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Introduction: Ankyrin repeat domain 27 (ANKRD27) has been found to be associated with certain cancers. However, its clinical potential in pan-cancer remains unclear. Methods: Public datasets (TCGA and GTEx) were applied to analyze ANKRD27 expression in multiple cancer types and its correlations with immune scores, immune checkpoint genes, and immune modulatory genes. We also examined ANKRD27 expression in hepatocellular carcinoma (HCC) patients using TCGA and GSE14520 datasets. The upregulation of ANKRD27 was verified via qRT-PCR in vitro. Based on TCGA-HCC, external, and GSE14520 cohorts, the associations between ANKRD27 expression and survival outcome were explored via the Kaplan-Meier survival curve. The effects of ANKRD27 reduction on HCC cell growth, movement, and invasion were evaluated by CCK-8, Wound healing, and Transwell assays. Results: ANKRD27 exhibited aberrant expression in multiple cancers and was correlated with immune traits, including immune infiltration, immune checkpoint genes, and immune modulatory genes. Elevated expression of ANKRD27 was found in TCGA-HCC and GSE14520 cohorts and was confirmed in HCC cell lines. HCC patients with high ANKRD27 expression had poorer prognosis. In vitro , reducing ANKRD27 decreased the capability of proliferation, migration, and invasion in HCC cells. High ANKRD27 expression was associated with sensitivity to certain drugs. Conclusion: ANKRD27 displays abnormal levels of expression in different cancer types and is linked to immune status in cancer. Furthermore, ANKRD27 may serve as a prognostic predictor for HCC. [ABSTRACT FROM AUTHOR]

Background and aims: Myofibroblasts, the primary producers of extracellular matrix, primarily originate from hepatic stellate cells (HSCs), and their activation plays a pivotal role in liver fibrosis. This study aimed to investigate the function of CXC motif ligand 14 (CXCL14) in the progression of liver fibrosis. Approach and results: CXCL14 knockdown significantly reduced the extent of liver fibrosis. Using Ingenuity pathway analysis and qRT‐PCR, activating transcription factor 3 (ATF3) was identified as a key upstream regulator of CXCL14 expression. Mechanistically, ATF3 was shown to bind to the CXCL14 promoter, promoting its transactivation by TGF‐β in HSCs. Notably, both global CXCL14 deletion (CXCL14−/−) and HSC/myofibroblast‐specific CXCL14 knockdown significantly attenuated liver fibrosis in mice. RNA‐seq comparisons between CXCL14−/− and WT mice highlighted Jak2 as the most significantly downregulated gene, implicating its role in the antifibrotic effects of CXCL14 suppression on HSC inactivation. Moreover, Jak2 overexpression reversed the inhibition of liver fibrosis caused by CXCL14 knockdown in vivo. Conclusions: These findings unveil a novel ATF3/CXCL14/Jak2 signalling axis in liver fibrosis, presenting potential therapeutic targets for the disease. [ABSTRACT FROM AUTHOR]

Introduction: Liver fibrosis is primarily driven by the activation of hepatic stellate cells (HSCs), which involves various epigenetic modifications. Objectives: N6‐methyladenosine (m6A), the most prevalent RNA modification in eukaryotic cells, influences numerous physiological and pathological processes. Nevertheless, the role of insulin‐like growth factor 2 mRNA‐binding protein 3 (IGF2BP3), a reader gene mediating m6A modifications, in liver fibrosis remains unclear. Methods and results: This study demonstrated that IGF2BP3 knockout reduces liver fibrosis by promoting HSC ferroptosis (FPT) and inactivating HSCs. Multi‐omics analysis revealed that HSC‐specific IGF2BP3 knockout decreased m6A content in Jagged1 (Jag1), a key component of the Notch signalling pathway. Furthermore, IGF2BP3 deficiency significantly reduced the expression of hairy and enhancer of split‐1 (Hes1), a transcription factor in the Notch/Jag1 signalling pathway, with mRNA levels declining to 35%–62% and protein levels to 28%–35%. Additionally, it suppressed glutathione peroxidase 4 (GPX4) (decreased to approximately 31%–38%), a negative regulator of FPT, thereby facilitating HSC FPT progression and reducing profibrotic gene expression. Conclusion: These findings uncover a novel IGF2BP3/Notch/Jag1 signalling pathway involving HSC FPT, suggesting promising targets for ameliorating liver fibrosis. Key Points/Highlights: IGF2BP3 deficiency inactivates Jag1 signalling.IGF2BP3 deficiency‐mediated m6A modifications promote HSC ferroptosis.IGF2BP3 inhibition facilitates ferroptosis in HSCs via the Hes1/GPX4 axis.IGF2BP3 deficiency inactivates Jag1/Notch1/3/Hes1 signalling pathway inactivation, leading to the decrease in GPX4, which contributes to HSC ferroptosis. [ABSTRACT FROM AUTHOR]

Objective(s): Tadalafil can restore endothelial function and treat atherosclerosis. However, the effect of tadalafil on transplant arteriosclerosis remains unclear. In this study, we explore the effects of tadalafil on allograft vasculopathy. Materials and Methods: Male Brow-Norway rats supplied aorta grafts for Male Lewis rats. All recipients were divided into 3 groups: saline as placebo (control) treated group, low dose tadalafil (0.5 mg/kg/day) treated group, and high dose tadalafil (1.0 mg/kg/day) treated group. Eight weeks after transplantation, the grafts were harvested at and analyzed by histological and Western blot analysis. An enzyme-linked immunosorbent assay (ELISA) was used for measure of plasma cyclic guanylate monophosphate (cGMP). Results:the treatment with tadalafil significantly alleviated the neointimal thickness of aortas compared with the control group (P

It is known that ribonucleotide reductase M2 (RRM2) could be induced by hepatitis B virus (HBV) via DNA damage response. However, whether RRM2 is a potential biomarker for diagnosing and monitoring liver fibrosis in chronic hepatitis B (CHB) patients is still unclear. In this study, CHB patients from GSE84044 (a transcriptome data from GEO data set) were downloaded and RRM2 was selected as a hub gene. Interestingly, a positive correlation was found between serum RRM2 and liver fibrosis stage. The similar results were found in CHB patients with normal alanine aminotransferase (ALT). Notably, RRM2 could effectively differentiate preliminary fibrosis from advanced fibrosis in CHB patients with/without normal ALT. In addition, RRM2 had a better performance in diagnosing liver fibrosis than two commonly used noninvasive methods (aspartate aminotransferase‐to‐platelet ratio index and fibrosis index based on the four factors), two classic fibrotic biomarkers (hyaluronic acid and type IV collagen) as well as Mac‐2 binding protein glycosylation isomer, a known serum fibrosis marker. Moreover, CHB patients with high RRM2, who were associated with advanced fibrosis, had higher expressions of immune checkpoints. Overall, serum RRM2 may be a promising biomarker for diagnosing and monitoring liver fibrosis in CHB patients. [ABSTRACT FROM AUTHOR]

Objective To identify comorbid hub genes in psoriasis and atherosclerosis. Methods Transcriptomic datasets of three psoriatic samples and three atherosclerosis samples were downloaded from the GEO database. A deep learning algorithm (Batch Normalization) was utilized to merge and batch-correct the datasets of the two diseases. The limma package was employed to intersect the differentially expressed genes in the lesions and normal tissues of both diseases. The protein-protein interaction network was constructed using the STRING database and CytoHubba plugin to identify the hub genes. Results Intersection analysis revealed 132 up-regulated genes and 114 down-regulated genes in the lesions of these two diseases. Construction of the interaction network identified 10 hub genes: MX1, OASl, 0AS2, OASL, IFIT1, RSAD2, CXCL10, IFIT3, XAF1 and IL1B, among which the first six were enriched in the type I interferon signaling pathway. Two external validation sets independently verified the expression of CXCL10. Conclusions CXCL10 is a key comorbidity gene for psoriasis and atherosclerosis. The activation pattern of hub gene is similar to that of innate immune response to viral invasion. [ABSTRACT FROM AUTHOR]

Adenosine deaminase RNA specific 1 (ADAR1) has been identified as an enzyme that deaminates adenosine within the dsRNA region to produce inosine, whose amplification reinforced the exhaustion of the immune system. Although there were currently cellular and animal assays supporting the relationship between ADAR1 and specific cancers, there was no correlation analysis that has been performed at the pan-cancer level. Therefore, we first analyzed the expression of ADAR1 in 33 cancers based on the TCGA (The Cancer Genome Atlas) database. ADAR1 was highly expressed in most cancers, and there was a closely association between ADAR1 expression and prognosis of patients. Furthermore, pathway enrichment analysis revealed that ADAR1 was involved in multiple antigens presenting and processing inflammatory and interferon pathways. Moreover, ADAR1 expression was positively correlated with CD8+ T cell infiltration levels in renal papillary cell carcinoma, prostate cancer, and endometrial cancer and negatively correlated with Treg cell infiltration. In addition, we further found that ADAR1 expression was closely associated with various immune checkpoints and chemokines. Meanwhile, we observed that ADAR1 may be involved in the regulation of pan-cancer stemness. In conclusion, we provided a comprehensive understanding of the oncogenic role of ADAR1 in pan-cancer, and ADAR1 might serve as a new potential target for antitumor therapy. [ABSTRACT FROM AUTHOR]

We aimed to develop and validate a novel combined score to improve the assessment of liver fibrosis progression in patients with chronic hepatitis B (CHB). In this study, a total of 331 CHB patients from three cohorts who underwent liver biopsy were enrolled, and the Scheuer system was used for liver fibrosis classification. The combined score was derived by principal component analysis of key differentially expressed genes. For significant liver fibrosis (≥S2), the areas under the receiver operating characteristics curves (AUROCs) of the combined score were 0.838, 0.842, and 0.881 in the three cohorts, respectively. And for advanced liver fibrosis (≥S3), the AUROCs were 0.794, 0.801, and 0.901, respectively. Compared with the results of AUROCs for aspartate aminotransferase≥to≥platelet ratio (APRI) and fibrosis index based on four factors (FIB‐4) in the validation cohorts, better clinical diagnostic value for assessing the progression of liver fibrosis was found in the combined score. Additionally, univariate ordered logistic regression analysis indicated that the combined score could serve as a more superior and stable risk factor than APRI and FIB‐4 in the assessment of liver fibrosis. For CHB patients with normal alanine aminotransferase (ALT), our results further emphasized the diagnostic value of the combined score for significant fibrosis (≥S2) and advanced fibrosis (≥S3). Moreover, it was found that patients with the high combined score, who were associated with the advanced fibrosis stage, had higher levels of drug sensitivity and immune checkpoint expression. In conclusion, the novel combined score could serve as a potential biomarker and contribute to improving the assessment of fibrosis stage in CHB patients. [ABSTRACT FROM AUTHOR]

Currently, the prognosis of hepatocellular carcinoma (HCC) is poor, and there is a lack of effective targeted therapy. As key mediators of the immune response, the prognostic value of antigen-presenting cells (APCs) in HCC still remains unclear. In this study, we aimed to identify APC-related genomic subtypes and develop a novel prognostic model in HCC. Our results indicated that overall survival (OS) and the level of immune infiltration significantly differed between different APC clusters. By analyzing the gene expression profile between APC clusters, APC-related genomic subtypes were identified. There was a significant difference in OS and tumor microenvironment infiltration in HCC patients with different genomic subtypes. With the aid of genomic subtypes, significantly differentially expressed genes were screened to generate a novel prognostic model. The risk score of the model had a significant positive correlation with APCs and was associated with immune checkpoint expressions. Through the clinical cohort collected from the First Affiliated Hospital of Wenzhou Medical University, the prognostic value of the risk score was further validated. Moreover, after the risk score and clinical characteristics were combined, a nomogram was constructed to evaluate the prognosis for HCC patients. In conclusion, we mainly identified the APC-related genomic subtypes and generated a novel prognostic model to improve the prognostic prediction and targeted therapy for HCC patients. [ABSTRACT FROM AUTHOR]

Kaempferol, a natural flavonoid molecule, has demonstrated anti-inflammatory, antimicrobial and antioxidant activities. Recent studies have shown the beneficial effects of kaempferol on liver fibrosis. Notch pathway has been reported to be involved in the aberrant activation of hepatic stellate cells (HSCs). However, whether Notch pathway plays a key role in the anti-fibrotic effects of kaempferol is largely unknown. In this study, kaempferol significantly suppressed liver fibrosis in CCl4 mice, with reduced collagen deposition as well as restored liver function. In vitro , kaempferol enhanced the suppression of HSC activation, with a decrease in α -SMA as well as collagen level. It was found that Notch pathway played an important role in kaempferol-reduced the activation of HSCs. Jag1, a ligand of Notch pathway, was obviously inhibited by kaempferol. Overexpression of Jag1 effectively abolished kaempferol-induced HSC inactivation. Furthermore, Jag1 was demonstrated as a target of microRNA-26b-5p (miR-26b-5p). Interestingly, miR-26b-5p inhibitor prevented HSC activation inhibition caused by kaempferol. Further studies indicated that kaempferol inhibited Notch pathway via miR-26b-5p and Jag1, leading to HSC inactivation. Collectively, we demonstrate that kaempferol could inhibit HSC activation, at least in part, via miR-26b-5p-mediated Jag1 axis and Notch pathway. Kaempferol may serve as a promising drug in the application of treating liver fibrosis. [ABSTRACT FROM AUTHOR]

Recently, the tumor microenvironment (TME) has been reported to be closely related to the tumor initiation, progression, and prognosis. Bladder urothelial carcinoma (BLCA), one of the most common subtypes of bladder cancer worldwide, has been associated with increased morbidity and mortality in the past decade. However, whether the TME status of BLCA contributes to the prediction of BLCA prognosis still remains uncertain. In this study, the ESTIMATE algorithms were used to estimate the division of immune and stromal components in 406 BLCA samples downloaded from The Cancer Genome Atlas database (TCGA). Based on the comparison between ESTIMATE scores, the differentially expressed genes (DEGs) were selected. Using the univariate Cox regression analysis, prognosis-related DEGs were further identified (p < 0.05). The LASSO regression analysis was then used to screen 11 genes that were highly related to the TME of BLCA to generate a novel prognostic gene signature. The following survival analyses showed that this signature could effectively predict the prognosis of BLCA. The clinical value of this signature was further verified in an external cohort obtained from the First Affiliated Hospital of Wenzhou Medical University (n = 120). Based on the stage-correlation analysis and differential expression analysis, IGF1 and MMP9 were identified as the hub genes in the signature. Additionally, using CIBERSORT algorithms, we found that both IGF1 and MMP9 were significantly associated with immune infiltration. Collectively, a novel TME-related prognostic signature contributes to accurately predict the prognosis of BLCA. [ABSTRACT FROM AUTHOR]

BACKGROUND: Long non-coding RNA-growth arrest specific transcript 5 (lncRNA-GAS5) plays a suppressive role in activated hepatic stellate cells (HSCs). LncRNAs could circulate in the blood in a cell-free form and serve as promising biomarkers for various human diseases. Herein, we investigated the feasibility of using serum GAS5 as a biomarker for liver fibrosis in chronic hepatitis B (CHB) patients and whether promoter methylation was responsible for GAS5 down-regulation. METHODS: Serum GAS5 levels were quantified using quantitative real-time PCR in CHB patients and healthy controls. GAS5 promoter methylation was examined in LX-2 cells and cirrhotic tissues. RESULTS: Compared with the sera from healthy controls, lower GAS5 levels were found in the sera from CHB patients. Receiver operating characteristic curve analysis indicated that serum GAS5 had a significant diagnostic value for liver fibrosis in CHB patients. Serum GAS5 negatively correlated with HAI scores as well as ALT values in CHB patients. GAS5 was additionally reduced in cirrhotic tissues, associated with its hypermethylation promoter. In LX-2 cells, transforming growth factor- β 1 treatment led to a reduction in GAS5 expression and an increase in promoter methylation. Hypermethylation of GAS5 was blocked down by DNA methyltransferase (DNMT) inhibitor and restored GAS5 inhibited HSC activation including proliferation and collagen production. Further studies confirmed that GAS5 methylation was mediated by DNMT1. CONCLUSION: We demonstrate that epigenetically-regulated serum GAS5 could serve as a potential biomarker in CHB patients. Loss of GAS5 is associated with DNMT1-mediated promoter methylation. [ABSTRACT FROM AUTHOR]

Bladder Urothelial Carcinoma (BLCA) is the major subtype of bladder cancer, and the prognosis prediction of BLCA is difficult. Ferroptosis is a newly discovered iron-dependent cell death pathway. However, the clinical value of ferroptosis-related genes (FRGs) on the prediction of BLCA prognosis is still uncertain. In this study, we aimed to construct a novel prognostic signature to improve the prognosis prediction of advanced BLCA based on FRGs. In the TCGA cohort, we identified 23 differentially expressed genes (DEGs) associated with overall survival (OS) via univariate Cox analysis (all P < 0.05). 8 optimal DEGs were finally screened to generate the prognostic risk signature through LASSO regression analysis. Patients were divided into two risk groups based on the median risk score. Survival analyses revealed that the OS rate in the high-risk group was significantly lower than that in the low-risk group. Moreover, the risk score was determined as an independent predictor of OS by the multivariate Cox regression analysis (Hazard ratio > 1, 95% CI = 1.724-2.943, P < 0.05). Many potential ferroptosis-related pathways were identified in the enrichment analysis in BLCA. With the aid of an external FAHWMU cohort (n = 180), the clinical predication value of the signature was further verified. In conclusion, the prognosis of advanced BLCA could be accurately predicted by this novel FRG-signature. [ABSTRACT FROM AUTHOR]