👤 Zhihang Xiao

GPIHBP1 is a protein found in the endothelial cells of capillaries that is anchored by glycosylphosphatidylinositol and binds to high-density lipoproteins. GPIHBP1 attaches to lipoprotein lipase (LPL), subsequently carrying the enzyme and anchoring it to the capillary lumen. Enabling lipid metabolism is essential for the marginalization of lipoproteins alongside capillaries. Studies underscore the significance of GPIHBP1 in transporting, stabilizing, and aiding in the marginalization of LPL. The intricate interplay between GPIHBP1 and LPL has provided novel insights into chylomicronemia in recent years. Mutations hindering the formation or reducing the efficiency of the GPIHBP1-LPL complex are central to the onset of chylomicronemia. This review delves into the structural nuances of the GPIHBP1-LPL interaction, the consequences of mutations in the complex leading to chylomicronemia, and cutting-edge advancements in chylomicronemia treatment. Show less

Lipoprotein lipase (LPL) deficiency, the most common familial chylomicronemia syndrome (FCS), is a rare autosomal recessive disease characterized by chylomicronemia and severe hypertriglyceridemia (HTG), with limited clinical and genetic characterization. To describe the manifestations and management of 19 pediatric patients with LPL-FCS. LPL-FCS patients from 2014 to 2022 were divided into low-fat (LF), very-low-fat (VLF) and medium-chain-triglyceride (MCT) groups. Their clinical data were evaluated to investigate the effect of different diets. The genotype-phenotype relationship was assessed. Linear regression comparing long-chain triglyceride (LCT) intake and TG levels was analyzed. Nine novel LPL variants were identified in 19 LPL-FCS pediatric patients. At baseline, eruptive xanthomas occurred in 3/19 patients, acute pancreatitis in 2/19, splenomegaly in 6/19 and hepatomegaly in 3/19. The median triglyceride (TG) level (30.3 mmol/L) was markedly increased. The MCT group and VLF group with LCT intakes <20 en% (energy percentage) had considerably lower TG levels than the LF group (both p<0.05). The LF group presented with severe HTG and significantly decreased TG levels after restricting LCT intakes to <20 en% (p<0.05). Six infants decreased TG levels to <10 mmol/L by keeping LCT intake <10 en%. TG levels and LCT intake were positively correlated in both patients under 2 years (r=0.84) and those aged 2-9 years (r=0.89). No genotype-phenotype relationship was observed. This study broadens the clinical and genetic spectra of LPL-FCS. The primary therapy for LPL-FCS pediatric patients is restricting dietary LCTs to <10 en% or <20 en% depending on different ages. MCTs potentially provide extra energy. Show less

Thioredoxin-interacting protein (TXNIP) plays a pivotal role in regulation of blood glucose homeostasis and is an emerging therapeutic target in diabetes and its complications. Celastrol, a pentacyclic triterpene extracted from the roots of Tripterygium wilfordii Hook F, can reduce insulin resistance and improve diabetic complications. This study aimed to untangle the mechanism of celastrol in ameliorating type 2 diabetes (T2DM) and evaluate its potential benefits as an anti-diabetic agent. db/db mice was used to evaluate the hypoglycemic effect of celastrol in vivo; Enzyme-linked immunosorbent assay (ELISA) and 2-NBDG assay were used to detect the effect of celastrol on insulin secretion and glucose uptake in cells; Western blotting, quantitative reverse transcription PCR (RT-qPCR) and immunohistological staining were used to examine effect of celastrol on the expression of TXNIP and the carbohydrate response element-binding protein (ChREBP). Molecular docking, cellular thermal shift assay (CETSA), drug affinity responsive targets stability assay (DARTS) and mass spectrometry were used to test the direct binding between celastrol and ChREBP. Loss- and gain-of-function studies further confirmed the role of ChREBP and TXNIP in celastrol-mediated amelioration of T2DM. Celastrol treatment significantly reduced blood glucose level, body weight and food intake, and improved glucose tolerance in db/db mice. Moreover, celastrol promoted insulin secretion and improved glucose homeostasis. Mechanistically, celastrol directly bound to ChREBP, a primary transcriptional factor upregulating TXNIP expression. By binding to ChREBP, celastrol inhibited its nuclear translocation and promoted its proteasomal degradation, thereby repressing TXNIP transcription and ultimately ameliorating T2DM through breaking the vicious cycle of hyperglycemia deterioration and TXNIP overexpression. Celastrol ameliorates T2DM through targeting ChREBP-TXNIP aix. Our study identified ChREBP as a new direct molecular target of celastrol and revealed a novel mechanism for celastrol-mediated amelioration of T2DM, which provides experimental evidence for its possible use in the treatment of T2DM and new insight into diabetes drug development for targeting TXNIP. Show less

Insulin signaling pathway plays an important role in metabolic associated fatty liver disease (MAFLD), however, the association between polymorphisms of genes related to insulin signaling pathway and MAFLD remains unclear. This study aims to investigate the association between insulin signaling pathway-related gene polymorphisms and gene-gene interactions with MAFLD susceptibility in obese children so as to provide scientific basis for further study of genetic mechanism. A total of 502 obese children with MAFLD who admitted to Hunan Provincial Children's Hospital from September 2019 to October 2021, were recruited as a case group, and 421 obese children with non-MAFLD admitted during the same period were recruited as a control group. Socio-demographic information, preterm birth history, eating habits, and exercise status of the subjects were collected by inquiry survey, and anthropometric information was collected by physical measurement. At the same time, 2 mL of venous blood was collected to extract DNA, and the polymorphism of insulin signaling pathway-related genes (5 representative candidate genes, 12 variants) was detected. Multivariate Logistic regression analysis was used to investigate the association between insulin signaling pathway-related gene polymorphisms and MAFLD in obese children. After adjusting for confounder factors, The Show less

Vitiligo is the most common depigmenting disorder to which both genetic and environmental factors contribute. The aim of the current work was to evaluate the relationship between polymorphisms of the gene nuclear receptor subfamily 1 Group H member 3 (NR1H3) and the risk of vitiligo and phototherapy effects in the Chinese Han population. Two independent samples were enrolled to form the discovery set (comprised of 1668 nonsegmental vitiligo [NSV] patients and 2542 controls) and the validation set (comprised of 745 NSV patients and 1492 controls). A total of 13 tag single nucleotide polymorphisms (SNPs) were genotyped in the samples from the discovery stage. SNPs that achieved nominal significance were validated in another independent sample set. The serum level of NR1H3 protein was assayed using enzyme-linked immunosorbent assay kits in the validation set. Genetic association analysis was carried out at allelic and genotypic levels. The therapeutic effects of significant SNPs were examined in the validation set. The SNP rs3758672 was significantly associated with NSV. The A allele was correlated with NSV risk and poorer therapeutic effects. The A allele was strongly correlated with the increased level of serum NR1H3 in both controls and patients. In summary, SNP rs3758672 in NR1H3 was significantly associated with both disease susceptibility and individualized therapeutic effects of NSV in study participants with Han Chinese ancestry. Show less

Colorectal cancer (CRC) is a prevalent cause of cancer and mortality on a global scale. SNAI1, a member of the zinc finger transcription superfamily, is a significant contributor to embryonic development and carcinogenesis through the process of epithelial-mesenchymal transition (EMT). While prior research utilizing CRC cells and clinical data has demonstrated that SNAI1 facilitates CRC progression through diverse mechanisms, the precise manner in which epithelial SNAI1 regulates CRC development in vivo remains unclear. In this study, colitis and colitis-associated CRC were induced through the use of intestinal epithelium-specific Snai1 knockout (Snai1 cKO) mice. Our findings indicate that Snai1 cKO mice exhibit a reduced susceptibility to acute colitis and colitis-associated CRC compared to control mice. Western-blot analysis of colon tissues revealed that Snai1 cKO mice exhibited a higher overall apoptosis level during tumor formation than control mice. No significant differences were observed in the activation of the classical p53 signaling pathway. However, Snai1 cKO mice exhibited weakened EMT and Wnt/β-catenin pathway activation. In summary, our study has provided evidence in vivo that the intestinal epithelial SNAI1 protein suppresses apoptosis, amplifies the EMT, and activates the Wnt/β-catenin signaling pathways in both early and late phases of CRC formation, thus promoting the development and progression of colitis-associated CRC. Show less

Structural maintenance of chromosomes protein 1 A (SMC1A) is a crucial subunit of the cohesion protein complex and plays a vital role in cell cycle regulation, genomic stability maintenance, chromosome dynamics. Recent studies demonstrated that SMC1A participates in tumorigenesis. This reseach aims to explore the role and the underlying mechanisms of SMC1A in gastric cancer (GC). RT-qPCR and western blot were used to examine the expression levels of SMC1A in GC tissues and cell lines. The role of SMC1A on GC cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) were analyzed. Furthermore,the mechanism of SMC1A action was investigated. SMC1A was highly expressed in GC tissues and cell lines. The high expression of SMC1A indicated the poor overall survival of GC patients from Kaplan-Meier Plotter. Enhancing the expression of SMC1A in AGS cells remarkably promoted cell proliferation in vitro and in vivo, migration and invasion, Conversely, knockdown of SMC1A in HGC27 cells inhibited cell proliferation, migration and invasion. Moreover, it's observed that SMC1A promoted EMT and malignant cell behaviors via regulating SNAIL. Our study revealed that SMC1A promotes EMT process by upregulating SNAIL, which contributes to gastric cancer cell proliferation, migration and invasion. Therefore, targeting SMC1A may be a potential strategy to improve GC therapy. Show less

Endothelial-mesenchymal transition (EndMT) and endothelial cell apoptosis have been documented to have a role in atherosclerosis (AS) progression. To deepen knowledge in this aspect, our study investigated the effect of LIM homeobox 2 (LHX2) and adhesion-regulating molecule 1 (ADRM1) on EndMT and endothelial cell apoptosis in the oxidized low-density lipoprotein (ox-LDL) -stimulated AS cell model.Ox-LDL was utilized to treat human umbilical vein endothelial cells (HUVECs) for constructing an AS model in vitro, followed by measurement of LHX2 and ADRM1 expressions. Afterward, gain- and loss-of-function assays were performed in HUVECs, followed by detection of cell viability, invasion, migration, and apoptosis and the expression of inflammatory factors [tumor necrosis factor (TNF) -α, interleukin (IL) -1β, and IL-6], EndMT-related proteins [CD31, vascular epithelium (VE) -cadherin, vimentin, α-smooth muscle actin (SMA), Snai1, Snai2, and Twist1], and the apoptotic protein cleaved caspase-3. Interactions between LHX2 and ADRM1 were analyzed with dual-luciferase reporter gene and chromatin immunoprecipitation assays.High levels of LHX2 and ADRM1 were observed in ox-LDL-induced HUVECs. In ox-LDL-treated HUVECs, LHX2, or ADRM1 knockdown promoted CD31 and VE-cadherin levels, viability, invasion, and migration and reduced apoptosis and the expressions of TNF-α, IL-1β, IL-6, vimentin, α-SMA, Snai1, Snai2, Twist1, and cleaved caspase-3. Mechanistically, LHX2 bound to the ADRM1 promoter to promote ADRM1 transcription. Overexpression of ADRM1 annulled the aforementioned effects of LHX2 knockdown on ox-LDL-induced HUVECs.LHX2 facilitates the pathological progression of ox-LDL-stimulated AS cell models by increasing ADRM1 transcription. Show less

Triple-negative breast cancer (TNBC) is the most aggressive subtype with limited effective therapies because of the absence of definitive targets. Here, we demonstrate that the expression of ZNF451, a poorly characterized vertebrate zinc-finger protein, is upregulated in TNBC and associated with a poor prognosis. Elevated ZNF451 expression facilitates TNBC progression by interacting with and enhancing the activity of the transcriptional activator snail family transcriptional repressor 2 (SLUG). Mechanistically, the ZNF451-SLUG complex preferentially recruits the acetyltransferase p300/CBP-associated factor (PCAF) to the CCL5 promoter, selectively facilitating CCL5 transcription by enhancing the acetylation of SLUG and local chromatin, leading to recruitment and activation of tumor-associated macrophages (TAMs). Disturbing the ZNF451-SLUG interaction using a peptide suppresses TNBC progression by reducing CCL5 expression and counteracting the migration and activation of TAMs. Collectively, our work provides mechanistic insights into the oncogene-like functions of ZNF451 and suggests that ZNF451 is a potential target for development of effective therapies against TNBC. Show less

Although great progress has made in gastric cancer (GC) in the past years, the overall 5-year survival rate remains to be low for advanced GC patients. A recent study showed that PLAGL2 was increased in GC and enhanced the proliferation and metastasis of GC. Nevertheless, the underlying mechanism still needs to be investigated. Gene and protein expressions were assessed using RT-qPCR and western blot. The migration, proliferation and invasion of GC cells were examined using scratch assay, CCK-8 assay and Transwell assay, respectively. ChIP-PCR, dual-luciferase assay, RIP-qPCR and CoiP were utilized to confirm the interaction among PLAGL2, UCA1, miR-145-5p and YTHDF1 as well as METTL3, YTHDF1 and eEF-2. A mouse xenograft model was used utilized to further confirm the regulatory network. PLAGL2 bound to the upstream promoter of UCA1, which regulated YTHDF1 by sponging miR-145-5p. METTL3 can mediate the m6A modification level of Snail. YTHDF1 recognized m6A-modified Snail by interacting with eEF-2 and thus promoted Snail expression, which eventually induced epithelial-mesenchymal transition (EMT) in GC cells and metastasis of GC. Overall, our study demonstrates that PLAGL2 enhances Snail expression and GC progression via the UCA1/miR-145-5p/YTHDF1 axis, suggesting that PLAGL2 may become a therapeutic target for GC treatment. Show less

Genome-wide association studies (GWASs) have identified numerous susceptibility loci for Parkinson's disease (PD), but its genetic architecture remains underexplored in populations of non-European ancestry. To identify genetic variants associated with PD in the Chinese population, we performed a GWAS using whole-genome sequencing (WGS) in 1,972 cases and 2,478 controls, and a replication study in a total of 8209 cases and 9454 controls. We identified one new risk variant rs61204179 (P Show less

(1) Background: This work aims to investigate the metabolomic changes in PIGinH11 pigs and investigate differential compounds as potential therapeutic targets for metabolic diseases. (2) Methods: PIGinH11 pigs were established with a CRISPR/Cas9 system. PNPLA3 Show less

Deoxynivalenol (DON), the most naturally-occurring trichothecenes, may affect animal and human health by causing vomiting as a hallmark of food poisoning. Deoxynivalenol-3-glucoside (D3G) usually co-occurs with DON as its glucosylated form and is another emerging food safety issue in recent years. However, the toxicity of D3G is not fully understood compared to DON, especially in emetic potency. The goals of this research were to (1) compare emetic effects to D3G by oral and intraperitoneal (IP) routes and relate emetic effects to brain-gut peptides glucose-dependent insulinotropic polypeptide (GIP) and substance P (SP) in mink; (2) determine the roles of calcium-sensing receptor (CaSR) and transient receptor potential (TRP) channel in D3G's emetic effect. Both oral and IP exposure to D3G elicited marked emetic events. This emetic response corresponded to an elevation of GIP and SP. Blocking the GIP receptor (GIPR) diminished emetic response induction by GIP and D3G. The neurokinin 1 receptor (NK-1R) inhibitor Emend Show less

Lung adenocarcinoma (LUAD) is a common malignant tumor with a poor prognosis. Recent studies have found that angiopoietin-like 4 (ANGPTL4) is abnormally expressed in many tumors, so it can serve as a potential prognostic marker and therapeutic target. However, its prognostic value in LUAD remains unclear. We downloaded RNA sequence data for LUAD from The Cancer Genome Atlas (TCGA) database, methylation data from the University of California Santa Cruz genome database, and clinical information. R software (version 4.1.1) was applied to analyze the ANGPTL4 expression in LUAD and nontumor samples, and the correlation with clinical characteristics to assess its prognostic and diagnostic value. In addition, we analyzed the relationship between the ANGPTL4 expression and methylation levels. Tumor IMmune Estimation Resource (TIMER) tool was taken for immune infiltration analysis, and two Gene Expression Omnibus (GEO) datasets were combined for meta-analysis. Finally, differentially expressed genes (DEGs) related to ANGPTL4 were analyzed to clarify its function. As shown in our results, ANGPTL4 was upregulated in LUAD and was an independent risk factor for the diagnosis and prognosis of LUAD. The general methylation level and eight ANGPTL4 methylation sites were significantly negatively correlated with the ANGPTL4 expression. Furthermore, we found that B cell infiltration was negatively correlated with ANGPTL4 expression and was an independent risk factor. Meta-analysis showed that the high expression of ANGPTL4 was closely associated with a poor prognosis. 153 DEGs, including the matrix metalloproteinase family, the chemokines subfamily, and the collagen family, were correlated with ANGPTL4. In this study, we found that ANGPTL4 was significantly elevated in LUAD and was closely associated with the development and poor prognosis of LUAD, suggesting that ANGPTL4 may be a prognostic biomarker and a potential therapeutic target for LUAD. Show less

Stomatitis is inflammation of the oral mucosa. Angiopoietin-like protein 4 (ANGPTL4) has pleiotropic functions both anti-inflammatory and pro-inflammatory properties. In the present study, we tested whether there is a correlation between increased ANGPTL4 expression and inflammation in stomatitis mice and the mechanisms involved. In this study, the oral mucosa of mice was burned with 90% phenol and intraperitoneal injection of 5-fluorouracil to establish the model of stomatitis mice. The pathological changes of stomatitis mice were observed by H&E staining of paraffin section. The expressions of cytokines and ANGPTL4 were detected by fluorescence quantitative PCR, and the protein levels of ANGPTL4 were detected by western blot. Compared with control group, the oral mucosal structure of model mice was damaged. The expression of ANGPTL4 were significantly increased concomitantly with elevated production of anti-inflammatory cytokine (peroxisome proliferator-activated receptor alpha) and pro-inflammatory cytokines [nuclear transcription factor-kappa B, interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α] in mice with stomatitis. This study suggests that ANGPTL4 may be a double-edged sword in multiple inflammatory responses in stomatitis mice. Show less

Secreted proteins are important proteins in the human proteome, accounting for approximately one-tenth of the proteome. However, the prognostic value of secreted protein-related genes has not been comprehensively explored in lung adenocarcinoma (LUAD). In this study, we screened 379 differentially expressed secretory protein genes (DESPRGs) by analyzing the expression profile in patients with LUAD from The Cancer Genome Atlas database. Following univariate Cox regression and least absolute shrinkage and selection operator method regression analysis, 9 prognostic SPRGs were selected to develop secreted protein-related risk score (SPRrisk), including CLEC3B, C1QTNF6, TCN1, F2, FETUB, IGFBP1, ANGPTL4, IFNE, and CCL20. The prediction accuracy of the prognostic models was determined by Kaplan-Meier survival curve analysis and receiver operating characteristic curve analysis. Moreover, a nomogram with improved accuracy for predicting overall survival was established based on independent prognostic factors (SPRrisk and clinical stage). The DESPRGs were validated by quantitative real-time PCR and enzyme-linked immunosorbent assay by using our clinical samples and datasets. Our results demonstrated that SPRrisk can accurately predict the prognosis of patients with LUAD. Patients with a higher risk had lower immune, stromal, and ESTIMATE scores and higher tumor purity. A higher SPRrisk was also negatively associated with the abundance of CD8 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 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

Geiparvarin (GN) is a natural compound with anticancer activity. However, the effect of GN on osteosarcoma (OS) and the anticancer mechanism of GN are still unclear. Cell viability was measured by MTT assay. Invasion and migration were measured by transwell assay. The miRNAs, genes, and signaling pathways affected by GN were confirmed by whole-genome sequencing and bioinformatics analysis. The expression level of mRNA and protein was measured by qRT-PCR and western blot. Animal experiment was performed for confirming the GN anticancer effect and side effect Our results show that GN significantly inhibits OS cell growth and metastasis Our data clearly indicate that GN is a candidate drug for OS treatment, and GN plays its role through miR-3912-3p/ANGPTL4 in OS. Show less

Angiopoietin-like protein (ANGPTL) 4 is a key factor in the regulation of lipid and glucose metabolism in metabolic diseases. ANGPTL4 is highly expressed in various cancers, but the regulation of energy metabolism in tumours remains to be determined. This study explored the role of ANGPTL4 in aerobic glycolysis, glutamine consumption and fatty acid oxidation in nonsmall cell lung cancer (NSCLC) cells. Two NSCLC cell lines (A549 and H1299) were used to investigate the role of ANGPTL4 in energy metabolism by tracer techniques and with Seahorse XF technology in ANGPTLs4 knockdown cells. RNA microarrays and specific inhibitors were used to identify targets in ANGPTLs4-overexpressing cells. The results showed that knockdown of ANGPTLs4 could inhibit energy metabolism and proliferation in NSCLC. ANGPTLs4 had no significant effect on glycolysis but affected glutamine consumption and fatty acid oxidation. Knockdown of ANGPTLs4 also significantly inhibited tumour metastasis and energy metabolism in mice and had a weak effect on glycolysis. RNA microarray analysis showed that ANGPTLs4 significantly affected glutaminase (GLS) and carnitine palmitoyl transferase 1 (CPT1). ANGPTLs4-overexpressing cells were exposed to a glutamine deprivation environment, and cell proliferation and energy metabolism were significantly decreased but still differed from normal NSCLC cells. Treatment of ANGPTLs4-overexpressing cells with GLS and CPT1 inhibitors simultaneously prevented the regulatory effects on cell proliferation and energy metabolism. ANGPTLs4 could promote glutamine consumption and fatty acid oxidation but not glycolysis or accelerate energy metabolism in NSCLC. Show less

The aggregation and interaction of metabolic risk factors leads to highly heterogeneous pathogeneses, manifestations, and outcomes, hindering risk stratification and targeted management. To deconstruct the heterogeneity, we used baseline data from phase II of the Fangshan Family-Based Ischemic Stroke Study (FISSIC), and a total of 4632 participants were included. A total of 732 individuals who did not have any component of metabolic syndrome (MetS) were set as a reference group, while 3900 individuals with metabolic abnormalities were clustered into subtypes using multi-trait limited mixed regression (MFMR). Four metabolic subtypes were identified with the dominant characteristics of abdominal obesity, hypertension, hyperglycemia, and dyslipidemia. Multivariate logistic regression showed that the hyperglycemia-dominant subtype had the highest coronary heart disease (CHD) risk (OR: 6.440, 95% CI: 3.177-13.977) and that the dyslipidemia-dominant subtype had the highest stroke risk (OR: 2.450, 95% CI: 1.250-5.265). Exome-wide association studies (EWASs) identified eight SNPs related to the dyslipidemia-dominant subtype with genome-wide significance, which were located in the genes Show less

Long-term use of olanzapine, an antipsychotic drug, induces hypertriglyceridemia, resulting in a higher risk of cardiovascular disease. However, the effects and underlying mechanisms of short-term use of olanzapine on circulating triglyceride levels remain poorly understood. Here, the role of apolipoprotein A5 (apoA5), a regulator of triglyceride metabolism, was investigated in olanzapine-induced hypertriglyceridemia. Our multi-center clinical study recruited 36 schizophrenia patients who received short-term (8 weeks) of olanzapine. Besides, female C57BL/6J mice were treated with olanzapine (3 mg/kg/day versus 6 mg/kg/day) for 6 weeks. We demonstrated that short-term use of olanzapine increased plasma triglyceride and decreased plasma apoA5 levels in the patients and mice, with a negative correlation between the two factors. However, no obesity was observed in the patients and mice. Interestingly, olanzapine increased hepatic apoA5 protein in the mice, without significant changes in hepatic Show less

The liver is the center for uptake, synthesis, packaging, and secretion of lipids and lipoproteins. The research on lipid metabolism in pigs is limited. The objective of the present study is to identify the genes related to lipid metabolism and oxidative stress in pigs by using transcriptomic analysis. Liver segments were collected from 60 Jinhua pigs for the determination of liver lipid content. The 7 pigs with the highest and lowest liver lipid content were set as group H and group L, respectively. Liver segments and serum samples were collected from each pig of the H and L groups for RNA sequencing and the determination of triglycerides (TG) content and high-density lipoprotein cholesterol (HDL) content, respectively. The HDL content in the serum of pigs in the H group was significantly higher than the L group ( Show less

Axin1 is a key regulator of canonical Wnt signaling pathway. Roles of Axin1 in skeletal development and in disease occurrence have not been fully defined. Here, we report that Axin1 is essential for lower limb development. Specific deletion of Show less

Acute respiratory infection by influenza virus is a persistent and pervasive public health problem. Antiviral innate immunity initiated by type I interferon (IFN) is the first responder to pathogen invasion and provides the first line of defense. We discovered that Axin1, a scaffold protein, was reduced during influenza virus infection. We also found that overexpression of Axin1 and the chemical stabilizer of Axin1, XAV939, reduced influenza virus replication in lung epithelial cells. This effect was also observed with respiratory syncytial virus and vesicular stomatitis virus. Axin1 boosted type I IFN response to influenza virus infection and activated JNK/c-Jun and Smad3 signaling. XAV939 protected mice from influenza virus infection. Thus, our studies provide new mechanistic insights into the regulation of the type I IFN response and present a new potential therapeutic of targeting Axin1 against influenza virus infection. Show less

Axin1 is a fundamental scaffolding protein of the destruction complex in the canonical Wnt signaling pathway, which plays a critical role in various biological processes. However, how Axin1 is regulated in the activation of the canonical Wnt signaling pathway remains elusive. Here, we report that Axin1 is constitutively acetylated in resting cells. Upon stimulation with Wnt, SIRT4 translocates from mitochondria to the cytoplasm and catalyzes Axin1 deacetylation, thus turning off the destruction complex. In this process, Lys147, a residue in the RGS domain of Axin1, plays a key role. We proved that the Axin1-K147R mutant impairs the assembly of β-TrCP to the destruction complex, which leads to β-catenin accumulation even without Wnt stimulation. In summary, our work proposes a new model for better understanding the initial stage of the canonical Wnt signaling pathway in which SIRT4 translocates from mitochondria into the cytoplasm to deacetylate Axin1-K147 after Wnt stimulation, which results in reduced assembly of β-TrCP to the destruction complex. Show less

M6A reader YTH structural domain family 2 (YTHDF2) has been recognized to play an oncogenic role in numerous tumors, but its role in cervical cancer has not been extensively discussed yet. This paper was designed to explore the role of YTHDF2 in cervical cancer and identify its underlying mechanism. The expression of YTHDF2 was first determined in cervical cancer cells by quantitative reverse-transcription polymerase chain reaction and western blot. Then, the migration, invasion, and epithelial-mesenchymal transition (EMT) process were observed in YTHDF2-knockdown Hela cells using wound healing, transwell and immunofluorescence assays. The cisplatin chemosensitivity of Hela cells was also investigated by assessing cell activity with cell counting kit-8 and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling). After MeRIP-Seq assay and actinomycin D treatment to confirm the binding relationship between YTHDF2 and AXIN1, the migration, invasion, EMT process, and cisplatin chemosensitivity were assessed again in Hela cells silenced by YTHDF2 and AXIN1 or treated with Wnt agonist. YTHDF2 was increased in cervical cancer cells, and depletion of YTHDF2 led to reduced migration, invasion and EMT process but enhanced chemosensitivity of cisplatin in Hela cells. Furthermore, YTHDF2 could bind to and stabilize the expression of AXIN1. When the YTHDF2-knockdown Hela cells were further transfected with AXIN1 knockdown or treated with Wnt agonist, the effects of YTHDF2 knockdown on the migration, invasion and EMT process were partially abolished, together with reduced cisplatin chemosensitivity. To sum up, we reported that YTHDF2 interference could suppress the EMT of cervical cancer cells and enhance cisplatin chemosensitivity by regulating AXIN1. Show less

Ovarian cancer (OC) is the most fatal gynecologic cancer. The branched-chain First, the expression level of BCKDK in OC cell lines or tissues was determined using tissue microarray- (TMA-) based immunohistochemistry or western blotting. Then, growth curve analysis, anchorage-independent cell transformation assays, wound healing assays, cell migration assays, and tumor xenografts were used to test whether BCKDK could promote cell transformation or metastasis. Finally, the signaling pathways involved in this process were investigated by western blotting or immunoprecipitation. We found that the expression of BCKDK was upregulated in OC tissues and the high expression of BCKDK was correlated with an advanced pathological grade in patients. The ectopic overexpression of BCKDK promoted the proliferation and migration of OC cells, and the knockdown of BCKDK with shRNAs inhibited the proliferation and migration of OC ex vivo and Our results demonstrate that BCKDK promotes OC proliferation and migration by activating the MEK/ERK signaling pathway. Targeting the BCKDK-MEK axis may provide a new therapeutic strategy for treating patients with OC. Show less

Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by asthma-like attacks in its early stage, which is easily misdiagnosed as severe asthma. Therefore, new biomarkers for the early diagnosis of EGPA are needed, especially for differentiating the diagnosis of asthma. To identify serum biomarkers that can be used for early diagnosis of EGPA and to distinguish EGPA from severe asthma. Data-independent acquisition (DIA) analysis was performed to identify 45 healthy controls (HC), severe asthma (S-A), and EGPA patients in a cohort to screen biomarkers for early diagnosis of EGPA and to differentiate asthma diagnosis. Subsequently, parallel reaction monitoring (PRM) analysis was applied to a validation cohort of 71 HC, S-A, and EGPA patients. Four candidate biomarkers were identified from DIA and PRM analysis-i.e., serum amyloid A1 (SAA1), fibrinogen-α (FGA), and serum amyloid P component (SAP)-and were upregulated in the EGPA group, while cholesteryl ester transfer protein (CETP) was downregulated in the EGPA group compared with the S-A group. Receiver operating characteristics analysis shows that, as biomarkers for early diagnosis of EGPA, the combination of SAA1, FGA, and SAP has an area under the curve (AUC) of 0.947, a sensitivity of 82.35%, and a specificity of 100%. The combination of SAA1, FGA, SAP, and CETP as biomarkers for differential diagnosis of asthma had an AUC of 0.921, a sensitivity of 78.13%, and a specificity of 100%, which were all larger than single markers. Moreover, SAA1, FGA, and SAP were positively and CETP was negatively correlated with eosinophil count. DIA-PRM combined analysis screened and validated four previously unexplored but potentially useful biomarkers for early diagnosis of EGPA and differential diagnosis of asthma. Show less

The sensitivity and specificity of current biomarkers for gastric cancer were insufficient. The aim of the present study was to screen novel biomarkers and determine the diagnostic values of ornithine aminotransferase (OAT) and carbamoyl phosphate synthetase 1 (CPS1) for detecting gastric cancer. With stable isotope tags, we labelled an initial discovery group of four paired gastric cancer tissue samples and identified with LC-ESI-MS/MS. A validation group of 159 gastric cancer samples and 30 healthy controls were used to validate the candidate targets. GSEA was used to explore the pathways activated in gastric cancer. Four hundred and thirty one proteins were found differentially expressed in gastric cancer tissues. Of these proteins, OAT and CPS1 were found over-expressed in gastric cancer patients, with sensitivity of 70.4% (95% CI: 63.3%-77.6%) and specificity of 80.5% (95% CI: 74.3%-86.7%) for ornithine aminotransferase, and with sensitivity of 68.6% (95% CI: 61.3%-75.8%) and specificity of 73% (95% CI: 66%-79.9%) for carbamoyl phosphate synthetase 1. The co-expression of OAT and CPS1 in gastric cancer tissues has a sensitivity of 81% (95% CI: 73.2%-88.8%) and specificity of 89% (95% CI: 83%-95%). Furthermore, both OAT and CPS1 were overexpressed in patients with local invasion T3 and T4 stages than those in patients with T1 and T2 stages. The co-expression of OAT and CPS1 was strongly correlated with histological grade I 68% (95% CI: 58.7%-77.3%) and TNM stage I/II 52% (95% CI: 42%-62%). The areas under ROC curves were up to 0.758 for the co-expression of OAT and CPS1 in gastric cancer. GSEA results showed that two gene sets and 30 gene sets were activated in OAT high- and CPS1 high-expression patients with gastric cancer, respectively. The present findings indicated a tight correlation between the co-expression of OAT and CPS1 and the histological grade, local invasion, and TNM stages of gastric cancer. Therefore, OAT and CPS1 might be predictors for gastric cancer invasion and potential targets for anticancer drug design for gastric cancer. Show less