Prostacyclin Synthase Deficiency Leads to Exacerbation or Occurrence of Endothelium-Dependent Contraction and Causes Cardiovascular Disorders Mainly via the Non-TxA2 Prostanoids/TP Axis.

BACKGROUND: Prostaglandin I2 synthesized by endothelial COX (cyclooxygenase) evokes potent vasodilation in some blood vessels but is paradoxically responsible for endothelium-dependent constriction (EDC) in others. Prostaglandin I2 production and EDC may be enhanced in diseases such as hypertension. However, how PGIS (prostaglandin I2 synthase) deficiency affects EDC and how this is implicated in the consequent cardiovascular pathologies remain largely unknown. METHODS: Experiments were performed with wild-type, Pgis knockout (Pgis-/-) and Pgis/thromboxane-prostanoid receptor gene (Tp) double knockout (Pgis-/-Tp-/-) mice and Pgis-/- mice transplanted with unfractionated wild-type or Cox-1-/- bone marrow cells, as well as human umbilical arteries. COX-derived prostanoids were measured by high-performance liquid chromatography-mass spectrometry. Vasomotor responses of distinct types of arteries were assessed by isometric force measurement. Parameters of hypertension, vascular remodeling, and cardiac hypertrophy in mice at different ages were monitored. RESULTS: PGF2α, PGE2, and a trace amount of PGD2, but not thromboxane A2 (TxA2), were produced in response to acetylcholine in Pgis-/- or PGIS-inhibited arteries. PGIS deficiency resulted in exacerbation or occurrence of EDC ex vivo and in vivo. Endothelium-dependent hyperpolarization was unchanged, but phosphorylation levels of eNOS (endothelial nitric oxide synthase) at Ser1177 and Thr495 were altered and NO production and the NO-dependent relaxation evoked by acetylcholine were remarkably reduced in Pgis-/- aortas. Pgis-/- mice developed high blood pressure and vascular remodeling at 16 to 17 weeks and subsequently cardiac hypertrophy at 24 to 26 weeks. Meanwhile, blood pressure and cardiac parameters remained normal at 8 to 10 weeks. Additional ablation of TP (TxA2 receptor) not only restrained EDC and the downregulation of NO signaling in Pgis-/- mice but also ameliorated the cardiovascular abnormalities. Stimulation of Pgis-/- vessels with acetylcholine in the presence of platelets led to increased TxA2 generation. COX-1 disruption in bone marrow-derived cells failed to affect the development of high blood pressure and vascular remodeling in Pgis-/- mice though it largely suppressed the increase of plasma TxB2 (TxA2 metabolite) level. CONCLUSIONS: Our study demonstrates that the non-TxA2 prostanoids/TP axis plays an essential role in mediating the augmentation of EDC and cardiovascular disorders when PGIS is deficient, suggesting TP as a promising therapeutic target in diseases associated with PGIS insufficiency.

Corrigendum: Rational design of a Gd(III)-Cu(II) nanobooster for chemodynamic therapy against cancer cells.

[This corrects the article DOI: 10.3389/fchem.2022.856495.].

Two copper(II) compounds derived from tetrazole carboxylates for chemodynamic therapy against hepatocellular carcinoma cells.

Two Cu(II) compounds based on tetrazole-carboxylate ligands, [Cu(phtza)2(H2O)2]∙3H2O (1) and [Cu(atzipa)2]∙2H2O (2) (phtza = 2,2'-(5,5'-(1,3-phenylene)bis(2H-tetrazole-5,2-diyl))diacetate, atzipa = 3-(5-amino-1H-tetrazol-1-yl)isopropanoic anion), were designed and synthesized by hydrothermal reactions. The X-ray diffraction results show that the two compounds show two-dimensional (2D) layer structures. Nanoprecipitation with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG-2000) contributes to the formation of the nanoparticles (NPs) with excellent water dispersity. In vitro study indicates that the two NPs exert considerable cytotoxicity toward human hepatocellular carcinoma cells (HepG2 and Huh7) with low half-maximal inhibitory concentration (IC50). However, the cytotoxicity of such NPs is negligible in normal cells (HL-7702). The cytotoxicity of these NPs was also investigated by the flow cytometry and Calcein-AM/PI (live/dead) co-stained experiments. The results promise the great potential of these NPs for chemodynamic therapy against cancer cells.

Rational Design of a Gd(III)-Cu(II) Nanobooster for Chemodynamic Therapy Against Cancer Cells.

Copper (II) containing coordination complexes have attracted much attention for chemodynamic therapy (CDT) against cancer cells. In this study, the bimetallic nanobooster [Gd2Cu(L)2(H2O)10]·6H2O was prepared by a solvothermal method based on tetrazole carboxylic acid ligand H4L [H4L = 3,3-di (1H-tetrazol-5-yl) pentanedioic acid]. It showed considerable cytotoxicity toward three kinds of human cancer cells (HeLa, HepG2, and HT29). The MTT assay showed that the IC50 (half-maximal inhibitory concentration) of the complex NPs on HeLa cells (4.9 µg/ml) is superior to that of HepG2 (11.1 µg/ml) and HT29 (5.5 µg/ml). This result showed that [Gd2Cu(L)2(H2O)10]·6H2O NPs can inhibit cell proliferation in vitro and may be potential candidates for chemodynamic therapy. In addition, the cytotoxicity was also confirmed by the trypan blue staining experiment. The results promise the great potential of Gd(III)-Cu(II) for CDT against cancer cells.

Identification of microRNA Signature and Key Genes Between Adenoma and Adenocarcinomas Using Bioinformatics Analysis.

BACKGROUND: In worldwide, colorectal cancer (CRC) is very common and the mechanisms remain unclear. This study aims to identify between adenomas with epithelial dislocation (false invasion) and adenomas with early adenocarcinoma (true invasion). METHODS: GSE41655 and GSE57965 datasets were obtained in the Gene Expression Omnibus (GEO) database. microRNA expression profiles and clinicopathological data from the TCGA (The Cancer Genome Atlas) database were downloaded to further validate the results in GEO. GEO software and the GEO2R calculation method were used to analyze two gene profiles. The co-expression of differentially expressed microRNAs (DEMs) and genes (DEGs) were identified and searched in the FunRich databases for pathway and ontology analysis. Cytoscape was utilized to construct the mRNA-microRNA network. Validation of gene expression levels was conducted by online databases and qRT-PCR and IHC experiments. RESULTS: In total, 6 DEMs and 34 DEGs are selected after calculating. KEGG results indicated that genes are enriched in certain tumor associated pathways. Four out of 6 microRNAs had a significant relationship with the overall survival (P < 0.05) and showed a good performance in predicting the survival risk of patients with colorectal carcinoma. Furthermore, expression levels of hsa-miR-455 and hsa-miR-125a were then verified by qRT-PCR which all target BCL2L12. IHC results showed that the expression level of BCL2L12 was higher in adenocarcinoma than in adenoma. Based on the selected gene, the top 10 small molecules were screened out as potential drugs. CONCLUSION: By using microarray and bioinformatics analyses, DEMs and DEGs were selected and a complete gene network was constructed. To our knowledge, BCL2L12 and related molecules including hsa-miR-455 and hsa-miR-125a were firstly identified as potential biomarkers in the progression from adenoma to adenocarcinoma.

HS3ST2 and Its Related Molecules as Potential Biomarkers for Predicting Lymph Node Metastasis in Patients with Colorectal Cancer.

BACKGROUND: Lymph node metastasis is a major cause of cancer-related death in patients with colorectal cancer (CRC), but current strategies are limited to predicting this clinical behavior. Our study aims to establish a lymph node metastasis prediction model based on miRNA and mRNA to improve the accuracy of prediction. METHODS: GSE56350, GSE70574, and GSE95109 were downloaded from the Gene Expression Omnibus (GEO) database and 569 colorectal cancer statistics were also downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed miRNAs were calculated by using R software. Besides, gene ontology and enriched pathway analysis of target mRNAs were analyzed by using FunRich. Furthermore, the mRNA-miRNA network was constructed using Cytoscape software. Gene expression level was also detected by performing qRT-PCR (quantitative real-time PCR) in colorectal cancer and lymph node tissues. RESULTS: In total, 5 differentially expressed miRNAs were selected, and 34 mRNAs were identified after filtering. The research of KEGG indicated that mRNAs are enriched in many cancer pathways. Differentially expressed miRNAs were most enriched in the cytoplasm, nucleoside, transcription factor activity, and RNA binding. KEGG pathway analysis of these target genes was mainly enriched in 5 pathways including fatty acid elongation, MAPK signaling pathway, autophagy, signaling pathways regulating pluripotency of stem cells, and Th17 cell differentiation. The results of qRT-PCR indicated that hsa-miR-100 and hsa-miR-99a were differentially expressed in lymph node metastatic colorectal cancer tissues and lymph node non-metastasis tissues which all target HS3ST2. Besides, we also found they have a significant difference in colorectal cancer tissues compared with normal tissues. CONCLUSION: By using microarray and bioinformatics analyses, differentially expressed miRNAs were identified and a complete gene network was constructed. To our knowledge, HS3ST2 and related molecules including hsa-miR-100 and hsa-miR-99a were firstly identified as potential biomarkers in the development of lymph node metastatic colorectal cancer.

High Expression of N-Acetylgalactosaminyl-transferase 1 (GALNT1) Associated with Invasion, Metastasis, and Proliferation in Osteosarcoma.

BACKGROUND Osteosarcoma (OS) is very common worldwide, and the mechanisms underlying its development remain unclear. This study aims to identify key genes promoting the reproduction, invasion, and transfer of osteosarcoma cells. MATERIAL AND METHODS Gene expression profile data (GSE42352 and GSE42572) were downloaded from the Gene Expression Omnibus database. Differentially expressed genes were calculated using R software. Gene ontology and enriched pathway analysis of mRNAs were analyzed by using FunRich. Verification of the genes was conducted by using quantitative real-time polymerase chain reaction and western blot analyses to measure gene expression. Transwell and wound-healing assays were performed on osteosarcoma cells after knockdown to detect whether the genes enhanced the aggressiveness of osteosarcoma. RESULTS In total, 34 genes were selected after filtering. Kyoto Encyclopedia of Genes and Genomes enrichment analysis demonstrated that the genes were enriched in multiple tumor pathways. N-acetylgalactosaminyltransferase 1 (GALNT1) was identified for further study, and its expression was higher in osteosarcoma cells than in human osteoblasts. The invasion ability of cells was significantly decreased after gene knockdown. CONCLUSIONS Through the use of microarray and bioinformatics analysis, differentially expressed genes were selected and a complete gene network was constructed. Our findings provide new biomarkers for the treatment and prognosis of osteosarcoma. These biomarkers may contribute to the discovery of new therapeutic targets for clinical application.

Identification of lymph node metastasis-related microRNAs in breast cancer using bioinformatics analysis.

BACKGROUND: Lymph node metastasis is a significant problem in breast cancer, and its underlying molecular mechanism is still unclear. The purpose of this study is to research the molecular mechanism and to explore the key RNAs and pathways that mediate lymph node metastasis in breast cancer. METHODS: GSE100453 and GSE38167 were downloaded from the Gene Expression Omnibus (GEO) database and 569 breast cancer statistics were also downloaded from the TCGA database. Differentially expressed miRNAs were calculated by using R software and GEO2R. Gene ontology and Enriched pathway analysis of target mRNAs were analyzed by using the Database for Database of Annotation Visualization and Integrated Discovery (DAVID) and R software. The protein-protein interaction (PPI) network was performed according to Metascape, String, and Cytoscape software. RESULTS: In total, 6 differentially expressed miRNAs were selected, and 499 mRNAs were identified after filtering. The research of the Kyoto Encyclopedia of Genes and Genomes (KEGG) demonstrated that mRNAs enriched in certain tumor pathways. Also, certain hub mRNAs were highlighted after constructed and analyzed the PPI network. A total of 3 out of 6 miRNAs had a significant relationship with the overall survival (P < .05) and showed a good ability of risk prediction model of over survival. CONCLUSIONS: By utilizing bioinformatics analyses, differently expressed miRNAs were identified and constructed a complete gene network. Several potential mechanisms and therapeutic and prognostic targets of lymph node metastasis were also demonstrated in breast cancer.

The prognostic and clinicopathological significance of RBM3 in the survival of patients with tumor: A Prisma-compliant meta-analysis.

BACKGROUND: RNA-binding motif protein 3 (RBM3) plays an important role in carcinogenesis and tumor progression. However, the prognostic role of RBM3 in human carcinomas remains controversial. Therefore, we took a meta-analysis to research the association between the overall survival of patients with cancer and the expression of RBM3. METHODS: Systematic literature research identified 17 potentially eligible studies comprising 4976 patients in ten different cancer types. Two researchers independently screened the content and quality of studies and extracted data. Correlations of RBM3 expression and survival were analyzed and the hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated. RESULTS: In the pooled analysis, overexpression of RBM3 was related to improved overall survival (OS), recurrence-free survival (RFS), and disease-free survival (DFS) in patients with cancer having a pooled HR of 0.61 (HR = 0.61; 95% CI: 0.47-0.69), 0.57 (HR = 0.60; 95% CI: 0.50-0.71) and 0.54 (HR 0.54; 95% CI: 0.38-0.78). Besides, subgroup analysis proved that overexpression of RBM3 was related to improved OS in colorectal cancer (HR = 0.61, 95% CI: 0.43-0.86), melanoma (HR = 0.32, 95% CI: 0.20-0.52), and gastric cancer (HR = 0.51, 95% CI: 0.35-0.73). However, subgroup analysis according to tumor type revealed that overexpression of RBM3 was not related to better OS in breast carcinoma (HR = 0.52, 95% CI: 0.17-0.61). CONCLUSIONS: Our results indicated that RBM3 overexpression was significantly predictive of better prognosis in various human cancers. For certain tumors, overexpression RBM3 might be a marker of improved survival in humans with cancer, except for breast cancer.