundance of Erysipelotrichaceae decreased, which have been beneficial to lipid metabolism. Nine potential metabolic biomarkers, including acetate, butyrate, propionate, alanine, succinate, valerate, xylose, choline, glutamate, were identified, which were related to fatty acid metabolism. Further, the pathway of fatty acid was detected by the RT-qPCR and western blotting. Compared with model group, the level of LXR-α and SREBP1 decreased significantly in DXR IV group while LXR-β, SREBP2 showed no statistical significance. It indicated that DXR IV modulated lipid metabolism by LXR-α/SREBP1 but not LXRβ and SREBP2. DXR IV exhibits potential anti-atherosclerosis effect, which is closely related to lipid metabolism and the gut microbiota. This study may provide novel insights into the mechanism of DXR IV on atherosclerosis and a basis for promising clinical usage. 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

MicroRNAs (miRNAs) show considerable promise as therapeutic agents to improve tumor treatment, as they have been revealed as crucial modulators in tumor progression. However, our understanding of their roles in gastric carcinoma (GC) metastasis is limited. Here, we aimed to identify novel miRNAs involved in GC metastasis and explored their regulatory mechanisms and therapeutic significance in GC. The microRNA expression profiles of GC tumors at different stages and at different metastasis statuses were compared respectively using the stomach adenocarcinoma (STAD) miRNASeq dataset in TCGA. Using the above method, miR-4521 was picked out for further study. miR-4521 expression in GC tissues was examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH). Highly and lowly invasive cell sublines were established using a repetitive transwell assay. Gain-of-function and loss-of-function analyses were performed to investigate the functions of miR-4521 and its upstream and downstream regulatory mechanisms in vitro and in vivo. Moreover, we investigated the therapeutic role of miR-4521 in a mouse xenograft model. In this study, we found that miR-4521 expression was downregulated in GC tissues compared with adjacent normal tissues and that its downregulation was positively correlated with advanced clinical stage, metastasis status and poor patient prognosis. Functional experiments revealed that miR-4521 inhibited GC cell invasion and metastasis in vitro and in vivo. Further studies showed that hypoxia repressed miR-4521 expression via inducing ETS1 and miR-4521 mitigated hypoxia-mediated metastasis, while miR-4521 inactivated the AKT/GSK3β/Snai1 pathway by targeting IGF2 and FOXM1, thereby inhibiting the epithelial-mesenchymal transition (EMT) process and metastasis. In addition, we demonstrated that therapeutic delivery of synthetic miR-4521 suppressed gastric carcinoma progression in vivo. Our results suggest an important role for miR-4521 in regulating GC metastasis and hypoxic response of tumor cells as well as the therapeutic significance of this miRNA in GC. Show less

Testicular germ cell tumours (TGCTs) are the most common cancer in young male adults (aged 15 to 40). Unlike most other cancer types, identification of molecular signatures in TGCT has rarely reported. In this study, we developed a novel integrative analysis framework to identify co-methylated and co-expressed genes [mRNAs and microRNAs (miRNAs)] modules in two TGCT subtypes: non-seminoma (NSE) and seminoma (SE). We first integrated DNA methylation and mRNA/miRNA expression data and then used a statistical method, CoMEx ( Show less

The growth of antler is driven by endochondral ossification in the growth center of the apical region. Antler grows faster than cancer tissues, but it can be stably regulated and regenerated periodically. To elucidate the molecular mechanisms of how antler grows rapidly without carcinogenesis, in this study, we used RNA-seq technology to evaluate the changes of miRNA and mRNA profiles in antler at four different developmental stages, including 15, 60, 90, and 110 days. We identified a total of 55004 unigenes and 246 miRNAs of which, 10182, 13258, 10740 differentially expressed (DE) unigenes and 35, 53, 27 DE miRNAs were identified in 60-day vs. 15-day, 90-day vs. 60-day, and 110-day vs. 90-day. GO and KEGG pathway analysis indicated that DE unigenes and DE miRNA were mainly associated with chondrogenesis, osteogenesis and inhibition of oncogenesis, that were closely related to antler growth. The interaction networks of mRNA-mRNA and miRNA-mRNA related to chondrogenesis, osteogenesis and inhibition of oncogenesis of antler were constructed. The results indicated that mRNAs (COL2A1, SOX9, WWP2, FGFR1, SPARC, LOX, etc.) and miRNAs (miR-145, miR-199a-3p, miR-140, miR-199a-5p, etc.) might have key roles in chondrogenesis and osteogenesis of antler. As well as mRNA (TP53, Tpm3 and ATP1A1, etc.) and miRNA (miR-106a, miR-145, miR-1260b and miR-2898, etc.) might play important roles in inhibiting the carcinogenesis of antler. In summary, we constructed the mRNA-mRNA and miRNA-mRNA regulatory networks related to chondrogenesis, osteogenesis and inhibition of oncogenesis of antler, and identified key candidate mRNAs and miRNAs among them. Further developments and validations may provide a reference for in-depth analysis of the molecular mechanism of antler growth without carcinogenesis. Show less

Genetic risk score (GRS) is more informative to identify the complicated associations between variants of genes and disease. Considering similar pathogenesis and shared genetic predispositions between gestational diabetes mellitus (GDM) and type 2 diabetes/obesity, we conducted this study to explore whether the GRS model integrating variants related to type 2 diabetes/obesity is also associated with GDM risk. A population-based case-control study that included 1429 subjects was conducted to investigate the association between the GRS model and GDM risk, which were analyzed employing stratified logistic regression analysis with the adjustment for age, BMI, parity and family history of diabetes. We have screened 23 SNPs and further filtered six SNPs that were significantly associated with the risk of GDM: four risk SNPs (MTNR1B: rs10830963, rs1387153, rs2166706; MC4R: rs2229616) and two protective SNPs (MTNR1B: rs1447352 and rs4753426). The GRS model with a higher score indicated a higher genetic predisposition to develop GDM, especially in the highest quartile of GRS (all P < 0.001) and the strata of advanced maternal age (all P < 0.001) and obesity (all P = 0.005). In this study, six SNPs were explored and further identified to be associated with GDM risk, which suggested GRSs including these polymorphisms might participate in facilitating GDM risk. These findings offer the potential to improve our understanding of the etiology of GDM. Show less

Increasing evidence shows that Angptl4 affects proteinuria in podocytes injured kidney disease, however, whether there is a relationship between Angptl4 and IgA nephropathy (IgAN) has not been studied yet. Plasma and urine samples were obtained from 71 patients with IgAN and 61 healthy controls. Glomeruli from six renal biopsy specimens (three IgAN patients and three healthy controls) were separated by RNA-Seq. Differentially expressed genes (DEGs) related to podocytes and Angptl4 between IgAN patients and healthy controls were performed using the Limma package. Gene set enrichment analysis was used to determine whether there was a statistically significant difference between the two groups. STRING was used to create a protein-protein interaction network of DEGs. Association analysis between Angptl4 levels and clinical features of IgAN was performed. Thirty-three podocyte-related and twenty-three Angpt4-related DEGs were found between IgAN patients and healthy controls. By overlapping the genes, Our findings show that Angptl4 levels in plasma and urine are related to podocyte damage and, therefore, may be a promising tool for assessing the severity of IgAN patients to identify and reverse the progression to ESRD. Show less

Angiopoietin-like 4 (ANGPLT4) regulates lipid metabolism by inhibiting lipoprotein lipase. Abnormal ANGTPL4 levels are associated with metabolic syndrome, atherosclerosis, inflammation, and cancer. We show here that ANGPTL4-deficient mice have abnormally large numbers of macrophages in the spleen, and that these macrophages produce large amounts of TNF-α, CD86, and inducible nitric oxide synthase. However, recombinant ANGPTL4 protein did not inhibit macrophage function Show less

Dietary protein deficiency and amino acid imbalance cause hepatic fat accumulation. We previously demonstrated that only arginine deficiency or total amino acid deficiency in a diet caused significant hepatic triglyceride (TG) accumulation in young Wistar rats. In this study, we explored the mechanisms of fatty liver formation in these models. We fed 6-week-old male Wistar rats a control diet (containing an amino acid mixture equivalent to 15% protein), a low-total-amino acid diet (equivalent to 5% protein; 5PAA), and a low-arginine diet (only the arginine content is as low as that of the 5PAA diet) for 2 weeks. Much greater hepatic TG accumulation was observed in the low-arginine group than in the low-total-amino acid group. The lipid consumption rate and fatty acid uptake in the liver did not significantly differ between the groups. In contrast, the low-total-amino acid diet potentiated insulin sensitivity and related signaling in the liver and enhanced de novo lipogenesis. The low-arginine diet also inhibited hepatic very-low-density lipoprotein secretion without affecting hepatic insulin signaling and lipogenesis. Although the arginine content of the low-arginine diet was as low as that of the low-total-amino acid diet, the two diets caused fatty liver via completely different mechanisms. Enhanced lipogenesis was the primary cause of a low-protein diet-induced fatty liver, whereas lower very-low-density lipoprotein secretion caused low-arginine diet-induced fatty liver. Show less

Gastric cancer is the third leading cause of cancer-related deaths worldwide. The present study aims to identify key long non-coding RNAs (lncRNAs) and their potential roles in the pathogenesis of gastric adenocarcinoma. The lncRNA and mRNA expression profile between gastric adenocarcinoma and adjacent non-tumor tissues were obtained from The Cancer Genome Atlas (TCGA). Differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) between gastric adenocarcinoma and adjacent non-tumor tissues were identified after bioinformatics analysis. DElncRNA-DEmRNA co-expression network and DElncRNA-nearby DEmRNA interaction network were constructed, respectively. Functional annotation for DEmRNAs interacted with DElncRNAs was performed. Receiver operating characteristic (ROC) analysis of selected DElncRNAs was conducted. Based on TCGA, the mRNA and lncRNA expression profiles of 375 gastric adenocarcinoma and 32 adjacent non-tumor tissues were downloaded. A total of 1502 DEmRNAs and 928 DElncRNAs between gastric adenocarcinoma and adjacent non-tumor tissues were identified. HOXC-AS3 might involve with gastric adenocarcinoma by regulating a set of HOX genes (HOXC8, HOXC9, HOXC10, HOXC11, HOXC12 and HOXC13) with cis-effect. AC115619.1-APOA4/APOB and AP006216.2-APOA1/APOA4 integrations might play roles in gastric adenocarcinoma through regulating pathways of Fat digestion and absorption and Vitamin digestion and absorption. Six lncRNAs including (HOTAIR, C20orf166-AS1, PGM5-AS1, HOXC-AS3, HOXC-AS2 and AC012531.1) have excellent diagnostic value for gastric adenocarcinoma. This study identifies key lncRNAs in gastric adenocarcinoma which provides clues for exploring the pathogenesis and developing potential biomarkers for gastric adenocarcinoma. Show less

Thyroid hormone is crucial for regulating lipid and glucose metabolism, which plays essential role in maintaining the health of pregnant women and their offspring. However, the current literature is just focusing on the development of offspring born to the untreated mothers with hypothyroidism, rather than mothers themselves. Additionally, the interaction between hypothyroidism and pregnancy, and its impact on the women's health are still elusive. Therefore, this study was designed to compare the metabolic differences in dams with hypothyroidism starting before pregnancy and after pregnancy. Pre-pregnant hypothyroidism was generated in 5-week-old female C57/BL/6J mice using iodine-deficient diet containing 0.15% propylthiouracil for 4 weeks, and the hypothyroidism was maintained until delivery. Gestational hypothyroidism was induced in dams after mating, using the same diet intervention until delivery. Compared with normal control, gestational hypothyroidism exhibited more prominent increase than pre-pregnant hypothyroidism in plasma total cholesterol and low-density lipoprotein cholesterol, and caused hepatic triglycerides accumulation. Similarly, more significant elevations of protein expressions of SREBP1c and p-ACL, while more dramatic inhibition of CPT1A and LDL-R levels were also observed in murine livers with gestational hypothyroidism than those with pre-pregnant hypothyroidism. Moreover, the murine hepatic levels of total cholesterol and gluconeogenesis were dramatically and equally enhanced in two hypothyroid groups, while plasma triglycerides and protein expressions of p-AKT, p-FoxO1 and APOC3 were reduced substantially in two hypothyroid groups. Taken together, our current study illuminated that gestational hypothyroidism may elicit more pronounced lipid dysregulation in dams than dose the pre-pregnant hypothyroidism. Show less

Hepatocellular carcinoma (HCC) is one of the most prevalent human malignancies worldwide and has high morbidity and mortality. Elucidating the molecular mechanisms underlying HCC recurrence and metastasis is critical to identify new therapeutic targets. This study aimed to determine the roles of aminopeptidase N (APN, also known as CD13) in HCC proliferation and metastasis and its underlying mechanisms. We detected APN expression in clinical samples and HCC cell lines using immunohistochemistry, flow cytometry, real-time PCR, and enzyme activity assays. The effects of APN on HCC metastasis and proliferation were verified in both in vitro and in vivo models. RNA-seq, phosphoproteomic, western blot, point mutation, co-immunoprecipitation, and proximity ligation assays were performed to reveal the potential mechanisms. We found that APN was frequently upregulated in HCC tumor tissues and high-metastatic cell lines. Knockout of APN inhibited HCC cell metastasis and proliferation in vitro and in vivo. Functional studies suggested that a loss of APN impedes the ERK signaling pathway in HCC cells. Mechanistically, we found that APN might mediate the phosphorylation at serine 31 of BCKDK (BCKDK Show less

Cip1, a newly identified yeast analog of p21, is a Cln3-CDK inhibitor that negatively regulates cell-cycle START. However, its function remains poorly understood. In this study, we found that deletion of Show less

Macrophages differentiated into a classically activated (M1) or alternatively activated phenotype (M2) in infection and tumor, but the precise effects of glycolysis and oxidative phosphorylation (OXPHOS) metabolic pathway remain unclear. Herein, the effects of glycolysis or OXPHOS on macrophage polarizations were investigated using a pharmacological approach in mice. 2-Deoxy-D-glucose (2-DG) treatments, which blocks the key enzyme hexokinase of glycolysis, efficiently inhibits a specific switch to M1 lineage, decreasing the secretion of pro-inflammatory cytokines and expressions of co-stimulatory molecules associated with relieving infectious inflammation 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

Dietary L-proline (proline) supplementation during gestation enhances fetal survival and placental development in mice. The objective of the present study was to test the hypothesis that this beneficial effect of proline was associated with alterations in inflammatory response at the placenta and fetus interface. Populations of immune cells present in peripheral blood mononuclear cells (PBMC) were determined by flow cytometry analysis. The concentrations of immunoglobulins in plasma, and the concentrations of cytokines in plasma, uterus, placenta, and amniotic fluid were measured using a bead-based immunoassay. The data showed that proline supplementation led to higher (P < 0.05) populations of B lymphocytes (CD3 Show less

Rheumatoid arthritis and juvenile idiopathic arthritis are two types of autoimmune diseases with inflammation at the joints, occurring to adults and children respectively. There are phenotypic overlaps between these two types of diseases, despite the age difference in patient groups. To systematically compare the genetic architecture of them, we conducted analyses at gene and pathway levels and constructed protein-protein-interaction network based on summary statistics of genome-wide association studies of these two diseases. We examined their difference and similarity at each level. We observed extensive overlap in significant SNPs and genes at the human leukocyte antigen region. In addition, several SNPs in other regions of the human genome were also significantly associated with both diseases. We found significantly associated genes enriched in 32 pathways shared by both diseases. Excluding genes in the human leukocyte antigen region, significant enrichment is present for pathways like interleukin-27 pathway and NO2-dependent interleukin-12 pathway in natural killer cells. The identification of commonly associated genes and pathways may help in finding population at risk for both diseases, as well as shed light on repositioning and designing drugs for both diseases. Show less

Bicuspid aortic valve (BAV) is a common congenital heart defect (0.5-2.0% in the adult), potentially an onset factor of aortic stenosis (AS). Increasing evidence demonstrates that genetic risk factors play a key role in the pathogenesis of BAV, but the genetic basis underlying this cardiac malformation remains poorly understood. Whole exome sequencing (WES) was utilized to uncover genetic variants associated with BAV. Pathogenicity score and mode of inheritance through bioinformatics tools were undertook to identify the possible disease-causing mutation. A heterozygous Ala58Val mutation in Myosin binding protein C (Mybpc3) was identified out of 2,840 variants in an 11-year-old female patient. The proband and her father were confirmed to be heterozygous carriers of 173 C>T hybridization, and her mother was homozygous negative of the mutation as confirmed through Sanger sequencing. Expression of mRNA in the proband and her father, who also carries the mutation, were almost half of proband's mother. Indicating Mybpc3 (p.Ala58Val) mutation affected its expression, and may play crucial roles for heritable BAV. To our knowledge, this is the first time to report Mybpc3 heterozygous variant associated with heritable BAV. The relationship between the location of Mybpc3 mutation and BAV may provide a novel perspective of understanding this disorder. Show less

Diabetes is a recognized high-risk factor for the development of atherosclerosis, in which macroautophagy/autophagy is emerging to play essential roles. The retention of low-density lipoprotein (LDL) particles in subendothelial space following transcytosis across the endothelium is the initial step of atherosclerosis. Here, we identified that high glucose could promote atherosclerosis by stimulating transcytosis of LDL. By inhibiting AMPK-MTOR-PIK3C3 pathway, high glucose suppresses the CAV-CAVIN-LC3B-mediated autophagic degradation of CAV1; therefore, more CAV1 is accumulated in the cytosol and utilized to form more caveolae in the cell membrane and facilitates the LDL transcytosis across endothelial cells. For a proof of concept, higher levels of lipids were accumulated in the subendothelial space of umbilical venous walls from pregnant women with gestational diabetes mellitus (GDM), compared to those of pregnant women without GDM. Our results reveal that high glucose stimulates LDL transcytosis by a novel CAV1-CAVIN1-LC3B signaling-mediated autophagic degradation pathway. 3-MA: 3-methyladenine; ACTB: actin beta; AMPK: AMP-activated protein kinase; Bafi: bafilomycin A Show less

Snail is a master inducer of epithelial-mesenchymal transition (EMT) and metastasis, however, Snail protein is labile and is quickly degraded through the predominate ubiquitination-mediated proteasome pathway. Deubiquitinases (DUBs) can counteract the Snail degradation process to maintain high level of Snail protein in cancer cells. In this study, we screened a cDNA library containing 79 DUBs, and discovered that a panel of DUBs consisting of USP13, USP28, USP29, USP37, OTUD6A, and DUB3 can markedly stabilize Snail protein, with USP29 displaying the strongest activity to prevent Snail degradation. Mechanistically, USP29 enhances the interaction of Snail and SCP1, resulting in simultaneous dephosphorylation and deubiquitination of Snail and thereafter cooperative prevention of Snail degradation. Biologically, ectopic expression of USP29 promotes gastric cancer cell migration, and depletion of Snail abolishes USP29-mediated cell migration; and USP29 can be induced by major EMT and metastatic inducing factors such as TGFβ, TNFα, and hypoxia. More importantly, high expression levels of Snail, USP29, and SCP1 are associated with poor survival and prognosis. Collectively, these data indicate that Snail is a crucial substrate for USP29 to promote cell migration and USP29/SCP1 complex may be new therapeutic targets to treat metastatic cancer. Show less

Tyrosine-protein kinase Fyn (FYN) plays a crucial role in Src family, which participates in the signal transduction of brain nerves and the development and activation of T lymphocytes in physiological conditions. We probed into the roles and mechanisms of FYN in lung adenocarcinoma (LUAD). Cell activity, apoptosis, invasion, and migration were detected by CCK-8, FCM, transwell, and wound-healing assays, respectively. The angiogenesis capacity was evaluated by in vitro angiogenesis test. Relative mRNA and protein expressions were determined by qRT-PCR, Western blot, and immunohistochemistry assays, respectively. Insulin-like growth factors-I (IGF-I) was used as an agonist of PI3K/AKT pathway. We demonstrated that FYN expression correlated with LUAD prognosis and was down-regulated in LUAD tissues and LUAD cells. Overexpression of FYN suppressed the cell viability, together with invasion and migration abilities of A549 cells. FYN overexpression accelerated the cell apoptosis and reduced the angiogenesis capacity of A549 cells. Overexpression of FYN suppressed E-cadherin, Vimentin, Snail, and PI3K/AKT expressions in A549 cells. High expression level of FYN reduced the migration and invasion capacities of A549 cells via down-regulating the PI3K/AKT pathway. Collectively, our findings reveal that overexpression of FYN inhibits the epithelial-to-mesenchymal transition (EMT) through down-regulating the PI3K/AKT pathway in A549 cells. Show less

Lysyl oxidase‑like 2 (LOXL2), a member of the lysyl oxidase gene family, is involved in the progression of hepatocellular carcinoma progression and metastasis. Increased expression of LOXL2 has been identified in several types of cancer, including hepatocellular carcinoma. Recently, LOXL2 has been reported to promote epithelial‑mesenchymal transition by reducing E‑cadherin expression via the upregulation of Snail expression. The present study provided evidence demonstrating that LOXL2 inhibited the expression of fructose‑1, 6‑biphosphatase (FBP1) and enhanced the glycolysis of Huh7 and Hep3B hepatocellular carcinoma cell lines in a Snail‑dependent manner. Overexpression of the point‑mutated form of LOXL2 [LOXL2(Y689F)], which lacks enzymatic activity, does not affect the expression of Snail1 or FBP1. Notably, targeting extracellular LOXL2 of Huh7 cells with a therapeutic antibody was unable to abolish its regulation on the expression of Snail and FBP1. Knockdown of LOXL2 also interrupted the angiogenesis of Huh7 and Hep3B cells, and this effect could be rescued by the overexpression of Snail. Furthermore, upregulation of hypoxia‑inducible factor 1α (HIF‑1α) and vascular endothelial growth factor (VEGF) expression was observed in Huh7 and Hep3B cells expressing wild‑type LOXL2. Notably, the selective LOXL2 inhibitor LOXL2‑IN‑1 could upregulate the expression of FBP1 and inhibit the expression of Snail, HIF‑1α and VEGF in HCC cells, but not in FBP1‑knockdown cells. The results of the present study indicated that the intracellular activity of LOXL2 upregulated HIF‑1α/VEGF signaling pathways via the Snail‑FBP1 axis, and this phenomenon could be inhibited by LOXL2 inhibition. Collectively, these findings further support that LOXL2 exhibits an important role in the progression of hepatocellular carcinoma and implicates LOXL2 as a potential therapeutic agent for the treatment of this disease. Show less

Hepatocellular carcinoma (HCC), the sixth most common malignancy worldwide, is characterized by a dismal prognosis due to high recurrence and metastasis rates. Thus, the need for the development of novel chemotherapeutic drugs is urgent. Cyclovirobuxine D (CVB-D), a steroidal alkaloid extracted from Show less

Increasing evidence shows that long non-coding RNAs (lncRNAs) are closely associated with the development of cancers, including triple-negative breast cancer (TNBC). LncRNA FAM201A has been identified as a key regulator in some cancers. However, its role has not been explored in TNBC. In this work, we investigated the biological role and regulatory mechanism of FAM201A in TNBC. The expression pattern of FAM201A was determined by RT-qPCR analysis. The biological effect of FAM201A on cellular process of TNBC was tested using colony formation, EdU, caspase-3 activity detection, flow cytometry, wound healing, and Transwell assays. ChIP and luciferase reporter assays were performed to verify the interaction between transcription factor 3 (TCF3) and FAM201A. The interaction among FAM201A, microRNA-186-5p (miR-186-5p), and tankyrase 1 binding protein 1 (TNKS1BP1) was evaluated by luciferase reporter and RIP assays. The results showed that FAM201A expression was significantly upregulated in TNBC tissues and cells. Functionally, FAM201A knockdown inhibited TNBC cell proliferation, migration and invasion, and accelerated cell apoptosis. In mechanism, it was confirmed that FAM201A was transcriptionally activated by TCF3 and served as a sponge for miR-186-5p to upregulate TNKS1BP1 expression in TNBC cells. Collectively, our study revealed that TCF3-activated FAM201A promoted aggressive phenotypes of TNBC cells by upregulating TNKS1BP1 expression. Show less

Inflammation is an important element of the pathophysiological process of heart failure (HF) and is correlated with subtypes of HF. The association between multiple biomarkers of inflammation and HF subtypes in Chinese subjects remains unclear. This study aimed to compare the differences in inflammation biomarkers among Chinese patients with different subtypes of HF who have been identified to date. We included 413 consecutive patients with HF, including 262 with preserved ejection fraction (HFpEF), 55 with middle-ranged ejection fraction (HFmrEF) and 96 with reduced ejection fraction (HFrEF). Ten inflammation biomarkers were analyzed and compared according to the HF subtypes. One hundred contemporary non-HF subjects were also recruited as the control group. Moreover, the correlations between the inflammatory biomarkers and left ventricular ejection fraction of the HF subtypes were assessed. The mean age of the HF patients was 65.0 ± 12.0 years, 65.8% were male. Distinct subtypes of HF demonstrated different inflammation biomarker panels. IL-6, PTX-3, ANGPTL-4 and TNF-α were correlated with HFrEF; IL-1β and PTX-3 were correlated with HFmrEF; and IL-1β and IL-6 were correlated with HFpEF. The multivariable logistic regression showed that IL-1β [relative ratio (RR) = 1.08, 95% CI: 1.02-1.15, Diverse inflammation biomarkers have multifaceted presentations according to the subtype of HF, which may illustrate the diverse mechanisms of inflammation in Chinese HF patients. IL-6, PTX-3, and ANGPTL-4 were independent inflammation factors associated with HFrEF and HF. Show less

To study the protein profile of the serum exosomes of patients with coronary artery aneurysms (CAA) caused by Kawasaki disease (KD). Two-dimensional electrophoresis (2-DE) was used to identify proteins from the exosomes of serum obtained from children with CAA caused by KD, as well as healthy controls. Differentially expressed proteins were identified using matrix-assisted laser desorption/ionization time-of-flight/timeof-flight mass spectrometry (MALDI-TOF/TOF MS) analysis. Thirty two differentially expressed proteins were identified (18 up-regulated and 14 downregulated) from serum exosomes of children with CAA and were compared to healthy controls. The expression levels of 4 proteins (TN, RBP4, LRG1, and APOA4) were validated using Western blotting. Classification analysis and protein-protein network analysis showed that they are associated with multiple functional groups, including host immune response, inflammation, apoptotic process, developmental process, and biological adhesion process. These findings establish a comprehensive proteomic profile of serum exosomes from children with CAA caused by KD, and provide additional insights into the mechanisms of CAA caused by KD. Show less

Although the prognosis of patients with occult hepatitis B virus (HBV) infection (OBI) is usually benign, a small portion may undergo cirrhosis and subsequently hepatocellular carcinoma (HCC). We studied the mechanism of life-long Integration of virus DNA into OBI host's genome, of which may induce hepatocyte transformation. We applied HBV capture sequencing on single cells from an OBI patient who, developed multiple HCC tumors and underwent liver resection in May 2013 at Tongji Hospital in China. Despite with the undetectable virus DNA in serum, we determined the pattern of viral integration in tumor cells and adjacent non-tumor cells and obtained the details of the viral arrangement in host genome, and furthermore the HBV integrated region in cancer genome. HBV captured sequencing of tissues and individual cells revealed that samples from multiple tumors shared two viral integration sites that could affect three host genes, including CSMD2 on chr1 and MED30/EXT1 on chr8. Whole genome sequencing further indicated one hybrid chromosome formed by HBV integrations between chr1 and chr8 that was shared by multiple tumors. Additional 50 poorly differentiated liver tumors and the paired adjacent non-tumors were evaluated and functional studies suggested up-regulated EXT1 expression promoted HCC growth. We further observed that the most somatic mutations within the tumor cell genome were common among the multiple tumors, suggesting that HBV associated, multifocal HCC is monoclonal in origin. Through analyzing the HBV integration sites in multifocal HCC, our data suggested that the tumor cells were monoclonal in origin and formed in the absence of active viral replication, whereas the affected host genes may subsequently contribute to carcinogenesis. Show less