Establishment of a neutrophil extracellular trap-related prognostic signature for colorectal cancer liver metastasis and expression validation of CYP4F3.

Liver metastasis stands as the primary contributor to mortality among patients diagnosed with colorectal cancer (CRC). Neutrophil extracellular traps (NETs) emerge as pivotal players in the progression and metastasis of cancer, showcasing promise as prognostic biomarkers. Our objective is to formulate a predictive model grounded in genes associated with neutrophil extracellular traps and identify novel therapeutic targets for combating CRLM. We sourced gene expression profiles from the Gene Expression Omnibus (GEO) database. Neutrophil extracellular trap-related gene set was obtained from relevant literature and cross-referenced with the GEO datasets. Differentially expressed genes (DEGs) were identified through screening via the least absolute shrinkage and selection operator regression and random forest modeling, leading to the establishment of a nomogram and subtype analysis. Subsequently, a thorough analysis of the characteristic gene CYP4F3 was undertaken, and our findings were corroborated through immunohistochemical staining. We identified seven DEGs (ATG7, CTSG, CYP4F3, F3, IL1B, PDE4B, and TNF) and established nomograms for the occurrence and prognosis of CRLM. CYP4F3 is highly expressed in CRC and colorectal liver metastasis (CRLM), exhibiting a negative correlation with CRLM prognosis. It may serve as a potential therapeutic target for CRLM. A novel prognostic signature related to NETs has been developed, with CYP4F3 identified as a risk factor and potential target for CRLM.

Extraction, rapid preparation and neuroprotective effect of texasin, a main active constituent from Caragana jubata (Pall.) Poir.

Searching for new anti-ischemic stroke (anti-IS) drugs has always been a hot topic in the pharmaceutical industry. Natural products are an important source of discovering anti-IS drugs. The aim of the present study is to extract, rapidly prepare and explore the neuroprotective effect of texasin, a main active constituent from Caragana jubata (Pall.) Poir., which is a kind of Tibetan medicine with a clear anti-IS effect. The results showed that 95% ethanol was the optimal extraction solvent. A three-step rapid preparation method for texasin was successfully established, with a purity of 99.2%. Texasin at the concentration of 25-100 µM had no effect on the viability of normal cultured PC12 cells; 12.5 and 25 µM texasin could enhance the viability of PC12 cells damaged by oxygen and glucose deprivation/reoxygenation (OGD/R), and their effects are comparable to the positive drug edaravone at the concentration of 50 µM. Compared with the normal group, the expression of Bcl-2 protein in OGD/R-injured PC12 cells was downregulated (p < 0.01), and that of PERK, eIF2α, ATF4, CHOP, Bax and Cleaved caspase-3 proteins were upregulated (p < 0.01, p < 0.001). Compared with the OGD/R group, 25 µM texasin could upregulate the expression of Bcl-2 protein (p < 0.01), and downregulate that of PERK, eIF2α, ATF4, CHOP, Bax and Cleaved caspase-3 proteins (p < 0.01, p < 0.001). The 7-OH and 1-O of texasin formed H-bonds with residues Cys891 of the hinge ß-strand of PERK, which is crucial for kinase inhibitors. The above results suggest that the method established in the present study achieved rapid preparation of high-purity texasin. Texasin might inhibit neuronal apoptosis via the regulation of endoplasmic reticulum stress PERK/eIF2α/ATF4/CHOP signalling pathway to exert a protective effect on OGD/R-injured PC12 cells. Aiding by molecular docking, texasin was assumed to be a potential PERK inhibitor.

Misdiagnosis and delayed diagnosis of atypical autoimmune pancreatitis: Experience from clinical cases.

Autoimmune pancreatitis (AIP) is a fibro-inflammatory disease characterized by inflammation and fibrosis of the pancreas. It is a systemic disease that can affect multiple organs, including the bile ducts, kidneys, lungs, and other organs. However, due to its complex presentation, AIP is often challenging to diagnose, and misdiagnosis with pancreatic tumors can occur. In our study, we reviewed three cases of atypical AIP where patients had normal serum IgG4 levels, leading to initial misdiagnosis with pancreatic tumors. Delayed diagnosis resulted in irreversible pathologies such as retroperitoneal fibrosis. All three patients had bile duct involvement, and imaging findings were similar to those of tumors, further complicating the diagnosis. The correct diagnosis was confirmed only after diagnostic therapy. Our study aims to raise awareness of atypical AIP and improve diagnostic efficiency by analyzing the clinical characteristics of these patients.

Emerging Role and Mechanism of the FTO Gene in Cardiovascular Diseases.

The fat mass and obesity-associated (FTO) gene was the first obesity-susceptibility gene identified through a genome-wide association study (GWAS). A growing number of studies have suggested that genetic variants of FTO are strongly associated with the risk of cardiovascular diseases, including hypertension and acute coronary syndrome. In addition, FTO was also the first N6-methyladenosine (m6A) demethylase, suggesting the reversible nature of m6A modification. m6A is dynamically deposited, removed, and recognized by m6A methylases, demethylases, and m6A binding proteins, respectively. By catalyzing m6A demethylation on mRNA, FTO may participate in various biological processes by modulating RNA function. Recent studies demonstrated that FTO plays a pivotal role in the initiation and progression of cardiovascular diseases such as myocardial fibrosis, heart failure, and atherosclerosis and may hold promise as a potential therapeutic target for treating or preventing a variety of cardiovascular diseases. Here, we review the association between FTO genetic variants and cardiovascular disease risk, summarize the role of FTO as an m6A demethylase in cardiovascular disorders, and discuss future research directions and possible clinical implications.

Dissecting cellular heterogeneity and intercellular communication in cholangiocarcinoma: implications for individualized therapeutic strategies.

Background: Cholangiocarcinoma is characterized by significant cellular heterogeneity and complex intercellular communication, which contribute to its progression and therapeutic resistance. Therefore, unraveling this complexity is essential for the development of effective treatments. Methods: We employed single-cell RNA sequencing (scRNA-seq) to investigate cellular heterogeneity and intercellular communication in cholangiocarcinoma and adjacent normal tissues from two patients. Distinct cell types were identified, and gene ontology analyses were conducted to determine enriched pathways. Moreover, cell-cell communications were analyzed using CellChat, a computational framework. Additionally, we performed sub-clustering analysis of T cells and fibroblasts. Results: The scRNA-seq analysis revealed distinct cell clusters and diverse cellular compositions of cholangiocarcinoma. CellChat analysis underscored an amplified outgoing signal from fibroblasts within the tumor, suggesting their pivotal role in the tumor microenvironment. Furthermore, T cell sub-clustering analysis revealed an active immune response within the tumor and new tumor-specific T cell clonotypes, suggesting scope for targeted immunotherapies. Moreover, fibroblast sub-clustering analysis indicated distinct functional states and highlighted the role of activated fibroblasts in shaping intercellular communication, particularly via CD99 and FN1 signaling. Conclusion: Our findings reveal the intricate cellular heterogeneity and dynamic intercellular communication in cholangiocarcinoma, providing valuable insights into disease progression and potential therapeutic strategies.

Oncolytic Adenovirus with SPAG9 shRNA Driven by DD3 Promoter Improved the Efficacy of Docetaxil for Prostate Cancer.

Prostate cancer (PCa) is a common malignant tumor of the male urinary system and ranks the second in the causes of tumor-related deaths. Differential display code 3 (DD3) is a noncoding gene that is specifically expressed in PCa. High expression of sperm-associated antigen 9 (SPAG9) is closely related to tumorigenesis of PCa, and SPAG9 is a therapeutic target for PCa. In this study, a new oncolytic adenovirus DD3-ZD55-SPAG9 was constructed by using DD3 promoter to enhance the efficacy and safety of adenovirus. The combined use of DD3-ZD55-SPAG9 and docetaxel showed that DD3-ZD55-SPAG9 significantly improved the anti-tumor efficacy of docetaxel in PCa both in vitro and in vivo. The mechanism was related to the induction of tumor cell apoptosis and the inhibition of tumor cell invasion. In conclusion, DD3-ZD55-SPAG9 combined with docetaxel is an effective strategy for PCa therapy.

A circular intronic RNA ciPVT1 delays endothelial cell senescence by regulating the miR-24-3p/CDK4/pRb axis.

Circular RNAs (circRNAs) have been established to be involved in numerous processes in the human genome, but their function in vascular aging remains largely unknown. In this study, we aimed to characterize and analyze the function of a circular intronic RNA, ciPVT1, in endothelial cell senescence. We observed significant downregulation of ciPVT1 in senescent endothelial cells. In proliferating endothelial cells, ciPVT1 knockdown induced a premature senescence-like phenotype, inhibited proliferation, and led to an impairment in angiogenesis. An in vivo angiogenic plug assay revealed that ciPVT1 silencing significantly inhibited endothelial tube formation and decreased hemoglobin content. Conversely, overexpression of ciPVT1 in old endothelial cells delayed senescence, promoted proliferation, and increased angiogenic activity. Mechanistic studies revealed that ciPVT1 can sponge miR-24-3p to upregulate the expression of CDK4, resulting in enhanced Rb phosphorylation. Moreover, enforced expression of ciPVT1 reversed the senescence induction effect of miR-24-3p in endothelial cells. In summary, the present study reveals a pivotal role for ciPVT1 in regulating endothelial cell senescence and may have important implications in the search of strategies to counteract the development of age-associated vascular pathologies.

Tropism and transduction of oncolytic adenovirus vectors in prostate cancer therapy.

Oncolytic adenovirus has been applied in cancer therapy because of several advantages such as cost-effective production, high transduction efficiency and low toxicity. Recent efforts have been focused on the modification of oncolytic adenovirus by encoding transgenes within the viral genome to efficiently and selectively replicate within cancer cells, destroy cancerous cells, induce tumor cell apoptosis, and stimulate the recruitment of immune cells to the tumor site. Nevertheless, there are still big challenges for translational research of oncolytic virotherapy in clinical cancer management. Therefore, here we summarize current status on the design and application of oncolytic adenovirus vectors for prostate cancer therapy. In particular, we describe the main receptors associated with the tropism and transduction of oncolytic adenovirus vectors, and propose new directions in future studies for prostate cancer virotherapy.

circGNAQ, a circular RNA enriched in vascular endothelium, inhibits endothelial cell senescence and atherosclerosis progression.

Endothelial cell senescence is one of the most important causes of vascular dysfunction and atherosclerosis. Circular RNAs (circRNAs) are endogenous RNA molecules with covalently closed-loop structures, which have been reported to be abnormally expressed in many human diseases. However, the potential role of circRNAs in endothelial cell senescence and atherosclerosis remains largely unknown. Here, we compared the expression patterns of circRNAs in young and senescent human endothelial cells with RNA sequencing. Among the differentially expressed circRNAs, circGNAQ, a circRNA enriched in vascular endothelium, was significantly downregulated in senescent endothelial cells. circGNAQ silencing triggered endothelial cell senescence, as determined by a rise in senescence-associated ß-galactosidase activity, reduced cell proliferation, and suppressed angiogenesis; circGNAQ overexpression showed the opposite effects. Mechanistic studies revealed that circGNAQ acted as an endogenous miR-146a-5p sponge to increase the expression of its target gene PLK2 by decoying the miR-146a-5p, thereby delaying endothelial cell senescence. In vivo studies showed that circGNAQ overexpression in the endothelium inhibited endothelial cell senescence and atherosclerosis progression. These results suggest that circGNAQ plays critical roles in endothelial cell senescence and consequently the pathogenesis of atherosclerosis, implying that the management of circGNAQ provides a potential therapeutic approach for limiting the progression of atherosclerosis.