Role of gut microbiota in doxorubicin-induced cardiotoxicity: from pathogenesis to related interventions.

Doxorubicin (DOX) is a broad-spectrum and highly efficient anticancer agent, but its clinical implication is limited by lethal cardiotoxicity. Growing evidences have shown that alterations in intestinal microbial composition and function, namely dysbiosis, are closely linked to the progression of DOX-induced cardiotoxicity (DIC) through regulating the gut-microbiota-heart (GMH) axis. The role of gut microbiota and its metabolites in DIC, however, is largely unelucidated. Our review will focus on the potential mechanism between gut microbiota dysbiosis and DIC, so as to provide novel insights into the pathophysiology of DIC. Furthermore, we summarize the underlying interventions of microbial-targeted therapeutics in DIC, encompassing dietary interventions, fecal microbiota transplantation (FMT), probiotics, antibiotics, and natural phytochemicals. Given the emergence of microbial investigation in DIC, finally we aim to point out a novel direction for future research and clinical intervention of DIC, which may be helpful for the DIC patients.

Comprehensive bioinformatics analysis and systems biology approaches to identify the interplay between COVID-19 and pericarditis.

Background: Increasing evidence indicating that coronavirus disease 2019 (COVID-19) increased the incidence and related risks of pericarditis and whether COVID-19 vaccine is related to pericarditis has triggered research and discussion. However, mechanisms behind the link between COVID-19 and pericarditis are still unknown. The objective of this study was to further elucidate the molecular mechanisms of COVID-19 with pericarditis at the gene level using bioinformatics analysis. Methods: Genes associated with COVID-19 and pericarditis were collected from databases using limited screening criteria and intersected to identify the common genes of COVID-19 and pericarditis. Subsequently, gene ontology, pathway enrichment, protein-protein interaction, and immune infiltration analyses were conducted. Finally, TF-gene, gene-miRNA, gene-disease, protein-chemical, and protein-drug interaction networks were constructed based on hub gene identification. Results: A total of 313 common genes were selected, and enrichment analyses were performed to determine their biological functions and signaling pathways. Eight hub genes (IL-1ß, CD8A, IL-10, CD4, IL-6, TLR4, CCL2, and PTPRC) were identified using the protein-protein interaction network, and immune infiltration analysis was then carried out to examine the functional relationship between the eight hub genes and immune cells as well as changes in immune cells in disease. Transcription factors, miRNAs, diseases, chemicals, and drugs with high correlation with hub genes were predicted using bioinformatics analysis. Conclusions: This study revealed a common gene interaction network between COVID-19 and pericarditis. The screened functional pathways, hub genes, potential compounds, and drugs provided new insights for further research on COVID-19 associated with pericarditis.

The Transcriptome Analysis of Circular RNAs Between the Doxorubicin- Induced Cardiomyocytes and Bone Marrow Mesenchymal Stem Cells- Derived Exosomes Treated Ones.

AIM: To analyze the sequencing results of circular RNAs (circRNAs) in cardiomyocytes between the doxorubicin (DOX)-injured group and exosomes treatment group. Moreover, to offer potential circRNAs possibly secreted by exosomes mediating the therapeutic effect on DOX-induced cardiotoxicity for further study. METHODS: The DOX-injured group (DOX group) of cardiomyocytes was treated with DOX, while an exosomes-treated group of injured cardiomyocytes were cocultured with bone marrow mesenchymal stem cells (BMSC)-derived exosomes (BEC group). The high-throughput sequencing of circRNAs was conducted after the extraction of RNA from cardiomyocytes. The differential expression of circRNA was analyzed after identifying the number, expression, and conservative of circRNAs. Then, the target genes of differentially expressed circRNAs were predicted based on the targetscan and Miranda database. Next, the GO and KEGG enrichment analyses of target genes of circRNAs were performed. The crucial signaling pathways participating in the therapeutic process were identified. Finally, a real-time quantitative polymerase chain reaction experiment was conducted to verify the results obtained by sequencing. RESULTS: Thirty-two circRNAs are differentially expressed between the two groups, of which twenty-three circRNAs were elevated in the exosomes-treated group (BEC group). The GO analysis shows that target genes of differentially expressed circRNAs are mainly enriched in the intracellular signalactivity, regulation of nucleic acid-templated transcription, Golgi-related activity, and GTPase activator activity. The KEGG analysis displays that they were involved in the autophagy biological process and NOD-like receptor signaling pathway. The verification experiment suggested that mmu_circ_0000425 (ID: 116324210) was both decreased in the DOX group and elevated in BEC group, which was consistent with the result of sequencing. CONCLUSION: mmu_circ_0000425 in exosomes derived from bone marrow mesenchymal stem cells (BMSC) may have a therapeutic role in alleviating doxorubicin-induced cardiotoxicity (DIC).

Analysis and Validation of Critical Signatures and Immune Cell Infiltration Characteristics in Doxorubicin-Induced Cardiotoxicity by Integrating Bioinformatics and Machine Learning.

Purpose: Doxorubicin-induced cardiotoxicity (DIC) is a severe side reaction in cancer chemotherapy that greatly impacts the well-being of cancer patients. Currently, there is still an insufficiency of effective and reliable biomarkers in the field of clinical practice for the early detection of DIC. This study aimed to determine and validate the potential diagnostic and predictive values of critical signatures in DIC. Methods: We obtained high-throughput sequencing data from the GEO database and performed data analysis and visualization using R software, GO, KEGG and Cytoscape. Machine learning methods and weighted gene coexpression network (WGCNA) were used to identify key genes for diagnostic model construction. Receiver operating characteristic (ROC) analysis and a nomogram were used to assess their diagnostic values. A multiregulatory network was built to reveal the possible regulatory relationships of critical signatures. Cell-type identification by estimating relative subsets of RNA transcript (CIBERSORT) analysis was used to investigate differential immune cell infiltration. Additionally, a cell and animal model were constructed to investigate the relationship between the identified genes and DIC. Results: Among the 3713 differentially expressed genes, three key genes (CSGALNACT1, ZNF296 and FANCB) were identified. A nomogram and ROC curves based on three key genes showed excellent diagnostic predictive performance. The regulatory network analysis showed that the TFs CREB1, EP300, FLI1, FOXA1, MAX, and MAZ modulated three key genes. An analysis of immune cell infiltration indicated that many immune cells (activated NK cells, M0 macrophages, activated dendritic cells and neutrophils) might be related to the progression of DIC. Furthermore, there may be various degrees of correlation between the three critical signatures and immune cells. RT‒qPCR demonstrated that the mRNA expression of CSGALNACT1 and ZNF296 was significantly upregulated, while FANCB was significantly downregulated in DOX-treated cardiomyocytes in vitro and in vivo. Conclusion: Our study suggested that the differential expression of CSGALNACT1, ZNF296 and FANCB is associated with cardiotoxicity and is also involved in immune cell infiltration in DIC. They might be potential biomarkers for the early occurrence of DIC.

Transcriptional and functional analysis of plasma exosomal microRNAs in acute viral myocarditis.

AIM: To assess the differential expression profiles of exosome-derived microRNA (miRNA) and reveal their potential functions in patients with acute viral myocarditis (AVMC). MATERIALS & METHODS: Peripheral blood samples were collected from 9 patients diagnosed with AVMC and 9 healthy controls (HC) in the Affiliated Hospital of Qingdao University from July 2021 to September 2022. The exosomal miRNA expression were tested using RNA high-throughput sequencing. We conducted the GO and KEGG functional analysis to predict the potential molecular, biological functions and related signaling pathways of miRNAs in exosomes. Target genes of exosomal miRNAs were predicted and miRNA-target gene network was mapped using gene databases. Differentially expressed exosomal miRNAs were selected and their expression levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR) to verify the sequencing results. RESULTS: P < 0.05 and Fold Change>2 were considered as cut-off value to screen miRNAs that were differently expressed. This study identified 14 upregulated and 14 downregulated exosome-derived miRNAs. GO and KEGG analysis showed that differentially expressed miRNAs may be related to ß-catenin binding, DNA transcription activities, ubiquitin ligase, PI3K-Akt, FoxO, P53, MAPK, and etc.. The target genes of differentially expressed miRNAs were predicted using gene databases. Real-time PCR confirmed the upregulation of hsa-miR-548a-3p and downregulation of hsa-miR-500b-5p in AVMC. CONCLUSIONS: Hsa-miR-548a-3p and hsa-miR-500b-5p could serve as a promising biomarker of AVMC. Exosomal miRNAs may have substantial roles in the mechanisms of AVMC.

MINOCA biomarkers: Non-atherosclerotic aspects.

Myocardial infarction in the absence of obstructive coronary artery disease (MINOCA) is an important subtype of myocardial infarction. Although comprising less than 50% stenosis in the main epicardial coronary arteries, it constitutes a severe health risk. A variety of approaches have been recommended, but definitive diagnosis remains elusive. In addition, the lack of a comprehensive understanding of underlying pathophysiology makes clinical management difficult and unpredictable. This review highlights ongoing efforts to identify relevant biomarkers in MINOCA to improve diagnosis, individualize treatment and better predict outcomes.

Roles of long non-coding RNAs in angiogenesis-related diseases: Focusing on non-neoplastic aspects.

Angiogenesis is a key process in organ and tissue morphogenesis, as well as growth during human development, and is coordinated by pro- and anti-angiogenic factors. When this balance is affected, the related physiological and pathological changes lead to disease. Long non-coding RNAs (lncRNAs) are an important class of non-coding RNAs that do not encode proteins, but play a dynamic role in regulating gene expression. LncRNAs have been reported to be extensively involved in angiogenesis, particularly tumor angiogenesis. The non-tumor aspects have received relatively little attention and summary, but there is a broad space for research and exploration on lncRNA-targeted angiogenesis in this area. In this review, we focus on lncRNAs in angiogenesis-related diseases other than tumors, such as atherosclerosis, myocardial infarction, stroke, diabetic complications, hypertension, osteoporosis, dermatosis, as well as, endocrine, neurological, and other systemic disorders. Moreover, multiple cell types have been implicated in lncRNA-targeted angiogenesis, but only endothelial cells have attracted widespread attention. Thus, we explore the roles of other cells. Finally, we summarize the potential research directions in the area of lncRNAs and angiogenesis that can be undertaken by combining cutting-edge technology and interdisciplinary research, which will provide new insights into the involvement of lncRNAs in angiogenesis-related diseases.

STAT3 as a therapeutic target in the metformin-related treatment.

Signal transducers and activators of transcription 3 (STAT3) signaling plays an important role in mediating tumor progression, inflammation, cardiovascular disease, and other pathological processes.In recent years, STAT3 as a therapeutic target has received extensive attention. It is well known that metformin can play the role of hypoglycemia by activating AMP-activated protein kinase (AMPK) through inhibition of mitochondrial ATP production.However, AMPK is not required for metformin activity.Although the application of STAT3 as a therapeutic target of metformin is still in the initial research stage, the importance of STAT3 in the mechanism of metformin is gradually being recognizedand further studies are needed to demonstrate the important role of the STAT3 regulatory network in the regulation of diseases by metformin. Here, we reviewed in detail that metformin inhibits the progression of various diseases like tumors, autoimmune diseases and hormone-related diseases by regulating multiple signaling pathways such as JAK/STAT3 and mTOR/STAT3 signaling centered on STAT3. We also summarized recent advances of STAT3 inhibitors combined with metformin in the treatment of diseases.We emphasized that STAT3 signaling, as an AMPK-independent signaling pathway, may be an important target for metformin in clinical therapy.

Glucose control independent mechanisms involved in the cardiovascular benefits of glucagon-like peptide-1 receptor agonists.

Patients with type 2 diabetes mellitus (T2DM) face a high risk of developing cardiovascular diseases. However, traditional hypoglycemic drugs have limited effects on macrovascular complications of the disease. Clinical trials have confirmed that glucagon-like peptide-1 receptor agonists (GLP-1RAs), in addition to their capability of controlling blood glucose, can also decrease the risk of cardiovascular events in T2DM. The protective influence of GLP-1RAs on coronary heart disease and heart failure has been proven in recent clinical studies. Therefore, the international guidelines recommend GLP-1 RAs as the first-line therapy for patients with T2DM having cardiovascular disease. Notwithstanding the widespread clinical application of GLP-1RAs, the underlying mechanisms through which GLP-1RAs exert cardiovascular benefits in patients with DM remain unclear. In this review, we systematically summarize the mechanisms of action of GLP-1RAs responsible for producing favorable effects on the cardiovascular system, beyond their capability of blood glucose regulation. GLP-1RA-mediated cardiovascular protection is manifested through multiple mechanisms, including oxidative stress, inflammation, endoplasmic reticulum stress, apoptosis, and vascular/cardiac remodeling. The understanding of these mechanisms will facilitate the development of new and promising therapeutic modalities for T2DM. Furthermore, we have identified several promising targets for future research in this area.

Doxorubicin-Induced Cardiotoxicity May Be Alleviated by Bone Marrow Mesenchymal Stem Cell-Derived Exosomal lncRNA via Inhibiting Inflammation.

Purpose: To explore the therapeutic mechanism of bone marrow mesenchymal stem cells derived exosomes (BMSC-Exos) for doxorubicin (DOX)-induced cardiotoxicity (DIC) and identify the long noncoding RNAs' (lncRNAs') anti-inflammation function derived by BMSC-Exos. Materials and Methods: High-throughput sequencing and transcriptome bioinformatics analysis of lncRNA were performed between DOX group and BEC (bone marrow mesenchymal stem cells derived exosomes coculture) group. Elevated lncRNA (ElncRNA) in the cardiomyocytes of BEC group compared with DOX group were confirmed. Based on the location and co-expression relationship between ElncRNA and its target genes, we predicted two target genes of ElncRNA, named cis_targets and trans_targets. The target genes were analyzed by enrichment analyses. Then, we identified the key cellular biological pathways regulating DIC. Experiments were performed to verify the therapeutic effects of exosomes and the origin of lncRNAs in vitro and in vivo. Results: Three hundred and one lncRNAs were differentially expressed between DOX and BEC groups (fold change >1.5 and p < 0.05), of which 169 lncRNAs were elevated in the BEC group compared with the DOX group. GO enrichment analysis of target genes of ElncRNAs showed that they were predominantly involved in inflammation-associated processes. KEGG analysis indicated that their regulatory pathways were mainly involved in oxidative stress-induced inflammation and proliferation of cardiomyocyte. The verification experiments in vitro showed that the oxidative stress and cell deaths were decreased in BEC groups. Moreover, from the top 10 ElncRNAs identified in the sequencing results, MSTRG.98097.4 and MSTRG.58791.2 were both decreased in the DOX group and elevated in BEC group. While in verification experiments in vivo, only the expression of MSTRG.58791.2 is consistent with the result in vitro. Conclusion: Our results show that ElncRNA, MSTRG.58791.2, is possibly secreted by the BMSC-Exos and able to alleviate DIC by suppressing inflammatory response and inflammation-related cell death.