Open a new epoch of arsenic trioxide investigation: ATOdb.

Arsenic trioxide (ATO) is a great discovery in the treatment of acute promyelocytic leukemia (APL), which has been used in an increasing number of malignant diseases. Systematic integrative analysis will help to precisely understand the mechanism of ATO and find new combined drugs. Therefore, we developed a one-stop comprehensive database of ATO named ATOdb by manually compiling a wealth of experimentally supported ATO-related data from 3479 articles, and integrated analysis tools. The current version of ATOdb contains 8373 associations among 2300 ATO targets, 80 conditions and 262 combined drugs. Each entry in ATOdb contains detailed information on ATO targets, therapeutic/side effects, systems, cell names, cell types, regulations, detection methods, brief descriptions, references, etc. Furthermore, ATOdb also provides data visualization and analysis results such as the drug similarities, protein-protein interactions, and miRNA-mRNA relationships. An easy-to-use web interface was deployed in ATOdb for users to easily browse, search and download the data. In conclusion, ATOdb will serve as a valuable resource for in-depth study of the mechanism of ATO, discovery of new drug combination strategies, promotion of rational drug use and individualized treatments. ATOdb is freely available at http://bio-bigdata.hrbmu.edu.cn/ATOdb/index.jsp.

An overview of arsenic trioxide-involved combined treatment algorithms for leukemia: basic concepts and clinical implications.

Arsenic trioxide is a first-line treatment drug for acute promyelocytic leukemia, which is also effective for other kinds of leukemia. Its side effects, however, limit its clinical application, especially for patients with complex leukemia symptoms. Combination therapy can effectively alleviate these problems. This review summarizes the research progress on the combination of arsenic trioxide with anticancer drugs, vitamin and vitamin analogs, plant products, and other kinds of drugs in the treatment of leukemia. Additionally, the new progress in arsenic trioxide-induced cardiotoxicity was summarized. This review aims to provide new insights for the rational clinical application of arsenic trioxide.

The involvement and therapeutic potential of lncRNA Kcnq1ot1/miR-34a-5p/Sirt1 pathway in arsenic trioxide-induced cardiotoxicity.

BACKGROUND/AIMS: Arsenic trioxide (ATO) is the first-line therapeutic drug for acute promyelocytic leukemia. However, the cardiotoxicity of ATO limits its clinical application. This study aims to explore the long noncoding RNA (lncRNA) involved molecular mechanism in ATO-induced cardiotoxicity and to identify available prevention strategies. METHODS: ATO was administered to mice or primary cultured mouse cardiomyocytes. Small interfering RNA targeting lncRNA Kcnq1ot1 (si-Kcnq1ot1) was used to knockdown lncRNA Kcnq1ot1. MiR-34a-5p mimic and antisense morpholino oligonucleotide targeting miR-34a-5p (AMO-34a-5p) were used to upregulate and downregulate the expression of miR-34a-5p, respectively. TUNEL staining was conducted to detect cell DNA damage. Flow cytometry assay was used to detect cell apoptosis. Western blot was conducted to detect Bcl-2, Bax and Sirt1 protein expression. Real-time PCR was used to detect lncRNA Kcnq1ot1, miR-34a-5p, and Sirt1 mRNA expression. Dual-luciferase reporter assay was performed to validate the predicted binding site. RESULTS: ATO induced apoptosis in cardiomyocytes both in vivo and in vitro. Simultaneously, the expression of lncRNA Kcnq1ot1 and Sirt1 was downregulated, and miR-34a-5p was upregulated. MiR-34a-5p has binding sites with lncRNA Kcnq1ot1 and Sirt1. Knockdown of lncRNA Kcnq1ot1 induced apoptosis of cardiomyocytes, with increased miR-34a-5p and decreased Sirt1 expression. Inhibition of miR-34a-5p attenuated si-Kcnq1ot1-induced apoptosis in cardiomyocytes. Therefore, the lncRNA Kcnq1ot1/miR-34a-5p/Sirt1 signaling pathway is involved in ATO-induced cardiotoxicity. Propranolol alleviated ATO-induced apoptosis in cardiomyocytes both in vivo and in vitro, which was related to the lncRNA Kcnq1ot1/miR-34a-5p/Sirt1 signaling pathway. CONCLUSION: The lncRNA Kcnq1ot1/miR-34a-5p/Sirt1 pathway is involved in ATO-induced cardiotoxicity. Propranolol can attenuate ATO-induced cardiotoxicity at least partially through the lncRNA Kcnq1ot1/miR-34a-5p/Sirt1 pathway. Combined administration with propranolol may be a new strategy for alleviating the cardiotoxicity of ATO.

The whole transcriptome analysis and the circRNA-lncRNA network construction in arsenic trioxide-treated mice myocardium.

BACKGROUND/AIMS: Arsenic trioxide (ATO) is an effective anti-cancer drug. Nonetheless, it possesses cardiotoxic effects which limit its clinical application. The present study aims to elucidate the molecular basis of ATO-induced cardiotoxicity through using whole transcriptome analysis. METHODS: The whole transcriptome in ATO-treated mice myocardium was analyzed using RNA sequencing technique. These results were confirmed by real-time PCR. The lncRNA-mRNA and circRNA-mRNA co-expression networks were constructed. Finally, a circRNA-lncRNA co-regulated competing endogenous RNA (ceRNA) network was constructed. GO and KEGG pathway analyses were performed. The expression levels of Txnip and Spp1 in ATO-treated neonatal mouse cardiomyocytes were validated by real-time PCR. RESULTS: A total of 113 mRNAs, 159 lncRNAs, 35 miRNAs, and 94 circRNAs were differentially expressed in ATO-treated mice myocardium. A lncRNA-circRNA co-regulation network was constructed. Function annotation revealed that aberrantly expressed genes may be enriched in the 'Wnt signaling pathway', 'Hippo signaling pathway', 'Notch signaling pathway', etc. Finally, the expression levels of Txnip and Spp1 were validated in ATO-treated cardiomyocytes, which was in accordance with the RNA-sequencing results. CONCLUSION: ATO altered coding and noncoding RNA profiles in myocardium of mice. The ATO-related lncRNA-circRNA co-regulation network was constructed. Genes in the co-regulation network are likely to play important roles in the cardiotoxicity of ATO. This study provides new insights into the prevention and treatment of ATO-induced cardiotoxicity.

Comprehensive molecular characterization of hypertension-related genes in cancer.

BACKGROUND: During cancer treatment, patients have a significantly higher risk of developing cardiovascular complications such as hypertension. In this study, we investigated the internal relationships between hypertension and different types of cancer. METHODS: First, we comprehensively characterized the involvement of 10 hypertension-related genes across 33 types of cancer. The somatic copy number alteration (CNA) and single nucleotide variant (SNV) of each gene were identified for each type of cancer. Then, the expression patterns of hypertension-related genes were analyzed across 14 types of cancer. The hypertension-related genes were aberrantly expressed in different types of cancer, and some were associated with the overall survival of patients or the cancer stage. Subsequently, the interactions between hypertension-related genes and clinically actionable genes (CAGs) were identified by analyzing the co-expressions and protein-protein interactions. RESULTS: We found that certain hypertension-related genes were correlated with CAGs. Next, the pathways associated with hypertension-related genes were identified. The positively correlated pathways included epithelial to mesenchymal transition, hormone androgen receptor, and receptor tyrosine kinase, and the negatively correlated pathways included apoptosis, cell cycle, and DNA damage response. Finally, the correlations between hypertension-related genes and drug sensitivity were evaluated for different drugs and different types of cancer. The hypertension-related genes were all positively or negatively correlated with the resistance of cancer to the majority of anti-cancer drugs. These results highlight the importance of hypertension-related genes in cancer. CONCLUSIONS: This study provides an approach to characterize the relationship between hypertension-related genes and cancers in the post-genomic era.

Identification of LTF as a Prognostic Biomarker for Osteosarcoma.

Osteosarcoma remains a major health problem in teenagers. However, its pathogenesis mechanism remains not fully elucidated. This study aims to identify the prognostic biomarkers for osteosarcoma. In this study, we selected genes with a median absolute deviation (MAD) value of the top 5000 in the GSE32981 dataset for subsequent analysis. Weighted correlation network analysis (WGCNA) was used to construct a coexpression network. WGCNA showed that the tan module and midnight blue module were highly correlated with origin and metastases of osteosarcoma, respectively. Enrichment analysis was conducted using genes in the tan module and midnight blue module. A gene coexpression network was constructed by calculating the Spearman correlation coefficients. Four key genes (LTF, C10orf107, HIST1H2AK, and NEXN) were identified to be correlated with the prognosis of osteosarcoma patients. LTF has the highest AUC value, and its effect on osteosarcoma cells was then evaluated. The effect of LTF overexpression on proliferation, migration, and invasion of MG63 and 143B cells was detected by the CCK-8 assay, transwell cell migration assay, and transwell invasion assay, respectively. The overexpression of LTF promoted the proliferation, migration, and invasion of MG63 and 143B cells. In conclusion, LTF may serve as a prognostic biomarker for osteosarcoma.

The Expression and Function of Circadian Rhythm Genes in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is among the most common and lethal form of cancer worldwide. However, its diagnosis and treatment are still dissatisfactory, due to limitations in the understanding of its pathogenic mechanism. Therefore, it is important to elucidate the molecular mechanisms and identify novel therapeutic targets for HCC. Circadian rhythm-related genes control a variety of biological processes. These genes play pivotal roles in the initiation and progression of HCC and are potential diagnostic markers and therapeutic targets. This review gives an update on the research progress of circadian rhythms, their effects on the initiation, progression, and prognosis of HCC, in a bid to provide new insights for the research and treatment of HCC.

Resveratrol on the Metabolic Reprogramming in Liver: Implications for Advanced Atherosclerosis.

Background/Aims: Atherosclerosis (AS) is one of the major leading causes of death globally, which is highly correlated with metabolic abnormalities. Resveratrol (REV) exerts beneficial effects on atherosclerosis. Our aim is to clarify the involvement of liver metabolic reprogramming and the atheroprotective effects of REV. Methods: ApoE-deficient mice were administered with normal diet (N), high-fat diet (H), or HFD with REV (HR). Twenty-four weeks after treatment, Oil Red O staining was used to assess the severity of AS. Non-targeted metabolomics was employed to obtain metabolic signatures of the liver from different groups. Results: High-fat diet-induced AS was alleviated by REV, with less lipid accumulation in the lesions. The metabolic profiles of liver tissues from N, H, and HR groups were analyzed. A total of 1,146 and 765 differentially expressed features were identified between N and H groups, and H and HR groups, respectively. KEGG enrichment analysis uncovered several metabolism-related pathways, which are potential pathogenesis mechanisms and therapeutic targets including "primary bile acid biosynthesis," "phenylalanine metabolism," and "glycerophospholipid metabolism." We further conducted trend analysis using 555 metabolites with one-way ANOVA, where p < 0.05 and PLS-DA VIP >1. We found that REV could reverse the detrimental effect of high-fat diet-induced atherosclerosis. These metabolites were enriched in pathways including "biosynthesis of unsaturated fatty acids" and "intestinal immune network for IgA production." The metabolites involved in these pathways could be the potential biomarkers for AS-related liver metabolic reprogramming and the mechanism of REV treatment. Conclusions: REV exerted atheroprotective effects partially by modulating the liver metabolism.