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Cataract causes vision loss and blindness due to formation of opacities of the lens. The regulatory mechanisms of cataract formation and progression remain unclear, and no effective drug treatments are clinically available. In the present study, we tested the effect of ataxia telangiectasia mutated (Atm) inhibitors using an ex vivo model in which rat lenses were cultured in galactose-containing medium to induce opacity formation. After lens opacities were induced by galactose, the lenses were further incubated with the Atm inhibitors AZD0156 or KU55933, which decreased lens opacity. Subsequently, we used microarray analysis to investigate the underlying molecular mechanisms of action, and extracted genes that were upregulated by galactose-induced opacity, but not by inhibitor treatment. Quantitative measurement of mRNA levels and subsequent STRING analysis revealed that a functional network consisting primarily of actin family and actin-binding proteins was upregulated by galactose treatment and downregulated by both Atm inhibitors. In particular, Acta2 is a known marker of epithelial-mesenchymal transition (EMT) in epithelial cells, and other genes connected in this functional network (Actn1, Tagln, Thbs1, and Angptl4) also suggested involvement of EMT. Abnormal differentiation of lens epithelial cells via EMT could contribute to formation of opacities; therefore, suppression of these genes by Atm inhibition is a potential therapeutic target for reducing opacities and alleviating cataract-related visual impairment. Show less

Angiopoietin-like 3 (ANGPTL3) and 4 (ANGPTL4) are regulators of triglyceride storage and utilization. Bariatric surgery (BS) leads to profound changes in adipose tissue composition and energy metabolism. We evaluated the impact of BS on plasma levels of ANGPTL3 and ANGPTL4. Twenty-seven subjects affected by morbid obesity with or without type 2 diabetes (T2D) underwent Roux-en-Y gastric bypass (RYGB) and 18 patients with advanced T2D received Biliopancreatic Diversion (BPD). Fasting ANGPTL proteins levels, insulin sensitivity (evaluated by euglycemic hyperinsulinemic clamp), total bile acids (TBA) and free fatty acids (FFA) were measured at baseline and 1 year after surgery. Both surgical procedures resulted in the loss of fat mass, improved glucose control, and a ∼2-fold increase of insulin sensitivity. ANGPTL4 levels decreased significantly with both RYGB (26.6 ± 0.6 to 24.4 ± 0.3 ng/mL, p = 0.001) and BPD (27.9 ± 1.5 to 24.0 ± 0.5 ng/mL, p = 0.003). In contrast, ANGPTL3 concentrations did not change after RYGB but rose following BPD (225 ± 20 to 300 ± 15 ng/mL, p = 0.003). By multiple regression analysis, changes after BS in ANGPTL4 were independently associated with changes in blood glucose, (p = 0.0169) whereas changes in ANGPTL3 were associated with variations in FFA (p = 0.008) and insulin sensitivity (p = 0.043). Circulating ANGPTL4 is reduced by BS, probably due to the loss of fat mass and improved insulin sensitivity. Conversely, ANGPTL3 levels increased after BPD, but not after RYGB, presumably because of the metabolic changes induced by the malabsorptive effect of BPD. Show less

Cannabidiolic acid (CBDA) can activate peroxisome proliferator-activated receptor-α (PPARα) and PPARγ. Whether CBDA can activate PPARβ/δ has not been examined sufficiently to date. Since previous studies showed that triple-negative breast cancer cells respond to activation of PPARβ/δ, the present study examined the effect of CBDA in MDA-MB-231 cells and compared the activities of CBDA with known PPARβ/δ agonists/antagonists. Expression of the PPARβ/δ target genes angiopoietin-like 4 (ANGPTL4) and adipocyte differentiation-related protein (ADRP) was increased by CBDA. Interestingly, ligand activation of PPARβ/δ with GW501516 caused an increase in expression of both ANGPTL4 and ADRP, but the magnitude of this effect was markedly increased when co-treated with CBDA. Specificity of these effects were confirmed by showing that CBDA-induced expression of ANGPTL4 and ADRP is mitigated in the presence of either a PPARβ/δ antagonist or an inverse agonist. Results from these studies suggest that CBDA can synergize with PPARβ/δ and might interact with endogenous agonists that modulate PPARβ/δ function. Show less

Osteoarthritis (OA) is a frequently observed condition in aged people. OA cartilage is characterized by chondrocyte apoptosis, chondrocyte inflammation, and hyperactive catabolism of extracellular matrix. However, the specific molecular mechanisms remain unclear. Recent data has shown that Angptl4, a multifunctional cytokine, is involved in the regulation of inflammatory and apoptosis responses in different tissues. This study is aimed at defining the role of Angptl4 in the development of OA. We employed X-ray analysis, safranin O-fast green (S-O) staining, and hematoxylin staining to evaluate histomorphological characteristics in the knee joint of mice. Real-time quantitative polymerase chain reaction, Western blot assays, immunofluorescence staining, and enzyme-linked immunosorbent assays (ELISA) were performed to analyze the changes in gene and protein expression. Mechanically, our data demonstrated that Angptl4 knockdown improved the degradation of extracellular matrix and reduced TNF- Show less

Cigarette smoke exposure has a harmful impact on health and increases the risk of disease. However, studies on cigarette-smoke-induced adverse effects from the perspective of the gut-liver axis are lacking. In this study, we evaluated the adverse effects of cigarette smoke exposure on mice through physiological, biochemical, and histopathological analyses and explored cigarette-smoke-induced gut microbiota imbalance and changes in liver gene expression through a multiomics analysis. We demonstrated that cigarette smoke exposure caused abnormal physiological indices (including reduced body weight, blood lipids, and food intake) in mice, which also triggered liver injury and induced disorders of the gut microbiota and liver transcriptome (especially lipid metabolism). A significant correlation between intestinal bacterial abundance and the expression of lipid-metabolism-related genes was detected, suggesting the coordinated regulation of lipid metabolism by gut microbiota and liver metabolism. Specifically, Show less

In rats, the time of birth is characterized by a transient rise in beta cell replication, as well as beta cell neogenesis and the functional maturation of the endocrine pancreas. However, the knowledge of the gene expression during this period of beta cell expansion is incomplete. The aim was to characterize the perinatal rat pancreas transcriptome and to identify regulatory pathways differentially regulated at the whole organ level in the offspring of mothers fed a regular control diet (CO) and of mothers fed a low-protein diet (LP). We performed mRNA expression profiling via the microarray analysis of total rat pancreas samples at embryonic day (E) 20 and postnatal days (P) 0 and 2. In the CO group, pancreas metabolic pathways related to sterol and lipid metabolism were highly enriched, whereas the LP diet induced changes in transcripts involved in RNA transcription and gene regulation, as well as cell migration and apoptosis. Moreover, a number of individual transcripts were markedly upregulated at P0 in the CO pancreas: growth arrest specific 6 ( Show less

It is well known that hypoxia and ferroptosis are intimately connected with tumor development. The purpose of this investigation was to identify whether they have a prognostic signature. To this end, genes related to hypoxia and ferroptosis scores were investigated using bioinformatics analysis to stratify the risk of lung adenocarcinoma. Hypoxia and ferroptosis scores were estimated using The Cancer Genome Atlas (TCGA) database-derived cohort transcriptome profiles via the single sample gene set enrichment analysis (ssGSEA) algorithm. The candidate genes associated with hypoxia and ferroptosis scores were identified using weighted correlation network analysis (WGCNA) and differential expression analysis. The prognostic genes in this study were discovered using the Cox regression (CR) model in conjunction with the LASSO method, which was then utilized to create a prognostic signature. The efficacy, accuracy, and clinical value of the prognostic model were evaluated using an independent validation cohort, Receiver Operator Characteristic (ROC) curve, and nomogram. The analysis of function and immune cell infiltration was also carried out. Here, we appraised 152 candidate genes expressed not the same, which were related to hypoxia and ferroptosis for prognostic modeling in The Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) cohort, and these genes were further validated in the GSE31210 cohort. We found that the 14-gene-based prognostic model, utilizing Our research found a 14-gene signature and established a nomogram that accurately predicted the prognosis in patients with lung adenocarcinoma. Clinical decision-making and therapeutic customization may benefit from these results, which may serve as a valuable reference in the future. Show less

Hypertension (HTN) is considered one of the most important and well-established reasons for cardiovascular abnormalities, strokes, and premature mortality globally. This study was designed to explore possible differentially expressed genes (DEGs) that contribute to the pathophysiology of hypertension. To identify the DEGs of HTN, we investigated 22 publicly available cDNA Affymetrix datasets using an integrated system-level framework. Gene Ontology (GO), pathway enrichment, and transcriptional factors were analyzed to reveal biological information. From 50 DEGs, we ranked 7 hypertension-related genes ( Show less

Epithelial ovarian cancer (EOC) is a fatal gynecological malignancy. This study explored the mechanism of TAZ in regulating drug sensitivity of cisplatin (DDP-)-resistant EOC cells through the ANGPTL4/SOX2 axis. The A2780/DDP cells were prepared by stepwise progressive concentration method. The drug resistance and TAZ expression in EOC cells were determined. Drug sensitivity was measured after TAZ overexpression in A2780 cells and TAZ downregulation in A2780/DDP cells, respectively. The effects of TAZ knockdown on apoptosis rate, stemness, and cancer stem cell (CSC) marker (CD44, OCT4, and ALDH1A) levels in A2780/DDP and DDP-treated A2780/DDP cells were assessed. The binding of TAZ and ANGPTL4 was verified using ChIP-qPCR, and ANGPTL4 and SOX2 levels were determined. The effects of different combined treatments of TAZ, ANGPTL4, and SOX2 on drug sensitivity of A2780/DDP cells and DDP-treated A2780/DDP cells were evaluated. TAZ was upregulated in drug-resistant EOC cells. TAZ knockdown significantly increased the drug sensitivity of A2780/DDP cells, while TAZ overexpression markedly decreased the drug sensitivity of A2780 cells. TAZ silencing promoted apoptosis of drug-resistant EOC cells and inhibited cell stemness. TAZ targeted ANGPTL4 and TAZ silencing enhanced drug sensitivity of A2780/DDP cells by inhibiting ANGPTL4. ANGPTL4 overexpression elevated SOX2 expression, and SOX2 downregulation reduced the drug resistance and promoted the apoptosis of A2780/DDP cells. TAZ regulates DDP sensitivity of drug-resistant EOC cells via the ANGPTL4/SOX2 axis. 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

Various pathways and cytokines are implicated in pathogenesis of diabetic macular edema (DME). Computational imaging biomarkers (CIBs) of vessel tortuosity from ultra-widefield fluorescein angiography (UWFA) and texture patterns from OCT images have been associated with anti-vascular endothelial growth factor (VEGF) therapy treatment response in DME. This analysis was a radiogenomic assessment of the association between underlying cytokines, UWFA, and OCT-based DME CIBs. Biclustering analysis based on UWFA and OCT CIBs to identify a common imaging phenotype across patients with subsequent assessment of underlying cytokine signatures and treatment response attributes. The IMAGINE DME study was a post hoc study of cytokine expressions that included 24 eyes with sufficient baseline aqueous humor samples and an in-depth assessment of the imaging studies obtained during the phase I/II DmeAntiVEgf study (DAVE) that measured different cytokine expressions. A total of 151 graph or morphologic features quantifying leakage shape, size, density, interobject distance, and architecture of leakage spots and 5 vessel tortuosity features were extracted from the baseline UWFA scans, and 494 texture-based radiomics features were extracted from each of the fluid and retinal tissue compartments of OCT images. Biclustering enables simultaneous clustering of patients and features and was used to aggregate patients in terms of their commonality of phenotypes (based on similar imaging attributes) and to identify commonality in terms of cytokine expression and treatment response to anti-VEGF therapy. Identification of eyes with similar imaging phenotypes to evaluate commonalities of patterns and underlying cytokine expression. Strong correlations between VEGF and 7 UWFA leakage morphologic features (Pearson correlation coefficient [PCC], 0.45-0.51; This study identified groups of eyes with similar imaging phenotypes as defined by UWFA and OCT CIBs that demonstrated similar treatment response patterns and cytokine expression, including a strong association between VEGF with UWFA-derived leakage morphologic and vessel tortuosity features. Show less

Enthusiasm for using polygenic risk scores (PRSs) in clinical practice is tempered by concerns about their portability to diverse ancestry groups, thus motivating genome-wide association studies in non-European ancestry cohorts. We conducted a genome-wide association study for coronary heart disease in a Middle Eastern cohort using whole genome sequencing and assessed the performance of 6 PRSs developed with methods including LDpred (PGS000296), metaGRS (PGS000018), Pruning and Thresholding (PGS000337), and an EnsemblePRS we developed. Additionally, we evaluated the burden of rare variants in lipid genes in cases and controls. Whole genome sequencing at 30× coverage was performed in 1067 coronary heart disease cases (mean age=59 years; 70.3% males) and 6170 controls (mean age=40 years; 43.5% males). The majority of PRSs performed well; odds ratio (OR) per 1 SD increase (OR Overall, we demonstrate that PRSs derived from European ancestry genome-wide association studies performed well in a Middle Eastern cohort, suggesting these could be used in the clinical setting while ancestry-specific PRSs are developed. Show less

Danlou tablet (DLT), the traditional Chinese medicine has been commonly used for dyslipidemia, atherosclerosis, and coronary heart disease. Whether it was effective against vascular injury caused by CIH has remained unknown. The aim of the current study was to observe the effects of DLT on chronic intermittent hypoxia (CIH)-induced vascular injury via regulation of blood lipids and to explore potential mechanisms. Sixteen 12-week-old male ApoE CIH exposure increases serum lipid levels, decreases serum LPL activity, and exacerbates atherosclerosis. Both Angptl4-ab and DLT treatment reversed the changes in lipid concentration, LPL activity, and atherosclerosis caused by CIH. In the epididymal fat pad, CIH exposure decreased the expression of FIH-1 and increased the expression of HIF-1, whereas DLT treatment increased the expression of FIH-1 and LPL and inhibited the expression of HIF-1 and Angptl4. In heart tissue, the expression levels of LPL and Angptl4 were not affected by modeling or treatment. DLT improved vascular damage by improving the increase in blood lipids induced by CIH, potentially by upregulating FIH-1 and downregulating HIF-1 and Angptl4 in adipose tissue. Therefore, DLT may be a promising agent for the prevention and treatment of CIH-induced vascular injury. Show less

The efficiency of feed utilization determines the cost and economic benefits of pig production. In the present study, two pairs of full-sibling and two pairs of half-sibling female Landrace finishing pigs were selected, with each pair including individuals with different feed conversion rates, with liver and longissimus muscle tissue samples collected from each group for transcriptome analysis. A total of 561 differentially expressed genes (DEGs), among which 224 were up-regulated and 337 were down-regulated, were detected in the liver transcriptomes in the high-feed efficiency group compared to the low-feed efficiency group. The DEGs related to phosphorus and phosphate metabolism, arginine biosynthesis, chemical carcinogenesis, cytokine-cytokine receptor interaction, the biosynthesis of amino acids, and drug metabolism-cytochrome P450 in liver tissue were also associated with feed efficiency. In total, 215 DEGs were screened in the longissimus muscle tissue and were mainly related to disease and immune regulation, including complement and coagulation cascades, systemic lupus erythematosus, and prion diseases. The combination of gene expression and functional annotation results led to the identification of candidate feed efficiency-related biomarkers, such as Show less

The aim of the study was to reveal whether marathon running influences regulators of lipid metabolism i.e. angiopoietin-like protein 4 (ANGPTL4), interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α). Plasma concentration of ANGPTL4, IL-6, TNF-α and lipids were determined in samples collected from 11 male runners before the marathon, immediately after the run and at 90 min of recovery. Plasma ANGPTL4 increased during exercise from 55.5 ± 13.4 to 78.1 ± 15.0 ng/ml (P < 0.001). This was accompanied by a significant increase in IL-6, TNF-α, free fatty acids (FFA) and glycerol (Gly) and a decrease in triacylglycerols (TG). After 90 min of recovery ANGPTL4 and TG did not differ from the exercise values, while plasma IL-6, TNF-α, FFA and Gly concentration were significantly lower. The exercise-induced increase in plasma concentration of ANGPTL4 correlated positively with the rise in plasma IL-6, TNF-α, FFA and Gly and negatively with the duration of the run. The increase in plasma IL-6 and TNF-α correlated positively with the rise in Gly. Summarizing, marathon running induced an increase in plasma ANGPTL4 and the value was higher in faster runners. The increase in plasma FFA, IL-6 and TNF-α concentration during a marathon run may be involved in plasma ANGPTL4 release, which could be a compensatory mechanism against FFA-induced lipotoxicity and oxidative stress. All of the analyzed cytokines may stimulate lipolysis during exercise. Show less

Schizophrenia (SCZ) is a serious mental condition with an unknown cause. According to the reports, Brodmann Area 10 (BA10) is linked to the pathology and cortical dysfunction of SCZ, which demonstrates a number of replicated findings related to research on SCZ and the dysfunction in tasks requiring cognitive control in particular. Genetics' role in the pathophysiology of SCZ is still unclear. Therefore, it may be helpful to understand the effects of these changes on the onset and progression of SCZ to find novel mechanisms involved in the regulation of gene transcription. In order to determine the molecular regulatory mechanisms affecting the SCZ, the long non-coding RNA (lncRNA)-associated competing endogenous RNAs (ceRNAs) axes in the BA10 area were determined using a bioinformatics approach in the present work. A microarray dataset (GSE17612) consisted of brain post-mortem tissues of the BA10 area from SCZ patients and matched healthy subjects was downloaded from the Gene Expression Omnibus (GEO) database. This dataset included probes for both lncRNAs and mRNAs. Using the R software's limma package, the differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) were found. The RNA interactions were also discovered using the DIANA-LncBase and miRTarBase databases. In the ceRNA network, positive correlations between DEmRNAs and DElncRNAs were evaluated using the Pearson correlation coefficient. Finally, lncRNA-associated ceRNA axes were built by using the co-expression and DElncRNA-miRNA-DEmRNA connections. We identified the DElncRNA-miRNA-DEmRNA axes, which included two key lncRNAs ( Show less

To investigate the effect of conbercept on macular microvascular system and retinal blood supply in the treatment of nonischemic branch retinal vein occlusion macular edema (BRVO-ME). Patients were divided into three groups: group A (containing 12 nonischemic BRVO-ME eyes), group B (containing contralateral 12 healthy eyes), and group C (containing 30 cataract eyes to obtain normal aqueous humor cytokine levels). Group A received monthly intravitreal injections of conbercept for 3 months. General data and best-corrected visual acuity (BCVA) were compared among the three groups. Optical coherence tomography angiography (OCTA) results (including central macular thickness [CMT], retinal vascular density and perfusion, and foveal avascular zone [FAZ]) at baseline were compared among groups A and B. Aqueous humor cytokine levels (including VEGF, IL-8, PDGF-AA, TNF-α, and ANGPTL-4) at baseline were compared between groups A and C. Moreover, BCVA, OCTA results, and aqueous humor cytokine levels of group A before and after conbercept treatment were compared. At baseline, group A had a significantly worse BCVA, lower retinal vascular density and perfusion, and numerically larger CMT and FAZ area comparing to the group B, and had a higher aqueous cytokine level (IL-8, VEGF, and ANGPTL-4) comparing to the group C (all ps < 0.05). After the injection of conbercept, group A presented a better BCVA (at initial diagnosis vs. after three conbercept injections: 1.16 ± 0.51 vs. 0.81 ± 0.30, logMAR, p < 0.05), higher retinal vascular density (11.56 ± 4.73 vs. 15.88 ± 2.31, mm This study demonstrated that intraocular injection of conbercept could effectively improve macular microcirculation and increase retinal blood supply in the treatment of nonischemic BRVO-ME based on the combination of visual acuity, OCTA parameters, and aqueous humor cytokine assay results. However, further study with a larger sample size and longer observation period is still needed in the future. Show less

Allocation of morbidly obese patients to either conservative therapy options-such as lifestyle intervention and/or low-calorie diet (LCD)-or to bariatric surgery-preferably sleeve gastrectomy or Roux-en-Y gastric bypass (RYGB)-represents a crucial decision in order to obtain sustainable metabolic improvement and weight loss. The present study encompasses 160 severely obese patients, 81 of whom participated in an LCD program, whereas 79 underwent RYGB surgery. The post-interventional dynamics of physiologically relevant adipokines and hepatokines (ANGPTL4, CCL5, GDF15, GPNMB, IGFBP6), as well as their correlation with fat mass reduction and improvement of liver fibrosis, were analyzed. Systemic GDF15 was characterized as an excellent predictive marker for hepatic fibrosis as well as type 2 diabetes mellitus. Of note, baseline GDF15 serum concentrations were positively correlated with NFS and HbA1c levels after correction for BMI, suggesting GDF15 as a BMI-independent marker of hepatic fibrosis and T2D in obese individuals. Specific GDF15 cut-off values for both diseases were calculated. Overall, the present data demonstrate that circulating levels of specific adipokines and hepatokines are regulated with therapy-induced fat loss and metabolic improvement and might, therefore, serve as biomarkers for the success of obesity therapy strategies. Show less

Glioblastoma (GBM) is the most common primary brain tumor in adults. Despite conventional treatment, consisting of a chirurgical resection followed by concomitant radio-chemotherapy, the 5-year survival rate is less than 5%. Few risk factors are clearly identified, but women are 1.4-fold less affected than men, suggesting that hormone and particularly estrogen signaling could have protective properties. Indeed, a high GPER1 (G-protein-coupled estrogen receptor) expression is associated with better survival, especially in women who produce a greater amount of estrogen. Therefore, we addressed the anti-tumor effect of the GPER agonist G-1 in vivo and characterized its molecular mechanism of action in vitro. First, the antiproliferative effect of G-1 was confirmed in a model of xenografted nude mice. A transcriptome analysis of GBM cells exposed to G-1 was performed, followed by functional analysis of the differentially expressed genes. Lipid and steroid synthesis pathways as well as cell division processes were both affected by G-1, depending on the dose and duration of the treatment. ANGPTL4, the first marker of G-1 exposure in GBM, was identified and validated in primary GBM cells and patient samples. These data strongly support the potential of G-1 as a promising chemotherapeutic compound for the treatment of GBM. Show less

Narrowband-UVB (NB-UVB) is a common and effective psoriasis treatment. It exerts its effect locally and is therefore a better model for exploring dynamics of serum biomarkers reflecting psoriasis skin disease activity compared to other treatments with systemic uptake. To perform an exploratory study to assess potential roles of multiple disease mediators as biomarkers for psoriasis disease activity, and increase understanding of NB-UVB treatment effects in psoriatic skin. Patients with plaque psoriasis were sampled (lesional, non-lesional skin, serum) before and after full NB-UVB treatment. Samples were assessed for 78 different mediators using Luminex assays. Correlation networks were analysed to explore interactions between lesional skin mediators before and after NB-UVB treatment. None of the studied serum mediators were significantly affected by NB-UVB treatment after correction for multiple testing. Thirty mediators revealed a significant difference in lesional skin compared to non-lesional skin before treatment including interleukin 23 (IL-23) and C-C motif chemokine ligand 20 (CCL20), but also novel mediators such as angiopoietin-like 4 (ANGPTL4) and pentraxin 3 (PTX3). The levels of 25 mediators in skin decreased significantly, and network analysis revealed markedly reduced cluster formations and correlations after NB-UVB. NB-UVB treatment reduced the concentration of mediators of the Th17 inflammatory pathway and chemotaxis in psoriatic lesional skin, but also affected less studied and novel mediators. Although the treatment affected the levels of a majority of mediators in skin, no corresponding effect was observed in serum, thus challenging the possibility of a serum biomarker reflecting skin disease activity. Show less

Prior research has identified ANGPTL4 as a key player in the control of the body's lipid and glucose metabolism and a contributor to the onset of numerous cardiovascular conditions. Recently, it has been shown that ANGPTL4 also plays a critical role in tumor growth and progression. Nowadays, the number of EGFR-TKI resistant patients is increasing, and it is important to investigate the role of ANGPTL4 in regulating gefitinib resistance in PC9/GR non-small-cell lung cancer (NSCLC). The expression of ANGPTL4 in A549, PC9, H1975, BEAS-2B and PC9/GR cells was verified by Western blot and qRT-PCR assays, and the effect of gefitinib on the proliferative ability of each cell was probed by CCK-8 assay. By using shRNA to inhibit ANGPTL4 expression in cells, the effect of ANGPTL4 on cell migratory ability was examined and the effect of ANGPTL4 on cellular gefitinib sensitivity was confirmed using the CCK-8 assay and the edu proliferation test. Mouse transplantation tumors were constructed, and the effect of ANGPTL4 on cellular gefitinib sensitivity was investigated in vivo by flow cytometry, Tunel staining assay, immunohistochemical staining, and ROS fluorescence staining assay. ANGPTL4 expression in homoRNA overexpression cells was constructed, and the changes in the expression levels of ASC\NLRP3\Caspase 8 pathway and focal and apoptotic proteins were investigated in vitro, in vivo, afterknockdown and overexpression of ANGPTL4 expression by Westen blot assay. ANGPTL4 was highly expressed in PC9/GR cells. Interfering with ANGPTL4 expression resulted in decreased proliferation and migration ability, decreased resistance to gefitinib, and increased scorching and apoptosis in PC9/GR cells. Interfering with ANGPTL4 expression in PC9/GR cells was shown to promote sensitivity to gefitinib and to mediate the NLRP3/ASC/Caspase 8 pathway to induce cell scorching and apoptosis. ANGPTL4 promotes gefitinib resistance in PC9/GR cells by regulating the NLRP3/ASC/Caspase 8 pathway to inhibit scorch death. ANGPTL4 may be an effective new target for inhibiting EGFR-TKI resistance in lung adenocarcinoma cells. Show less

Psoriasis, vitiligo and lichen planus (LP) are autoimmune skin diseases associated with metabolic syndrome. Angiopoietin-like 4 (ANGPTL4) is a member of angiopoietin-like proteins, which play an important role in lipid metabolism, and its serum concentration has been proposed as a biomarker of cardiometabolic complications, especially coronary artery disease (CAD). The study involved 56 patients with abovementioned dermatoses and 29 sex- and age-matched volunteers without dermatoses. ANGPTL4 serum concentration was measured by ELISA. ANGPTL4 concentration was statistically significantly higher in patients with LP compared to the control group (p < 0.01); moreover, it was significantly higher than in patients with psoriasis and vitiligo (p < 0.001, p < 0.01, respectively). There was no statistically significant difference in ANGPTL4 concentration between patients with psoriasis or vitiligo and controls. There was no correlation between ANGPTL4 concentration and age or BMI in all study groups. There was a positive correlation between ANGPTL4 concentration and fasting glucose (R = 0.43) and AST activity (R = 0.39) in psoriatic patients and ALT activity in patients with vitiligo (R = 0.44). ANGPTL4 could be a potential marker of metabolic complications in patients with LP, especially CAD. Perhaps patients with LP are more prone to CAD compared to the other two dermatoses, which requires further research. Show less

Angiopoietin-like 4 (ANGPTL4) is highly expressed in a variety of neoplasms and promotes cancer progression. Nevertheless, the mechanism of ANGPTL4 in ovarian cancer (OC) metastasis remains unclear. This study aimeds to explore whether ANGPTL4 regulates OC progression and elucidate the underlying mechanism. ANGPTL4 expression in clinical patient tumor samples was determined by immunohistochemistry (IHC) and high-throughput sequencing. ANGPTL4 knockdown (KD) and the addition of exogeneous cANGPTL4 protein were used to investigate its function. An in vivo xenograft tumor experiment was performed by intraperitoneal injection of SKOV3 cells transfected with short hairpin RNAs (shRNAs) targeting ANGPTL4 in nude mice. Western blotting and qRT-PCR were used to detect the levels of ANGPTL4, CDH5, p-AKT, AKT, ETV5, MMP2 and MMP9 in SKOV3 and HO8910 cells transfected with sh-ANGPTL4 or shRNAs targeting ETV5. Increased levels of ANGPTL4 were associated with poor prognosis and metastasis in OC and induced the angiogenesis and metastasis of OC cells both in vivo and in vitro. This tumorigenic effect was dependent on CDH5, and the expression levels of ANGPTL4 and CDH5 in human OC werepositively correlated. In addition, CDH5 activated p-AKT, and upregulated the expression of MMP2 and MMP9. We also found that the expression of ETV5 was upregulated by ANGPTL4, which could bind the promoter region of CDH5, leading to increased CDH5 expression. Our data indicated that an increase in the ANGPTL4 level results in increased ETV5 expression in OC, leading to metastasis via activation of the CDH5/AKT/MMP9 signaling pathway. Show less

Colorectal cancer (CRC) is one of the most common malignant tumors in the world. CRC recurrence and metastasis cause poor prognosis. ANGPTLs (angiopoietin-like proteins) are a family of proteins that are widely involved in metabolic disease and tumorigenesis. The roles of ANGPTLs in CRC are still controversial and deserve further research. In this study, several databases were employed to explore the expression profiles, prognostic values, genetic alterations, potential biological function, and immune infiltration correlation of ANGPTLs in CRC. The expression of Show less

Radiotherapy (RT) is one of the most important treatments for patients with colorectal cancer (CRC). Radioresistance is the crucial cause of poor therapeutic outcomes in colorectal cancer. However, the underlying mechanism of radioresistance in colorectal cancer is still poorly defined. Herein we established a radioresistant colorectal cancer cell line and performed transcriptomics analyses to search for the underlying genes that contribute to radioresistance and investigate its association with the prognosis of CRC patients. The radioresistant cell line was developed from the parental HCT116 cell by a stepwise increased dose of irradiation. Differential gene analysis was performed using cellular transcriptome data to identify genes associated with radioresistance, from which extracellular matrix (ECM) and cell adhesion-related genes were screened. Survival data from a CRC cohort in the TCGA database were used for further model gene screening and validation. The correlation between the risk score model and tumor microenvironment, clinical phenotype, drug treatment sensitivity, and tumor mutation status were also investigated. A total of 493 different expression genes were identified from the radioresistant and wild-type cell line, of which 94 genes were associated with ECM and cell adhesion-related genes. The five model genes The risk score model built with five radioresistance genes in this study, including Show less

Hypoxia-mediated radioresistance is a major reason for the adverse radiotherapy outcome of non-small cell lung cancer (NSCLC) in clinical, but the underlying molecular mechanisms are still obscure. Cellular and exosomal ANGPTL4 proteins under different oxygen status were examined. Colony survival, lipid peroxidation and hallmark proteins were employed to determine the correlation between ferroptosis and radioresistance. Gene regulations, western blot and xenograft models were used to explore the underlying mechanisms of the role of ANGPTL4 in radioresistance. ANGPTL4 had a much higher level in hypoxic NSCLC cells compared to normoxic cells. Up- or down- regulation of ANGPTL4 positively interrelated to the radioresistance of NSCLC cells and xenograft tumours. GPX4-elicited ferroptosis suppression and lipid peroxidation decrease were authenticated to be involved in the hypoxia-induced radioresistance. ANGPTL4 encapsulated in the exosomes from hypoxic cells was absorbed by neighbouring normoxic cells, resulting in radioresistance of these bystander cells in a GPX4-dependent manner, which was diminished when ANGPTL4 was downregulated in the donor exosomes. Hypoxia-induced ANGPTL4 rendered radioresistance of NSCLC through at least two parallel pathways of intracellular ANGPTL4 and exosomal ANGPTL4, suggesting that ANGPTL4 might applicable as a therapeutic target to improve the therapeutic efficacy of NSCLC. Show less

We isolated primary CFs from Sprague-Dawley rats (1-3 days old) and treated them with lipopolysaccharide (LPS) and LPS+sEVs. RNA sequencing analysis revealed that angiopoietin-like 4 (Angptl4) was increased in the LPS+sEVs group more than in the LPS group. After inhibition of Angptl4 expression in sEVs and CFs, cell proliferation, Transwell migration, and tube formation assays were used to detect the angiogenic activity of human umbilical vein endothelial cells. The sEVs regulated CFs to promote angiogenesis via Angptl4 in an inflammatory environment. This may provide a research basis for treating myocardial injury with sEVs. Show less