👤 Guoyu Lan

Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a novel enteric coronavirus that causes severe clinical diarrhea and intestinal pathological injury in pigs. Selective autophagy is an important mechanism of host defense against virus invasion. However, the mechanism through which SADS-CoV-mediated selective autophagy mediates the innate immune response remains unknown. Here, we report that the host protein PABPC4 can inhibit SADS-CoV replication through targeting and degrading its N protein. Furthermore, we demonstrate that PABPC4 recruits MARCHF8 (an E3 ubiquitin ligase), which ubiquitinates the N protein and is degraded via NDP52/CALCOCO2 (a selective autophagy cargo receptor). Taken together, these findings reveal a new mechanism by which PABPC4 inhibits virus replication, and reveal a new target for antiviral drug development. Show less

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fatal disease characterized by the activation of lung fibroblasts (LFs). Wogonoside (WG), a natural compound with multiple pharmacological properties including anti-fibrotic activities, shows promise in treating IPF. This study aims to investigate the pharmacological effects and underlying mechanisms of WG on LF activation and the progression of IPF. Initially, we validated the anti-fibrotic properties of WG using a bleomycin (Bleomycin)-induced IPF model in mice, followed by RNA sequencing to identify its pharmacological targets. Subsequent in vitro experiments assessed the activities of key enzymes involved in the whole processes of glycolysis and lactic acid production, the changes of cellular energy metabolism and mitophagy-related pathways in LFs treated with transforming growth factor beta (TGF-β) or WG. Finally, reverse validation experiments were performed by further administration of lactic acid or cyclosporin A (CsA) into mice. We demonstrated that WG reduced the production of lactic acid and the lactylation of lactate of snail homolog 1 (Snail1) at K9 site by promoting pyruvate kinase isozymes R/l (PKLR) and inhibiting glyceraldehyde-3-phosphate dehydrogenase (GAPDH), while triggered mitophagy and reduced reactive oxygen species production and mtDNA release by promoting peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) and PTEN-induced kinase 1 (PINK1)/PARKIN pathways. These two processes compatibly inhibited the TGF-β transcription and ultimately LF activation, which were reversed by lactic acid supplementation or mitophagy depletion in mice. Overall, our findings first underscore the potential pharmacological benefits of WG in the treatment of IPF by impeding lactate accumulation and mitophagy damage, thereby providing a novel theoretical framework for therapies targeting pulmonary diseases. Show less

Type 2 Diabetes Mellitus (T2D) and Osteoarthritis (OA) are both prevalent diseases that significantly impact the health of patients. Increasing evidence suggests that there is a big correlation between T2D and OA, but the molecular mechanisms remain elusive. The aims of this study are to investigate the shared biomarkers and potential molecular mechanisms in T2D combined with OA. T2D and OA-related differentially expressed genes (DEGs) were identified via bioinformatic analysis on Gene Expression Omnibus (GEO) datasets GSE26168 and GSE114007 respectively. Subsequently, extensive target prediction and network analysis were finished with Gene Ontology (GO), protein-protein interaction (PPI), and pathway enrichment with DEGs. The transcription factors (TFs) and miRNAs coupled in co-expressed DEGs involved in T2D and OA were predicted as well. The key genes expressed both in the clinical tissues of T2D and OA were detected with western blot and qRT-PCR assay. Finally, the most promising candidate compounds were predicted with the Drug-Gene Interaction Database (DGIdb) and molecular docking. In this study, 209 shared DEGs between T2D and OA were identified. Functional analysis disclosed that these DEGs are predominantly related to ossification, regulation of leukocyte migration, extracellular matrix (ECM) structural constituents, PI3K/AKT, and Wnt signaling pathways. Further analysis via Protein-Protein Interaction (PPI) analysis and validation with external datasets emphasized MMP9 and ANGPTL4 as crucial genes in both T2D and OA. Our findings were validated through qRT-PCR and Western blot analyses, which indicated high expression levels of these pivotal genes in T2D, OA, and T2D combined with OA cases. Additionally, the analysis of Transcription Factors (TFs)-miRNA interactions identified 7 TFs and one miRNA that jointly regulate these important genes. The Receiver Operating characteristic (ROC) analysis demonstrated the significant diagnostic potential of MMP9 and ANGPTL4.Moreover, we identified raloxifene, ezetimibe, and S-3304 as promising agents for patients with both T2D and OA. This study uncovers the shared signaling pathways, biomarkers, potential therapeutics, and diagnostic models for individuals suffering from both T2D and OA. These findings not only present novel perspectives on the complex interplay between T2D and OA but also hold significant promise for improving the clinical management and prognosis of patients with this concurrent condition. Show less

To investigate the distribution of arteriosclerotic vessels of arteriosclerosis, differential serum lipid profiles, and differences in the proportion of dyslipidaemia between patients with single-site arteriosclerosis and multi-site arteriosclerosis (significant hardening of ≥2 arteries). The data of 6581 single-site arteriosclerosis patients and 5940 multi-site arteriosclerosis patients were extracted from the hospital medical record system. Serum total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein (Apo) A1, ApoB concentrations and C-reactive protein (CRP) between patients with single-site arteriosclerosis and multi-site arteriosclerosis were collected and analyzed. The most diseased arteries were coronary arteries (n=7099, 33.7%), limb arteries (n=6546, 31.1%), and carotid arteries (n=5279, 25.1%). TC, LDL-C, TC/HDL-C, and LDL-C/HDL-C levels were higher and CRP level was lower in multi-site arteriosclerosis patients than those in single-site arteriosclerosis patients. The TC, LDL-C levels in non-elderly (<65 years old) female patients were higher and TG/HDL-C, TC/HDL-C, LDL-C/HDL-C levels were lower than those in non-elderly male patients, while the TG, TC, LDL-C, and TG/HDL-C levels in elderly (≥65 years old) female patients were higher and LDL-C/HDL-C level was lower than those in elderly male patients. The proportion of dyslipidemia in descending order was as follows: low HDL-C (31.9%), elevated TG (16.9%), elevated TC (9.0%), and elevated LDL-C (4.2%). The levels of TC, LDL-C, TC/HDL-C, and LDL-C/HDL-C in patients with peripheral arteriosclerosis were higher than those in patients with cardio-cerebrovascular arteriosclerosis. There were differences in serum lipid levels in patients with arteriosclerosis with different age, gender and distribution of arteriosclerotic vessels. Show less

There is a decline in the quality and nutritive value of eggs in aged laying hens. Fruit pomaces with high nutritional and functional values have gained interest in poultry production to improve the performance. The performance, egg nutritive value, lipid metabolism, ovarian health, and cecal microbiota abundance were evaluated in aged laying hens (320 laying hens, 345-day-old) fed on a basal diet (control), and a basal diet inclusion of 0.25%, 0.5%, or 1.0% fermented The results show that 0.5% FAMP reduced the saturated fatty acids (such as C16:0) and improved the healthy lipid indices in egg yolks by decreasing the atherogenicity index, thrombogenic index, and hypocholesterolemia/hypercholesterolemia ratio and increasing health promotion index and desirable fatty acids ( Overall, FAMP improved the nutritive value of eggs in aged laying hens by improving the liver-blood-ovary function and cecal microbial and metabolite composition, which might help to enhance economic benefits. Show less

Hepatocellular carcinoma (HCC) is among the most prevalent digestive system malignancies and is associated with a poor prognosis. Necroptosis, a form of regulated death mediated by death receptors, exhibits characteristics of both necrosis and apoptosis. Long non-coding RNAs (lncRNAs) have been identified as crucial regulators in tumor necroptosis. This study aims to identify the necroptosis-related lncRNAs (np-lncRNA) in HCC and investigate their relationships with prognosis. The RNA-sequencing data, along with clinicopathological and survival information of HCC patients were sourced from The Cancer Genome Atlas (TCGA) database. The np-lncRNAs were analyzed to assess their potential in predicting HCC prognosis. Prognostic signatures related to necroptosis were constructed using stepwise multivariate Cox regression analysis. The prognosis of patients was compared using Kaplan-Meier (KM) analysis. The accuracy of the prognostic signature was evaluated using Receiver operating characteristic (ROC) analysis and decision curve analysis (DCA). Quantitative real-time polymerase chain reaction(qPCR) was employed to validate the lncRNAs expression levels of lncRNAs among samples from an independent cohort. The np-lncRNAs ZFPM2-AS1, AC099850.3, BACE1-AS, KDM4A-AS1 and MKLN1-AS were identified as potential prognostic biomarkers. The prognostic signature constructed from these np-lncRNAs achieved an Area Under the Curve (AUC) of 0.773. Based on the risk score derived from the signature, patients were divided into two groups, with the high-risk group exhibiting poorer overall survival. Gene Set Enrichment Analysis (GSEA) revealed significantly different between the low risk and high risk groups in tumor-related pathways (such as mTOR, MAPK and p53 signaling pathways) and immune-related functions (like T cell receptor signaling pathway and natural killer cell mediated cytotoxicity). The increased expression of np-lncRNAs was confirmed in another independent HCC cohort. This signature offers a dependable method for forecasting the prognosis of HCC patients. Our findings indicate a subset of np-lncRNA biomarkers that could be utilized for prognosis prediction and personalized treatment strategies of HCC patients. Show less

Circular RNAs (circRNAs) are engaged in various types of cancers. This study aimed to investigate the roles of circ₀₀₀₆₇₄₃ (circ_JMJD1C) in breast cancer. The downstream of circ_JMJD1C and their interaction network was determined by bioinformatic analyses. Gene expression were analyzed through western blot and qRT-PCR assays. Functional assays were conducted in vitro and in vivo to verify circ_JMJD1C role in BC. FISH and confocal analysis indicated the cellular distribution of circ_JMJD1C. Luciferase reporter, RNA immune-precipitation (RIP) assays, as well as Pearson's correlation analysis, were implemented to test the relation of miR-182-5p, JMJD1C and circ_JMJD1C. Circ_JMJD1C and JMJD1C expression were both elevated, and their expression was positively correlated in BC. Circ_ JMJD1C knockdown hindered BC cell proliferation, invasion, and migration, along with epithelial-mesenchymal transition (EMT) in vitro and in vivo. Circ_JMJD1C facilitated BC progression by the miR-182-5p-JMJD1C axis. Circ_JMJD1C epigenetically upregulated SOX4. Circ_JMJD1C promotes the aggressiveness of BC via regulating miR-182-5p/JMJD1C/SOX4 axis. This may provide a novel and promising therapy targeting BC. Show less

Gastrointestinal symptoms constitute a frequent complication in postoperative patients with valvular heart disease (VHD), impacting their postoperative recovery. Probiotics contribute to regulating human gut microbiota balance and alleviating postoperative gastrointestinal symptoms. Our objective involved assessing the potential of Show less

SNAP25 plays an essential role in the glucose-stimulated insulin secretion (GSIS) of pancreatic β-cells. Carbohydrate response element-binding protein (ChREBP) is an important transcription factor in β-cells and, in this study, we aimed to explore whether ChREBP regulates SNAP25 expression in β-cells. We show that diabetic Goto-Kakizaki (GK) rats exhibited impaired insulin secretion and hyperglycemia, along with decreased SNAP25 expression and ChREBP phosphorylation in islets. SNAP25 knockdown decreased GSIS in β-cells, while SNAP25 overexpression increased GSIS in β-cells. Activation or overexpression of ChREBP led to reduced SNAP25 expression and subsequent suppression of GSIS. Conversely, ChREBP knockdown mitigated the reduction in SNAP25 expression caused by high glucose. Mechanistically, the activation of ChREBP by high glucose increased its occupancy and decreased the level of H3K4me3 at the Snap25 promoter. Our findings reveal the novel regulatory mechanisms of SNAP25 expression in β-cells and suggest that SNAP25 may be involved in the regulation of β-cell secretory function controlled by ChREBP. Show less

Diabetic kidney disease (DKD) is the primary contributor to renal failure and poses a severe threat to human health. Accumulating studies demonstrated that competing endogenous RNA (ceRNA) network is involved in cuproptosis and DKD progression. However, the role of cuproptosis-associated ceRNA network and immune infiltration in DKD remains largely unclear. This study aimed to investigate the cuproptosis-related ceRNA regulation network and immune infiltration in DKD. The rat model of DKD was induced by combining the nephrectomy of the left kidney, high-fat diet, and streptozotocin. Differentially expressed genes (DEGs), miRNAs (DEMs), and lncRNAs (DELs) between normal and DKD rats were obtained. DEGs were intersected with cuproptosis-related genes (CRGs) to obtain DE-CRGs. LncRNAs and miRNAs were predicted based on the DE-CRGs, and they were intersected with DEMs and DELs, respectively. Subsequently, a cuproptosis-associated lncRNA-miRNA-mRNA network was established in DKD. In addition, the relative proportion of 22 infiltrating immune cell types in each sample was calculated, and the relationship between hub DE-CRGs and immune cells was explored. In total, there were 429 DEGs, 22 DEMs, and 48 DELs between CON and MOD groups. Then, 73 DE-CRGs were obtained, which were significantly enriched in 22 pathways, such as MAPK signaling pathway, IL-17 signaling pathway, and TNF signaling pathway. In addition, a core cuproptosis-related ceRNA network that included one lncRNA (USR0000B2476D), one miRNA (miR-34a-3p), and eight mRNAs (Mmp9, Pik3c3, Prom1, Snta1, Slc51b, Ntrk3, Snca, Egf) was established. In addition, 18 hub DE-CRGs were obtained. CIBERSORT algorithms showed that resting dendritic cells and resting NK cells were more infiltrated whereas regulatory T cells were less infiltrated in DKD rats than in normal rats. Spearman's correlation analysis revealed that hub DE-CRGs showed significant positive or negative correlations with naive B cells, regulatory T cells, resting NK cells, M0 macrophages, resting dendritic cells, and resting mast cells. A ceRNA network was comprehensively constructed, and 18 hub DE-CRGs were obtained, which will provide novel insights into the pathologic mechanism elucidation and targeted therapy development of DKD. Show less

Metastasis is the primary culprit behind cancer-related fatalities in multiple cancer types, including prostate cancer. Despite great advances, the precise mechanisms underlying prostate cancer metastasis are far from complete. By using a transgenic mouse prostate cancer model (TRAMP) with and without Phf8 knockout, we have identified a crucial role of PHF8 in prostate cancer metastasis. By complexing with E2F1, PHF8 transcriptionally upregulates SNAI1 in a demethylation-dependent manner. The upregulated SNAI1 subsequently enhances epithelial-to-mesenchymal transition (EMT) and metastasis. Given the role of the abnormally activated PHF8/E2F1-SNAI1 axis in prostate cancer metastasis and poor prognosis, the levels of PHF8 or the activity of this axis could serve as biomarkers for prostate cancer metastasis. Moreover, targeting this axis could become a potential therapeutic strategy for prostate cancer treatment. © 2024 The Pathological Society of Great Britain and Ireland. Show less

Florfenicol is a commonly used antibiotic for the treatment of bacterial diseases of the Chinese soft-shelled turtle (Pelodiscus sinensis). The study investigated the effects of florfenicol on the antioxidant and immune system of P. sinensis. Results showed that the total antioxidant capacity (T-AOC), superoxide dismutase (SOD), and catalase (CAT) activities were significantly increased in the 10 mg/kg and 40 mg/kg florfenicol treatment groups compared with the control group. Besides, the malondialdehyde (MDA) content was significantly increased, and the glutathione peroxidase (GSH-Px) activity was significantly decreased with 40 mg/kg florfenicol treatment. In addition, florfenicol has effects on the immune system, 10 mg/kg of florfenicol significantly promoted the activities of acid phosphatase (ACP) and alkaline phosphatase (AKP), whereas 40 mg/kg of florfenicol significantly inhibited their activities. To elucidate the molecular mechanisms, a comparative transcriptome analysis was conducted. A total of 59 differentially expressed genes (DEGs) and 12 significantly enriched KEGG pathways were identified in the 10 mg/kg group; 150 DEGs and 10 significantly enriched KEGG pathways were identified in the 40 mg/kg group. Among them, the complement and coagulation cascade pathways were the most significant which may play an important regulatory role in the immune response. The MADCAM1, STAT3, and IL4I1 genes may be the key genes of florfenicol affecting the immune response. The APOA1, APOA4, SPLA2, FADS1, and FADS2 genes may play a key role in anti-inflammatory and antioxidant effects through redox-related pathways. The study lays the foundation for a deeper understanding of the mechanism of the florfenicol effect on P. sinensis. Show less

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P Show less

Hand, foot, and mouth disease (HFMD) is a common viral childhood illness caused most commonly by enterovirus 71 (EV71) and coxsackievirus A16. The pathogenesis of EV71 has been extensively studied, and the regulation of the host immune response is suspected to aggravate the serious complications induced by EV71. Our previous research showed that EV71 infection significantly increased the release of circulating interleukin (IL)-6, IL-10, IL-13, and IL-27. Notably, these cytokines are related to the EV71 infection risk and clinical stage. Polyamines are compounds that are ubiquitous in mammalian cells and play a key role in various cellular processes. Several studies have shown that targeting polyamine metabolic pathways can reduce infections caused by viruses. However, the significance of polyamine metabolism in EV71 infection remains largely unknown. Serum samples from 82 children with HFMD and 70 healthy volunteers (HVs) were collected to determine the polyamine metabolites spermidine (SPD) and spermine (SPM), and IL-6 levels. In addition, peripheral blood mononuclear cells (PBMCs) were treated with EV71 viral protein 1 (VP1) and EV71 VP4, and the cells and supernatant were then collected to analyze the expression of polyamine metabolism-related enzymes by western blot. The data were analyzed using GraphPad Prism 7.0 software (USA). The serum polyamine metabolites SPD and SPM were elevated in the HFMD patients, especially in the EV71-infected children. Further, a positive correlation was found between serum SPD and IL-6 levels in the EV71-infected children. We also found that the upregulation of peripheral blood polyamine metabolites in the EV71-infected HFMD children was related to EV71 capsid protein VP1, but not VP4. VP1 may promote the expression of polyamine metabolism-related enzymes and promote the production of polyamine metabolites, thereby upregulating the SPD/nuclear factor kappa B/IL-6 signaling pathway. However, VP4 has the opposite effect in this process. Our results suggest that EV71 capsid protein may regulate the polyamine metabolic pathways of infected cells in a variety of ways. This study provides insights into the mechanism of EV71 infection and polyamine metabolism and has good reference value for the development of EV71 vaccine. Show less

The objective of this study was to evaluate the age-related changes in hepatic lipid metabolism, adipocyte hyperplasia, hypertrophy, and lipid metabolism in the abdominal adipose tissue of yellow-feathered broilers. Blood, liver, and abdominal adipose samples were collected on days 1, 7, 14, 21, 28, 35, 42, 49, and 56. Body, liver, and abdominal weight increased ( Show less

The poor prognosis of serous ovarian cancer (SOC) is due to its high invasive capacity and cisplatin resistance of SOC cells, whereas the molecular mechanisms remain poorly understood. In the present study, the expression and function of non-muscle myosin heavy chain IIB (MYH10) in SOC are identified by immunohistochemistry, in vitro, and in vivo studies, respectively. The mechanism of MYH10 is demonstrated by co-immunoprecipitation, GST pull-down, confocal laser assays, and so on. The results show that the knockdown of MYH10 suppressed SOC cell proliferation, migration, invasion, metastasis, and cisplatin resistance both in vivo and in vitro. Further studies confirm that the MYH10 protein functional domain combines with non-muscle myosin heavy chain IIA (MYH9) to recruit the deubiquitinating enzyme Ubiquitin-specific proteases 45 and deubiquitinates snail to inhibit snail degradation, eventually promoting tumorigenesis, progression, and cisplatin resistance in SOC. In clinical samples, MYH10 expression is significantly elevated in SOC samples compared to the paratumor samples. And the expression of MYH10 is positively correlated with MYH9 expression. MYH10+/MYH9+ co-expression is an independent prognostic factor for predicting SOC patient survival. These findings uncover a key role of the MYH10-MYH9-snail axis in SOC carcinogenesis, progression, and cisplatin resistance, and provide potential novel therapeutic targets for SOC intervention. Show less

Previous studies have shown that ovarian estrogens are involved in the occurrence and pathology of Alzheimer's disease (AD) through regulation on hippocampal synaptic plasticity and spatial memory; however, the underlying mechanisms have not yet been elucidated at the genomic scale. In this study, we established the postmenopausal estrogen-deficient model by ovariectomy (OVX). Then, we used high-throughput Affymetrix Clariom transcriptomics and found 143 differentially expressed genes in the hippocampus of OVX mice with the absolute fold change ≥ 1.5 and P < 0.05. GO analysis showed that the highest enrichment was seen in long-term memory. Combined with the response to steroid hormone enrichment and GeneMANIA network prediction, the serum and glucocorticoid-regulated kinase 1 gene (Sgk1) was found to be the most potent candidate for ovarian estrogenic regulation. Sgk1 overexpression viral vectors (oSgk1) were then constructed and injected into the hippocampus of OVX mice. Morris water maze test revealed that the impaired spatial learning and memory induced by OVX was rescued by Sgk1 overexpression. Additionally, the altered expression of synaptic proteins and actin remodeling proteins and changes in CA1 spine density and synapse density induced by OVX were also significantly reversed by oSgk1. Moreover, the OVX-induced increase in Aβ-producing BACE1 and Aβ and the decrease in insulin degrading enzyme were significantly reversed by oSgk1. The above results show that multiple pathways and genes are involved in ovarian estrogenic regulation of the function of the hippocampus, among which Sgk1 may be a novel potent target against estrogen-sensitive hippocampal dysfunctions, such as Aβ-initiated AD. Show less

Carbon emission trading is not only a market-based instrument but also one of the government's macro-policies, which is extremely crucial to fulfilling both carbon peak attainment and carbon neutrality goals. For this purpose, this paper adopts a 30-region dataset for the period from 2008 to 2020 in China and employs the difference-in-difference (DID) method to quantify the effect of the carbon emission trading pilot policy (CETP) on carbon emissions on the basis of introducing industrial structure upgrading and green technology innovation as moderating variables. The results show that (1) CETP has a statistically significant dampening effect on carbon emissions, while its carbon emission reduction effect follows a significant strengthening trend as the policy year of CETP implementation is delayed. (2) CETP has a significant carbon emission reduction effect. However, its effect demonstrates a gradual decrease from the eastern to the central and finally to the western regions. (3) CETP can inhibit carbon emissions depending on industrial structure upgrading to a certain extent, and this dependence is significant in the national and eastern regions but not in the central and western regions. (4) CETP's carbon emission reduction effect is dependent on green technology innovation, which is only revealed in the western region and performs as a dampening effect in the national, eastern, and central regions, but not significantly. 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

Investigation of associated risk factors of valproic acid (VPA)-induced tremor helped in increasing tolerance and optimizing treatment scheme individually. To determine the risk factors of VPA-induced tremor, with particular attention on identifying tremor-susceptible gene mutations. Epileptic patients taking VPA were divided into a tremor and a non-tremor groups. A mutation of rs9652490 in the leucine-rich repeat and immunoglobulin domain-containing Nogo-receptor-interacting protein 1 (LINGO-1) gene was determined by Sanger sequencing. Cerebellar atrophy was assessed, and various cerebellar dimensions were measured on magnetic resonance imaging (MRI) scans. One hundred and eighty-one of 200 subjects were included. Multivariate regression analysis indicated several VPA-induced tremor-related factors: females (OR = 2.718, p = 0.014), family history of tremor (OR = 7.595, p = 0.003), treatment duration (> 24 months; OR = 3.294, p = 0.002), and daily dosage (> 1,000 mg/d; OR = 19.801, p = 0.008) of VPA. Chi-square tests revealed that treatment with VPA magnesium-ER (p = 0.030) and carbamazepine combination (p = 0.040) reduced the incidence of tremor. One hundred and seventy-six gene sequencing and 86 MRI results excluded any significant difference between the two groups in the mutation of rs9652490 within LINGO-1, the ratio of cerebellar atrophy or the cerebellar-dimension values (p > 0.05). However, mutation of rs9652490 within LINGO-1 was correlated with increased cerebellar atrophy (p = 0.001), reduced cerebellar hemisphere thickness (p = 0.025), and right cerebellar hemisphere longitudinal diameter (p = 0.047). Our cohort indicated risk (female, positive family history of tremor, daily dosage > 1000 mg and treatment duration > 24 months of VPA) and protective factors (VPA magnesium-ER and combination with CBZ) of VPA-induced tremor. Mutation of rs9652490 within LINGO-1 correlated with cerebellar atrophy, neither was correlated with VPA-induced tremor. Show less

Pyroptosis was recently demonstrated to be an inflammatory form of gasdermin-regulated programmed cell death characterized by cellular lysis and the release of several proinflammatory factors and participates in tumorigenesis. However, the effects of pyroptosis-related long noncoding RNAs (lncRNAs) on hepatocellular carcinoma (HCC) have not yet been completely elucidated. Based on the regression coefficients of ZFPM2-AS1, KDM4A-AS1, LUCAT1, NRAV, CRYZL2P-SEC16B, AL031985.3, SNHG4, AL049840.5, AC008549.1, MKLN1-AS, AC099850.3, and LINC01224, HCC patients were classified into a low- or high-risk group. The high-risk score according to pyroptosis-related lncRNA signature was significantly associated with poor overall survival even after adjusting for age and clinical stage. Receiver operating characteristic curves and principal component analysis further supported the accuracy of the model. Our study revealed that a higher pyroptosis-related lncRNA risk score was significantly associated with tumor staging, pathological grade, and tumor-node-metastasis stages. The nomogram incorporating the pyroptosis-related lncRNA risk score and clinicopathological factors demonstrated good accuracy. Furthermore, we observed distinct tumor microenvironment cell infiltration characteristics between high- and low-risk tumors. Notably, based on the risk model, we found that the risk score is closely related to the expression of immune checkpoint genes, immune subtypes of tumors, and the sensitivity of HCC to chemotherapy drugs and immunotherapy. In conclusion, our novel risk score of pyroptosis-related lncRNA can serve as a promising prognostic biomarker for HCC patients and provide help for HCC patients to guide precision drug treatment and immunotherapy. Show less

The Angiopoietin-like protein 4 (ANGPTL-4) has been proved to be a protein associated with multiple inflammatory responses. Nevertheless, whether it contributes to distinguishing brucella spondylitis (BS) from tuberculous spondylitis (TS) remains an open question. Our study aim is to explore the capability of the ANGPTL-4 to differentiating BS from TS. In our study, 53 patients were screened out according to the criteria precisely in Xinjiang Medical University Affiliated of the First Hospital from 1 January, 2016, to 31 December, 2018. Their clinical data were retrospectively reviewed. All of them underwent pathological biopsy and magnetic resonance imaging examination. All the frozen tissue sections were stained for testing ANGPTL-4. Among the 53 patients, BS had 26 patients, and TS had 27 patients. There was no significant difference between the baseline (P = 0.682) between the two groups. The positive rate of ANGPTL-4 in TS patients (24/27, 88.89%) was higher than that in BS patients (17/26, 65.83%) (P < 0.05). The incidence of microangiopathy and fibrous connective tissue hyperplasia in patients with BS was distinctly higher than those in the TS (P = 0.001, P = 0.008, respectively). Patients of TS frequently presented more granuloma, caseous necrosis, epithelial-like reaction, interleukin 6 (IL-6), and C-reactive protein (CRP) than those of BS. Our study provided novel insights into distinguishing BS from TS using the ANGPTL-4 combining with histopathology, which may become new supporting evidence. Key Points • Brucella spondylitis and tuberculous spondylitis are a significant public health concern and even have prolonged damage, contributing to severe health and economic outcomes in Xinjiang of China. • The granuloma, caseous necrosis, epithelioid reaction, microangiosis, and fibrous connective tissue of pathological tissue might play a critical significance for distinguishing brucella spondylitis from tuberculous spondylitis patients. • ANGPLT-4 may become new supporting evidence identify brucella spondylitis and tuberculous spondylitis which is implicated in inflammation angiogenesis-related disorders. Show less

The prevalence of metabolic syndrome (Mets) is closely related to an increased incidence of cardiovascular events. Angiopoietin-like protein 4 (ANGPTL4) is contributory to the regulation of lipid metabolism, herein, may provide a target for gene-aimed therapy of Mets. This observational case control study was designed to elucidate the relationship between ANGPTL4 gene single nucleotide polymorphism (SNP) rs1044250 and the onset of Mets, and to explore the interaction between SNP rs1044250 and weight management on Mets. We have recruited 1018 Mets cases and 1029 controls in this study. The SNP rs1044250 was genotyped with blood samples, base-line information and Mets-related indicators were collected. A 5-year follow-up survey was carried out to track the lifestyle interventions and changes in Mets-related indicators. ANGPTL4 gene SNP rs1044250 is an independent risk factor for increased waist circumference (OR 1.618, 95% CI [1.119-2.340]; p = 0.011), elevated blood pressure (OR 1.323, 95% CI [1.002-1.747]; p = 0.048), and Mets (OR 1.875, 95% CI [1.363-2.580]; p < 0.001). The follow-up survey shows that rs1044250 CC genotype patients with weight gain have an increased number of Mets components (M [Q1, Q3]: CC 1 (0, 1), CT + TT 0 [- 1, 1]; p = 0.021); The interaction between SNP rs1044250 and weight management is a risk factor for increased systolic blood pressure (β = 0.075, p < 0.001) and increased diastolic blood pressure (β = 0.097, p < 0.001), the synergistic effect of weight management and SNP rs1044250 is negative (S < 1). ANGPTL4 gene SNP rs1044250 is an independent risk factor for increased waist circumference and elevated blood pressure, therefore, for Mets. However, patients with wild type SNP 1044250 are more likely to have Mets when the body weight is increased, mainly due to elevated blood pressure. Show less

The occurrence and development of hepatocellular carcinoma (HCC) remain unclear. This study aimed to investigate potential diagnostic or prognostic markers for early HCC by applying bioinformatic analysis. The gene expression profiles of early HCC and normal tissues from a TCGA dataset were used to identify differentially expressed genes (DEGs) and then analysed by weighted gene coexpression network analysis. The integrated genes were selected to construct the protein-protein interaction (PPI) network and determine the hub genes. The prognostic impact of the hub genes was then analysed. A total of 508 integrated genes were selected from the 615 DEGs and 8956 genes in the turquoise module. A PPI network was constructed, and the top 20 hub genes, including apolipoprotein A-IV (APOA4), fibrinogen gamma chain (FGG), vitamin K-dependent protein Z (PROZ), secreted phosphoprotein 24 (SPP2) and fetuin-B (FETUB), were identified. Only PROZ was significantly associated with the prognosis of early HCC. In this study, we demonstrated that the expression of PROZ was decreased in early HCC compared with normal liver controls, and low PROZ expression might result in poor overall survival of early HCC. Show less

Breast cancer is one of the most frequently diagnosed cancers and the leading cause of cancer death in women. MIER3 (Mesoderm induction early response 1, family member3) is considered as a potential oncogene for breast cancer. However, the role of MIER3 in breast cancer remain largely unknown. The expression of MIER3 was detected and the relationship between its expression and clinicopathological characteristics was also analyzed. The effect of MIER3 on proliferation and migration of breast cancer cells was detected in vitro and in vivo. Western blot, IF, and Co-IP were employed to detect the relationship between MIER3, HDAC1, HDAC2, and Snail. ChIP assay was performed to determine the binding of MIER3/HDAC1/HDAC2/Snail complex to the promoter of E-cadherin. In this study, we found that MIER3 was upregulated in breast cancer tissue and closely associated with poor prognosis of patients. MIER3 could promote the proliferation, migration, and epithelial-mesenchymal transition (EMT) of breast cancer cells. Further studies showed that MIER3 interacted with HDAC1/HDAC2 and Snail to form a repressive complex which could bind to E-cadherin promoter and was related to its deacetylation. Our study concluded that MIER3 was involved in forming a co-repressor complex with HDAC1/HDAC2/Snail to promote EMT by silencing E-cadherin. Show less

The ruminal epithelium is continuously challenged by antigens released by the lysis of dead microbial cells within the rumen. However, the innate immune system of the ruminal epithelium can almost always actively respond to these challenges. The cross talk between the ruminal microbiota and innate immune cells in the ruminal epithelium has been suggested to play an important role in sustaining the balance of immune tolerance and inflammatory response in the rumen. We hypothesized that conjugated linoleic acid (CLA), a functional microbial metabolite in the rumen, may contribute to the immune regulation in rumen epithelial cells (RECs); therefore, we first established an immortal REC line and then investigated the regulatory effects of CLA on the immune responses in these RECs. The results showed that long-term REC cultures were successfully established via SV40T-induced immortalization. Transcriptome analysis showed that a 100 μM CLA mixture consisting of 50:50 Show less

Preterm birth severely threatens neonatal health and life. Although the detailed mechanism of preterm birth is not well understood, accurately predicting preterm birth can help people make preparations in advance, greatly reducing the subsequent health risk of neonates. Therefore, in this study, we aimed to identify potential protein biomarkers of preterm birth in amniotic fluid (AF). We first enrolled pregnant subjects and collected their AF samples when they underwent amniocentesis at the second trimester of gestation. After delivery, the collected AF samples were classified into a full-term birth (sample size n = 21) set or preterm birth (n = 36) set, followed by 2-D DIGE and MS/MS assays. By doing so, we identified seven potential protein biomarkers of preterm birth, three of which were further validated in all samples with ELISA, including Apolipoprotein A-IV (Apoa4), Lumican (Lum) and Kininogen-1 (Kng1). As a result, all three potential biomarkers were significantly differently expressed between preterm and full-term birth AF samples. Furthermore, without prior classification, we found that these three biomarkers were positively correlated with gestation age (correlation coefficient ranging from 0.25 to 0.38) and were able to predict the occurrence of preterm birth. In this study, by examining amniotic fluid, we identified three biomarker proteins that may facilitate the identification of preterm birth. There three proteins were never reported to be related to preterm birth. Their pathogenesis roles in preterm birth deserve further investigations by using in vitro cell model or in vivo animal model assays. Show less