Steroid induced osteonecrosis of the femoral head (ONFH) frequently leads to femoral head collapse and subsequent hip arthritis. This study aimed to investigate the potential therapeutic mechanism of Show more
Steroid induced osteonecrosis of the femoral head (ONFH) frequently leads to femoral head collapse and subsequent hip arthritis. This study aimed to investigate the potential therapeutic mechanism of miR-27a on steroid-induced ONFH. Levels of IL-6, TNF-α, miR-27a, Runx2, PPAR-γ and ApoA5 were first examined in bone marrow tissues from steroid-induced ONFH and controls. Subsequently, we overexpressed or knocked down miR-27a in bone marrow mesenchymal stem cells (BMSCs) and detected cell proliferation, osteogenic differentiation, adipogenic differentiation. In addition, miR-27a mimics and BMSCs were injected into the established steroid-induced ONFH rats, and the osteoprotective effects of both were evaluated. Dual luciferase reporter was used to test the targeting effect of miR-27a-3p and PPARG. miR-27a and Runx2 were lowly expressed in steroid-induced ONFH, PPAR-γ and ApoA5 were highly expressed. Overexpression of miR-27a in BMSCs promoted cell proliferation and osteogenic differentiation, inhibited adipogenic differentiation. Furthermore, increasing miR-27a and BMSCs obviously reduced bone loss in steroid induced ONFH rats. The expressions of Runx2 in BMSCs and steroid-induced ONFH rats was significantly up-regulated, while IL-6, TNF-α, PPAR-γ and ApoA5 were down-regulated with miR-27a overexpression. Additionally, PPARG was the target of miR-27a-3p. The results of the present study reveal a role for miR-27a in promoting osteogenesis and may have a synergistic effect with BMSCs. Show less
Oral squamous cell carcinoma (OSCC), the most common type of primary malignant tumor in the oral cavity, is a lethal disease with high recurrence and mortality rates. Butyrate, a metabolite produced b Show more
Oral squamous cell carcinoma (OSCC), the most common type of primary malignant tumor in the oral cavity, is a lethal disease with high recurrence and mortality rates. Butyrate, a metabolite produced by periodontal pathogens, has been linked to oral diseases. The purpose of this study was to evaluate the effect of sodium butyrate (NaB) on the proliferation, migration, and invasion of OSCC cells Two OSCC cell lines (HSC-4 and SCC-9) were treated with NaB at different concentrations. The cell proliferation was assayed by CCK-8, ethylene deoxyuridine (EdU), and flow cytometry. Wound healing and transwell assay were performed to detect cell migration and invasion. Changes in epithelial-mesenchymal transition (EMT) markers, including E-cadherin, Vimentin, and SNAI1, were evaluated by quantitative real-time PCR (qRT-PCR), western blot, and immunofluorescent staining. The expression levels of matrix metalloproteinases (MMPs) were analyzed by qRT-PCR and gelatin zymography. Our results showed that NaB inhibited the proliferation of OSCC cells and induced cell cycle arrest at G1 phase, but NaB significantly enhanced cell migration and invasion compared with the control group. Further mechanistic investigation demonstrated that NaB induced EMT by increasing the expression of Vimentin and SNAI1, decreasing the expression of membrane-bound E-cadherin, and correspondingly promoting E-cadherin translocation from the membrane to the cytoplasm. In addition, the overexpression of MMP1/2/9/13 was closely related to NaB treatment. Our study conclude that butyrate may promote the migration and invasion of OSCC cells by inducing EMT. These findings indicate that butyrate may contribute to OSCC metastasis. Show less
Fat mass and obesity-associated protein (FTO) regulates critical pathways in various diseases, including malignant tumours. However, the functional link between FTO and its target genes in epithelial Show more
Fat mass and obesity-associated protein (FTO) regulates critical pathways in various diseases, including malignant tumours. However, the functional link between FTO and its target genes in epithelial ovarian cancer (EOC) development remains to be elucidated. In this study, the biological functions of FTO were verified in vitro and in vivo. The m6A modification and the binding sites of SNAI1 mRNA were confirmed by m6A RNA immunoprecipitation (MeRIP) and RIP experiments. The actinomycin D assay was used to test the stability of RNA. We found that FTO was downregulated with increased m6A levels in EOC. Reduced expression of FTO was associated with a higher FIGO stage in patients with EOC. Mechanistically, FTO decreased the m6A level and stability of SNAI1 mRNA, causing downregulation of SNAI1 and inhibiting epithelial-mesenchymal transition (EMT). Furthermore, FTO-mediated downregulation of SNAI1 expression depended on IGF2BP2, which acted as an m6A reader binding to the 3' UTR region of SNAI1 mRNA to promote its stability. In conclusion, FTO inhibits SNAI1 expression to attenuate the growth and metastasis of EOC cells in an m6A-IGF2BP2-dependent manner. Our findings suggest that the FTO-IGF2BP2-SNAI1 axis is a potential therapeutic target in EOC. Show less
Tubby-like protein 3 (TULP3) is a member of the tubby family, has been related to the development of nervous system by gene knockout researches. Nevertheless, the role of TULP3 in the gastric cancer i Show more
Tubby-like protein 3 (TULP3) is a member of the tubby family, has been related to the development of nervous system by gene knockout researches. Nevertheless, the role of TULP3 in the gastric cancer is not clear. Western blotting and real-time polymerase chain reaction (PCR) were employed for the quantitative detection of TULP3 expression in the gastric cancer and consecutive non-cancerous tissues, and gastric cancer cells. The roles of TULP3 in invasion, migration as well as proliferation of the gastric cancer cell in vivo and in vitro through utilizing colony formation, MTT, wound-healing, transwell and mouse xenograft model. Western blotting assay was implemented in order to clarify the potential molecular mechanisms. Furthermore, electron microscopy and western blot were evaluated TULP3 expression in gastric cancer patient extracted serum exosomes. TULP3 expression levels were remarkably upregulated in the gastric cancer tissues and cells. Subsequent functional assays demonstrated that TULP3 downregulation suppressed invasion, migration as well as the proliferation of the gastric cancer cell. Mechanism assays depicted that the PTEN/Akt/Snail signaling pathway can inhibit invasion, migration as well as the proliferation of the gastric cancer cell via TULP3 silencing. Finally, we found that the expression of TULP3 could be determined in the extracted serum exosomes. The expression of TULP3 in gastric cancer group was higher in comparison with normal group. Our results reveal that TULP3 might serve as a potential prognostic biomarker and therapeutic target for the treatment of gastric cancer. Show less
The aim of this study is to identify potential serum biomarkers of Alzheimer's disease (AD) for early diagnosis and to evaluate these markers on a large cohort. We performed two-dimensional difference Show more
The aim of this study is to identify potential serum biomarkers of Alzheimer's disease (AD) for early diagnosis and to evaluate these markers on a large cohort. We performed two-dimensional difference gel electrophoresis to compare the serum of AD patients and normal controls. Western blot or enzyme-linked immunosorbent assay (ELISA) was used to identify the expression levels of proteins. In this study, a total of 13 differentially expressed proteins were identified. Among them, 2 proteins (inter-alpha-trypsin inhibitor heavy chain H4 [ITI-H4], Apolipoprotein A-IV) were validated by Western blot and 4 proteins (Cofilin 2, Tetranectin, Zinc-alpha-2-glycoprotein [AZGP1], Alpha-1-microglobulin/bikunin precursor [AMBP]) were validated by ELISA, respectively. Western blot results showed that the full size of the ITI-H4 protein was increased, while a fragment of ITI-H4 was decreased in AD patients. In contrast, 1 fragment of Apo A-IV was mainly found in control group and rare to be detected in AD patients. On the other hand, ELISA results showed that Cofilin 2, Tetranectin, AZGP1, and AMBP were significantly increased in AD patients, and Cofilin 2 is strongly correlated with the Mini-Mental State Examination scores of the AD patients. Serum Cofilin 2 was unchanged in Parkinson disease patients as compared to the control group, indicating a specific correlation of serum Cofilin 2 with AD. Moreover, Cofilin 2 was increased in both the serum and brain tissue in the APP/PS1 transgenic mice. Our study identified several potential serum biomarkers of AD, including: ITI-H4, ApoA-IV, Cofilin 2, Tetranectin, AZGP1, and AMBP. Cofilin 2 was upregulated in different AD animal models and might play important roles in AD pathology. Show less
As one of the common birth defects worldwide, nonsyndromic microtia is a complex disease that results from interactions between environmental and genetic factors. However, the underlying causes of non Show more
As one of the common birth defects worldwide, nonsyndromic microtia is a complex disease that results from interactions between environmental and genetic factors. However, the underlying causes of nonsyndromic microtia are currently not well understood. The present study determined transcriptomic and proteomic profiles of auricular cartilage tissues in 10 patients with third-degree nonsyndromic microtia and five control subjects by RNA microarray and tandem mass tag-based quantitative proteomics technology. Relative mRNA and protein abundances were compared and evaluated for their function and putative involvement in nonsyndromic microtia. A total of 3971 differentially expressed genes and 256 differentially expressed proteins were identified. Bioinformatics analysis demonstrated that some of these genes and proteins showed potential associations with nonsyndromic microtia. Thirteen proteins with the same trend at the mRNA level obtained by the integrated analysis were validated by parallel reaction monitoring analysis. Several key genes, namely, Show less
Appropriate decidualization is of great importance for embryo implantation, placental development and successful pregnancy. Although it has been well-acknowledged that decidualization relies on activa Show more
Appropriate decidualization is of great importance for embryo implantation, placental development and successful pregnancy. Although it has been well-acknowledged that decidualization relies on activation of progesterone-mediated signaling pathway, the exact mechanisms have not been elucidated. Here, we demonstrated that both IL-27 and IL27RA were highly expressed in decidua than those in endometrium during secretory phase. Estrogen plus progesterone significantly upregulated the expression of IL-27 and IL-27RA in endometrium stromal cells (ESCs). In addition, inhibiting IL-27 signaling with IL-27 neutralization antibody (anti-IL-27) suppressed the expression of decidualization-related molecules, receptors of estrogen (gene coded by ESR) and progesterone (PGR) induced by cAMP or estrogen plus progesterone. Similar results were obtained from Il27ra Show less
Fecundity in livestock is an economically important complex quantitative trait that is influenced by both genetics and the environment. However, the underlying genetic mechanism of reproductive perfor Show more
Fecundity in livestock is an economically important complex quantitative trait that is influenced by both genetics and the environment. However, the underlying genetic mechanism of reproductive performance in goats has not been well investigated. To investigate the genomic basis of fecundity in goats, genomic sequencing data of the Jining grey goat (a high prolificacy breed in China) were collected, as well as data for other commonly available goat breeds, and a mass of genomic variants were generated after variation calling. We screened the Jining grey goat (20 individuals) using a selective sweep with the Asian wild goat population (5 individuals), and potential candidate genes were proposed, such as STIM1, ESR1, LRRC14B and SLC9A3. Among, STIM1 is a most promising one associated with high reproductive capacity. When compared to Chinese domestic goats with low fecundity (17 individuals), the genes including MLLT10, SPIRE2, TCF25, ZNF276 and FANCA were screened, and the SPIRE2 gene was thought to be associated with fecundity traits. Meanwhile, the functional enrichment of these candidate genes revealed that they were involved in biological processes of mammary gland morphogenesis, uterus development, gastrulation, mesoderm morphogenesis and formation, and blood vessel development, which might undergo natural or artificial selection during reproductive trait formation in goats. Thus, our findings could enrich the genetic basis of reproductive trait selection during goat domestication, which may serve to improve goat breeding practices. Show less
Altered ubiquitin signaling and disrupted protein quality control have been implicated in the pathogenesis of PD. The aim of the study was to systematically examine the overlaps between E3 ubiquitin l Show more
Altered ubiquitin signaling and disrupted protein quality control have been implicated in the pathogenesis of PD. The aim of the study was to systematically examine the overlaps between E3 ubiquitin ligase genes and early onset PD (EOPD). A total of 695 EOPD patients were analyzed aggregate burden for rare variants (MAF <0.001 and MAF <0.0001) in a total of 44 E3 ubiquitin ligase genes causing disorders involved in the nervous system. There was significant enrichment of the rare and rare damaging variants in the E3 ubiquitin ligase genes in EOPD patients. Detailly, in the gene-based level, the strongest associations were found in HERC1, IRF2BPL, KMT2D, RAPSN, RLIM, RNF168 and RNF216. Our findings highlighted the importance of UPS mechanism in the pathogenesis of PD from the genetic perspective. Moreover, our study also expanded the susceptible gene spectrum for PD. Show less
Recently, attention has been focused on the central role of TREM2 in diverse pathologies. However, the role of TREM2 signaling in the tumor microenvironment of hepatocellular carcinoma (HCC) remains p Show more
Recently, attention has been focused on the central role of TREM2 in diverse pathologies. However, the role of TREM2 signaling in the tumor microenvironment of hepatocellular carcinoma (HCC) remains poorly understood. Herein, we systematically investigated the single-cell transcriptomes of human HCC tissues and found that Show less
Mounting evidence has linked both obesity and metabolic disorders with dysbiosis of the gut microbiota. Dietary inulin is conducive to modulating this dysbiosis, and represents a potential means to im Show more
Mounting evidence has linked both obesity and metabolic disorders with dysbiosis of the gut microbiota. Dietary inulin is conducive to modulating this dysbiosis, and represents a potential means to improve disorders of glucose and lipid metabolism. However, the mechanisms underlying these improvements are largely unclear. Obese ob/ob mice were fed a standard chow, a low fiber diet (LFD) or a high fiber diet (HFD) for 4 weeks, and the body weight, fecal short chain fatty acids (SCFAs) level, and plasma and liver lipid profiles were analyzed. Oral glucose tolerance testing, and gut microbiota sequencing were also conducted. Dietary inulin improved the dysbiosis of the gut microbiota, attenuated the decrease in phylum Bacteroidetes, repressed the increase of phylum Firmicutes, and led to an increase in the ratio of Firmicutes/Bacteroidetes. At the family level, inulin promoted the expansion of SCFAs-producing Ruminococcaceae and Lachnospiraceae bacteria, which increased the fecal SCFAs concentrations. At the genus level, inulin increased the levels of Bacteroides and Bifidobacteria. Furthermore, our results revealed that there was enhanced expression of angiopoietin-like protein 4 (ANGPTL4), which might be induced by the higher production of SCFAs, and this may underlie the improvements in the disorders of glucose and lipid metabolism seen in mice with added dietary inulin. In conclusion, inulin may ameliorate metabolic disorders by remodeling the gut microbiota and increasing the production of SCFAs, which might be mediated by the ANGPTL4-related signaling pathway. Interventions targeting the gut microbiota warrant further investigation as a novel therapy for metabolic diseases. PRACTICAL APPLICATIONS: Mounting evidence has linked both obesity and metabolic disorders with dysbiosis of the gut microbiota. Dietary inulin is conducive to modulating this dysbiosis, and represents a potential means to improve disorders of glucose and lipid metabolism. However, the mechanisms underlying these improvements are largely unclear. In the present study, we investigated the effects of dietary fiber (inulin) on metabolic homeostasis using ob/ob mice. The results of our study demonstrate that inulin-induced remodeling of the gut microbiota resulted in increased production of short chain fatty acids (SCFAs), leading to the enhanced expression of angiopoietin-like protein 4 (ANGPTL4), which improved the glucose and lipid metabolism. Our results suggest that the gut microbiota, SCFAs and ANGPTL4 pathway at least partially mediate the beneficial effects of inulin on metabolic disorders in ob/ob mice. Show less
To explore the correlation of cytochrome B-245 alpha chain ( The study was a case-control trial. A total of 372 GAgP patients and 133 periodontally healthy controls were recruited. The The mean age of Show more
To explore the correlation of cytochrome B-245 alpha chain ( The study was a case-control trial. A total of 372 GAgP patients and 133 periodontally healthy controls were recruited. The The mean age of GAgP group and control group was (27.5±5.2) years and (28.8±7.1) years respectively. There was significant difference in age between the two groups ( Show less
Angiopoietin-like 4 (ANGPTL4) is involved in inflammation-associated diseases, such as rheumatoid arthritis, type 2 diabetes, atherosclerosis, and chronic obstructive pulmonary disease. The role of AN Show more
Angiopoietin-like 4 (ANGPTL4) is involved in inflammation-associated diseases, such as rheumatoid arthritis, type 2 diabetes, atherosclerosis, and chronic obstructive pulmonary disease. The role of ANGPTL4 in the pathogenesis of inflammatory bowel disease (IBD) remains unknown. Here, the plasma ANGPTL4 levels peaked on days 3 and 5, and expression of ANGPTL4 of inflamed colons peaked on days 5 and 7 in mice with dextran sulfate sodium (DSS)-induced colitis. Simultaneously, CD8 Show less
Studies have shown that environmental carcinogens exerted an important function in the high incidence of esophageal cancer (EC). Nitrosamines have been identified as important environmental carcinogen Show more
Studies have shown that environmental carcinogens exerted an important function in the high incidence of esophageal cancer (EC). Nitrosamines have been identified as important environmental carcinogens for EC. This study aimed to investigate the metabolic disturbances and new key toxicological markers in the malignant transformation process of normal esophageal epithelial cells (Het-1A) induced by MNNG (N-methyl-N'-nitro-N-nitrosoguanidine). Untargeted metabolomic and lipidomic profiling analysis by using ultra-high-performance liquid chromatography coupled with mass spectrometry (UHPLC-MS) were applied to explore the metabolic network alterations of Het-1A cells. The metabolomic results showed that significant alterations were observed in metabolic signatures between different generations (P5, P15, P25, P35) and the control cell group (P0). A total of 48 differential endogenous metabolites were screened and identified, mainly containing fatty acids, amino acids, and nucleotides. The differential metabolites were predominantly linked to the pathway of biosynthesis of unsaturated fatty acids metabolism. The cell lipidomic profiling revealed that the most differential lipids contained fatty acids (FAs), phosphatidylcholines (PC), phosphatidylethanolamines (PE), and phosphatidylserines (PS). The enrichment of the lipidomic pathway also confirmed that the lipid metabolism of biosynthesis of unsaturated fatty acids was the significant variation during the cell malignant transformation. Furthermore, we detected the expression of the upstream regulatory enzymes related to the unsaturated fatty acids to explore the regulation mechanism. The expression of stearoyl-CoA desaturase (SCD), ELOVL fatty acid elongase 1 (ELOVL1) promoted, and fatty acid desaturase 1 (FADS1) inhibited the key fatty acids of unsaturated fatty acids metabolism compared to the control cell group. Overall, our results revealed that lipid fatty acid metabolism was involved in the malignant transformation of Het-1A cells induced by MNNG and deepened the awareness of the carcinogenic mechanism of environmental exposure pollutants. Show less
Weining cattle is a Chinese indigenous breed influenced by complex breeding and geographical background. The multi-ethnic breeding culture makes Weining cattle require more attention as livestock reso Show more
Weining cattle is a Chinese indigenous breed influenced by complex breeding and geographical background. The multi-ethnic breeding culture makes Weining cattle require more attention as livestock resources for its genetic diversity. Here, we used 10 Weining cattle (five newly sequenced and five downloaded) and downloaded another 48 genome data to understand the aspects of Weining cattle: genetic diversity, population structure, and cold-adapted performance. In the current study, a high level of genetic diversity was found in Weining cattle, and its breed comprised two potential ancestries, which were Show less
Lipid metabolic disorders pose a serious threat to human health, and currently no good treatments exist. In earlier studies by the authors, HepG2 cells with diacylglycerol kinase theta (DGKθ) knockout Show more
Lipid metabolic disorders pose a serious threat to human health, and currently no good treatments exist. In earlier studies by the authors, HepG2 cells with diacylglycerol kinase theta (DGKθ) knockout were found to cause significant lipid accumulation, suggesting that DGKθ may be a potential target for treating lipid metabolic disorders. A high-throughput screening of natural products targeting the potential signaling pathway of lipid metabolism was carried out in the DGKθ-T2A-luciferase knock-in HepG2 cell. RNA-sequencing and bioinformatic approaches were used to analyze the potential pathway by which rutaecarpin decreases lipids. Western blot and quantitative polymerase chain reaction were performed to investigate the mechanisms of rutaecarpin's reduction in lipid levels. Rutaecarpin was found to significantly enhance DGKθ expression, and the potential mechanisms by which rutaecarpin accelerates lipid metabolism by targeting DGKθ was explored in vitro and in vivo. The results indicated that rutaecarpin could markedly reduce lipid accumulation in oleic acid-induced HepG2 cells and in high-fat diet-induced obese C57BL/6J mice by targeting the hepatocyte nuclear factor 1-beta (HNF1B)-DGKθ-peroxisome proliferator-activated receptor alpha (PPARα)-apolipoprotein C3 (APOC3) pathway. Rutaecarpin is effective in reducing lipid accumulation, and the development of a high-throughput screening platform based on a reporter knock-in cell line may facilitate the discovery of effective drugs for lipid metabolic disorders based on the DGKθ target. Show less
Traditional Chinese herbal medicine draws more attention to explore an effective therapeutic strategy for Alzheimer's disease (AD). Shenqi Yizhi granule (SQYG), a Chinese herbal recipe, has been appli Show more
Traditional Chinese herbal medicine draws more attention to explore an effective therapeutic strategy for Alzheimer's disease (AD). Shenqi Yizhi granule (SQYG), a Chinese herbal recipe, has been applied to ameliorate cognitive impairment in mild-to-moderate AD patients. However, the overall molecular mechanism of SQYG in treating AD has not been clarified. This study aimed to investigate the molecular mechanism of SQYG on AD using an integration strategy of network pharmacology and molecular docking. The active compounds of SQYG and common targets between SQYG and AD were screened from databases. The herb-compound network, compound-target network, and protein-protein interaction network were constructed. The enrichment analysis of common targets and molecular docking were performed. 816 compounds and 307 common targets between SQYG and AD were screened. KEGG analysis revealed that common targets were mainly enriched in lipid metabolism, metal ion metabolism, IL-17 signaling pathway, GABA receptor signaling, and neuroactive ligand-receptor interaction. Molecular docking analysis showed high binding affinity between ginsenoside Rg1 and A The therapeutic mechanisms of SQYG on AD were associated with regulating lipid metabolism, metal ion metabolism, IL-17 signaling pathway, and GABA receptor signaling. Ginsenoside Rg1, tanshinone IIA, baicalin, astragaloside IV, and folic acid may play an important role in AD treatment. Show less
This study aims to explore the prognostic values of CT83 and CT83- related genes in lung adenocarcinoma (LUAD). We downloaded the mRNA profiles of 513 LUAD patients (RNA sequencing data) and 246 NSCLC Show more
This study aims to explore the prognostic values of CT83 and CT83- related genes in lung adenocarcinoma (LUAD). We downloaded the mRNA profiles of 513 LUAD patients (RNA sequencing data) and 246 NSCLC patients (Affymetrix Human Genome U133 Plus 2.0 Array) from TCGA and GEO databases. According to the median expression of CT83, the TCGA samples were divided into high and low expression groups, and differential expression analysis between them was performed. Functional enrichment analysis of differential expression genes (DEGs) was conducted. Univariate Cox regression analysis and LASSO Cox regression analysis were performed to screen the optimal prognostic DEGs. Then we established the prognostic model. A Nomogram model was constructed to predict the overall survival (OS) probability of LUAD patients. CT83 expression was significantly correlated to the prognosis of LUAD patients. A total of 59 DEGs were identified, and a predictive model was constructed based on six optimal CT83- related DEGs, including CPS1, RHOV, TNNT1, FAM83A, IGF2BP1, and GRIN2A, which could effectively predict the prognosis of LUAD patients. The nomogram could reliably predict the OS of LUAD patients. Moreover, the six important immune checkpoints (CTLA4, PD1, IDO1, TDO2, LAG3, and TIGIT) were closely correlated with the risk score, which were also differentially expressed between the LUAD samples with high and low risk scores, suggesting that the poor prognosis of LUAD patients with high risk score might be due to the immunosuppressive microenvironments. A prognostic model based on six optimal CT83 related genes could effectively predict the prognosis of LUAD patients. Show less
MicroRNAs (miRNAs) play an important role in the pathogenesis of atrial fibrillation (AF). Exosomal miRNAs may develop as promising biomarkers for AF. To explore significant exosomal miRNAs in AF, pla Show more
MicroRNAs (miRNAs) play an important role in the pathogenesis of atrial fibrillation (AF). Exosomal miRNAs may develop as promising biomarkers for AF. To explore significant exosomal miRNAs in AF, plasma exosomes were extracted from 3 patients with AF and 3 patients with sinus rhythm (SR), respectively. Differential expression of exosomal miRNAs were screened by high-throughput sequencing analysis and verified by qRT-PCR from 40 patients with AF and 40 patients with SR. The target genes prediction, biological function, and signaling pathways analysis were conducted by miRanda software, gene ontology (GO), and KEGG analysis. The results showed that there were 40 differently expressed exosomal miRNAs from AF patients compared with SR patients, of which 13 miRNAs were upregulated and 27 miRNAs were downregulated. qRT-PCR validation demonstrated that miR-124-3p, miR-378d, miR-2110, and miR-3180-3p were remarkably upregulated, while miR-223-5p, miR-574-3p, miR-125a-3p, and miR-1299 were downregulated. To explore the function of miR-124-3p associated with AF, plasma exosomes derived from AF patients were co-incubated with rat myocardial fibroblasts. The expression of miR-124-3p was upregulated in myocardial fibroblasts. The viability and proliferation of myocardial fibroblasts were elevated by transfecting with miR-124-3p overexpression plasmids using CCK8 and immunofluorescence-staining methods. AXIN1 was verified to be the target of miR-124-3p by luciferase assay in vitro. Expression of AXIN1 was reduced, while β-catenin, Collagen 1, and α-SMA were increased in myocardial fibroblasts with miR-124-3p overexpression. In conclusion, these findings suggested that circulating exosomal miRNAs may serve as novel biomarkers for AF, and miR-124-3p promotes fibroblast activation and proliferation through regulating WNT/β-catenin signaling pathway via AXIN1. Show less
Recent studies have identified that circular RNAs (circRNAs) have an important role in cancer via their well-recognized sponge effect on miRNAs, which regulates a large variety of cancer-related genes Show more
Recent studies have identified that circular RNAs (circRNAs) have an important role in cancer via their well-recognized sponge effect on miRNAs, which regulates a large variety of cancer-related genes. However, only a few circRNAs have been well-studied in renal cell carcinoma (RCC) and their regulatory function remains largely elusive. Bioinformatics approaches were used to characterize the differentially expressed circRNAs in our own circRNA-sequencing dataset, as well as two public circRNA microarray datasets. CircNTNG1 (hsa_circ₀₀₀₂₂₈₆₎ was identified as a potential tumor-suppressing circRNA. Transwell assay and CCK-8 assay were used to assess phenotypic changes. RNA pull-down, luciferase reporter assays and FISH experiment were used to confirm the interactions among circNTNG1, miR-19b-3p, and HOXA5 mRNA. GSEA was performed to explore the downstream pathway regulated by HOXA5. Immunoblotting, chromatin immunoprecipitation, and methylated DNA immunoprecipitation were used to study the mechanism of HOXA5. In all three circRNA datasets, circNTNG1, which was frequently deleted in RCC, showed significantly low expression in the tumor group. The basic properties of circNTNG1 were characterized, and phenotype studies also demonstrated the inhibitory effect of circNTNG1 on RCC cell aggressiveness. Clinically, circNTNG1 expression was associated with RCC stage and Fuhrman grade, and it also served as an independent predictive factor for both OS and RFS of RCC patients. Next, the sponge effect of circNTNG1 on miR-19b-3p and the inhibition of HOXA5 by miR-19b-3p were validated. GSEA analysis indicated that HOXA5 could inactivate the epithelial-mesenchymal transition (EMT) process, and this inactivation was mediated by HOXA5-induced SNAI2 (Slug) downregulation. Finally, it was confirmed that the Slug downregulation was caused by HOXA5, along with the DNA methyltransferase DNMT3A, binding to its promoter region and increasing the methylation level. Based on the experimental data, in RCC, circNTNG1/miR-19b-3p/HOXA5 axis can regulate the epigenetic silencing of Slug, thus interfering EMT and metastasis of RCC. Together, our findings provide potential biomarkers and novel therapeutic targets for future study in RCC. Show less
Hyperbilirubinemia is a serious hazard to human health due to its neurotoxicity and lethality. So far, successful therapy for hyperbilirubinemia with fewer side effects is still lacking. In this study Show more
Hyperbilirubinemia is a serious hazard to human health due to its neurotoxicity and lethality. So far, successful therapy for hyperbilirubinemia with fewer side effects is still lacking. In this study, we aimed to clarify the effects of oridonin (Ori), an active diterpenoid extracted from Rabdosia rubescens, on hyperbilirubinemia and revealed the underlying molecular mechanism in vivo and in vitro. Here, we showed that liver X receptor alpha (LXRα) deletion eliminated the protective effect of Ori on phenylhydrazine hydrochloride-induced hyperbilirubinemia mice, indicating that LXRα acted as a key target for Ori treatment of hyperbilirubinemia. Ori significantly increased the expression of LXRα and UDP-glucuronosyltransferase 1A1 (UGT1A1) in the liver of wild-type (WT) mice, which were lost in LXRα Show less
The formation of the leafy heads of Chinese cabbage is an important agricultural factor because it directly affects yield. In this study, we identified two allelic non-heading mutants,
Most patients with neovascular age-related macular degeneration (nvAMD), the leading cause of severe vision loss in elderly US citizens, respond inadequately to current therapies targeting a single an Show more
Most patients with neovascular age-related macular degeneration (nvAMD), the leading cause of severe vision loss in elderly US citizens, respond inadequately to current therapies targeting a single angiogenic mediator, vascular endothelial growth factor (VEGF). Here, we report that aqueous fluid levels of a second vasoactive mediator, angiopoietin-like 4 (ANGPTL4), can help predict the response of patients with nvAMD to anti-VEGF therapies. ANGPTL4 expression was higher in patients who required monthly treatment with anti-VEGF therapies compared with patients who could be effectively treated with less-frequent injections. We further demonstrate that ANGPTL4 acts synergistically with VEGF to promote the growth and leakage of choroidal neovascular (CNV) lesions in mice. Targeting ANGPTL4 expression was as effective as targeting VEGF expression for treating CNV in mice, while simultaneously targeting both was more effective than targeting either factor alone. To help translate these findings to patients, we used a soluble receptor that binds to both VEGF and ANGPTL4 and effectively inhibited the development of CNV lesions in mice. Our findings provide an assay that can help predict the response of patients with nvAMD to anti-VEGF monotherapy and suggest that therapies targeting both ANGPTL4 and VEGF will be a more effective approach for the treatment of this blinding disease. Show less
Heterogeneous nuclear ribonucleoprotein (HnRNP) F is a member of HnRNP family proteins that participate in splicing of cellular newly synthesized mRNAs by specifically recognizing tandem guanine-tract Show more
Heterogeneous nuclear ribonucleoprotein (HnRNP) F is a member of HnRNP family proteins that participate in splicing of cellular newly synthesized mRNAs by specifically recognizing tandem guanine-tracts (G-tracts) RNA sequences. Whether HnRNP F could recognize viral-derived tandem G-tracts and affect virus replication remain poorly defined. The effect of HnRNP F on porcine reproductive and respiratory syndrome virus (PRRSV) propagation was evaluated by real-time PCR, western blotting, and plaque-forming unit assay. The association between HnRNP F and PRRSV guanine-rich segments (GRS) were analyzed by RNA pulldown and RNA immunoprecipitation. The expression pattern of HnRNP F was investigated by western blotting and nuclear and cytoplasmic fractionation. Knockdown of endogenous HnRNP F effectively blocks the synthesis of viral RNA and nucleocapsid (N) protein. Conversely, overexpression of porcine HnRNP F has the opposite effect. Moreover, RNA pulldown and RNA immunoprecipitation assays reveal that the qRMM1 and qRRM2 domains of HnRNP F recognize the GRS in PRRSV antigenomic RNA. Finally, HnRNP F is redistributed into the cytoplasm and forms a complex with guanine-quadruplex (G4) helicase DHX36 during PRRSV infection. These findings elucidate the potential functions of HnRNP F in regulating the proliferation of PRRSV and contribute to a better molecular understanding of host-PRRSV interactions. Show less
Background Ischemic stroke is likely caused by interactions of multiple genes and environmental determinants. However, large-scale sequencing studies to discern functional genetic variants and their i Show more
Background Ischemic stroke is likely caused by interactions of multiple genes and environmental determinants. However, large-scale sequencing studies to discern functional genetic variants and their interactions with clinical and lifestyle risk factors on ischemic stroke are limited. Methods and Results We sequenced functional regions of 740 previously identified genes associated with atherosclerotic disease among 999 ischemic stroke cases and 1001 controls of Chinese ancestry. Multiple logistic regression models were used to examine the associations between variants and ischemic stroke and test interactions between variants and clinical and lifestyle risk factors. Functional variants achieving suggestive significance were replicated in an independent sample of 4724 ischemic stroke cases and 5029 controls. Driven by variant main effects, each minor allele of the correlated rs174535, rs174545, and rs3834458 variants at Show less
The endothelial glycocalyx regulates vascular permeability, inflammation, and coagulation, and acts as a mechanosensor. The loss of glycocalyx can cause endothelial injury and contribute to several mi Show more
The endothelial glycocalyx regulates vascular permeability, inflammation, and coagulation, and acts as a mechanosensor. The loss of glycocalyx can cause endothelial injury and contribute to several microvascular complications and, therefore, may promote diabetic retinopathy. Studies have shown a partial loss of retinal glycocalyx in diabetes, but with few molecular details of the changes in glycosaminoglycan (GAG) composition. Therefore, the purpose of our study was to investigate the effect of hyperglycemia on GAGs of the retinal endothelial glycocalyx. GAGs were isolated from rat retinal microvascular endothelial cells (RRMECs), media, and retinas, followed by liquid chromatography-mass spectrometry assays. Quantitative real-time polymerase chain reaction was used to study mRNA transcripts of the enzymes involved in GAG biosynthesis. Hyperglycemia significantly increased the shedding of heparan sulfate (HS), chondroitin sulfate (CS), and hyaluronic acid (HA). There were no changes to the levels of HS in RRMEC monolayers grown in high-glucose media, but the levels of CS and HA decreased dramatically. Similarly, while HA decreased in the retinas of diabetic rats, the total GAG and CS levels increased. Hyperglycemia in RRMECs caused a significant increase in the mRNA levels of the enzymes involved in GAG biosynthesis (including EXTL-1,2,3, EXT-1,2, ChSY-1,3, and HAS-2,3), with these increases potentially being compensatory responses to overall glycocalyx loss. Both RRMECs and retinas of diabetic rats exhibited glucose-induced alterations in the disaccharide compositions and sulfation of HS and CS, with the changes in sulfation including N,6-O-sulfation on HS and 4-O-sulfation on CS. Show less
Ren Zhang, Kezhong Zhang · 2022 · Progress in lipid research · Elsevier · added 2026-04-24
In mammals, triglyceride (TG), the main form of lipids for storing and providing energy, is stored in white adipose tissue (WAT) after food intake, while during fasting it is routed to oxidative tissu Show more
In mammals, triglyceride (TG), the main form of lipids for storing and providing energy, is stored in white adipose tissue (WAT) after food intake, while during fasting it is routed to oxidative tissues (heart and skeletal muscle) for energy production, a process referred to as TG partitioning. Lipoprotein lipase (LPL), a rate-limiting enzyme in this fundamental physiological process, hydrolyzes circulating TG to generate free fatty acids that are taken up by peripheral tissues. The postprandial activity of LPL declines in oxidative tissues but rises in WAT, directing TG to WAT; the reverse is true during fasting. However, the molecular mechanism in regulating tissue-specific LPL activity during the fed-fast cycle has not been completely understood. Research on angiopoietin-like (ANGPTL) proteins (A3, A4, and A8) has resulted in an ANGPTL3-4-8 model to explain the TG partitioning between WAT and oxidative tissues. Food intake induces A8 expression in the liver and WAT. Liver A8 activates A3 by forming the A3-8 complex, which is then secreted into the circulation. The A3-8 complex acts in an endocrine manner to inhibit LPL in oxidative tissues. WAT A8 forms the A4-8 complex, which acts locally to block A4's LPL-inhibiting activity. Therefore, the postprandial activity of LPL is low in oxidative tissues but high in WAT, directing circulating TG to WAT. Conversely, during fasting, reduced A8 expression in the liver and WAT disables A3 from inhibiting oxidative-tissue LPL and restores WAT A4's LPL-inhibiting activity, respectively. Thus, the fasting LPL activity is high in oxidative tissues but low in WAT, directing TG to the former. According to the model, we hypothesize that A8 antagonism has the potential to simultaneously reduce TG and increase HDL-cholesterol plasma levels. Future research on A3, A4, and A8 can hopefully provide more insights into human health, disease, and therapeutics. Show less