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.

The Molecular Mechanisms of Cardiotoxicity Induced by HER2, VEGF, and Tyrosine Kinase Inhibitors: an Updated Review.

AIM: In recent decades, there has been a revolutionary decrease in cancer-related mortality and an increase in survival due to the introduction of novel targeted drugs. Nevertheless, drugs targeting human epidermal growth factor receptor 2 (HER-2), angiogenesis, and other tyrosine kinases also come with unexpected cardiac side effects, including heart failure, hypertension, arterial thrombosis, and arrhythmias, and have mechanisms that are unlike those of classic chemotherapeutic agents. In addition, it is challenging to address some problems, as the existing guidelines need to be more specific, and further large-scale clinical trials and experimental studies are required to confirm the benefit of administering cardioprotective agents to patients treated with targeted therapies. Therefore, an improved understanding of cardiotoxicity becomes increasingly important to minimize the pernicious effects and maximize the beneficial effects of targeted agents. METHODS: "Cardiotoxicity", "targeted drugs", "HER2", "trastuzumab", "angiogenesis inhibitor", "VEGF inhibitor" and "tyrosine kinase inhibitors" are used as keywords for article searches. RESULTS: In this article, we report several targeted therapies that induce cardiotoxicity and update knowledge of the clinical evidence, molecular mechanisms, and management measures.

Key considerations on the development of biodegradable biomaterials for clinical translation of medical devices: With cartilage repair products as an example.

With the interdisciplinary convergence of biology, medicine and materials science, both research and clinical translation of biomaterials are progressing at a rapid pace. However, there is still a huge gap between applied basic research on biomaterials and their translational products - medical devices, where two significantly different perspectives and mindsets often work independently and non-synergistically, which in turn significantly increases financial costs and research effort. Although this gap is well-known and often criticized in the biopharmaceutical industry, it is gradually widening. In this article, we critically examine the developmental pipeline of biodegradable biomaterials and biomaterial-based medical device products. Then based on clinical needs, market analysis, and relevant regulations, some ideas are proposed to integrate the two different mindsets to guide applied basic research and translation of biomaterial-based products, from the material and technical perspectives. Cartilage repair substitutes are discussed here as an example. Hopefully, this will lay a strong foundation for biomaterial research and clinical translation, while reducing the amount of extra research effort and funding required due to the dissonance between innovative basic research and commercialization pipeline.

Role of acetylation in doxorubicin-induced cardiotoxicity.

As a potent chemotherapeutic agent, doxorubicin (DOX) is widely used for the treatment of a variety of cancers However, its clinical utility is limited by dose-dependent cardiotoxicity, and pathogenesis has traditionally been attributed to the formation of reactive oxygen species (ROS). Accordingly, the prevention of DOX-induced cardiotoxicity is an indispensable goal to optimize therapeutic regimens and reduce morbidity. Acetylation is an emerging and important epigenetic modification regulated by histone deacetylases (HDACs) and histone acetyltransferases (HATs). Despite extensive studies of the molecular basis and biological functions of acetylation, the application of acetylation as a therapeutic target for cardiotoxicity is in the initial stage, and further studies are required to clarify the complex acetylation network and improve the clinical management of cardiotoxicity. In this review, we summarize the pivotal functions of HDACs and HATs in DOX-induced oxidative stress, the underlying mechanisms, the contributions of noncoding RNAs (ncRNAs) and exercise-mediated deacetylases to cardiotoxicity. Furthermore, we describe research progress related to several important SIRT activators and HDAC inhibitors with potential clinical value for chemotherapy and cardiotoxicity. Collectively, a comprehensive understanding of specific roles and recent developments of acetylation in doxorubicin-induced cardiotoxicity will provide a basis for improved treatment outcomes in cancer and cardiovascular diseases.