Several studies have confirmed that the pathophysiological progression of Alzheimer's disease (AD) is closely related to changes in the intestinal microbiota; thus, modifying the intestinal microbiota Show more
Several studies have confirmed that the pathophysiological progression of Alzheimer's disease (AD) is closely related to changes in the intestinal microbiota; thus, modifying the intestinal microbiota has emerged as a new way to treat AD. Effective interventions for gut microbiota include the application of probiotics and other measures such as fecal microbiota transplantation (FMT). However, the application of probiotics ignores that the intestine is a complete microecosystem with competition among microorganisms. FMT also has issues when applied to patient treatment. In a previous study, we found that eight species of bacteria that are isolated with high frequency in the normal intestinal microbiota (i.e., intestinal dominant microbiota) have biological activities consistent with the effects of FMT. In this article, we confirmed that the treatment of intestinal dominant microbiota significantly restored intestinal microbiota abundance and composition to normal levels in APP/PS1 mice; downregulated brain tissue pro-inflammatory cytokines (IL-1β and IL-6) and amyloid precursor protein (APP) and β-site APP cleavage enzyme 1 (BACE1) expression levels; and reduced the area of Aβ plaque deposition in the brain hippocampus. Our study provides a new therapeutic concept for the treatment of AD, adjusting the intestinal microecological balance through dominant intestinal microbiota may be an alternative to FMT. Show less
Reactive oxygen species (ROS) damage to the intestinal barrier is a side effect of prolonged hyperoxia therapy in neonates, which impairs growth and development of the intestine and promotes intestina Show more
Reactive oxygen species (ROS) damage to the intestinal barrier is a side effect of prolonged hyperoxia therapy in neonates, which impairs growth and development of the intestine and promotes intestinal diseases. However, the research on clinical prevention and treatment is lacking. Therefore, we investigated the molecular mechanisms of the neonate intestinal response against hyperoxia-derived ROS to find targets for intestinal barrier damage prevention. Human intestinal epithelial cells were incubated under hyperoxia (85% oxygen) to build an in vitro model. ROS and the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway were inhibited to detect the MAPK/ERK pathway, nuclear factor erythroid factor 2-related factor 2 (Nrf2), hypoxia-inducible factor-1α (Hif-1α), and interleukin-17D (IL-17D) expression. Nrf2 was inhibited to detect Hif-1α and IL-17D expression. Hif-1α was inhibited to detect Nrf2, IL-17D, and tight junction proteins expression and apoptosis. Cells were treated with human recombinant IL-17D to detect TNF-α, IL-1β, IL-10, and tight junction proteins expression. ROS, Nrf2, Hif-1α, and IL-17D were upregulated and the MAPK/ERK pathway was activated under hyperoxia. But ROS inhibition downregulated the MAPK/ERK pathway, Nrf2, Hif-1α, and IL-17D. MAPK/ERK pathway inhibition downregulated Nrf2, Hif-1α, and IL-17D. Nrf2 inhibition downregulated Hif-1α and IL-17D. Hif-1α inhibition downregulated Nrf2, IL-17D, tight junction proteins, and exacerbated apoptosis. The recombinant IL-17D downregulated TNF-α, IL-1β, but upregulated IL-10 and tight junction proteins. We concluded that Hyperoxia-generated ROS activated the MAPK/ERK pathway to regulate Nrf2, Hif-1α, and IL-17D expression. Nrf2 and Hif-1α were interdependent and promoted IL-17D. Importantly, Hif-1α and IL-17D expression protected the intestinal epithelial barrier. Show less
Cancer cell stemness contributes significantly to intrahepatic cholangiocarcinoma (ICC) progression. However, the roles of deubiquitinating enzymes (DUBs) in ICC modulation are poorly understood. Ubiq Show more
Cancer cell stemness contributes significantly to intrahepatic cholangiocarcinoma (ICC) progression. However, the roles of deubiquitinating enzymes (DUBs) in ICC modulation are poorly understood. Ubiquitin specific peptidase 10 (USP10) was highly expressed in ICC spheres. The interaction between USP10 and snail family transcriptional repressor 1 (SNAI1) reduced the polyubiquitination of the SNAI1 protein and stabilized the SNAI1 protein. USP10 knockdown in RBE cells inhibited cell proliferation, promoted cell apoptosis and decreased the diameter of the formed spheres and the expression levels of CD44, EpCAM, OCT4 and SOX2. SNAI1 overexpression alleviated the effect of USP10 knockdown in RBE cells. In addition, the knockdown of USP10 attenuated the ability of RBE cells to form tumors subcutaneously in nude mice. Our results revealed that USP10 attenuates ICC cell malignancy by deubiquitinating SNAI1, indicating that USP10 could be developed as a therapeutic target for ICC treatment. Show less
Lysyl-oxidase-like 3 (LOXL3) was reported to be essential in epithelial-mesenchymal transition (EMT) of cancers. However, the role of LOXL3 in hepatocellular carcinoma (HCC) remained unclear. In this Show more
Lysyl-oxidase-like 3 (LOXL3) was reported to be essential in epithelial-mesenchymal transition (EMT) of cancers. However, the role of LOXL3 in hepatocellular carcinoma (HCC) remained unclear. In this study, we explored clinical significance, biological functions, and regulatory mechanisms of LOXL3 in HCC. Our study found that LOXL3 expression was markedly associated with the tumor size and clinical stage of HCC, and it was highly expressed in tumor tissues of metastatic HCC patients. High expression of LOXL3 predicted a poor prognosis of HCC. TGF-β1 treatment elevated LOXL3 protein expression and cell invasion, and reduced cell apoptosis in HCC cell lines (SMMC-7721 and Huh-7), while downregulation of LOXL3 reversed the promotive effects of TGF-β1 treatment on LOXL3 protein expression and cell invasion, and the inhibitory effect on cell apoptosis. Mechanistically, LOXL3 interacted with snail family transcriptional repressor 1 (Snail1) through STRING database and RIP assay, and Snail1 bound to ubiquitin-specific peptidase 4 (USP4) promoter by JASPAR database, luciferase reporter gene and Co-IP assays. Overexpression of USP4 reversed the inhibitory effect of LOXL3 silence on EMT in HCC cells through deubiquitinating and stabilizing the expression of Snail1. Moreover, LOXL3-promoted HCC EMT through Wnt/β-catenin/Snail1 signaling pathway. In vivo study revealed that silence of LOXL3-inhibited HCC tumor growth. In conclusion, LOXL3 silence inhibited HCC invasion and EMT through Snail1/USP4-mediated circulation loop and Wnt/β-catenin signaling pathway. Show less
DNA methylation plays a significant role in transducing external environmental signals to a cellular response in reptiles; however, whether the methylation patterns are conserved across species remain Show more
DNA methylation plays a significant role in transducing external environmental signals to a cellular response in reptiles; however, whether the methylation patterns are conserved across species remains unclear. Here, we examined the genome-wide DNA methylation differentiation between male and female hatchling gonads of the temperature-dependent sex determination (TSD) Mauremys mutica (M. mutica) using methylation-dependent restriction-site associated DNA sequencing (MethylRAD-seq) to test differentially methylated genes underlying sexual development. Several categories, including heat-shock genes (HSP90A, HSP30C), histone- (KDM8) and ubiquitin-related genes (TRIM39), kinases (WNK3), and gonad differentiation or gonadal-development-related genes (HSD17B8, HSD17B12), were identified as candidates for future study. Additionally, we identified several regulatory pathways potentially mediating TSD thermosensitivity such as the GnRH signaling pathway and calcium signaling pathway. These findings provide evidence that sexually dimorphic DNA methylation may be associated with sex determination or sex differentiation in TSD M. mutica. Show less
Lung adenocarcinoma (LUAD) is a familiar lung cancer with a very poor prognosis. This study investigated the immune- and stemness-related genes to develop model related with cancer immunity and progno Show more
Lung adenocarcinoma (LUAD) is a familiar lung cancer with a very poor prognosis. This study investigated the immune- and stemness-related genes to develop model related with cancer immunity and prognosis in LUAD. The Cancer Genome Atlas (TCGA) was utilized for obtaining original transcriptome data and clinical information. Differential expression, prognostic value, and correlation with clinic parameter of mRNA stemness index (mRNAsi) were conducted in LUAD. Significant mRNAsi-related module and hub genes were screened using weighted gene coexpression network analysis (WGCNA). Meanwhile, immune-related differential genes (IRGs) were screened in LUAD. Stem cell index and immune-related differential genes (SC-IRGs) were screened and further developed to construct prognosis-related model and nomogram. Comprehensive analysis of hub genes and subgroups, involving enrichment in the subgroup [gene set enrichment analysis (GSEA)], gene mutation, genetic correlation, gene expression, immune, tumor mutation burden (TMB), and drug sensitivity, used bioinformatics and reverse transcription polymerase chain reaction (RT-PCR) for verification. Through difference analysis, mRNAsi of LUAD group was markedly higher than that of normal group. Clinical parameters (age, gender, and T staging) were ascertained to be highly relevant to mRNAsi. MEturquoise and MEblue were found to be the most significant modules (including positive and negative correlations) related to mRNAsi The SC-IRG model and the prognostic nomogram could accurately predict LUAD survival. Our study used mRNAsi combined with immunity that may lay a foundation for the future research studies in LUAD. Show less
Alzheimer disease (AD) is a degenerative brain disease, which may lead to severe memory loss and other cognitive disorders. However, few effective drugs are available in the clinic at present. Curcumi Show more
Alzheimer disease (AD) is a degenerative brain disease, which may lead to severe memory loss and other cognitive disorders. However, few effective drugs are available in the clinic at present. Curcumin, a major ingredient of traditional Chinese medicine, Curcuma Longa, has various pharmacological activities. Therefore, exploring clinical drugs based on the inhibition of AD pathological features is imperative. First, we utilized the HERB database and Swisstarget Prediction database to get the related targets of curcumin and intersected with the AD targets. The intersection targets were used to construct the protein-protein interaction network and performed gene ontology and kyoto encyclopedia of genes and genomes analyses. Further, we obtained targets of curcumin against AD-related tau and aβ pathology via the AlzData database. These targets were applied to perform GEO and receiver operating characteristic analyses. Finally, the reliability of the core targets was evaluated using molecular docking technology. We identified 49 targets of curcumin against AD, and kyoto encyclopedia of genes and genomes pathway enrichment analysis demonstrated that the Alzheimer disease pathway (has05010) was significantly enriched. Even more, we obtained 16 targets of curcumin-related Aβ and tau pathology. Among these targets, 8 targets involved the Alzheimer disease pathway and the biological process analyses showed that positive regulation of cytokine production (GO:0001819) was significantly enriched. Bioinformatic analyses indicated that HMOX1, CSF1R, NFKB1, GSK3B, BACE1, AR, or PTGS1 expression was significantly different compared to the control group in the AD patients. Finally, molecular docking studies suggested these genes have a good binding force with curcumin. In this study, we identified curcumin exerted the effect of treating AD by regulating multitargets and multichannels through the method of network pharmacology. Show less
Systemic amyloidosis is classified according to the deposited amyloid fibril protein (AFP), which determines its best therapeutic scheme. The most common type of AFP found are immunoglobulin light cha Show more
Systemic amyloidosis is classified according to the deposited amyloid fibril protein (AFP), which determines its best therapeutic scheme. The most common type of AFP found are immunoglobulin light chains. The laser microdissection combined with mass spectrometry (LMD-MS) technique is a promising approach for precise typing of amyloidosis, however, the major difficulty in interpreting the MS data is how to accurately identify the precipitated AFP from background. The objective of the present study is to establish a complete data interpretation procedure for LMD-MS based amyloidosis typing. Formalin-fixed paraffin-embedded specimens from patients with renal amyloidosis and non-amyloid nephropathies (including diabetic nephropathy, fibrillary glomerulonephritis, IgA nephropathy, lupus nephritis, membranous nephropathy, and normal tissue adjacent to tumors) were analyzed by LMD-MS. Forty-two specimens were used to train the data interpretation procedure, which was validated by another 50 validation specimens. Area under receiver operating curve (AUROC) analysis of amyloid accompanying proteins (AAPs, including apolipoprotein A-IV, apolipoprotein E and serum amyloid P-component) for discriminating amyloidosis from non-amyloid nephropathies was performed. A stepwise data interpretation procedure that includes or excludes the types of amyloidosis group by group was established. The involvement of AFPs other than immunoglobulin was determined by P-score, as well as immunoglobulin light chain by variable of λ-κ, and immunoglobulin heavy chain by H-score. This achieved a total of 88% accuracy in 50 validation specimens. The AAPs showed significantly different expression levels between amyloidosis specimens and non-amyloid nephropathies. Each of the single AAP had a AUROC value more than 0.9 for diagnosis of amyloidosis from non-amyloid control, and the averaged level of the three AAPs showed the highest AUROC (0.966), which might be an alternative indicator for amyloidosis diagnosis. The proteomic data interpretation procedure for LMD-MS based amyloidosis typing was established successfully that has a high practicability in clinical application. Show less
The characterization of immortalized canine osteosarcoma (OS) cell lines used for research has historically been based on phenotypic features such as cellular morphology and expression of bone specifi Show more
The characterization of immortalized canine osteosarcoma (OS) cell lines used for research has historically been based on phenotypic features such as cellular morphology and expression of bone specific markers. With the increasing use of these cell lines to investigate novel therapeutic approaches prior to in vivo translation, a much more detailed understanding regarding the genomic landscape of these lines is required to ensure accurate interpretation of findings. Here we report the first whole genome characterization of eight canine OS cell lines, including single nucleotide variants, copy number variants and other structural variants. Many alterations previously characterized in primary canine OS tissue were observed in these cell lines, including TP53 mutations, MYC copy number gains, loss of CDKN2A, PTEN, DLG2, MAGI2, and RB1 and structural variants involving SETD2, DLG2 and DMD. These data provide a new framework for understanding how best to incorporate in vitro findings generated using these cell lines into the design of future clinical studies involving dogs with spontaneous OS. Show less
Lymph node metastasis is associated with poor prognosis of oral squamous cell carcinoma (OSCC), and few studies have explored the relevance of postoperative lymphatic drainage (PLD) in metastatic OSCC Show more
Lymph node metastasis is associated with poor prognosis of oral squamous cell carcinoma (OSCC), and few studies have explored the relevance of postoperative lymphatic drainage (PLD) in metastatic OSCC. Alpha-enolase (ENO1) is a metabolic enzyme, which is related to lymphatic metastasis of OSCC. However, the role of ENO1 in PLD in metastatic OSCC has not been elucidated. Herein, we collected lymphatic drainage after lymphadenectomy between metastatic and non-metastatic lymph nodes in OSCC patients to investigate the relationship between ENO1 expression and metastasis, and to identify the proteins which interacted with ENO1 in PLD of patients with metastatic OSCC by MS/GST pulldown assay. Results revealed that the metabolic protein apolipoprotein C-III (ApoC3) was a novel partner of ENO1. The ENO1 bound to ApoC3 in OSCC cells and elicited the production of interleukin (IL)-8, as demonstrated through a cytokine antibody assay. We also studied the function of IL-8 on Jurkat T cells co-cultured with OSCC cells in vitro. Western blot analysis was applied to quantitate STAT3 (signal transducer and activator of transcription 3) and p-STAT3 levels. Mechanistically, OSCC cells activated the STAT3 signaling pathway on Jurkat T cells through IL-8 secretion, promoted apoptosis, and inhibited the proliferation of Jurkat T cells. Collectively, these findings illuminate the molecular mechanisms underlying the function of ENO1 in metastasis OSCC and provide new strategies for targeting ENO1 for OSCC treatment. Show less
To detect differentially expressed genes in patients with neonatal necrotizing enterocolitis (NEC) by bioinformatics methods and to provide new ideas and research directions for the prevention, early Show more
To detect differentially expressed genes in patients with neonatal necrotizing enterocolitis (NEC) by bioinformatics methods and to provide new ideas and research directions for the prevention, early diagnosis and treatment of NEC. Gene chip data were downloaded from the Gene Expression Omnibus database. The genes that were differentially expressed in NEC compared with normal intestinal tissues were screened with GEO2R. The functions, pathway enrichment and protein interactions of these genes were analyzed with DAVID and STRING. Then, the core network genes and significant protein interaction modules were detected using Cytoscape software. Overall, a total of 236 differentially expressed genes were detected, including 225 upregulated genes and 11 downregulated genes, and GO and KEGG enrichment analyses were performed. The results indicated that the upregulated differentially expressed genes were related to the dimerization activity of proteins, while the downregulated differentially expressed genes were related to the activity of cholesterol transporters. KEGG enrichment analysis revealed that the differentially expressed genes were significantly concentrated in metabolism, fat digestion and absorption pathways. Through STRING analysis, 9 key genes in the protein network interaction map were identified: EPCAM, CDH1, CFTR, IL-6, APOB, APOC3, APOA4, SLC2A and NR1H4. Metabolic pathways and biological processes may play important roles in the development of NEC. The screening of possible core targets by bioinformatics is helpful in clarifying the pathogenesis of NEC at the gene level and in providing references for further research. Show less
Wanbei pig (WBP) is one of the indigenous pig resources in China and has many germplasm characteristics. However, research on its genome is lacking. To assess the genomic variation, population structu Show more
Wanbei pig (WBP) is one of the indigenous pig resources in China and has many germplasm characteristics. However, research on its genome is lacking. To assess the genomic variation, population structure, and selection signatures, we resequenced 18 WBP for the first time and performed a comprehensive analysis with resequenced data of 10 Asian wild boars. In total, 590.03 Gb of data and approximately 41 million variants were obtained. Polymorphism level (θπ) ratio and genetic differentiation (fixation index)-based cross approaches were applied, and 539 regions, which harbored 176 genes, were selected. Functional analysis of the selected genes revealed that they were associated with lipid metabolism ( Show less
The biological function of lncRNA ELF3-AS1 remains largely unknown in cancers. The cause of SNAI2 overexpression in tumor metastasis remains largely unclear. The molecular mechanisms underlying the hi Show more
The biological function of lncRNA ELF3-AS1 remains largely unknown in cancers. The cause of SNAI2 overexpression in tumor metastasis remains largely unclear. The molecular mechanisms underlying the high co-expression of antisense lncRNAs and adjacent protein-coding genes remains unclear. RNA-seq, CHIP and dual-luciferase reporter assay were performed to identify lncRNAs regulated by SNAI2. MicroRNA-seq and RNA-seq studies were conducted to reveal the biological function of ELF3-AS1 in GC. RNA pulldown and CHIRP assays were conducted to identify the protein that interacts with ELF3-AS1. A total of 123 lncRNAs were identified to be regulated by SNAI2 in GC by RNA sequencing. The ELF3 gene and antisense lncRNA ELF3-AS1 were both transcriptionally repressed by SNAI2 or SNAI1. Down-regulation of ELF3-AS1 and ELF3 predicted poor prognosis in GC. Nuclear localized lncRNA ELF3-AS1 negatively regulated GC cell cycle progression via suppressing G1/S transition and histone synthesis. ELF3-AS1 mainly inhibited GC metastasis by repressing SNAI2 signaling. Additionally, ELF3-AS1 modulated ELF3 mRNA stability by RNA-RNA interaction. The RNA duplexes formed by ELF3 mRNA and lncRNA ELF3-AS1 directly interacted with the double-stranded RNA (dsRNA) binding protein complex ILF2/ILF3 (NF45/NF90). In turn, the ILF2/ILF3 complex dynamically regulated the expression of ELF3-AS1 and ELF3 by affecting the dsRNA stability. The SNAI2-ELF3-AS1 feedback loop regulates ELF3 expression at transcriptional and post-transcriptional levels and drives gastric cancer metastasis by maintaining SNAI2 overexpression. The ILF2/ILF3 complex plays a critical role in regulating dsRNA stability. In addition, our work provides a direct evidence that head-to-head antisense lncRNAs can share promoters with neighboring coding genes, which make their expression subject to similar transcriptional regulation, leading to high co-expression. Show less
Ovarian cancer (OC) has the lowest survival rate among gynecologic malignancies. Ectopic lymphocyte aggregates, namely tertiary lymphoid structures (TLSs), have been reported as positive biomarkers fo Show more
Ovarian cancer (OC) has the lowest survival rate among gynecologic malignancies. Ectopic lymphocyte aggregates, namely tertiary lymphoid structures (TLSs), have been reported as positive biomarkers for tumor prognosis. However, the related gene signature of tertiary lymphoid structure in ovarian cancer was less understood. Therefore, this study first exhibited the organizational patterns of tertiary lymphoid structure by H&E staining and immunohistochemistry (IHC), and confirmed the improved survival values of tertiary lymphoid structure and quantified tumor-infiltrating lymphocytes (CD20 Show less
Gut microbiome may influence tumor growth and cancer treatment efficacy, so it is a potential target for tumor prevention/treatment. This pilot study investigated the preventive and therapeutic effect Show more
Gut microbiome may influence tumor growth and cancer treatment efficacy, so it is a potential target for tumor prevention/treatment. This pilot study investigated the preventive and therapeutic effects of a probiotic strain, Lacticaseibacillus rhamnosus Probio-M9 (Probio-M9), against murine mammary cancer. Thirty-six female mice were randomly divided into three groups (n = 12 per group): control (without tumor transplantation), model (tumor transplantation; no probiotic administration), and probiotic (30-day oral gavage of probiotic, started seven days before tumor transplantation). Changes in tumor size were recorded, and blood, tumor tissue, and stool samples were collected at the end of the trial for analyses. Comparing with the model group, the probiotic group had a significantly smaller tumor volume (p < 0.05), a higher fecal microbiota Shannon diversity index, with significant modifications in the gut microbiota structure (p < 0.05), characterized by more Alistipes sp.₂, Porphyromonadaceae bacterium₇, and Bacteroidales bacterium 55₉ (p < 0.05). Additionally, Probio-M9 administration elevated the serum IFN-γ, IL-9, IL-13, and IL-27 levels and several metabolites (e.g., pyridoxal, nicotinic acid, 3-hydroxybutyric acid, glutamine; p < 0.05), while reducing IL-5 (p < 0.05). These changes might be associated with the protective effect of Probio-M9 against mammary tumor growth. Thus, probiotic administration could harness host gut microbiome in anti-cancer responses. Show less
To investigate associations of genetic and environmental factors with coronary artery disease (CAD), we collected medical reports, lifestyle details, and blood samples of 2113 individuals, and then us Show more
To investigate associations of genetic and environmental factors with coronary artery disease (CAD), we collected medical reports, lifestyle details, and blood samples of 2113 individuals, and then used the polymerase chain reaction (PCR)-ligase detection reaction (LDR) to genotype the targeted 102 SNPs. We adopted elastic net algorithm to build an association model that considered simultaneously genetic and lifestyle/clinical factors associated with CAD in Chinese Han population. In this study, we developed an all covariates-based model to explain the risk of CAD, which incorporated 8 lifestyle/clinical factors and a gene-score variable calculated from 3 significant SNPs (rs671, rs6751537 and rs11641677), attaining an area under the curve (AUC) value of 0.71. It was found that, in terms of genetic variants, the AA genotype of rs671 in the additive (adjusted odds ratio (OR) = 2.51, p = 0.008) and recessive (adjusted OR = 2.12, p = 0.021) models, the GG genotype of rs6751537 in the additive (adjusted OR = 3.36, p = 0.001) and recessive (adjusted OR = 3.47, p = 0.001) models were associated with increased risk of CAD, while GG genotype of rs11641677 in additive model (adjusted OR = 0.39, p = 0.044) was associated with decreased risk of CAD. In terms of lifestyle/clinical factors, the history of hypertension (unadjusted OR = 2.37, p < 0.001) and dyslipidemia (unadjusted OR = 1.82, p = 0.007), age (unadjusted OR = 1.07, p < 0.001) and waist circumference (unadjusted OR = 1.02, p = 0.05) would significantly increase the risk of CAD, while height (unadjusted OR = 0.97, p = 0.006) and regular intake of chicken (unadjusted OR = 0.78, p = 0.008) reduced the risk of CAD. A significantinteraction was foundbetween rs671 and dyslipidemia (the relative excess risk due to interaction (RERI) = 3.36, p = 0.05). In this study, we constructed an association model and identified a set of SNPs and lifestyle/clinical risk factors of CAD in Chinese Han population. By considering both genetic and non-genetic risk factors, the built model may provide implications for CAD pathogenesis and clues for screening tool development in Chinese Han population. Show less
Memory deficits and loss are the earliest and most prominent features of Alzheimer's disease (AD). This study was aimed to clarify the mechanistic basis of an active fraction of
Small interfering RNA (siRNA) therapeutic is considered to be a promising modality for the treatment of hyperlipidemia. Establishment of a thermostable clinically applicable delivery system remains a Show more
Small interfering RNA (siRNA) therapeutic is considered to be a promising modality for the treatment of hyperlipidemia. Establishment of a thermostable clinically applicable delivery system remains a most challenging issue for siRNA drug development. Here, a series of ionizable lipid-like materials were rationally designed; 4 panels of lipid formulations were fabricated and evaluated on the basis of four representative structures. The lead lipid (A1-D1-5) was stable at 40°C, and the optimized formulation (iLAND) showed dose and time dual-dependent gene silencing pattern with median effective dose of 0.18 mg/kg. In addition, potent and durable reduction of serum cholesterol and triglyceride were achieved by administering siRNAs targeting Show less
PCBP-1, a multifunctional RNA binding protein, is expressed in various human cell/tissue types and involved in post-transcriptional gene regulation. PCBP-1 has important roles in cellular Iron homeost Show more
PCBP-1, a multifunctional RNA binding protein, is expressed in various human cell/tissue types and involved in post-transcriptional gene regulation. PCBP-1 has important roles in cellular Iron homeostasis, mitochondrial stability, and other cellular activities involved in the pathophysiological process of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). However, it remains enigmatic whether PCPB-1 is associated with the pathogenesis of PD. In this study, we cloned and constitutively overexpressed PCBP-1 in rat PC12 cells (PC12 cell is the common cell line studying neurodegenerative disease include PD). RNA-seq was performed to analyze PCBP-1-regulated differentially expressed genes (DEGs) and alternative splicing events (ASEs) between control and PCBP1-overexpressed cells. GO and KEGG pathway analyses were performed to identify functional DEGs and alternatively spliced genes. Consequently, we validated PCBP-1-regulated genes using RT-qPCR. Finally, we downloaded CLIP-seq data from GEO (GSE84700) to analyze the mechanisms of PCBP-1's regulation of gene expression and ASEs by revealing the binding profile of PCBP-1 on its target pre-mRNAs. Overexpression of PCBP-1 partially regulated the ASE and expression of genes enriched in neuroinflammation and protein ubiquitination, which were also associated with PD pathogenesis. Moreover, RT-qPCR assay verified the PCBP-1-modulated expression of neuroinflammatory genes, like Show less
Sepsis is a common cause of morbidity and mortality in the ICU patients. Early diagnosis and appropriate patient management is the key to improve the patient survival and to limit disabilities in seps Show more
Sepsis is a common cause of morbidity and mortality in the ICU patients. Early diagnosis and appropriate patient management is the key to improve the patient survival and to limit disabilities in sepsis patients. This study was aimed to find new diagnostic biomarkers of sepsis. In this study, serum proteomic profiles in sepsis patients by iTRAQ2D-LC-MS/MS. Thirty seven differentially expressed proteins were identified in patients with sepsis, and six proteins including ApoC3, SERPINA1, VCAM1, B2M, GPX3, and ApoE were selected for further verification by ELISA and immunoturbidimetry in 53 patients of non-sepsis, 37 patients of sepsis, and 35 patients of septic shock. Descriptive statistics, functional enrichment analysis, and ROC curve analysis were conducted. The level of ApoC3 was gradually decreased among non-sepsis, sepsis, and septic shock groups (p = 0.049). The levels of VCAM1 (p = 0.010), B2M (p = 0.004), and ApoE (p = 0.039) were showing an increased tread in three groups, with the peak values of B2M and ApoE in the sepsis group. ROC curve analysis for septic diagnosis showed that the areas under ROC curve (AUC) of ApoC3, VCAM1, B2M, and ApoE were 0.625, 0.679, 0.581, and 0.619, respectively, which were lower than that of PCT (AUC 0.717) and CRP (AUC 0.706), but there were no significant differences between each index and PCT or CRP. The combination including four validated indexes and two classical infection indexes for septic diagnosis had the highest AUC-ROC of 0.772. Proteins of ApoC3, VCAM1, B2M, and ApoE provide a supplement to classical biomarkers for septic diagnosis. Show less
To investigate if a traditional Chinese medicine formulation, called "Yiqihuoxue" (YQHX), could improve diabetic atherosclerosis (DA) and explore potential mechanisms based on DNA methylation. Apolipo Show more
To investigate if a traditional Chinese medicine formulation, called "Yiqihuoxue" (YQHX), could improve diabetic atherosclerosis (DA) and explore potential mechanisms based on DNA methylation. Apolipoprotein E-knockout mice were administered streptozotocin (50 mg/d, i.p.) for 5 days and fed a high-fat diet for 16 weeks. Mice were divided randomly into DA model, rosiglitazone, as well as low-, medium-, and high-dose YQHX groups. Ten healthy C57BL/6J mice were the control group. Serum levels of fasting insulin, blood glucose, homeostasis model-insulin resistance index (HOMA-IR), serum lipids, and inflammatory factors were analyzed after the final treatment. Aorta tissues were collected for staining (hematoxylin and eosin, and Oil red O). Genomic DNA was extracted for methyl-capture sequencing (MC-seq). Kyoto Encyclopedia of Genes and Genomes (KEGG) and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) databases were used to analyze differentially methylated genes. Pyrosequencing was used to verify MC-seq data. Low-dose and high-dose YQHX could reduce the HOMA-IR ( YQHX decoction had positive treatment effects against DA, because it could regulate aberrant hypomethylation of DNA. Show less
Cholangiocarcinoma (CCA) remains one of the most lethal malignancies with an increasing incidence globally. Through whole-exome sequencing of 67 CCA tissues, we identified new mutated genes in CCA, in Show more
Cholangiocarcinoma (CCA) remains one of the most lethal malignancies with an increasing incidence globally. Through whole-exome sequencing of 67 CCA tissues, we identified new mutated genes in CCA, including MACF1, METTL14, ROBO1, and so on. The study was designed to explore the effects and mechanism of ROBO1 wild type (ROBO1 Whole-exome sequencing was performed to identify novel mutations in CCAs. Through whole-exome sequencing, we identified a novel CCA-related mutation, ROBO1 These results suggest that ROBO1 may act as a tumor suppressor and potential prognostic marker for CCA. ROBO1 Show less
Tianxiao Zhang, Hang Wei, Miao Li+6 more · 2022 · Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · Springer · added 2026-04-24
Early studies have indicated that the risk of migraine is contributed by both genetic and environmental factors. We aimed to evaluate the association between the risk of migraine and genetic polymorph Show more
Early studies have indicated that the risk of migraine is contributed by both genetic and environmental factors. We aimed to evaluate the association between the risk of migraine and genetic polymorphisms in the ANKDD1B gene in a large sample of Chinese Han populations. A total of 882 patients with MO and 1,784 age-matched controls were recruited. A list of 12 tag SNPs located within the ANKDD1B gene region was genotyped. Distributions of SNP genotypes and alleles between patients and controls were examined to investigate the associations between the risk of migraine and genetic polymorphisms. The GTEx database was used to examine the effects of the significant SNPs on gene expressions. A stop-gain SNP, rs34358, was discovered to be significantly related with the risk of migraine (χ Show less
Fuzheng Xiaojijinzhan (FZXJJZF) decoction is an effective prescription for treating colorectal cancer liver metastasis (LMCRC). To elucidate the pharmacological mechanism of the FZXJJZF decoction ther Show more
Fuzheng Xiaojijinzhan (FZXJJZF) decoction is an effective prescription for treating colorectal cancer liver metastasis (LMCRC). To elucidate the pharmacological mechanism of the FZXJJZF decoction therapy on LMCRC. Firstly, a network pharmacological approach was used to characterize the underlying targets of FZXJJZF on LMCRC. Secondly, LMCRC-related genes are obtained from the public database TCGA, and those genes are further screened and clustered through Mfuzz, an R package tool. Then, targets of FZXJJZF predicted by network pharmacology were overlapped with LMCRC related genes screened by Mfuzz. Meanwhile, FZJZXJF intervened in LMCRC model,epithelial-to-mesenchymal transition (EMT), and migration and invasion of HCT-116 cells. Thirdly, the transcriptomics data of FZJZXJF inhibited HCT-116 cells of EMT cells were overlapped with EMT database data to narrow the possible range of targets. Based on this, the potential targets and signal pathways of FZJZXJF were speculated by combining the transcriptomics data with the targets from network pharmacology-TCGA. Finally, the anti-cancer mechanism of FZXJJZF on LMCRC was verified in vitro by Real-Time PCR and Western Blot in vitro. By network pharmacological analysis, 282 ingredients and 429 potential targets of FZXJJZF were predicted. The 9268 LMCRC-related genes in the TCGA database were classified into 10 clusters by the Mfuzz. The two clustering genes with the most similar clustering trends were overlapped with 429 potential targets, and 32 genes were found, such as CD34, TRPV3, PGR, VDR, etc. In vivo experiments, FZJZXJF inhibited the tumor size in LMCRC models, and the EMT, migration, and invasion of HCT-116 also be inhibited. Intersecting transcriptomics dates with 32 target genes, it is speculated that the VDR-TGF-β signaling pathway may be an effective mechanism of FZXJJZF. Additionally, it is shown that FZXJJZF up-regulated the expression levels of VDR and E-cadherin and down-regulated the expression levels of TGF-β and Snail1 in vitro. These results confirmed that FZXJJZF plays an effective role in LMCRC mainly by inhibiting EMT phenotype via the VDR-TGF-β signaling pathway. Collectively, this study reveals the anti-LMCRC effect of FZXJJZF and its potential therapeutic mechanism from the perspective of potential targets and potential pathways. Show less
To investigate the aqueous levels of angiogenic factors in nonproliferative diabetic retinopathy (NPDR) patients with diabetic macular edema (DME) and to ascertain their association with optical coher Show more
To investigate the aqueous levels of angiogenic factors in nonproliferative diabetic retinopathy (NPDR) patients with diabetic macular edema (DME) and to ascertain their association with optical coherence tomography angiography (OCTA) metrics. This study enrolled 21 NPDR eyes with DME (NPDR/DME+), 17 NPDR eyes without DME (NPDR/DME-), and 16 diabetic eyes without retinopathy (DWR). Luminex bead-based multiplex array was used to measure the levels of 25 cytokines. OCTA system with a scan area of 3 × 3 mm was used to measure retinal thickness (RT), retinal volume (RV), superficial vessel density (SVD), deep vessel density (DVD), foveal avascular zone (FAZ) area, perimeter and acircularity index. The levels of ANGPTL4 were significantly different among the three groups ( The level of ANGPTL4 in aqueous humor of NPDR patients with DME was significantly increased and ANGPTL4 might predict RT, RV, and parafoveal DVD of DME in NPDR patients. 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
Intestinal inflammation is a common disease which can further lead to inflammatory bowel disease and even intestinal cancer. The increasing focus has come to the role of short-chain fatty acid (SCFA) Show more
Intestinal inflammation is a common disease which can further lead to inflammatory bowel disease and even intestinal cancer. The increasing focus has come to the role of short-chain fatty acid (SCFA) in various bowel diseases. Hence, this study was designed to explore the specific role of SCFA in intestinal inflammation. In vivo and in vitro models of intestinal inflammation were constructed by lipopolysaccharide (LPS) injection in mice and LPS treatment on intestinal epithelial cells. A possible regulatory mechanism involving SCFA, CCAAT enhancer-binding protein beta (CEBPB), microRNA-145 (miR-145), and dual-specificity phosphatase 6 (DUSP6) in intestinal inflammation was verified by ChIP assay and dual-luciferase reporter gene assay. To evaluate the effects of SCFA on LPS-treated intestinal epithelial cells, the expression of relevant genes and inflammatory factors (IL-6, TNF-α, and IL-1β) were determined. Last, the role of SCFA in vivo was explored through the scoring of disease activity index (DAI) and observation of colonic histology of LPS-treated mice. SCFA decreased the CEBPB expression in mouse colon tissues and small intestine epithelial cells induced by LPS. Furthermore, CEBPB could bind to the miR-145 promoter to inhibit its expression, thereby promoting the expression of DUSP6. In addition, SCFA improved the DAI, colonic histology, and the expression of serum inflammatory factors in LPS-treated mice and cells, noting that SCFA alleviated intestinal inflammation in vitro and in vivo. To sum up, SCFA inhibited DUSP6 by upregulating miR-145 through CEBPB repression and thus prevented the development of intestinal inflammation. Show less